Methods for treating neurodevelopmental disorders

Abstract

Disease modification of specific neurodevelopmental disorders is demonstrated for preschool children through modulation of specific biogenic amine neurotransmitters and γ-aminobutyric acid (GABA) / glutamine. In specific, cumulative reductions in maladaptive behaviors that interfere with activities of daily living for preschool populations are achieved through staged, long term, treatment. Additionally, a prophylaxis for certain neurodegenerative disorders is presented. Provided herein are compositions comprising digestive enzyme preparations and methods of using same for treating neurological disease such as an Autism Spectrum Disorder (ASD).

Description

WSGR Docket No. 41012-760.601METHODS FOR TREATING NEURODEVELOPMENTAL DISORDERSCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 725,316, filed November 26, 2024, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Autism spectrum disorder (ASD) is a neurodevelopmental disorder in which individuals demonstrate persistent core deficits in social communication and social interaction along with restricted, repetitive patterns of behavior, interests, or activities. ASD appears to be increasing in global prevalence without a clear cause. ASD symptoms and their severity and presentation vary widely. Individuals with ASD possess a unique combination or matrix of behaviors and corresponding levels of function that affect quality of life. There is an urgent unmet need for a treatment addressing the core symptoms and associated maladaptive symptoms of autism spectrum disorder (ASD), especially in pediatric populations.SUMMARY

[0003] Provided herein are methods of treating neurological diseases in a subject in need thereof,

[0004] In one aspect, provided herein is a method of treating a neurological disease in a subject in need thereof, comprising administering a pharmaceutical composition comprising coated digestive enzyme particles to the subject daily for at least 12 weeks, wherein per day: a first dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition within about 2-3 hours of waking; a second dose comprises from about 700 mg to about 1100 mg of the pharmaceutical composition about mid-day; and a third dose comprises from about 700 mg to about 1100 mg of the pharmaceutical composition in the evening; wherein the subject is from about 9 to about 12 years of age; wherein the pharmaceutical composition is administered to the subj ect orally, via a gastrointestinal tube (G-tube), or a nasal gastrointestinal tube (NG-tube); and wherein the method improves irritability, agitation, hyperactivity, stereotypy, communication, or a combination thereof by at least 5% on an Aberrant Behavioral Checklist (ABC) score compared to a placebo or compared to the subject prior to treatment; whereby the neurological disease is treated.

[0005] In another aspect, provided herein is a method of treating a neurological disease in a subject in need thereof, comprising administering a pharmaceutical composition comprising coated digestive enzyme particles to the subject daily for at least 12 weeks, wherein per day: a first dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition within about 2-3 hours of waking; a second dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition about mid-day; and a third dose comprises from about 700 mg to about 1100 mg of the pharmaceutical composition in the evening; wherein the subject is from about 13 to about 17 years of age; wherein the pharmaceutical composition is administered to the subj ect orally, via a gastrointestinal tube (G-tube), or a nasal gastrointestinal tube (NG-tube); and wherein the method improves irritability, agitation, hyperactivity, stereotypy, communication, or a combination thereof by at least 5% on an AberrantWSGR Docket No. 41012-760.601Behavioral Checklist (ABC) score compared to a placebo or compared to the subject prior to treatment; whereby the neurological disease is treated.

[0006] In another aspect, provided herein is a method of treating a neurological disease in a subject in need thereof, comprising administering a pharmaceutical composition comprising coated digestive enzyme particles to the subject daily for at least 12 weeks, wherein per day: a first dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition within about 2-3 hours of waking; a second dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition about mid-day; and a third dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition in the evening; wherein the subject is about 18 years of age or older; wherein the pharmaceutical composition is administered to the subj ect orally, via a gastrointestinal tube (G-tube), or a nasal gastrointestinal tube (NG- tube); and

[0007] wherein the method improves irritability, agitation, hyperactivity, stereotypy, communication, or a combination thereof by at least 5% on an Aberrant Behavioral Checklist (ABC) score compared to a placebo or compared to the subject prior to treatment; whereby the neurological disease is treated.

[0008] In another aspect, provided herein is a method of treating a neurological disease in a subject in need thereof, comprising administering to the subject a dose of from about 700 mg to about 2000 mg of a pharmaceutical composition comprising coated digestive enzyme particles at least 4 times per day with a food for at least 12 weeks; wherein the subject is about 18 months of age or older; wherein the pharmaceutical composition is administered to the subj ect orally, via a gastrointestinal tube (G-tube), or a nasal gastrointestinal tube (NG-tube); wherein a first dose is administered within about 2-3 hours of waking, a second dose is administered from about 2 to about 4 hours after the first dose, a third dose is administered from about 2 to about 4 hours after the second dose, and wherein a fourth dose is administered from about 2 to about 4 hours after the third dose; wherein a total amount of a lipase administered to the subject does not exceed 2,500 lipase units / kg / dose; and wherein the method improves irritability, agitation, hyperactivity, stereotypy, communication, or a combination thereof by at least 5% on an Aberrant Behavioral Checklist (ABC) score compared to a placebo or compared to the subj ect prior to treatment; whereby the neurological disease is treated.

[0009] In another aspect, provided herein is a method of treating a level 1 autism, a level 2 autism, or a level 3 autism in a human subject of under 12 years of age, comprising administering to the human subject a pharmaceutical composition comprising lipid composition 1 daily, wherein the subject is administered per day: a first dose of two sachets comprising lipid composition 1 ingested with a food within about 2-3 hours of waking; a second dose of one or two sachets comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the first dose; and a third dose of one sachet comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the second dose; and optionally, a fourth dose of one sachet comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the third dose; wherein the lipid composition 1 is administered to the subject orally, via a gastrointestinal tube (G-tube), or a nasal gastrointestinal tube (NG-tube); wherein the pharmaceutical composition is administered to the subj ect orally, via a gastrointestinal tube (G-tube), or aWSGR Docket No. 41012-760.601 nasal gastrointestinal tube (NG- tube); wherein a total amount of a lipase administered to the subject does not exceed 2,500 lipase units / kg / dose; and wherein the method improves irritability, agitation, hyperactivity, stereotypy, communication, or a combination thereof by at least 5% on an Aberrant Behavioral Checklist (ABC) score compared to a placebo or compared to the subject prior to treatment; wherein a total amount of lipase administered to the subject does not exceed 10,000 U / kg / day or wherein a total amount of lipase does not exceed 2,500 lipase units / kg / dose, whereby autism is treated.

[0010] In another aspect, provided herein is a method of treating a level 1 autism, a level 2 autism, or a level 3 autism in a human subject of from about 13 to about 17 years of age, comprising administering to the human subject a pharmaceutical composition comprising lipid composition 1 daily, wherein the subject is administered per day: a first dose of two sachets comprising lipid composition 1 ingested with a food within about 2-3 hours of waking; a second dose of two sachets comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the first dose; and a third dose of one sachet comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the second dose; and optionally, a fourth dose of one sachet comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the third dose; wherein the lipid composition 1 is administered to the subject orally, via a gastrointestinal tube (G-tube), or anasal gastrointestinal tube (NG-tube); wherein the method improves irritability, agitation, hyperactivity, stereotypy, communication, or a combination thereof by at least 5% on an Aberrant Behavioral Checklist (ABC) score compared to a placebo or compared to the subject prior to treatment; and wherein a total amount of lipase administered to the subject does not exceed 10,000 U / kg / day or wherein a total amount of lipase does not exceed 2,500 lipase units / kg / dose, whereby autism is treated.

[0011] In another aspect, provided herein is a method of treating a level 1 autism, a level 2 autism, or a level 3 autism in a human subject of about 18 years of age or older, comprising administering to the human subject a pharmaceutical composition comprising lipid composition 1 daily, wherein the subject is administered per day: a first dose of two sachets comprising lipid composition 1 ingested with a food within about 2-3 hours of waking; a second dose of two sachets comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the first dose; and a third dose of two sachets comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the second dose; and a fourth dose of two sachets comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the third dose; wherein the lipid composition 1 is administered to the subject orally, via a gastrointestinal tube (G-tube), or a nasal gastrointestinal tube (NG-tube); wherein the method improves irritability, agitation, hyperactivity, stereotypy, communication, or a combination thereof by at least 5% on an Aberrant Behavioral Checklist (ABC) score compared to a placebo or compared to the subj ect prior to treatment; and wherein a total amount of lipase administered to the subject does not exceed 10,000 U / kg / day or wherein a total amount of lipase does not exceed 2,500 lipase units / kg / dose, whereby autism is treated.

[0012] In one aspect, provided herein is a method of treating a neurological disease in a subject in need thereof, comprising administering a pharmaceutical composition comprising coated digestive enzymeWSGR Docket No. 41012-760.601 particles to the subject daily, wherein per day: a first dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition ingested with food; a second dose comprises from about 700 mg to about 1100 mg of the pharmaceutical composition ingested with food; and a third dose comprises from about 700 mg to about 1100 mg of the pharmaceutical composition ingested with food.

[0013] In one embodiment, the method further comprising administering a fourth dose comprising from about 800 mg to about 1000 mg of the pharmaceutical composition ingested with food. In another embodiment, the method further comprising administering a fifth dose comprising from about 800 mg to about 1000 mg of the pharmaceutical composition ingested with food. In another embodiment, the method further comprising administering a sixth dose comprising from about 800 mg to about 1000 mg of the pharmaceutical composition ingested with food. In one embodiment, the first dose comprises about 1800 mg of the pharmaceutical composition. In one embodiment, the second and third dose each comprise about 900 mg of the pharmaceutical composition. In one embodiment, the fourth, fifth, or sixth dose each comprise about 900 mg of the pharmaceutical composition.

[0014] In another aspect, provided herein is a method of treating a neurological disease in a subject in need thereof, comprising administering a pharmaceutical composition comprising coated digestive enzyme particles to the subject daily, wherein per day: a first dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition ingested with food; a second dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition ingested with food; and a third dose comprises from about 700 mg to about 1100 mg of the pharmaceutical composition ingested with food.

[0015] In one embodiment, the method further comprising administering a fourth dose comprising from about 800 mg to about 1000 mg of the pharmaceutical composition ingested with food. In another embodiment, the method further comprising administering a fifth dose comprising from about 800 mg to about 1000 mg of the pharmaceutical composition ingested with food. In another embodiment, the method further comprising administering a sixth dose comprising from about 800 mg to about 1000 mg of the pharmaceutical composition ingested with food. In one embodiment, the first and second dose each comprise about 1800 mg of the pharmaceutical composition. In one embodiment, the third dose comprises about 900 mg of the pharmaceutical composition. In one embodiment, the fourth, fifth, or sixth dose each comprise about 900 mg of the pharmaceutical composition.

[0016] In another aspect, provided herein is a method of treating a neurological disease in a subject in need thereof, comprising administering a pharmaceutical composition comprising coated digestive enzyme particles to the subject daily, wherein per day: a first dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition ingested with food; a second dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition ingested with food; and a third dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition ingested with food.

[0017] In one embodiment, the method further comprising administering a fourth dose comprising from about 1600 mg to about 2000 mg of the pharmaceutical composition ingested with food. In another embodiment, the method further comprising administering a fifth dose comprising from about 1600 mg to about 2000 mg of the pharmaceutical composition ingested with food. In another embodiment, theWSGR Docket No. 41012-760.601 method further comprising administering a sixth dose comprising from about 1600 mg to about 2000 mg of the pharmaceutical composition ingested with food. In another embodiment, each dose comprises about 1800 mg of the pharmaceutical composition.

[0018] In another aspect, provided herein is a method of treating a neurological disease in a subject in need thereof, comprising administering to the subject a dose of from about 700 mg to about 2000 mg of a pharmaceutical composition comprising coated digestive enzyme particles at least 4 times per day with a food.

[0019] In another aspect, provided herein is a method of treating a level 1 autism, a level 2 autism, or a level 3 autism in a human subject of under 12 years of age, comprising orally administering to the human subject a pharmaceutical composition comprising lipid composition 1 daily, wherein the subject is administered per day: a first dose of one or two sachets comprising lipid composition 1 ingested with a food; a second dose of one or two sachets comprising lipid composition 1 ingested with a food; and a third dose of one sachet comprising lipid composition 1 ingested with a food; and optionally, a fourth dose of one sachet comprising lipid composition 1 ingested with a food; wherein a total amount of lipase administered to the subject does not exceed 10,000 U / kg / day or wherein a total amount of lipase does not exceed 2,500 lipase units / kg / dose, whereby autism is treated. In one embodiment, the method further comprises administering the fourth dose of lipid composition 1 ingested with a food. In another embodiment, the method further comprising administering a fifth dose of lipid composition 1 ingested with a food. In another embodiment, the method further comprising administering a sixth dose of lipid composition 1 ingested with a food.

[0020] In another aspect, provided herein is a method of treating a level 1 autism, a level 2 autism, or a level 3 autism in a human subject of from about 13 to about 17 years of age, comprising orally administering to the human subject a pharmaceutical composition comprising lipid composition 1 daily, wherein the subject is administered per day: a first dose of two sachets comprising lipid composition 1 ingested with a food; a second dose of two sachets comprising lipid composition 1 ingested with a food; and a third dose of one sachet comprising lipid composition 1 ingested with a food; and optionally, a fourth dose of one sachet comprising lipid composition 1 ingested with a food; wherein a total amount of lipase administered to the subject does not exceed 10,000 U / kg / day or wherein a total amount of lipase does not exceed 2,500 lipase units / kg / dose, whereby autism is treated. In one embodiment, the method further comprises administering the fourth dose of lipid composition 1 ingested with a food. In another embodiment, the method further comprising administering a fifth dose of lipid composition 1 ingested with a food. In another embodiment, the method further comprising administering a sixth dose of lipid composition 1 ingested with a food.

[0021] In another aspect, provided herein is a method of treating a level 1 autism, a level 2 autism, or a level 3 autism in a human subject of about 18 years of age or older, comprising orally administering to the human subject a pharmaceutical composition comprising lipid composition 1 daily, wherein the subject is administered per day: A first dose of two sachets comprising lipid composition 1 ingested with a food; a second dose of two sachets comprising lipid composition 1 ingested with a food; and a thirdWSGR Docket No. 41012-760.601 dose of two sachets comprising lipid composition 1 ingested with a food; and a fourth dose of two sachets comprising lipid composition 1 ingested with a food; wherein a total amount of lipase administered to the subject does not exceed 10,000 U / kg / day or wherein a total amount of lipase does not exceed 2,500 lipase units / kg / dose, whereby autism is treated. In one embodiment, the lipid composition 1 comprises coated digestive enzyme particles, each particle comprising a core and a coating. The core comprises digestive enzymes formulated as pancreatin with a protease activity of not less than 156 U. S.P. units / mg, an amylase activity of not less than 25 U. S.P. units / mg, and a lipase activity of not less than 2 U.S.P. units / mg. The coating comprises a pharmaceutical grade hydrogenated soy oil or food grade hydrogenated soy oil. The digestive enzymes are present in the composition in an amount of 80%±2.0 by weight. At least 90% of the coated digestive enzyme particles are from about 180 to about 425 pm in diameter. The lipid composition 1 comprises no more than (NMT) about 6% fat, no more than (NMT) about 5% loss on drying, and is substantially negative (less than 1%) for bacterial species such as Escherichia coli and Salmonella species.

[0022] Provided herein, in one aspect, is a method of treating or reducing the likelihood of developing ASD or administration to a subject with ASD in need thereof, the method comprising administering a pharmaceutical composition comprising digestive enzymes.

[0023] In one aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of about 146,700 U.S.P. units / dose or about 163,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 244,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of about 31,000 U. S.P. units / dose. In one instance, the protease is present in the coated particles in an amount of about 146,700 U.S.P. units / dose. Alternatively, in another instance, the protease is present in the coated particles in an amount of about 163,000 U.S.P. units / dose.

[0024] In one aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a hydrogenated soy oil, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of about 146,700 U.S.P. units / dose or about 163,000 U. S.P. units / dose, the amylase is present in the coated particles in an amount of about 244,000 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of about 31,000 U.S.P. units / dose. In one instance, the protease is present in the coated particles in an amount of about 146,700 U. S.P. units / dose. Alternatively, in another instance, the protease is present in the coated particles in an amount of about 163,000 U. S.P. units / dose.

[0025] In another aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of from about 98, 100WSGR Docket No. 41012-760.601 to about 193,500 U. S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U.S.P. units / dose.

[0026] In another aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a hydrogenated soy oil, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of from about 98, 100 to about 193,500 U. S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U.S.P. units / dose.

[0027] In another aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the digestive enzyme preparation comprises from about 400 to about 800 mg of the digestive enzyme and from about 100 to about 500 mg of the lipid. In one embodiment the digestive enzyme preparation comprises about 780 mg of the digestive enzyme and about 120 mg of the lipid. In one embodiment the digestive enzyme preparation comprises about 720 mg of the digestive enzyme and about 180 mg of the lipid. In one embodiment, the digestive enzyme preparation comprises from about 109±5 to about 215±5 U.S.P. units / mg of the protease. In one instance, the digestive enzyme preparation comprises about 163±5 U. S.P. units / mg of the protease. In one instance, the digestive enzyme preparation comprises about 195±5 U. S.P. units / mg of the protease. In one embodiment, the digestive enzyme preparation comprises from about 154±5 to about 575±5 U. S.P. units / mg of the amylase. In one instance, the digestive enzyme preparation comprises about 244±5 U.S.P. units / mg of the amylase. In one instance, the digestive enzyme preparation comprises about 390±5 U.S.P. units / mg of the amylase. In one embodiment, the digestive enzyme preparation comprises from about 10±5 to about 48±5 U. S.P. units / mg of the lipase. In one instance, the digestive enzyme preparation comprises about 31±5 U. S.P. units / mg of the lipase. In one instance, the digestive enzyme preparation comprises about 30±5 U. S.P. units / mg of the lipase.

[0028] In another aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a hydrogenated soy oil, wherein the coating coats the core; wherein the digestive enzyme preparation comprises from about 400 to about 800 mg of the digestive enzyme and from about 100 to about 500 mg of the lipid. In one embodiment, the digestive enzyme preparation comprises about 780 mg of the digestive enzyme and about 120 mg of the lipid. In one embodiment, the digestive enzyme preparation comprises about 720 mg of the digestive enzyme and about 180 mg of the lipid. In another aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b)WSGR Docket No. 41012-760.601 a coating comprising a hydrogenated soy oil, wherein the coating coats the core; wherein the digestive enzyme preparation comprises from about 760 to about 800 mg of the digestive enzyme and from about 100 to about 140 mg of the lipid. In one embodiment, the digestive enzyme preparation comprises about 780 mg of the digestive enzyme and about 120 mg of the lipid. In one embodiment, the unit dose comprises from about 400 to about 800 mg of the digestive enzymes and from about 100 to about 150 mg of the lipid. In another embodiment, the unit dose comprises from about 600 to about 800 mg of the digestive enzymes and from about 100 to about 300 mg of the lipid. In another embodiment, the unit dose comprises from about 780 to about 800 mg of the digestive enzymes and from about 100 to about 120 mg of the lipid. In other instances, the digestive enzyme preparation comprises about 700±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 710±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 720±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 730±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 740±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 750±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 760±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 770±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 780±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 790±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 800±2 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 440±5 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 440±4 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 440±3 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 440±2 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 615±5 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 615±4 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 615±3 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 615±2 mg of the digestive enzymes. In another embodiment, the unit dose comprises from about 109 to about 215 U.S.P units / mg of the protease, from about 154 to about 575 U.S.P. units / mg of the amylase, and from about 10 to about 48 U.S.P. units / mg of the lipase. In another embodiment, the unit dose comprises about 163 U. S.P units / mg of the protease, about 244 U. S.P. units / mg of the amylase, and about 31 U. S.P. units / mg of the lipase. In another embodiment, the unit dose comprises about 195 U.S.P units / mg of the protease, about 390 U.S.P. units / mg of the amylase, and about 30 U. S.P. units / mg of the lipase.

[0029] In one embodiment, the protease is present in the coated particles in an amount of from about 98,100 to about 193,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U.S.P. units / dose. In one embodiment, the protease is present in the coated particles in an amount of from about 165,000 to about 190,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 340,000 to about 360,000WSGR Docket No. 41012-760.601U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 22,000 to about 35,000 U. S.P. units / dose. In one embodiment, the protease is present in the coated particles in an amount of from about 170,000 to about 180,000 U. S.P. units / dose, the amylase is present in the coated particles in an amount of from about 345,000 to about 355,000 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 24,000 to about 30,000 U.S.P. units / dose. In one embodiment, the protease is present in the coated particles in an amount of from about 175,000 to about 176,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 350,000 to about 352,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 26,000 to about 28,000 U. S.P. units / dose. In one embodiment, the protease is present in the coated particles in an amount of about 175,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 351,000 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of about 27,000 U.S.P. units / dose. In one embodiment, the protease is present in the coated particles in an amount of from about 109,000 to about 215,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 154,000 to about 575,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 10,000 to about 48,000 U. S.P. units / dose. In another embodiment, the protease is present in the coated particles in an amount of from about 138,000 to about 215,500 U. S.P. units / dose, the amylase is present in the coated particles in an amount of from about 154,000 to about 575,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 10,000 to about 48,000 U.S.P. units / dose. In another embodiment, the protease is present in the coated particles in an amount of about 146,700 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 219,600 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of about 27,900 U.S.P. units / dose.

[0030] In certain instances, the amount of the lipase does not exceed 2,500 U.S.P. units / kg / dose. In other instances, the amount of the lipase does not exceed 10,000 U.S.P. units / kg / day.

[0031] The digestive enzymes are present in the coated particles may be present in the coated particles in an amount of from about 5% to about 99% by weight. In certain embodiments, the digestive enzymes are present in the coated particles in an amount of from about 70% to about 90% by weight. In other embodiments, the digestive enzymes are present in the coated particles in an amount of from about 75% to about 87% by weight. In other embodiments, the digestive enzymes are present in the coated particles in an amount of from about 77.5% to about 82.5% by weight. In other embodiments, the digestive enzymes are present in the coated particles in an amount of from about 82.5% to about 87.5% by weight. In other embodiments, the digestive enzymes are present in the coated particles in an amount of from about 84% to about 88% by weight. In other embodiments, the digestive enzymes are present in the coated particles in an amount of from about 86% to about 87%.

[0032] In any of such embodiments, the lipid can be a food grade lipid (e.g., a high-grade lipid that is suitable for administration to a human subject, a GMP-grade lipid, etc.). Food-grade lipid coatings include, but are not limited to, monoglycerides, diglycerides, triglycerides, a combination of monoglycerides and diglycerides, a combination of monoglycerides and triglycerides, a combination ofWSGR Docket No. 41012-760.601 diglycerides and triglycerides, or a combination of monoglycerides, diglycerides, and triglycerides. In one non-limiting embodiment, the lipid coating comprises a soy oil such as, for example, a hydrogenated soy oil.

[0033] In one aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing (e. g. , comprising) digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of about 175,500 U. S.P. units / dose, the amylase is present in the coated particles in an amount of about 351,000 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of about 27,000 U.S.P. units / dose.

[0034] In another aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing (e.g. , comprising) digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; the protease is present in the coated particles in an amount of about 146,700 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 219, 600 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of about 27,900 U. S.P. units / dose.

[0035] In another aspect, provided herein is a sachet comprising a digestive enzyme preparation as describe above. Sachets may, in certain embodiments, be stored in a trilaminar foil pouch. Alternatively, or in addition, provided herein is a digestive enzyme preparation is in the form of a sprinkle.

[0036] In another aspect, provided herein is a unit dose comprising about 900 mg of a digestive enzyme preparation, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase; and (b) a coating comprising a lipid, wherein the coating coats the core, wherein the protease is present in the coated particles in an amount of from about 98,100 to about 193,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U.S.P. units / dose. In one embodiment, the protease is present in the coated particles in an amount of from about 165,000 to about 190,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 340,000 to about 360,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 22,000 to about 35,000 U. S.P. units / dose. In one embodiment, the protease is present in the coated particles in an amount of from about 170,000 to about 180,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 345,000 to about 355,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 24,000 to about 30,000 U.S.P. units / dose. In one embodiment, the protease is present in the coated particles in an amount of from about 175,000 to about 176,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 350,000 to about 352,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 26,000 toWSGR Docket No. 41012-760.601 about 28,000 U. S.P. units / dose. In one embodiment, the protease is present in the coated particles in an amount of about 175,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 351,000 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of about 27,000 U. S.P. units / dose. In another embodiment, the protease is present in the coated particles in an amount of about 146,700 U. S.P. units / dose, the amylase is present in the coated particles in an amount of about 219,600 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of about 27,900 U.S.P. units / dose. In certain instances, the amount of the lipase does not exceed 2,500 U.S.P. units / kg / dose. In other instances, the amount of the lipase does not exceed 10,000 U.S.P. units / kg / day. In certain instances, unit dose comprises from about 400 to about 800 mg of the digestive enzymes and from about 100 to about 500 mg of the lipid. In other instances, the unit dose comprises from about 770 to about 790 mg of the digestive enzymes and from about 110 to about 130 mg of the lipid. In yet other instances, the unit dose comprises about 780 mg of the digestive enzymes and about 120 mg of the lipid. In yet other instances, the unit dose comprises about 720 mg of the digestive enzymes and about 180 mg of the lipid. In other instances, the unit dose comprises from about 400 to about 800 mg of the digestive enzymes and from about 100 to about 500 mg of the lipid. In other instances, the unit dose comprises from about 600 to about 800 mg of the digestive enzymes and from about 100 to about 300 mg of the lipid. In other instances, the unit dose comprises from about 780 to about 800 mg of the digestive enzymes and from about 100 to about 120 mg of the lipid. In other instances, the unit dose comprises about 780 mg of the digestive enzymes and about 120 mg of the lipid. In other instances, the unit dose comprises about 720 mg of the digestive enzymes and about 180 mg of the lipid. In other instances, the unit dose comprises about 440±5 mg of the digestive enzymes. In other instances, the unit dose comprises about 440±4 mg of the digestive enzymes. In other instances, the unit dose comprises about 440±3 mg of the digestive enzymes. In other instances, the unit dose comprises about 440±2 mg of the digestive enzymes. In other instances, the unit dose comprises about 615±5 mg of the digestive enzymes. In other instances, the unit dose comprises about 615±4 mg of the digestive enzymes. In other instances, the unit dose comprises about 615±3 mg of the digestive enzymes. In other instances, the unit dose comprises about 615±2 mg of the digestive enzymes. In other instances, the unit dose comprises from about 109 to about 215 U. S.P units / mg of the protease, from about 154 to about 575 U.S.P. units / mg of the amylase, and from about 10 to about 48 U. S.P. units / mg of the lipase. In other instances, the unit dose comprises about 165 U.S.P units / mg of the protease, about 245 U.S.P. units / mg of the amylase, and about 31 U. S.P. units / mg of the lipase. In other instances, the unit dose comprises about 195 U.S.P units / mg of the protease, about 390 U.S.P. units / mg of the amylase, and about 30 U. S.P. units / mg of the lipase.

[0037] The digestive enzymes are present in the coated particles may be present in the coated particles in an amount of from about 5% to about 99% by weight. In certain embodiments, the digestive enzymes are present in the coated particles in an amount of from about 70% to about 90% by weight. In other embodiments, the digestive enzymes are present in the coated particles in an amount of from about 75% to about 87% by weight. In other embodiments, the digestive enzymes are present in the coated particles in an amount of from about 77.5% to about 82.5% by weight. In other embodiments, the digestiveWSGR Docket No. 41012-760.601 enzymes are present in the coated particles in an amount of from about 82.5% to about 87.5% by weight. In other embodiments, the digestive enzymes are present in the coated particles in an amount of from about 84% to about 88% by weight. In other embodiments, the digestive enzymes are present in the coated particles in an amount of from about 86% to about 87%.

[0038] In any of such embodiments, the lipid can be a food grade lipid (e.g., a high-grade lipid that is suitable for administration to a human subject, a GMP-grade lipid, etc. ). Food-grade lipid coatings include, but are not limited to, monoglycerides, diglycerides, triglycerides, a combination of monoglycerides and diglycerides, a combination of monoglycerides and triglycerides, a combination of diglycerides and triglycerides, or a combination of monoglycerides, diglycerides, and triglycerides. In one non-limiting embodiment, the lipid coating comprises a soy oil such as, for example, a hydrogenated soy oil.

[0039] In another aspect, provided herein is a sachet comprising a unit dose as describe above. Sachets may, in certain embodiments, be stored in a trilaminar foil pouch.

[0040] In one aspect, provided herein is a method of treating an Autism Spectrum Disorder (ASD) in a subject in need thereof, comprising administering to the subject about 900 mg of a digestive enzyme preparation three times per day with a food; wherein the subject is from about 3 to about 8 years of age or from about 3 to about 6 years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the preparation comprises about 780±5 mg of the digestive enzymes and about 120±5 mg of the lipid, whereby the ASD is treated. In another aspect, provided herein is a method of treating an Autism Spectrum Disorder (ASD) in a subject in need thereof, comprising administering to the subject about 900 mg of a digestive enzyme preparation three times per day with a food; wherein the subject is from about 3 to about 8 years of age or from about 3 to about 6 years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the preparation comprises about 440±5 mg of the digestive enzymes and about 120±5 mg of the lipid, whereby the ASD is treated. In one aspect, provided herein is a method of treating an Autism Spectrum Disorder (ASD) in a subject in need thereof, comprising administering to the subject about 900 mg of a digestive enzyme preparation three times per day with a food; wherein the subject is from about 3 to about 8 years of age or from about 3 to about 6 years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the preparation comprises about 720±5 mg of the digestive enzymes and about 180±5 mg of the lipid, whereby the ASD is treated. In another aspect, provided herein is a method of treating an Autism Spectrum Disorder (ASD) in a subject in need thereof, comprising administering toWSGR Docket No. 41012-760.601 the subject about 900 mg of a digestive enzyme preparation three times per day with a food; wherein the subject is from about 3 to about 8 years of age or from about 3 to about 6 years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the preparation comprises about 440±5 mg of the digestive enzymes and about 120 mg of the lipid, whereby the ASD is treated. In another aspect, provided herein is a method of treating an Autism Spectrum Disorder (ASD) in a subject in need thereof, comprising administering to the subject about 900 mg of a digestive enzyme preparation three times per day with a food; wherein the subject is from about 3 to about 8 years of age or from about 3 to about 6 years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the preparation comprises about 615±5 mg of the digestive enzymes and about 120 mg of the lipid, whereby the ASD is treated. In certain embodiments, an improvement of50% of effect of one or more symptoms of the ASD preserved from a placebo-controlled double-blind study indicates disease modification. In other embodiments, an improvement of > 60% of effect of one or more symptoms of the ASD preserved from a placebo-controlled double-blind study indicates disease modification. In certain instances, the lipid comprises a hydrogenated soy oil. In certain embodiments, the subject is from about 3 to about 8 years of age at commencement of treatment. In other embodiments, the subject is from about 3 to about 6 years of age at commencement of treatment. In some embodiments, treatment commences when a subject is about 3 to about 8 years of age. In some embodiments, the treatment continues past the age of 8 years old. In some embodiments, treatment, commences when a subject is from about 3 to about 6 years of age at commencement of treatment. In some embodiments, the treatment continues past the age of 6 years old.

[0041] In another aspect, provided herein is a method of treating an Autism Spectrum Disorder (ASD) in a subject in need thereof, comprising administering to the subject about 900 mg of a digestive enzyme preparation three times per day with a food; wherein the subject is from about 3 to about 8 years of age or from about 3 to about 6 years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of from about 98, 100 to about 193,500 U. S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U.S.P. units / dose, whereby the ASD is treated. In certain embodiments, an improvement of > 50% of effect of one or more symptoms of the ASD preserved from a placebo-controlled double-blind study indicates disease modification. In other embodiments, an improvement of > 60% of effect of one or more symptoms of the ASD preserved from a placebo-controlled double-blind study indicates diseaseWSGR Docket No. 41012-760.601 modification. In certain instances, the lipid comprises a hydrogenated soy oil. In certain embodiments, the subject is from about 3 to about 8 years of age at commencement of treatment. In other embodiment^ the subject is from about 3 to about 6 years of age at commencement of treatment.

[0042] In another aspect, provided herein is a method of treating an Autism Spectrum Disorder (ASD) in a subject in need thereof, comprising administering to the subject about 900 mg of a digestive enzyme preparation three times per day with a food; wherein the subject is from about 3 to about 8 years of age or from about 3 to about 6 years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of about 146,700 U. S.P. units / dose or about 163,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 244,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of about 31,000 U.S.P. units / dose, whereby the ASD is treated. In certain embodiments, an improvement of > 50% of effect of one or more symptoms of the ASD preserved from a placebo-controlled double-blind study indicates disease modification. In other embodiments, an improvement of > 60% of effect of one or more symptoms of the ASD preserved from a placebo-controlled double-blind study indicates disease modification. In one instance, the protease is present in the coated particles in an amount of about 146,700 U.S.P. units / dose. Alternatively, in another instance, the protease is present in the coated particles in an amount of about 163,000 U.S.P. units / dose. In certain instances, the lipid comprises a hydrogenated soy oil.

[0043] In another aspect, provided herein is a method of treating an Autism Spectrum Disorder (ASD) in a subject in need thereof, comprising administering to the subject about 900 mg of a digestive enzyme preparation three times per day with a food; wherein the subject is from about 3 to about 8 years of age or from about 3 to about 6 years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a hydrogenated soy oil, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of about 146,700 U. S.P. units / dose or about 163,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 244,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of about 31,000 U.S.P. units / dose, whereby the ASD is treated. In certain embodiments, an improvement of > 50% of effect of one or more symptoms of the ASD preserved from a placebo-controlled double-blind study indicates disease modification. In other embodiments, an improvement of > 60% of effect of one or more symptoms of the ASD preserved from a placebo-controlled double-blind study indicates disease modification. In one instance, the protease is present in the coated particles in an amount of about 146,700 U.S.P. units / dose. Alternatively, in another instance, the protease is present in the coated particles in an amount of about 163,000 U.S.P. units / dose. In certain instances, the lipid comprises a hydrogenated soy oil.WSGR Docket No. 41012-760.601

[0044] In another aspect, provided herein is a method of treating an Autism Spectrum Disorder (ASD) in a subject in need thereof, comprising administering to the subject a digestive enzyme preparation three times per day with a food having a pH of about 4.5 or less; wherein the subj ect is from about 3 to about 8 years of age or from about 3 to about 6 years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of from about 98,100 to about 193,500 U. S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U. S.P. units / dose, whereby the ASD is treated. In certain embodiments, an improvement of > 50% of effect of one or more symptoms of the ASD preserved from a placebo-controlled double-blind study indicates disease modification. In other embodiments, an improvement of > 60% of effect of one or more symptoms of the ASD preserved from a placebo-controlled double-blind study indicates disease modification. In certain instances, the lipid comprises a hydrogenated soy oil.

[0045] In another aspect, provided herein is a method of treating an Autism Spectrum Disorder (ASD) in a subject having a low level of chymotrypsin, comprising administering to the subject a digestive enzyme preparation three times per day with a food; wherein the subject is from about 3 to about 8 years of age or from about 3 to about 6 years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of from about 98, 100 to about 193,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U.S.P. units / dose, whereby the ASD is treated. In certain embodiments, an improvement of > 50% of effect of one or more symptoms of the ASD preserved from a placebo-controlled double-blind study indicates disease modification. In other embodiments, an improvement of > 60% of effect of one or more symptoms of the ASD preserved from a placebo-controlled double-blind study indicates disease modification. In certain instances, the lipid comprises a hydrogenated soy oil.

[0046] In one embodiment of the above methods, the protease is present in the coated particles in an amount of from about 165,000 to about 190,000 U. S.P. units / dose, the amylase is present in the coated particles in an amount of from about 340,000 to about 360,000 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 22,000 to about 35,000 U.S.P. units / dose.

[0047] In another embodiment of the above methods, the protease is present in the coated particles in an amount of about 146,700 U.S.P. units / dose or about 163,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 244,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of about 31,000 U. S.P. units / dose. In one instance, the protease is presentWSGR Docket No. 41012-760.601 in the coated particles in an amount of about 146,700 U.S.P. units / dose. Alternatively, in another instance, the protease is present in the coated particles in an amount of about 163,000 U.S.P. units / dose.

[0048] In another aspect, provided herein is a method of treating irritability / agitation in an ASD subject in need thereof, comprising administering to the subject about 900 mg of a digestive enzyme preparation three times per day with a food; wherein the subject is from about 3 to about 8 years of age or from about 3 to about 6 years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of from about 98, 100 to about 193,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U.S.P. units / dose, whereby irritability / agitation in the subject is treated. In certain embodiments, an improvement of > 50% of effect of irritation / agitation preserved from a placebo-controlled double-blind study indicates disease modification. In other embodiments, an improvement of > 60% of effect of irritation / agitation preserved from a placebo-controlled double-blind study indicates disease modification. In certain instances, the lipid comprises a hydrogenated soy oil. In one embodiment, the protease is present in the coated particles in an amount of from about 165,000 to about 190,000 U. S.P. units / dose, the amylase is present in the coated particles in an amount of from about 340,000 to about 360,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 22,000 to about 35,000 U.S.P. units / dose.

[0049] In one instance, irritability / agitation improves by at least -2.49±10% versus a placebo compared to a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, irritability / agitation improves by at least about -3.07±10% for an early -start subject versus a delay ed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of doubleblind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, irritability / agitation improves by at least -2.49±9% versus a placebo compared to a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, irritability / agitation improves by at least about -3.07±9% for an early-start subject versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, irritability / agitation improves by at least -2.49±8% versus a placebo compared to a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, irritability / agitation improves by at least about -3.07±8% for an early-start subject versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and thenWSGR Docket No. 41012-760.601 drug thereafter. In one instance, irritability / agitation improves by at least -2.49±7% versus a placebo compared to a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, irritability / agitation improves by at least about -3.07±7% for an early-start subject versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, irritability / agitation improves by at least -2.49±6% versus a placebo compared to a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, irritability / agitation improves by at least about -3.07±6% for an early -start subject versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, irritability / agitation improves by at least -2.49±5% versus a placebo compared to a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, irritability / agitation improves by at least about -3.07±5% for an early-start subject versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, irritability / agitation improves by at least -2.49±4% versus a placebo compared to a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, irritability / agitation improves by at least about -3.07±4% for an early-start subject versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, irritability / agitation improves by at least -2.49±3% versus a placebo compared to a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, irritability / agitation improves by at least about -3.07±3% for an early -start subject versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, irritability / agitation improves by at least -2.49±2% versus a placebo compared to a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, irritability / agitation improves by at least about -3.07±2% for an early-start subject versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, irritability / agitation improves by at least -2.49±1% versus a placebo compared to a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, irritability / agitation improves by at least about -3.07±l% for an early-start subject versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12WSGR Docket No. 41012-760.601 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter.

[0050] In another instance, irritability / agitation improves by at least about -9.80±10% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, irritability / agitation improves by at least about -9.80±5% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, irritability / agitation improves by at least about -9.80±4% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, irritability / agitation improves by at least about -9.80±3% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, irritability / agitation improves by at least about -9.80±2% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, irritability / agitation improves by at least about -9.80±l% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, irritability / agitation improves by at least about -9.80±0.5% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, irritability / agitation improves by at least about -9.80±0.2% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, irritability / agitation improves by at least about -9.80±0. 1% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, irritability / agitation improves by at least about -9.80±0.05% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks.

[0051] In another aspect, provided herein is a method of treating lethargy / social withdrawal in an ASD subject in need thereof, comprising administering to the subject about 900 mg of a digestive enzyme preparation three times per day with a food; wherein the subject is from about 3 to about 8 years of age or from about 3 to about 6 years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of from about 98, 100 to about 193,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U.S.P. units / dose, whereby lethargy / social withdrawal in the subject is treated. In certain embodiments, an improvement of > 50% of effect of lethargy / social withdrawal preserved from a placebo -controlled double-blind study indicates disease modification. In other embodiments, an improvement of > 60% of effect of lethargy / social withdrawal preserved from a placebo-controlled double-blind study indicates disease modification. In certain instances, the lipid comprises a hydrogenated soy oil. In one embodiment, the protease is present in the coated particles in an amount of from about 165,000 to about 190,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 340,000 to about 360,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 22,000 to about 35,000 U.S.P. units / dose.WSGR Docket No. 41012-760.601

[0052] In one instance, lethargy / social withdrawal improves by at least about -1.03±10% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start lethargy / social withdrawal improves by at least about -2.57±10% for an early-start subject versus a delay ed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (z. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, lethargy / social withdrawal improves by at least about -1.03±9% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start lethargy / social withdrawal improves by at least about -2.57±9% for an early-start subject versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, lethargy / social withdrawal improves by at least about -1.03±8% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start lethargy / social withdrawal improves by at least about -2.57±8% for an early-start subject versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double- blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, lethargy / social withdrawal improves by at least about -1.03±7% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start lethargy / social withdrawal improves by at least about -2.57±7% for an early-start subject versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, lethargy / social withdrawal improves by at least about -1.03±6% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start lethargy / social withdrawal improves by at least about -2.57±6% for an early-start subject versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, lethargy / social withdrawal improves by at least about - 1.03±5% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start lethargy / social withdrawal improves by at least about -2.57±5% for an early-start subject versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, lethargy / social withdrawal improves by at least about -1.03±4% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start lethargy / social withdrawal improves by at least about -2.57±4% for an early-start subject versus aWSGR Docket No. 41012-760.601 delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, lethargy / social withdrawal improves by at least about -1.03±3% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start lethargy / social withdrawal improves by at least about -2.57±3% for an early-start subject versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double- blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, lethargy / social withdrawal improves by at least about -1.03±2% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start lethargy / social withdrawal improves by at least about -2.57±2% for an early-start subject versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, lethargy / social withdrawal improves by at least about -1.03±l% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start lethargy / social withdrawal improves by at least about -2.57±1% for an early-start subject versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter.

[0053] In another instance, lethargy / social withdrawal improves by at least about -9.56±10% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, lethargy / social withdrawal improves by at least about -9.56±5% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, lethargy / social withdrawal improves by at least about -9.56±4% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, lethargy / social withdrawal improves by at least about - 9.56±3% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, lethargy / social withdrawal improves by at least about -9.56±2% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, lethargy / social withdrawal improves by at least about -9.56±1% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, lethargy / social withdrawal improves by at least about -9.56±0.5% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, lethargy / social withdrawal improves by at least about -9.56±0.2% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, lethargy / social withdrawal improves by at least about -9.56±0. 1% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, lethargy / social withdrawal improves by at least about -9.56±0.05% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks.WSGR Docket No. 41012-760.601

[0054] A method of treating stereotypy in a subject in need thereof, comprising administering to the subject about 900 mg of a digestive enzyme preparation three times per day with a food; wherein the ASD subject is from about 3 to about 8 years of age or from about 3 to about 6 years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of from about 98, 100 to about 193,500 U. S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U.S.P. units / dose, whereby stereotypy in the subject is treated. In certain embodiments, an improvement of > 50% of effect of stereotypy preserved from a placebo-controlled double-blind study indicates disease modification. In other embodiments, an improvement of > 60% of effect of stereotypy preserved from a placebo-controlled double-blind study indicates disease modification. In one instance, the lipid comprises a hydrogenated soy oil. In one embodiment, the protease is present in the coated particles in an amount of from about 165,000 to about 190,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 340,000 to about 360,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 22,000 to about 35,000 U.S.P. units / dose.

[0055] In one instance, stereotypy improves by at least about -1.04±10% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start stereotypy improves by at least about -1.24±10% versus a delay ed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, stereotypy improves by at least about - 1.04±9% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start stereotypy improves by at least about -1.24±9% versus a delay ed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (z. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, stereotypy improves by at least about - 1.04±8% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start stereotypy improves by at least about -1.24±8% versus a delay ed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of doubleblind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, stereotypy improves by at least about -1.04±7% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start stereotypy improves by at least about -1.24±7% versus a delay ed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (z. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject wasWSGR Docket No. 41012-760.601 given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, stereotypy improves by at least about -1.04±6% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start stereotypy improves by at least about -1.24±6% versus a delay ed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, stereotypy improves by at least about -1.04±5% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start stereotypy improves by at least about -1.24±5% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, stereotypy improves by at least about - 1.04±4% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start stereotypy improves by at least about -1.24±4% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of doubleblind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, stereotypy improves by at least about -1.04±3% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start stereotypy improves by at least about -1.24±3% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, stereotypy improves by at least about -1.04±2% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start stereotypy improves by at least about -1.24±2% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, stereotypy improves by at least about -1.04±l% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start stereotypy improves by at least about -1.24±1% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter.

[0056] In one instance, stereotypy improves by at least about -3.83±10% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, stereotypy improves by at least about -3.83±5% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, stereotypy improves by at least about -3.83±4% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, stereotypy improves by atWSGR Docket No. 41012-760.601 least about -3.83±3% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, stereotypy improves by at least about -3.83±2% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, stereotypy improves by at least about -3.83±1% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, stereotypy improves by at least about -3.83±0.5% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, stereotypy improves by at least about -3.83±0.2% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, stereotypy improves by at least about -3. 83±0. 1% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, stereotypy improves by at least about -3.83±0.05% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks.

[0057] In another aspect, provided herein is a method of treating hyperactivity / non-compliance in an ASD subject in need thereof, comprising administering to the subject about 900 mg of a digestive enzyme preparation three times per day with a food; wherein the ASD subject is from about 3 to about 8 years of age or from about 3 to about 6 years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of from about 98, 100 to about 193,500 U. S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U.S.P. units / dose, whereby hyperactivity / non-compliance in the ASD subject is treated. In certain embodiments, an improvement of > 50% of effect of hyperactivity / non-compliance preserved from a placebo-controlled double-blind study indicates disease modification. In other embodiments, an improvement of > 60% of effect of hyperactivity / non-compliance preserved from a placebo-controlled double-blind study indicates disease modification. In one instance, the lipid comprises a hydrogenated soy oil. In one embodiment, the protease is present in the coated particles in an amount of from about 165,000 to about 190,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 340,000 to about 360,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 22,000 to about 35,000 U.S.P. units / dose.

[0058] In one instance, hyperactivity / noncompliance improves by at least about -2.72±10% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start hyperactivity / noncompliance improves by at least about -3.57±10% versus a delay ed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of doubleblind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, hyperactivity / noncompliance improves by at least about -2.72±9% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-startWSGR Docket No. 41012-760.601 hyperactivity / noncompliance improves by at least about -3.57±9% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, hyperactivity / noncompliance improves by at least about -2.72±8% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start hyperactivity / noncompliance improves by at least about -3.57±8% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, hyperactivity / noncompliance improves by at least about -2.72±7% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start hyperactivity / noncompliance improves by at least about -3.57±7% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, hyperactivity / noncompliance improves by at least about -2.72±6% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start hyperactivity / noncompliance improves by at least about -3.57±6% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, hyperactivity / noncompliance improves by at least about -2.72±5% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start hyperactivity / noncompliance improves by at least about -3.57±5% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, hyperactivity / noncompliance improves by at least about -2.72±4% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start hyperactivity / noncompliance improves by at least about -3.57±4% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, hyperactivity / noncompliance improves by at least about -2.72±3% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start hyperactivity / noncompliance improves by at least about -3.57±3% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double- blind + 24WSGR Docket No. 41012-760.601 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, hyperactivity / noncompliance improves by at least about -2.72±2% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start hyperactivity / noncompliance improves by at least about -3.57±2% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, hyperactivity / noncompliance improves by at least about -2.72±1% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start hyperactivity / noncompliance improves by at least about -3.57±1% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter.

[0059] In another instance, hyperactivity / non-compliance improves by at least about - 11. 19± 10% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, hyperactivity / non-compliance improves by at least about -11. 19±5% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, hyperactivity / non-compliance improves by at least about -11. 19±4% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, hyperactivity / non-compliance improves by at least about - 11. 19±3% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, hyperactivity / non-compliance improves by at least about -11.19±2% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, hyperactivity / non-compliance improves by at least about -11. 19±1% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, hyperactivity / non-compliance improves by at least about -11. 19±0.5% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, hyperactivity / non-compliance improves by at least about - 11. 19±0.2% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, hyperactivity / non-compliance improves by at least about -11.19±0.1 % from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, hyperactivity / non-compliance improves by at least about -11. 19±0.05% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks.

[0060] In another aspect, provided herein is a method of treating inappropriate speech in an ASD subj ect in need thereof, comprising administering to the subject about 900 mg of a digestive enzyme preparation three times per day with a food; wherein the ASD subject is from about 3 to about 8 years of age or from about 3 to about 6 years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coatingWSGR Docket No. 41012-760.601 comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of from about 98, 100 to about 193,500 U. S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U.S.P. units / dose, whereby inappropriate speech is treated. In certain embodiments, an improvement of > 50% of effect of inappropriate speech preserved from a placebo-controlled double-blind study indicates disease modification. In other embodiments, an improvement of > 60% of effect of inappropriate speech preserved from a placebo-controlled double-blind study indicates disease modification. In one instance, the lipid comprises a hydrogenated soy oil. In one embodiment, the protease is present in the coated particles in an amount of from about 165,000 to about 190,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 340,000 to about 360,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 22,000 to about 35,000 U. S.P. units / dose.

[0061] In one instance, inappropriate speech improves by at least about -1.00±10% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start inappropriate speech improves by at least about -1.36±10% versus a delay ed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (z. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, inappropriate speech improves by at least about -1.00±9% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start inappropriate speech improves by at least about -1.36±9% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, inappropriate speech improves by at least about -1.00±8% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start inappropriate speech improves by at least about -1.36±8% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, inappropriate speech improves by at least about -1.00±7% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start inappropriate speech improves by at least about -1.36±7% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of doubleblind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, inappropriate speech improves by at least about -1.00±6% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start inappropriate speech improves by at least about -1.36±6% versus a delayed-start subject as measured on the Aberrant Behavior ChecklistWSGR Docket No. 41012-760.601Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, inappropriate speech improves by at least about -1.00±5% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start inappropriate speech improves by at least about -1.36±5% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, inappropriate speech improves by at least about -1.00±4% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start inappropriate speech improves by at least about - 1.36±4% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, inappropriate speech improves by at least about -1.00±3% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start inappropriate speech improves by at least about -1.36±3% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, inappropriate speech improves by at least about - 1.00±2% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start inappropriate speech improves by at least about -1.36±2% versus a delayed-start subject as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i. e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter. In one instance, inappropriate speech improves by at least about -1.00±l% versus a placebo as measured on an Aberrant Behavior Checklist Subscale at 12 weeks. In another instance, an early-start inappropriate speech improves by at least about - 1.36± 1 % versus a delayed-start subj ect as measured on the Aberrant Behavior Checklist Subscale at 36 weeks (i.e., 12 weeks of double-blind + 24 weeks of open label = 36 weeks total) where the early-start subject was given drug and the late-start subject was given a placebo to week 12 and then drug thereafter.

[0062] In another instance, inappropriate speech improves by at least about -1.91±10% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, inappropriate speech improves by at least about -1.91±5% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, inappropriate speech improves by at least about - 1.91±4% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, inappropriate speech improves by at least about -1.91±3% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, inappropriate speech improves by at least about -1.91 ±2% from baseline as measured on the Aberrant Behavior ChecklistWSGR Docket No. 41012-760.601Subscale at 36 weeks. In another instance, inappropriate speech improves by at least about -1.91±1% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, inappropriate speech improves by at least about -1.91±0.5% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, inappropriate speech improves by at least about -1.91±0.2% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, inappropriate speech improves by at least about -1.91±0. 1% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks. In another instance, inappropriate speech improves by at least about -1.91±0.05% from baseline as measured on the Aberrant Behavior Checklist Subscale at 36 weeks.

[0063] A method of inducing serotonin (5-hydroxytryptamine, 5-HT) production in an ASD subject in need thereof, comprising administering to the subject about 900 mg of a digestive enzyme preparation three times per day with a food; wherein the ASD subject is from about 3 to about 8 years of age or from about 3 to about 6 years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of from about 98, 100 to about 193,500 U. S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U.S.P. units / dose, and wherein serotonin production is increased by at least 2% or by at least 2-fold compared to baseline or compared to a placebo. In one instance, the lipid comprises a hydrogenated soy oil. In one embodiment, the protease is present in the coated particles in an amount of from about 165,000 to about 190,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 340,000 to about 360,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 22,000 to about 35,000 U.S.P. units / dose. serotonin production is increased by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to baseline or compared to a placebo, or wherein serotonin production is increased by at least about 5-fold, 10-fold, 20- fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, or more compared to baseline or compared to a placebo.

[0064] A method of treating an Autism Spectrum Disorder (ASD) in a subject in need thereof, comprising administering to the subject a placebo three times per day with a food for about 12 weeks followed by administering to the subject about 900 mg of a digestive enzyme preparation three times per day with the food for from about 12 to about 48 weeks; wherein the subject is from about 3 to about 8 years of age or from about 3 to about 6 years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of from about 98, 100 to about 193,500 U. S.P. units / dose, theWSGR Docket No. 41012-760.601 amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U. S.P. units / dose, whereby the ASD is treated. In one instance, the lipid comprises a hydrogenated soy oil. In one embodiment, the protease is present in the coated particles in an amount of from about 165,000 to about 190,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 340,000 to about 360,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 22,000 to about 35,000 U.S.P. units / dose.

[0065] In one embodiment, the subject to be treated is diagnosed with a moderate or a severe Autism Spectrum Disorder (ASD) as measured on an ABC checklist, an Autism Spectrum Disorder (ASD) Diagnostic Interview-Revised (ADI-R), and / or a Social Communication Questionnaire (SCQ) assessment. In another embodiment, the subject to be treated has a baseline Caregiver Global Impression (CGI) score of > 4 prior to treatment. In another embodiment, the subject to be treated has a baseline Aberrant Behavior Checklist - Irritability (ABC-I) score of 5s18 prior to treatment.

[0066] In the described methods, the subject can be treated for at least 12, 24, 36, 48, or 60 weeks. In one instance, the subject is treated for at least 12 weeks. In another instance, the subject is treated for at least 24 weeks. In another instance, the subject is treated for at least 36 weeks. In another instance, the subject is treated for at least 48 weeks. In another instance, the subject is treated for at least 60 weeks. Alternatively, in the described methods, the subject can be treated for from about 1 to about 6 years. In one instance, the subject is treated for about 1 year. In another instance, the subject is treated for about 2 years. In another instance, the subject is treated for about 3 years. In another instance, the subject is treated for about 4 years. In another instance, the subject is treated for about 5 years. In another instance, the subject is treated for about 6 years. In another instance, the subject is treated for about 7 years. In another instance, the subject is treated for about 8 years. In another instance, the subject is treated for about 9 years. In another instance, the subject is treated for about 10 years. In another instance, the subject is treated for about 11 years. In another instance, the subject is treated for about 12 years. In another instance, the subject is treated for about 13 years. In another instance, the subject is treated for about 14 years. In another instance, the subject is treated for about 15 years. In another instance, the subject is treated for about 16 years. In another instance, the subject is treated for about 17 years. In another instance, the subject is treated for about 18 years. In another instance, the subject is treated for about 19 years. In another instance, the subject is treated for about 20 years. In another instance, the subject is treated for about 25 years. In another instance, the subject is treated for about 30 years. In another instance, the subject is treated for about 35 years. In another instance, the subject is treated for about 40 years. In another instance, the subject is treated for about 45 years. In another instance, the subject is treated for about 50 years. In another instance, the subject is treated for about 55 years. In another instance, the subject is treated for about 60 years. In another instance, the subject is treated for about 65 years. In another instance, the subject is treated for about 70 years. In another instance, the subject is treated for about 75 years, or more.WSGR Docket No. 41012-760.601

[0067] In the described methods, the subject can be from about 1 day of age to about 100 years of age. In one embodiment, the subject is an infant of from about 1 day to about 2 years of age. In another embodiment, the subject is a child of from about 18 to about 72 months of age at commencement of treatment. In another embodiment, the subject is a child of from about 3 to about 6 years of age at commencement of treatment. In another embodiment, the subject is a child of from about 3 to about 8 years of age at commencement of treatment. In another embodiment, the subject is a young adult of from about 9 years to about 19 years of age. In another embodiment, the subject is a young adult of from about 9 years to about 12 years of age. In another embodiment, the subject is a young adult of from about 13 years to about 17 years of age. In another embodiment, the subject is a young adult of from about 15 years to about 17 years of age. In another embodiment, the subject is an adult of from about 20 years to about 60 years of age. In another embodiment, the subject is an elderly person of about 61+ years of age. In one non-limiting example, the subject is about 3 years of age at commencement of treatment. In another non-limiting example, the subject is about 4 years of age at commencement of treatment. In another non-limiting example, the subject is about 5 years of age at commencement of treatment. In another non-limiting example, the subject is about 6 years of age at commencement of treatment. In another non-limiting example, the subject is about 7 years of age at commencement of treatment. In another non-limiting example, the subject is about 8 years of age (or more) at commencement of treatment. In another non-limiting example, the subject is under 17 years of age at commencement of treatment. In another non-limiting example, the subject is under 12 years of age at commencement of treatment. In another non-limiting example, the subject is under 8 years of age at commencement of treatment. In another non-limiting example, the subject is under 6 years of age at commencement of treatment. In any of such methods, the subject does not have (exhibit) any adverse events during or following treatment. In any of such methods, the subject does not have (exhibit) any severe adverse events during or following treatment. In any of such methods, the subject does not have (exhibit) an adverse event during or following treatment related to treatment. In any of such methods, the subject does not have (exhibit) an severe adverse event during or following treatment related to treatment.

[0068] In any of such methods, an improvement of > 50% of effect of one or more symptom preserved from a placebo-controlled double-blind study indicates disease modification. In other embodiments, an improvement of > 60% of effect of one or more symptom preserved from a placebo-controlled doubleblind study indicates disease modification.

[0069] In one embodiment of such methods, the protease is present in the coated particles in an amount of from about 98,100 to about 193,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U. S.P. units / dose. In another embodiment of such methods, the protease is present in the coated particles in an amount of from about 170,000 to about 180,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 345,000 to about 355,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 24,000 to about 30,000 U.S.P. units / dose. In another embodiment of suchWSGR Docket No. 41012-760.601 methods, the protease is present in the coated particles in an amount of from about 175,000 to about 176,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 350,000 to about 352,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 26,000 to about 28,000 U.S.P. units / dose. In another embodiment of such methods, the protease is present in the coated particles in an amount of about 175,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 351,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of about 27,000 U.S.P. units / dose. In another embodiment of such methods, the protease is present in the coated particles in an amount of about 146,700 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 219,600 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of about 27,900 U.S.P. units / dose.

[0070] In another aspect, provided herein is a method of treating an Autism Spectrum Disorder (ASD) in a subject in need thereof, comprising administering to the subject about 900 mg of a digestive enzyme preparation three times per day with a food for from about 12 weeks to about 99 years; wherein the subject is from about 1 day to about 2 years of age, from about 3 to about 8 years of age, from about 9 to about 19 years of age, from about 20 to about 60 years of age, or 61+ years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of from about 98,100 to about 193,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U. S.P. units / dose, whereby the ASD is treated. In certain embodiments, an improvement of > 50% of effect of inappropriate speech preserved from a placebo- controlled double-blind study indicates disease modification. In other embodiments, an improvement of > 60% of effect of inappropriate speech preserved from a placebo-controlled double-blind study indicates disease modification. In one instance, the lipid comprises a hydrogenated soy oil.

[0071] In one embodiment, the subject is from about 1 day to about 2 years of age. In another embodiment, the subject is from about 3 to about 8 years of age at commencement of treatment. In another embodiment, the subject is from about 9 to about 19 years of age. In another embodiment, the subject is from about 20 to about 60 years of age. In another embodiment, the subject is 61+ years of age at commencement of treatment.

[0072] In one embodiment, the protease is present in the coated particles in an amount of from about 165,000 to about 190,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 340,000 to about 360,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 22,000 to about 35,000 U.S.P. units / dose. In another embodiment, the protease is present in the coated particles in an amount of from about 170,000 to about 180,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 345,000 to about 355,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 24,000 toWSGR Docket No. 41012-760.601 about 30,000 U. S.P. units / dose. In another embodiment, the protease is present in the coated particles in an amount of from about 175,000 to about 176,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 350,000 to about 352,000 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 26,000 to about 28,000 U.S.P. units / dose. In another embodiment, the protease is present in the coated particles in an amount of about 175,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 351,000 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of about 27,000 U. S.P. units / dose. In another embodiment, the protease is present in the coated particles in an amount of about 146,700 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 219,600 U. S.P. units / dose. and the lipase is present in the coated particles in an amount of about 27,900 U.S.P. units / dose.

[0073] In any of such methods, in one instance, the food has a pH of 4.5 or less.

[0074] In any of such methods, in one instance, the subject exhibits an improvement of at least 2%compared to treatment with a placebo or compared to the subject prior to treatment. Alternatively, or in addition, in any of such methods, in one instance, irritability / agitation, lethargy / social withdrawal, stereotypy, hyperactivity / non-compliance, and / or inappropriate speech are improved by at least 2% or more compared to treatment with a placebo or compared to the subject prior to treatment. Alternatively, or in addition, in any of such methods, in one instance, the subject exhibits an improvement of at least by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or more compared to treatment with the placebo or compared to the subject prior to treatment. Alternatively, or in addition, in any of such methods, in one instance, irritability / agitation, lethargy / social withdrawal, stereotypy, hyperactivity / non-compliance, and / or inappropriate speech are improved by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or more compared to treatment with the placebo or compared to the subject prior to treatment.

[0075] Improvement can be assessed using any art-recognized assessment including, but not limited to, an ABC checklist (ABC-I), an Autism Spectrum Disorder (ASD) Diagnostic Interview -Revised (ADI-R), a Social Communication Questionnaire (SCQ) assessment, an EVT-2 test, a PPVT-2 test, and / or a Connors test.

[0076] In any of such methods, the subject to be treated can be white, Asian, black or African American, multiracial, American Indian or Alaska Native, or other. In any of such methods, the subject to be treated is not Hispanic or Latino, or wherein the subject to be treated is Hispanic or Latino.

[0077] In any of such methods, the subject to be treated meets the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV-TR) diagnostic criteria for Autism or the (DSM-V-TR) Autistic Spectrum Disorder (ASD). In any of such methods, the subject to be treated is assessed by SCQ screening. In any of such methods, the subject to be treated is confirmed as being autistic by an Autism Diagnostic Interview-Revised (ADI-R).WSGR Docket No. 41012-760.601

[0078] In any of such methods, the subject to be treated weighs less than about 13 kg. Alternatively, the subject to be treated weighs less than about 22 kg. Alternatively, the subject to be treated weighs more than 22 kg.

[0079] In any of such methods, the subject to be treated is not allergic to a pork product. In any of such methods, the subject to be treated is not sensitized or does not have an allergy to trypsin, pancreatin, or pancrealipase. In any of such methods, the subject to be treated does not have a history of severe head trauma, as defined by loss of consciousness, hospitalization, skull fracture, or stroke. In any of such methods, the subject to be treated has not had a seizure within a year prior to treatment, or the subject does not have a past or present need for seizure medication. In any of such methods, the subject to be treated is not diagnosed with HIV, cancer, cerebral palsy, muscular dystrophy, a known genetic disorder, blood dyscrasia, ongoing gastrointestinal disease (e.g. , Celiac disease), an endocrine disorder (e.g , hypothyroidism, diabetes, etc.), a pancreatic disease (endocrine or exocrine), depression, bipolar disorder, Alzheimer’s disease, Parkinson’s disease, a pervasive development disorder (PDD), obsessive compulsive disorder (OCD), oppositional defiant disorder (ODD), schizophrenia, a schizophreniform disorder, and / or another psychiatric disease. In any of such methods, the subject to be treated does not have evidence of a severe, moderate, or uncontrolled systemic disease. In any of such methods, the subject to be treated does not have a co-morbid condition which in the Investigator’s or Medical Director’s opinion makes it undesirable for the subject to be treated or would jeopardize compliance with treatment. In any of such methods, the subject to be treated does not consume any of the following within 30 days of treatment: an enzyme product or a product containing pancreatic / digestive enzymes of plant or animal origin; a pancreatin, thyroid, or adrenal extract (either synthetic plant or animal -based); an essential fatty acids / omega / or other supplement containing product; an Amino acid or an amino acid containing product; a secretin product (transdermal, oral, or injectable); Vitamin B12 / folate (oral or injectable); a chelating agent or a chelation therapy; another investigational drug or therapy / oncology drug / anti-helminthic / anti-yeast drug; and / or an off-label medication.

[0080] In any of such methods, the subject to be treated can be biologically a male. Alternatively, in any of such methods, the subject to be treated can be biologically a female.

[0081] In any of such methods, improvement (e.g , percent improvement) can be calculated as percentage improvement = [1- Measurement mean / baseline mean]. In one embodiment, the subject to be treated has a baseline social interaction of about 21.7±10% as measured on an Autism Spectrum Disorder (ASD) Diagnostic Interview- Revised (ADI-R) Subscale. In another embodiment, the subject to be treated has a baseline verbal communication of about 15±10% as measured on an ADI-R Subscale. In another embodiment, the subject to be treated has a baseline non-verbal communication of about 10.5±10% as measured on an ADI-R Subscale. In another embodiment, the subject to be treated has a baseline restricted, repetitive and stereotyped pattern of behavior of about 6.9±10% as measured on an ADI-R Subscale. In another embodiment, the subject to be treated has a baseline abnormality of development evident at or before 36 months as measured on an ADI-R Subscale. In another embodiment,WSGR Docket No. 41012-760.601 the subject to be treated has a neurodevelopmental gap compared to a neurotypical child. In another embodiment, the neurodevelopmental gap is from about 0.008 to about 0.012 K-complex (ml / g / min).

[0082] In another embodiment, the subject to be treated has a fetal chymotrypsin (FCT) level of from about 7.20 to about 8.2 prior to treatment. For example, the subject may have a FCT level of from about 10 to about 12 as measured at week 12 of treatment. In one instance, the subject exhibits a FCT increase of from about 2 to about 4 as measured at week 12 of treatment.

[0083] In another embodiment, at least 65% of subjects treated exhibit an improvement of one or more symptoms of Autism Spectrum Disorder (ASD) of > 30% compared to baseline as measured at week 12, 24, 36, 48, or 60 of treatment. In a non-limiting example, at least 75%, 76%, 77%, 78%, or 79% of subjects treated exhibit an improvement of one or more symptoms of Autism Spectrum Disorder (ASD) of > 30% compared to baseline as measured at week 12, 24, 36, 48, or 60 of treatment.

[0084] In another embodiment, the subject exhibits an improvement of at least -0.3 as measured on a Caregiver Global Impression (CGI) scale as measured at week 12 of treatment. In another embodiment, the subject exhibits an improvement of about 2±0. 1 as measured on a Caregiver Global Impression (CGI) scale as measured at week 12 of treatment. In another embodiment, the subject exhibits an improvement of about 1.8±0.15 as measured on a Caregiver Global Impression (CGI) scale as measured at week 12 of treatment.

[0085] In any of such methods, treatment improves a maladaptive behavior associated with the ASD. In one instance, the ASD comprises autism.INCORPORATION BY REFERENCE

[0086] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application is specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0087] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0088] FIGS. 1A-1B are graphical illustrations of exemplary trends from a Delayed Start study expected from treatment that is either symptom-modifying (FIG. 1A) or disease- modifying (FIG. IB).

[0089] FIG. 1A shows a line chart pattern expected from an exemplary symptom-modifying treatment after administration of a drug or placebo across a study comprising an initial 12 weeks of a placebo- controlled double-blind study and 24 weeks of an open-label study. Improvement is exhibited as a reduction of an evaluated symptom in negative percentages. A more negative value indicates greater reduction of a symptom, and correspondingly, a greater improvement. In a symptom-modifying treatment, the treatment condition comprising drug administration (lower line, “early-start” group) shows a steeper slope in the placebo-controlled double-blind study phase, and the condition comprising placebo administration shows a shallower slope (upper line, “delayed-start” group). Upon initiation of the open-WSGR Docket No. 41012-760.601 label study phase when both treatment groups receive the drug, a symptom-modifying treatment would show that there is a rapid convergence of early-start and delay ed-start treatment results such that by, for example, about week 4 of the open-label phase, the level of improvement in both groups is about the same. In this illustration of a symptom-modifying treatment study, at about week 4 of the open-label phase, both treatment groups can be seen to have an equivalence of slopes after convergence that lasts for the remainder of the study duration. The equivalence of slopes by the end of the study period reflects equivalence in the improvement of symptoms in both early-start treatment and delayed-start treatment groups.

[0090] FIG. IB shows a line chart pattern expected from an exemplary disease-modifying treatment after administration of a drug or placebo across a study comprising an initial 12 weeks of a placebo - controlled double-blind study and 24 weeks of an open-label study. Improvement is exhibited as a reduction of an evaluated symptom in negative percentages. A more negative value indicates greater reduction of a symptom, and correspondingly, a greater improvement. In a disease-modifying treatment, the treatment condition comprising drug administration (lower line, “early-start” group) shows a steeper slope in the placebo-controlled double-blind study phase, and the condition comprising placebo administration shows a shallower slope (upper line, “delayed-start” group) as is similarly seen in the symptom-modifying treatment example from FIG. 1A. Upon initiation of the open-label study phase when both treatment groups receive the drug, however, a disease-modifying treatment would show that there is an absence of convergence of early-start and delayed-start treatment results across the duration of the open-label phase. More than about 50% of the effect (e.g. , level of improvement) is preserved in each group from the placebo-controlled double-blind study phase. The early-start treatment group has superior results relative to the delayed-start treatment group as interpreted by the sustained, greater percentage reduction in symptoms in the early-start group.

[0091] FIGS. 2A-2B are line charts illustrating data from a 36-week (FIG. 2A) and a 60-week (FIG. 2B) delayed-start study in subjects with autism treated with high- protease pancreatic replacement compositions described herein (CM- AT). The delayed-start studies each comprised 12 weeks of placebo- controlled double-blind phase, followed by an open-label phase of either 24 weeks (FIG. 2A) or 48 weeks (FIG. 2B). Improvement is measured as a reduction in percentage of an Aberrant Behavior Checklist - Irritability subscale (ABC-I) score. Both the 36-week (FIG. 2A) and 60-week (FIG. 2B) studies can be seen to follow the pattern corresponding to the disease-modifying treatment model shown in FIG. IB: at least about 50% of the treatment effect from CM- AT administration is preserved from the placebo-controlled double-blind study in the open-label phases of each study.

[0092] FIG. 3 is a graphical illustration of the neurodevelopmental gap between neurotypical children and children with autism between birth and 15 years of age (x-axis) as measured by K-complex in ml / g / min (y-axis).

[0093] FIG. 4 is a graphical illustration of serotonin synthesis in the brain in non-autistic children. K complex is the uptake rate content for labeled tryptophan, which has been termed the serotonin synthesis capacity the absolute serotonin synthesis rate (pmol / g / min) by using plasma tryptophan levels has notWSGR Docket No. 41012-760.601 been calculated. Serotonin synthesis capacity in non-autistic children (n=24). Global brain values for K complex (mL / g / min) for the siblings of autistic children and children with epilepsy were fitted according to a five-parameter developmental model. Parameter a (0.0122 ±0.0008 [±SD]) represents the magnitude of the plateau phase and parameter C (0.0047± 0.0064) describes the adult values. The shape parameters P and y represent the rate of increase (P=2.33±1.06) and decline (y = 0.2066±0.3177) of the developmental process with age. The parameter A (5. 16±2.03) indicates the age at which the plateau phase ends and the decline to adult values begins. Source: Chugani et al., 1999.

[0094] FIG. 5 is a graphical illustration of serotonin synthesis capacity in autistic children as compared with non-autistic children. Serotonin synthesis capacity in autistic children (n=30; open circle) compared with non-autistic children for ages less than non-autistic (n=8; closed circle). Global brain values for K complex (mL / g / min) for the autistic children were fitted to a two-parameter function representing the increase to the plateau phase because no decline phase was detected. The magnitude of the plateau a was significantly lower for the autistic than the non-autistic group (p=0.0036). Source: Chugani et al., 1999.

[0095] FIG. 6 is a graphical illustration of core and non-core symptoms of autism.

[0096] FIGS. 7A-7D provide an example of an ABC checklist that can be utilized to assess and monitor subjects before, during, and following treatment (Aman et al., 1994, Slosson Educational Publications, Inc.). FIG. 7A provides guidance regarding general health information of the subject. FIG. 7B provides instructions regarding the symptoms to be assessed, the scoring index, and questions 1 -20 of the assessment. FIG. 7C provides questions 21-58 of the assessment. FIG. 7D is an exemplary summary page for the medical practitioner to score for Subscale I (Irritability), Subscale II (Lethargy), Subscale III (Stereotypy), Subscale IV (Hyperactivity), and Subscale V (Inappropriate Speech).

[0097] FIG. 8 provides an example of a Caregiver Global Impressions (CGI) assessment form that can be utilized to assess and monitor subjects before, during, and following treatment.

[0098] FIG. 9A is a line chart illustrating ABC lethargy data from a 36-week delayed-start study in subjects with autism treated with high-protease pancreatic replacement compositions described herein (CM- AT) where a >50% of effect preserved from placebo-controlled double-blind study demonstrates disease modification.

[0099] FIG. 9B is a line chart illustrating ABC lethargy data from a 60-week delayed-start study in subjects with autism treated with high-protease pancreatic replacement compositions described herein (CM- AT) where a >50% of effect preserved from placebo-controlled double-blind study demonstrates disease modification.

[0100] FIG. 10A is a line chart illustrating ABC hyperactivity data from a 36-week delayed-start study in subjects with autism treated with high-protease pancreatic replacement compositions described herein (CM- AT) where a >50% of effect preserved from placebo-controlled double-blind study demonstrates disease modification.

[0101] FIG. 10B is a line chart illustrating ABC hyperactivity data from a 60-week delayed-start study in subjects with autism treated with high-protease pancreatic replacement compositions described hereinWSGR Docket No. 41012-760.601(CM- AT) where a >50% of effect preserved from placebo-controlled double-blind study demonstrates disease modification.

[0102] FIG. 11A is a line chart illustrating ABC inappropriate speech data from a 36-week delay ed-start study in subjects with autism treated with high-protease pancreatic replacement compositions described herein (CM- AT) where a >50% of effect preserved from placebo -controlled double-blind study demonstrates disease modification.

[0103] FIG. 1 IB is a line chart illustrating ABC inappropriate speech data from a 60-week delay ed-start study in subjects with autism treated with high-protease pancreatic replacement compositions described herein (CM- AT) where a >50% of effect preserved from placebo -controlled double-blind study demonstrates disease modification.

[0104] FIG. 12A is a line chart illustrating ABC stereotypy data from a 36-week delayed-start study in subjects with autism treated with high-protease pancreatic replacement compositions described herein (CM- AT) where a >50% of effect preserved from placebo-controlled double-blind study demonstrates disease modification.

[0105] FIG. 12B is a line chart illustrating ABC stereotypy data from a 60-week delayed-start study in subjects with autism treated with high-protease pancreatic replacement compositions described herein (CM- AT) where a >50% of effect preserved from placebo-controlled double-blind study demonstrates disease modification.

[0106] FIG. 13A is a line chart illustrating ABC total score from a 36-week delayed-start study in subjects with autism treated with high-protease pancreatic replacement compositions described herein (CM- AT) where a >50% of effect preserved from placebo-controlled double-blind study demonstrates disease modification.

[0107] FIG. 13B is a line chart illustrating ABC total score data from a 60-week delayed-start study in subjects with autism treated with high-protease pancreatic replacement compositions described herein (CM- AT) where a >50% of effect preserved from placebo-controlled double-blind study demonstrates disease modification.DETAILED DESCRIPTION

[0108] Certain specific details of this description are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the present disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments.

[0109] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods, and materials are described below.

[0110] There is an urgent unmet need for a treatment addressing treatment of neurodevel opmental disorders in children. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) Neurodevelopmental Disorders are a group of conditions with onset in theWSGR Docket No. 41012-760.601 developmental period. The disorders typically manifest early in development, often before the child enters grade school and are characterized by developmental deficits that produce impairments of personal, social, academic, or occupational functioning. The range of development deficits varies from very specific limitations of learning or control of executive functions to global impairments of social skills or intelligence.

[0111] Neurodevelopmental disorders frequently co-occur, for example, individuals with Autism Spectrum Disorder (ASD) often have intellectual disability (intellectual development disorder), and many children with attention-deficit / hyperactivity disorder (ADHD) also have a specific learning disorder. For some disorders, the clinical presentation includes symptoms of excess as well as deficits and delays in achieving expected milestones. For example, ASD is only diagnosed only when the characteristic deficits of social communications are accompanied by excessively repetitive behaviors, restricted interests, and insistence on sameness.

[0112] As will be shown by the present application, co-morbidities amongst various neurodevelopmental disorders arise from early onset disturbances in one or more of the biogenic amine neurotransmitters and / or y- aminobutyric acid (GABA) / glutamine. Specific biogenic amine neurotransmitters include at least Serotonin and Dopamine.

[0113] The present invention comprises compositions of matter and methods of treatment for neurodevelopmental diseases including: Intellectual Disability, Global Developmental Delay, Communication Disorders (including language disorder, speech sound disorder, social (pragmatic) communication disorder, and childhood-onset fluency disorder (stuttering); Autism Spectrum Disorder (ASD), Attention-Deficit / Hyperactivity Disorder (ADHD); Neurodevelopmental Motor Disorders (including developmental coordination disorder, stereotypic movement disorder, and tic disorders); and Specific Learning Disorder.

[0114] For the purposes of discussion, and in accordance with DSM-V, Intellectual disability (intellectual developmental disorder) is characterized by deficits in general mental abilities, such as reasoning, problem solving, planning, abstract thinking, judgment, academic learning, and learning from experience. The deficits result in impairments of adaptive functioning, such that the individual fails to meet standards of personal independence and social responsibility in one or more aspects of daily life, including communication, social participation, academic or occupational functioning, and personal independence at home or in community settings. Global developmental delay, as its name implies, is diagnosed when an individual fails to meet expected developmental milestones in several areas of intellectual functioning. The diagnosis is used for individuals who are unable to undergo systematic assessments of intellectual functioning, including children who are too young to participate in standardized testing. Intellectual disability may also result from an acquired insult during the developmental period from, for example, a severe head injury, in which case a neurocognitive disorder also may be diagnosed.

[0115] Communication disorders include language disorder, speech sound disorder, social (pragmatic) communication disorder, and childhood-onset fluency disorder (stuttering). The first three disorders areWSGR Docket No. 41012-760.601 characterized by deficits in the development and use of language, speech, and social communication, respectively. Childhood-onset fluency disorder is characterized by disturbances of the normal fluency and motor production of speech, including repetitive sounds or syllables, prolongation of consonants or vowel sounds, broken words, blocking, or words produced with an excess of physical tension. Like other neurodevelopmental disorders, communication disorders begin early in life and may produce lifelong functional impairments.

[0116] Autism spectrum disorder is characterized by persistent deficits in social communication and social interaction across multiple contexts, including deficits in social reciprocity, nonverbal communicative behaviors used for social interaction, and skills in developing, maintaining, and understanding relationships. In addition to the social communication deficits, the diagnosis of autism spectrum disorder requires the presence of restricted, repetitive patterns of behavior, interests, or activities. Because symptoms change with development and may be masked by compensatory mechanisms, the diagnostic criteria may be met based on historical information, although the current presentation must cause significant impairment.

[0117] Within the diagnosis of autism spectrum disorder, individual clinical characteristics are noted through the use of specifiers (with or without accompanying intellectual impairment; with or without accompanying structural language impairment; associated with a known medical / genetic or environmental / acquired condition; associated with another neurodevelopmental, mental, or behavioral disorder), as well as specifiers that describe the autistic symptoms (age at first concern; with or without loss of established skills; severity). These specifiers provide clinicians with an opportunity to individualize the diagnosis and communicate a richer clinical description of the affected individuals. For example, many individuals previously diagnosed with Asperger's disorder would now receive a diagnosis of autism spectrum disorder without language or intellectual impairment.

[0118] ADHD is a neurodevelopmental disorder defined by impairing levels of inattention, disorganization, and / or hyperactivity -impulsivity. Inattention and disorganization entail inability. to stay on task, seeming not to listen, and losing materials, at levels that are inconsistent with age or developmental level. Hyperactivity-impulsivity entails overactivity, fidgeting, inability. to stay seated, intruding into other people's activities, and inability to wait-symptoms that are excessive for age or developmental level. In childhood, ADHD frequently overlaps with disorders that are often considered to be "externalizing disorders," such as oppositional defiant disorder and conduct disorder. ADHD often persists into adulthood, with resultant impairments of social, academic and occupational functioning.

[0119] The neurodevelopmental motor disorders include developmental coordination disorder, stereotypic movement disorder, and tic disorders. Developmental coordination disorder is characterized by deficits in the acquisition and execution of coordinated motor skills and is manifested by clumsiness and slowness or inaccuracy of performance of motor skills that cause interference with activities of daily living. Stereotypic movement disorder is diagnosed when an individual has repetitive, seemingly driven, and apparently purposeless motor behaviors, such as hand flapping, body rocking, head banging, self- biting, or hitting. The movements interfere with social, academic, or other activities. If the behaviorsWSGR Docket No. 41012-760.601 cause self-injury, this should be specified as part of the diagnostic description. Tic disorders are characterized by the presence of motor or vocal tics, which are sudden, rapid, recurrent, nonrhythmic, stereotyped motor movements or vocalizations. The duration, presumed etiology, and clinical presentation define the specific tic disorder that is diagnosed: Tourette's disorder, persistent (chronic) motor or vocal tic disorder, provisional tic disorder, other specified tic disorder, and unspecified tic disorder. Tourette's disorder is diagnosed when the individual has multiple motor and vocal tics that have been present for at least 1 year and that have a waxing-waning symptom course.

[0120] Specific learning disorder, as the name implies, is diagnosed when specific deficits. in an individual's ability to perceive or process information efficiently and accurately. This neurodevelopmental disorder first manifests during the years of formal schooling and is characterized by persistent and impairing difficulties with learning foundational academic skills in reading, writing, and / or math. The individual's performance of the affected academic skills is well below average for age, or acceptable performance levels are achieved only with extraordinary effort. Specific learning disorder may occur in individuals identified as intellectually gifted and manifest only when the learning demands or assessment procedures (e.g. , timed tests) pose barriers that cannot be overcome by their innate intelligence and compensatory strategies. For all individuals, specific learning disorder can produce lifelong impairments in activities dependent on the skills, including occupational performance.

[0121] The urgent unmet need is most apparent in the treatment for the core symptoms and associated maladaptive symptoms of autism spectrum disorder (ASD), especially in preschool populations. Autism spectrum disorder (ASD) is a neurodevelopmental disorder in which individuals demonstrate persistent core deficits in social communication and social interaction along with restricted, repetitive patterns of behavior, interests, or activities. ASD appears to be increasing in global prevalence without a clear cause. There is a large, global unmet need for ASD treatments, as no pharmacologic intervention has been approved in the US or worldwide for the treatment of the core symptoms of ASD. ASD symptoms and their severity and presentation vary widely. Individuals with ASD possess a unique combination or matrix of behaviors and corresponding levels of function that affect quality of life. To date, other than the present invention, there are no known treatments for ASD that are disease modifying.

[0122] The Center for Disease Control and Prevention (CDC) Autism and Developmental Disabilities Monitoring (ADDM) Network estimates that, overall, about 1 in 36 children have been identified with ASD. California and other places have higher incidents, with California estimated at 1 in 22 children with an ASD. ASD is reported to occur in all racial, ethnic, and socioeconomic groups. ASD is nearly 4 times more common among boys than among girls. About 1 in 6 (17%) children aged 3 through to 17 years have been diagnosed with a developmental disability. These included autism, attention- deficit / hyperactivity disorder, blindness, and cerebral palsy, among others.

[0123] Multiple causes for ASD have been hypothesized, including genetic and environmental, but none to date has been clearly identified. Early developmental years are important in the formation of autistic behaviors and the need for commencement of treatments during those early years. Ninety percent of brainWSGR Docket No. 41012-760.601 growth and development occurs between the ages of 0 and 6 years; therefore, targeting treatment during this time is important for autism research and drug development.

[0124] Disruptions of neurotransmitter systems have been associated with the pathogenesis of ASD including serotonin, dopamine, and y-aminobutyric acid (GABA) / glutamine. Proper functioning of the serotonin and dopamine neurotransmitter systems requires essential amino acids, tryptophan and phenylalanine, that can only be obtained exogenously from ingested food through protein digestion. The GABA glutamine system requires a nonessential amino acid, glutamic acid. It has long been known that there are deficits in brain synthesis and utilization of serotonin in ASD. Previous research has demonstrated that individuals with ASD have low levels of circulating amino acids. Sixty -five percent (65%) of children with ASD have deficient levels of chymotrypsin enzyme activity. This will result in a lowered pool of essential amino acids including tryptophan (serotonin), phenylalanine (dopamine), leucine, and methionine (initiation codon for all protein synthesis).

[0125] Serotonin is manufactured mainly in the gastrointestinal tract and in the brain utilizing tryptophan from exogenous protein digestion resulting in a pool of tryptophan. Because serotonin cannot pass the blood brain barrier, it must be manufactured locally in the brain from tryptophan starting around the age of 2 years. Tryptophan is released from polypeptide breakdown of protein in the gut through the action of proteases, mainly chymotrypsin. Tryptophan subsequently becomes available for the brain to manufacture serotonin. Tryptophan is transported into the brain circulatory system through the action of specific receptors for tryptophan and other amino acids that facilitate transport. The enzyme chymotrypsin is responsible for cleaving essential amino acids such as phenylalanine, tryptophan, methionine, and leucine from exogenously ingested protein. This action is driven in part by the ability of chymotrypsin to cleave near aromatic residues of some amino acids, an activity not found in trypsin and elastase.

[0126] There are significant differences in brain-based serotonin synthesis between autistic and non- autistic children as well as age-based and gender-based differences. FIG. 4 shows serotonin production in non- autistic individuals (e.g. , siblings of children with ASD and non-autistic individuals with epilepsy) over time. Serotonin synthesis in the brain is at its peak in non-autistic subjects aged 2 through to 6 (through the fifth year) years followed by a gradual decline toward adult values between the ages of 6 and 14 years. A sharp rise in brain serotonin synthesis is seen at 2 years of age; prior to the age of 2 years, serotonin made in the gut can cross the Blood Brain Barrier (BBB). This is a result of changes in the BBB that block serotonin passage in order to facilitate tight local control over the manufacturing of this key neurotransmitter in the Central Nervous System (CNS). This control is necessary to avoid exposing sensitive neurons in the CNS to large and fluctuating serotonin levels from the body. Thus, this change in the BBB and the manufacturing of serotonin in the brain is critical for proper CNS function.

[0127] Studies of children with autism have characteristically shown that many patients have high blood serotonin levels, with that serotonin being sequestered primarily in platelets when compared to normal controls. Actual circulating levels of free serotonin in platelet poor plasma of autistic patients were low.WSGR Docket No. 41012-760.601Additionally, synthesis of serotonin within the brain of autistic children is deficient compared to non- autistic controls through the age of 15 years.

[0128] As shown in FIG. 5, the deficit in serotonin production in autistic children compared with non- autistic children is greatest in children less than 5 years of age. Non-autistic subjects have peak brain serotonin levels that are two-fold higher than those seen in autistic subjects starting at 5 years of age. While serotonin levels plateau around 5 to 6 years of age in both groups, autistic children still do not reach the same level of serotonin production seen in non-autistic controls. This is further illustrated in FIG. 3

[0129] The serotonergic hypothesis in autism can be summarized as follows: Levels of serotonin production in the brain are age-related, the largest deficit in brain serotonin production in autistic children is seen between 0-6 years of age, critical milestones in serotonin production in the brain are seen early in life, with rapid acquisition of endogenous serotonin synthesis in the brain by 2 years of age, with higher serotonin levels seen in the brain for non-autistic compared with autistic children. This is followed by a peak in serotonin synthesis by 6 years of age followed by a gradual decline to a lower adult level by the age of 15 years in non-autistic individuals.

[0130] Peak serotonin synthesis in the brain in autistic children through 5 years of age is always lower than that seen in non-autistic children. This deficiency is apparent from infancy. The consumption of exogenous tryptophan- containing proteins does affect CNS regulated behaviors such as pacing, whirling, and self-hitting in autistic individuals. The sole supply of exogenous tryptophan in the body requires the action of chymotrypsin and other gut proteases. A large number of autistic children have a chymotrypsin deficiency detected by the fecal chymotrypsin (FCT) test. This raises the possibility, that in addition to low levels of endogenous chymotrypsin, other functional derangements are likely present in autistic children because of lower pools of tryptophan and other amino acids, including a derangement in serotonin synthesis. The addition of exogenous chymotrypsin could help to overcome the chymotrypsin deficiency in autistic children and thus, help to restore both tryptophan and serotonin levels in autistic children.

[0131] As previously stated, ASD presents as a complex picture of maladaptive behaviors and associated symptoms and poses unique challenges in the development of novel drug treatments. In examining potential treatments for ASD, there are two important concepts: looking at sustained reductions in maladaptive behaviors over time that can determine the durability of the pharmacodynamic action of the treatment and distinguishing between symptom modification from disease or disorder modification.

[0132] One important aspect of autism and autism treatment is that autism is a progressive neurodevelopmental condition. Symptoms and maladaptive behaviors do not manifest all at once, the developmental aspect of growth and change is the hallmark of childhood development. In a neurotypical child, once they have gained a particular functional aspect of their development such as the ability to walk or talk, that developmental milestone is achieved and remains. What it took to achieve thatWSGR Docket No. 41012-760.601 milestone varies from child to child, but it is marked by a steady achievement of small gains until the ultimate milestone is achieved. It is a slow and steady course of continued skill attainment over time.

[0133] During the course of treatment of a disease such as ASD in clinical trials, the goal is to change and improve one or more symptoms of manifestation of the disease during the course of the clinical trial. This is known as symptom modification. Generally improving one or more symptoms in the time allotted during the trial should be sufficient given that the “power” of the trial is sufficient to validate symptom modification of the disease.

[0134] The surprising and unexpected discovery in accordance with the instant invention is that while children with ASD treated with drug obtained significance in various symptoms over a placebo - controlled group in a double-blind placebo controlled clinical trial, an unexpected parallel improvement of both the placebo controlled and drug groups continued well into a rollover open label study where both the placebo and drug subjects received drug. All rollover subjects (both placebo and drug) were blinded to whether they received drug or placebo in the double-blind portion of the trial. The achieved result is known as disease modification and to date no known drug or treatment has achieved disease modification for ASD.

[0135] Further, and equally surprising, the unexpected parallel improvement of both the placebo controlled and drug groups in the rollover open label studies occurred in a cascading fashion, as neurodevelopment was gained back in a specific order, much the way it is gained but in the opposite direction. The results are characterized by the ensuing delayed start analyses and results presented herein.

[0136] Delayed start design, as employed herein, has been developed to try to avoid a symptomatic confound when testing for disease modification. Prior to the instant application, no known treatment for ASD exists that is disease-modifying. A delay ed-start analysis as employed in this disclosure provides an appropriate context for the study of a neurodev el opmental disease in determining symptom modification from disease or disorder modification. In this type of design, the first phase of the study involves active treatment (early-start group) vs placebo (delayed-start group). In the second phase, all participants receive active treatment, and the results were used to determine whether the treatment is symptom modifying or disease-modifying.

[0137] As illustrated in FIG. 1A, Symptom Modifying Treatment, when a treatment is symptommodifying, participants receiving the active treatment will show a greater reduction in symptoms vs placebo during the double-blind segment, and during the open-label segment, both groups achieve symptom reduction. If a treatment is disease- or disorder-modifying, both groups will demonstrate continued reductions in maladaptive behaviors in the open label segment, with the early-start treatment group maintaining a greater improvement over the late start (placebo) group (see, FIG. IB Disease Modifying Treatment). In short, if the benefits achieved after the double-blind segment persist through the open-label segment, then the effects cannot be explained by a symptomatic effect (as both groups are receiving the same active treatment), and thus the benefit achieved by the early-start group must be due to the earlier start of active treatment.WSGR Docket No. 41012-760.601

[0138] As will be discussed, the inventors arrived at the surprising discovery that their treatment for ASD provided disease modification in many core and non-core symptoms of ASD.

[0139] FIG. 6: Core and Non-Core Symptoms of Autism, illustrates the complex interaction of Core, Non-Core Associated Systemic Issues, Associate Systemic Issues and Related Disorders. Core symptoms are the fundamental aspects of ASD that are present in all individuals diagnosed with this disorder. According to current diagnostic criteria (Diagnostic and Statistical Manual, Fifth Edition DSM-V) [American Psychiatric Association, 2013], an individual with ASD must show deficits in two broad categories: 1. Deficits in social interactions and communication, including deficits in social -emotional reciprocity, deficits in nonverbal communicative behaviors used for social interaction, and deficits in developing, maintaining, and understanding relationships and 2. Restricted or repetitive patterns of behavior and interests, including stereotyped or repetitive motor movements, insistence on sameness or inflexible adherence to routines, highly restricted, fixated interests, hyper or hypo -reactivity to sensory input, or unusual interest in the sensory aspects of the environment. Manifestations of core symptoms must be observed in the first 3 years of life and must cause clinically significant impairment affecting the ability of children with ASD to interact with others, especially people of their own age. Core symptoms, however, may not become fully manifest until social demands exceed limited capacities or may be masked by learned strategies in later life. The core deficits that are frequently seen in children with ASD and their manifestations are summarized below.

[0140] Social Deficits - Social Deficits include difficulty in managing emotions, appreciating the perspectives of others, developing prosocial goals, using interpersonal skills to handle developmentally appropriate tasks, differentiating one's own feelings from the feelings of others (i. e., Theory of Mind), integrating diverse information to construct meaning in context (i.e., central coherence).

[0141] Language / Communication Difficulties - Language / Communication Difficulties include: failing to respond to his or her name or appears not to hear you at times, resists cuddling and holding, and seems to prefer playing alone, retreating into his or her own world, poor eye contact and lacks facial expression doesn't speak or has delayed speech, or loses previous ability to say words or sentences, can't start a conversation or keep one going, or only starts one to make requests or label items, speaks with an abnormal tone or rhythm and may use a singsong voice or robot-like speech, repeats words or phrases verbatim, but doesn't understand how to use them, doesn't appear to understand simple questions or directions, doesn't express emotions or feelings and appears unaware of others' feelings, doesn't point at or bring objects to share interest, inappropriately approaches a social interaction by being passive, aggressive, or disruptive. The earliest signs and symptoms of ASD are communication difficulties; these symptoms may improve over time but are likely to persist into adolescence.

[0142] Repetitive or restricted behaviors or participates in the same activities - Repetitive or restricted behaviors or participates in the same activities includes performing repetitive movements, such as rocking, spinning or hand flapping, performs activities that could cause self-harm, such as biting or headbanging, develops specific routines or rituals and becomes disturbed at the slightest change, has problems with coordination or has odd movement patterns, such as clumsiness or walking on toes, and has odd,WSGR Docket No. 41012-760.601 stiff or exaggerated body language, is fascinated by details of an object, such as the spinning wheels of a toy car, but doesn't understand the overall purpose or function of the object, is unusually sensitive to light, sound or touch, yet may be indifferent to pain or temperature, doesn't engage in imitative or make- believe play, fixates on an object or activity with abnormal intensity or focus, has specific food preferences, such as eating only a few foods, or refusing foods with a certain texture.

[0143] In addition to core symptoms, associated neurologic and systemic issues and related disorders may be present in autistic individuals Non-core symptoms include irritability, aggression, attention deficit hyperactivity disorder, GI problems, and sleep problems. In FDA’s public meeting on patient- focused drug development for autism with individuals with autism and their caregivers, 32% of participants noted that irritability or disruptive behavior (the primary endpoint for the Sponsor’s ASD studies) as a challenging health effect, with 36% of participants favoring treatment options that reduced irritability or disruptive behavior. Additionally, people with ASD have an increased risk of psychiatric problems such as anxiety, depression, obsessive-compulsive disorder, mood disorders, and eating disorders. GI problems, including abdominal pain, constipation, diarrhea and irritable and inflammatory bowel conditions, are among the most common medical conditions associated with ASD.

[0144] Disease Control and Prevention (CDC), children with ASD are more than 3.5 times more likely to suffer chronic diarrhea or constipation than are their normally developing peers. Children with ASD also often have feeding problems compared with their peers and exhibit severe food selectivity in the form of a preference for starches, snack foods, and processed foods instead of proteins, fruits, and vegetables. Food selectivity has been postulated to be caused by the underlying GI symptoms.Autism Spectrum Disorder

[0145] In some aspects, provided herein are compositions and methods for the treatment of Autism Spectrum Disorder. Autism spectrum disorder (ASD) is a disorder related to brain development that results in ongoing challenges in areas like social communication and interaction. It also involves limited, repetitive behavior patterns, activities, or interests. The symptoms of ASD, their intensity, and their manifestation differ significantly from one individual to another. Each person with ASD displays a distinct set of behaviors and performance levels that can influence their quality of life.

[0146] Multiple causes have been hypothesized, including genetic and environmental, but none to date has been clearly identified in ASD. Early developmental years appear to be important in the formation of autistic behaviors and the need for commencement of treatments during those early years. Ninety percent of brain growth and development occurs between the ages of 0 and 6 years; therefore, targeting treatment during this time is important for autism research and drug development.

[0147] Disruptions of neurotransmitter systems comprising, for example, serotonin, dopamine, and y- aminobutyric acid (GABA) / glutamine, have been associated with the pathogenesis of ASD. Proper functioning of the serotonin and dopamine neurotransmitter systems requires essential amino acids, tryptophan, and phenylalanine, which are obtained exogenously from food through protein digestion. The GABA / glutamine system requires a nonessential amino acid, glutamic acid. ASD is characterized by, for example, deficits in brain synthesis and utilization of serotonin. Individuals with ASD have low levels ofWSGR Docket No. 41012-760.601 circulating amino acids. About 65% of children with ASD have deficient levels of chymotrypsin enzyme activity, resulting in a lowered pool of essential amino acids including, for example, tryptophan (a serotonin precursor), phenylalanine (a dopamine precursor), leucine, and methionine.

[0148] Serotonin is manufactured mainly in the gastrointestinal tract and in the brain from exogenous protein digestion resulting in a pool of tryptophan. Because serotonin cannot pass the blood brain barrier, it must be manufactured locally in the brain from tryptophan around the age of 2 years. Tryptophan is released from polypeptide breakdown of protein in the gut through the action of proteases, mainly chymotrypsin. Tryptophan subsequently becomes available for the brain to manufacture serotonin. Tryptophan is transported into the brain circulatory system through the action of specific receptors for tryptophan and other amino acids that facilitate transport. The enzyme chymotrypsin is responsible for cleaving essential amino acids such as phenylalanine, tryptophan, methionine, and leucine from exogenously ingested protein. This action is driven in part by the ability of chymotrypsin to cleave near aromatic residues of some amino acids, an activity not found in trypsin and elastase.

[0149] ASD presents as a complex picture of maladaptive behaviors and associated symptoms and poses unique challenges in the development of novel drug treatments. Some maladaptive behaviors can include, for example, deficits in socialization, deficits in sleep, deficits in cognition, presence of anxiety, obsessive compulsive behaviors, depression, and / or suicidality. In examining potential treatments for ASD, there are two important considerations: (1) looking at sustained reductions in maladaptive behaviors over time that can determine the durability of the pharmacodynamic action of the treatment, and (2) distinguishing between symptom modification from disease or disorder modification. A delay ed- start analysis used in the study described herein provides an appropriate context for the study of a neurodevelopmental disease in determining symptom modification from disease or disorder modification In this type of design, the first phase of the study involves active treatment (early -start group) vs. placebo (delayed-start group). In the second study phase (open-label), all participants received active treatment (CM- AT) and the results were used to determine whether the treatment is symptom-modifying or disease-modifying. As illustrated in FIG. 1A, when a treatment is symptom-modifying, participants receiving the active treatment will show a greater reduction in symptoms vs. placebo during the doubleblind segment, and during the open-label segment, both groups achieve symptom reduction. If a treatment is disease- or disorder-modifying, both groups will demonstrate continued reductions in maladaptive behaviors in the open-label segment, with the early-start treatment group maintaining a greater improvement over the late start (placebo) group (FIG. IB).

[0150] The objective of the study described herein was to use a delayed-start analysis to assess the longterm safety, tolerability, and durability of high-protease pancreatic replacement (CM- AT) for treatment of ASD. Although delayed-start analysis is applicable to both symptom-modifying vs. disease- modifying treatments, the disorder-modifying outcomes of CM- AT on maladaptive behaviors in ASD are the main concern identified in the study described herein.WSGR Docket No. 41012-760.601Criteria of Neurological or Mental Health Disorders

[0151] The American Psychiatric Association's Diagnostic and Statistical Manual -V, Text Revision (DSM-V-TR) 1 provides standardized criteria to help diagnose Autism.

[0152] Psychiatric Diagnoses are categorized by the Diagnostic and Statistical Manual of Mental Disorders, 5th. Edition. Better known as the DSM-V, the manual is published by the American Psychiatric Association and covers all mental health disorders for both subjects and adults. It also lists known causes of these disorders, statistics in terms of gender, age at onset, and prognosis as well as some research concerning the optimal treatment approaches.

[0153] Mental Health Professionals use this manual when working with subjects in order to better understand their illness and potential treatment and to help 3rd party payers (e.g. , insurance) understand the needs of a subject. The book is typically considered the ‘bible’ for any professional who makes psychiatric diagnoses in the United States and many other countries. Much of the diagnostic information on these pages is gathered from the DSM IV.

[0154] The DSM V is published by the American Psychiatric Association. Much of the information from the Psychiatric Disorders pages is summarized from the pages of this text. Should any questions arise concerning incongruencies or inaccurate information, you should always default to the DSM as the ultimate guide to mental disorders. The DSM uses a multiaxial or multidimensional approach to diagnosing because rarely do other factors in a person's life not impact their mental health.DSM-IV Diagnostic Criteria for Autism Spectrum Disorder

[0155] A subject must meet criteria (A) Social interaction, (B) Communication, (C) Behavior, and (D) Onset. With regard to social interaction, a subject must have at least two of the following characteristics: impaired use of nonverbal behaviors like eye contact, facial expressions, and gestures; inability to develop peer relationships; lack of sharing interests or achievements with others; and / or lack of social or emotional reciprocity. With regard to communication a subject must have at least one of the following characteristics: delayed or absent spoken language development; difficulty initiating or maintaining conversations; repetitive or idiosyncratic language use; and / or lack of make-believe or social imitative play. With regard to behavior, a subject must have at least one of the following characteristics: preoccupation with restricted interests; inflexible adherence to routines or rituals; repetitive motor mannerisms like hand flapping or twisting; and / or preoccupation with parts of objects. With regard to onset, a subject must have delays or abnormal functioning in at least one of the above areas must occur before age 3.Aberrant Behavior Checklist

[0156] The Aberrant Behavior Checklist (ABC) scale is a standardized set of questions used for assessing subjects and can be found, for example, published in the 1994 Slosson Educational Publications, Inc. (Aman et al.) and the assessment serves as the standard for assessing subjects. Behavioral attributes are rated as follows: 0 = not at all a problem; 1 = the behavior is a problem, but slight in decree; 2 = the problem is moderately serious; or 3 = the problem is severe in degree. The factors (subscales) of the ABC scale are as follows: (I) irritability, agitation, crying; (II) lethargy, socialWSGR Docket No. 41012-760.601 withdrawal; (III) stereotypic behavior; (IV) hyperactivity, noncompliance; and (V) inappropriate speech. A series of questions is asked with respect to each of the scales and each is rated 0-3.

[0157] Three scales have significant number of data points and validated: Irritability / Agitation (noncore) Primary; Lethargy / Social Withdrawal (core) Secondary; and Hyperactivity (non-core, high morbidity). Two minor scales are: Stereotypic Behavior and Inappropriate Speech. The numbers of questions on each subscale are as follows: 1) Irritability, agitation, crying (15 items); 2) Lethargy, social withdrawal (16 items); 3) Stereotypic behavior (7 items); 4) Hyperactivity, non-compliance (16 items); and 5) Inappropriate speech (4 items)

[0158] The questions on the ABC test are as follows: 1) Excessively active at home, school, work or elsewhere, 2) Injures self on purpose, 3) Listless, sluggish, inactive, 4) Aggressive to other subjects or adults (verbally or physically), 5) Seeks isolation from others, 6) Meaningless, recurring body movements, 7) Boisterous (inappropriately noisy and rough),) Screams inappropriately, 9) Talks excessively, 10) Temper tantrums / outbursts, 11) Stereotyped behavior; abnormal, repetitive movements, 12) Preoccupied; stares into space, 13) Impulsive (acts without thinking), 14) Irritable and whiny, 15) Restless, unable to sit still, 16) Withdrawn; prefers solitary activities, 17) Odd, bizarre in behavior, 18) Disobedient; difficult to control, 19) Yells at inappropriate times, 20) Fixed facial expression / lacks emotional responsiveness, 21) Disturbs others, 22) Repetitive speech, 23) Does nothing but sit and watch others, 24) Uncooperative, 25) Depressed mood, 26) Resists any form of physical contact, 27) Moves or rolls head back and forth repetitively, 28) Does not pay attention to instructions, 29) Demands must be met immediately, 30) Isolates himself / herself from other subjects or adults, 31) Disrupts group activities, 32) Sits or stands in one position for a long time, 33) Talks to self loudly, 34) Cries over minor annoyances and hurts, 35) Repetitive hand, body, or head movements, 36) Mood changes quickly, 37) Unresponsive to structured activities (does not react), 38) Does not stay in seat (e.g , during lesson or training periods, meals, etc., 39) Will not sit still for any length of time, 40) Is difficult to reach, contact, or get through to, 41) Cries and screams inappropriately, 42) Prefers to be alone, 43) Does not try to communicate by words or gestures, 44) Easily distractible, 45) Waves or shakes the extremities repeatedly, 46) Repeats a word or phrase over and over, 47) Stamps feet or bangs objects or slams doors, 48) Constantly runs or jumps around the room, 49) Rocks body back and forth repeatedly, 50) Deliberately hurts himself / herself, 51) Pays no attention when spoken to, 52) Does physical violence to self, 53) Inactive, never moves spontaneously, 54) Tends to be excessively active, 55) Responds negatively to affection, 56) Deliberately ignores directions, 57) Has temper outbursts or tantrums when he / she does not get own way, 58) Shows few social reactions to others

[0159] The ABC is utilized by practitioners because it has the characteristics of validity, reliability, and drug sensitivity. All three are necessary to make the ABC useable as an outcome measure for clinical trials for drugs for autism. It is a predictor of maladaptive behavior. Extensive psychometric assessment of the ABC has indicated that its subscales have high internal consistency, adequate reliability, and established validity.WSGR Docket No. 41012-760.601

[0160] Further information regarding information assessed in the ABC checklist can be found in FIGS.7A-7D.Caregiver Global Impressions (CGI)

[0161] The Caregiver Global Impressions (CGI) is an assessment tool used in studies of autism spectrum disorder (ASD). Details of the CGI form are provided in, for example, FIG. 8.The EVT-2 Test

[0162] The Expressive Vocabulary Test-2 (EVT-2) test builds on the strength of the Expressive Vocabulary Test (EVT) in that is brief and easy to administer; the EVT-2 assessment has been designed to coordinate with the PPVT™-4 (Peabody Picture Vocabulary Test, Fourth Edition) test. Together, these tools give provide a comprehensive system for comparing receptive and expressive vocabulary.

[0163] Unlike some other measures of vocabulary, the EVT-2 supplies two equivalent forms of the test which contain different vocabulary items - helping ensure a subject has not “learned” the test. One form can be used prior to intervention to assess subjects’ vocabulary knowledge and the alternative form can be used for re-testing to evaluate and document progress. EVT-2 also includes a unique Growth Scale Value (GSV) which is sensitive to small changes over time. Users & Applications

[0164] The EVT-2 test is individually administered and norm-referenced. It meets the needs of a wide variety of professionals to help: (1) Quickly assess expressive vocabulary with a test that requires no reading or writing; (2) Evaluate English Language Learners’ (ELL) vocabulary acquisition as a flexible measure of their English word knowledge; (3) Make comparisons with receptive vocabulary to pinpoint a student’s strengths / weaknesses and identify potential word retrieval concerns; (4) Move immediately into evidence-based interventions using those embedded directly into and linked into the ASSIST softwareWSGR Docket No. 41012-760.601(SAS; www.sas.com / products / assist / index.html); (5) Assess oral expression as a foundation of writing skills; and (5) Measure progress using one or both parallel forms.

[0165] Features & Benefits and benefits of the EVT-2 test include, for example, two parallel forms for easier progress monitoring; identical administration and scoring procedures to the EVT; broader and more mixed use of labeling and synonym item types; five levels of diagnostic analysis; and new Growth Scale Value (GSV) for measuring progress over time.

[0166] Developed over a five-year period, the EVT-2 test was co-normed along with the PPVT-4 test with a national sample of subjects ranging in age from 2 years 6 months to 90+ years. More than 5,500 subjects were tested; data from approximately 3,500 subjects were used for the normative scores. The remaining data contributed to the validation studies. The sample was tightly controlled and was matched to the U.S. Census on gender, race / ethnicity, region, socioeconomic status (SES), and clinical diagnosis or special education placement. The EVT-2 test provides extremely reliable scores, with reliability coefficients in the 0.90s for almost every age or grade. Additionally, the PPVT-4 test offers many enhancements to a vocabulary assessment that has been well respected for 50 years. This latest edition has been co-normed with the Expressive Vocabulary Test, Second Edition (EVT™-2), allowing for direct comparisons between receptive and expressive vocabulary performance.The PPVT-2 Test

[0167] Unlike some other measures of vocabulary, the Peabody Picture Vocabulary Test, 2nd Edition (PPVT-2) supplies two equivalent forms of the test which contain different vocabulary items, thereby helping ensure a subject has not “learned” the test. One form can be used prior to intervention to assess subjects’ vocabulary knowledge and the alternative form can be used for re-testing to evaluate and document progress. PPVT-2 also includes a unique Growth Scale Value (GSV) which is sensitive to small changes over time.

[0168] The PPVT-4 test is individually administered and norm-referenced. It may be used to quickly evaluate receptive vocabulary with a test that requires no reading or writing; monitor progress using two parallel forms; directly compare receptive and expressive vocabulary when you also administer the EVT- 2; move immediately into evidence-based interventions using those embedded directly into and linked into the ASSIST software; and meet guidelines for universal screening, identifying strengths and weaknesses, and diagnostic testing in an Reading to Learn (RTL) environment.

[0169] In normally developing subjects the EVT and the PPVT should demonstrate similar growth. The growth scales seen over a 12-month period should keep pace with one another. In the case of neurologically or otherwise impaired subjects the scales will often not keep pace with one another.The Connors Test

[0170] Changes in hyperactivity can be measured in the Conners’ 3- which is a Gold Standard for diagnosing as well as adjusting established medications for autism spectrum disorder (ASD). Connors’ 3 can be administered according to conventional methods and scored according to the T-score guidelines. Attributes that are assessed include: restless or overactive behavior; excitability and impulsiveness; failing to finish tasks; inattentiveness and ease of distraction; temper outbursts; fidgeting; disturbances ofWSGR Docket No. 41012-760.601 other subjects; demands to be met immediately and ease of frustration; ease and frequency of crying; and rapid and drastic mood changes. Each attribute is scored on a scale of 0-3 where 0 = never, seldom; 1 = occasionally; 2 = often, quite a bit; and 3 = very often; very frequent.Compositions of Matter

[0171] Provided herein is a method of treating a symptom of a disease or condition in a human subject in need thereof, comprising administering to the human subject a composition comprising a high-protease pancreatic replacement (CM- AT), wherein the disease or condition is autism spectrum disorder (ASD). In one embodiment, the high-protease pancreatic replacement (CM- AT) is administered as a free-flowing powder supplied in a single-use trilaminar foil pouch / sachet.

[0172] Provided herein are digestive enzyme preparations containing (e.g , comprising) one or more protease(s), one or more amylase(s), one or more lipase(s), or a combination thereof. In one embodiment a digestive enzyme preparation comprises a protease. In another embodiment, a digestive enzyme preparation comprises an amylase. In another embodiment, a digestive enzyme preparation comprises a lipase. In another embodiment a digestive enzyme preparation comprises a protease and an amylase. In another embodiment a digestive enzyme preparation comprises a protease and a lipase. In another embodiment a digestive enzyme preparation comprises an amylase and a lipase. In another embodiment a digestive enzyme preparation comprises a protease, an amylase, and a lipase. An added benefit of a protease only or a protease and amylase preparation is for very young infants who are not yet able to tolerate lipase activity.

[0173] The one or more protease(s) can comprise, for example, papain, bromelain, chymotrypsin, trypsin, Carboxypeptidase B, serine proteases (e.g. , Kallikrein), or a combination thereof. In one instance, the one or more protease(s) comprise chymotrypsin. In one instance, the one or more protease(s) comprise trypsin. In one instance, the one or more protease(s) comprise chymotrypsin and trypsin. Other enzymes that may be utilized in the pharmaceutical compositions described herein include, but are not limited to, an elastase, a sucrase, a maltase, a cellulase, a hydrolase, a colipase, a Phospholipase A2, a Cholesterol Esterase, or a combination thereof. Digestive enzymes may also be provided, in some instances, as pancreatin, pancrealipase, or derived therefrom. Pancreatin may be, for example, a crystalline pancreatin. In some embodiments, the digestive enzyme composition comprises at least one amylase, a mixture of proteases comprising chymotrypsin and trypsin, and at least one lipase. The pharmaceutical composition can, optionally, further include papain (e.g. , from papaya) or bromelain.

[0174] The one or more digestive enzyme(s) can be, independently, derived from an animal source, a microbial source, a plant source, are recombinantly -prepared, or are synthetically -prepared. In some embodiments, the animal source is a pig, e.g. , a pig pancreas, or avian, e.g. , "bird" proventriculus or small intestine. The digestive enzymes can be any combination of digestive enzymes of a type produced by the pancreas, including, but not limited to digestive enzymes from a pancreatic source or other source. The scope of the disclosure is not limited to pancreatic enzymes of porcine origin but can be of animal origin, microbial origin, plant origin, as well as those that are recombinantly -derived or synthetically -WSGR Docket No. 41012-760.601 derived. In one embodiment, the digestive enzyme is derived from mammalian sources such as porcine derived digestive enzymes.

[0175] In another embodiment, the digestive enzyme includes one or more enzymes, and is plant- derived, synthetically-derived, or recombinantly-produced in microbial cells, yeast cells, or mammalian cells, or includes a mixture of enzymes from one or more source(s). For example, digestive enzymes may include one or more enzyme(s) from one or more source(s) mixed together. This includes, for example, the addition of single digestive enzymes to digestive enzymes derived from pancreatic sources in order to provide appropriate levels of specific enzymes that provide more effective treatment for a selected disease or condition.

[0176] Compositions (preparations) comprising digestive enzymes may be manufactured using any appropriate technology including, but not limited to, enteric coating, polymer coating, lipid coating, lipid blend coating, lipid encapsulation, direct compression, dry granulation, wet granulation, and any combination thereof. The one or more digestive enzyme(s) may be utilized with one or more existing, emergent, or future coating technologies. A variety of physical and chemical methods are then used to combine the drug with the coating material such as coacervation, emulsions, meltable dispersion, spray drying, pan coating and fluidized bed granulations. In this manner, coatings and digestive enzymes or other active pharmaceutical ingredients can be combined to control the kinetics, duration, time, control of peak concentration, pharmacokinetics, dose, and location of drug release in the body. A composition may be an oral dosage formulation such as, for example, a suspension, solution, a slurry, pill, tablet (mini -tab, etc. ), capsule (e.g. , microcapsule, mini-capsule, time- released capsule, etc. ), sprinkle, or any combination thereof. One or more of the compositions described herein may be administered to a subject. In one embodiment, the digestive enzymes and the amount of each digestive enzyme present in such compositions may be empirically determined by a physician based upon the patient to be treated. A physician can readily determine and prescribe the effective amount of the composition required. For example, the physician could start doses of the compounds employed in the composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. Alternatively, a dose can remain constant.

[0177] One exemplary source of pancreatin digestive enzymes can be obtained, for example, from Scientific Protein Laboratories. In one non-limiting embodiment provided herein utilizes one or more of the following enzymes: trypsin, chymotrypsin, elastase, kallikrein, carboxypeptidase b, alpha-amylase, lipase, colipase, phospholipase A2, cholesterol, esterase, or a combination thereof. In one embodiment the digestive enzymes are pancreatic digestive enzymes. In one embodiment, the animal enzyme is derived from a mammal. In one embodiment the mammal is a pig. In one embodiment, digestive enzymes are derived from a mammalian pancreas. In one embodiment the pancreas is a pig pancreas or avian, e.g., "bird" proventriculus or small intestine. In yet another embodiment, digestive enzymes as well as other proteins (e. g. , those secreted in a mammal) that affect the digestive process either directly or indirectly may be included in a composition.WSGR Docket No. 41012-760.601

[0178] In any of such targeted delivery systems described above, the one or more digestive enzyme(s) can comprise one or more protease(s), one or more lipase(s), one or more amylase(s), or a combination thereof. For example, the one or more digestive enzyme(s) can comprise one or more protease(s); the digestive enzymes can comprise one or more lipase(s); the digestive enzymes can comprise one or more amylase(s ); the digestive enzymes can comprise one or more protease(s) and one or more lipase(s ); the digestive enzymes can comprise one or more protease(s) and one or more amylase(s ); the digestive enzymes can comprise one or more lipase(s) and one or more amylase(s); or the digestive enzymes can comprise one or more protease(s ), one or more lipase(s), and one or more amylase(s). In one nonlimiting embodiment, the digestive enzymes in the targeted delivery system are provided as pancreatin.

[0179] Compositions provided herein may include not only one or more digestive enzyme(s), but optionally, also one or more pharmaceutically acceptable carriers, excipients, buffers, fillers, binders, stabilizers, surfactants, diluents, extracts, lubricants, fillers, flavorings, preservatives, colorants, diluents, anti-microbials, disintegrants, and coating agents, such as for example, taste maskers, sweeteners, etc. In one embodiment, digestive enzymes are provided as a pharmaceutical composition.

[0180] In another embodiment, the digestive enzymes in the targeted delivery system are uncoated and, optionally, may be formulated with one or more carriers, excipients, buffers, fdlers, binders, stabilizers, surfactants, diluents, extracts, lubricants, fillers, flavorings, preservatives, colorants, diluents, and coating agents, such as taste maskers, sweeteners, etc.

[0181] In one embodiment, a total amount of protease in a composition ranges from about 1,000 to about 15,00,0000 U. S.P. Units / dose. In another embodiment the amount of lipase in a composition ranges from about 190 to about 2,850,000 Units / dose. In another embodiment the amount of amylase in a composition ranges from about 1,400 to 22,450,000 Units / dose. Any of the compositions may be optionally supplemented with additional protease.

[0182] Provided herein is a composition comprising digestive enzymes for use in the methods described herein, wherein the digestive enzymes comprise about 147,000 U.S.P. Units / dose of protease, 28,000 U.S.P. Units / dose of lipase, and about 220,000 U.S.P. Units / dose of amylase.

[0183] Provided herein is a composition comprising digestive enzymes for use in the methods described herein, wherein the digestive enzymes comprise from about 98,300 to 193,900 U.S.P. Units / dose of protease, 9,000 to 43,500 U.S.P. Units / dose of lipase, and about 138,900 to 518,00 U.S.P. Units / dose of amylase.

[0184] In some embodiments, the digestive enzyme composition comprises a protease where the activity is: protease in an amount of from about 1,000 to about 15,000,000 U. S.P. Units / dose including about 10,000, 100,000, 150,000, 200 000, 250,000, 300,000, 350,000, 400,000, 450,000, 500,000, 550,000, 600,000, 650,000, 700,000, 750,000, 800,000, 850,000, 900,000, 950,000, 1,000,000, 1,250,000, 1,500,000, 2,000,000, 2,500,000, 3,000,000, 3,500,000, 4,000,000, 4,500,000, 5,000,000, 5,500,000, 6,000,000, 6,500,000, 7.000,000, 7,500,000, 8,000,000, 8,500,000, 9,000,000, 9,500,000, 10,000,000, 10,500,000, 11,000,000, 11,500,000, 12,000,000, 12,500,000, 13,000,000, 13,500,000, 14,000,000, 14,500,000, or about 15,000,0000 U. S.P. Units / per dose, along with all values in-between. In someWSGR Docket No. 41012-760.601 embodiments the enzyme includes a protease, a lipase, and an amylase wherein the ratio of protease to lipase is such that the amount of lipase is never more than 0. 188 times the amount of protease and where the ratio of protease activity to amylase activity is between 1 :0.1 and 1 : 10. In some embodiments the ratio of protease to lipase is such that the amount of lipase is never more than 0. 188 times the amount of protease.

[0185] In some embodiments a pharmaceutical composition is comprised of one or more of protease, lipase, and amylase with a protease activity level of about 1,000 to about 15,000,000 U. S.P. Units / dose including about 10,000, 100,000, 150,000, 200 000, 250,000, 300,000, 350,000, 400,000, 450,000, 500,000, 550,000, 600,000, 650,000, 700,000, 750,000, 800,000, 850,000, 900,000, 950,000, 1,000,000, 1,250,000, 1,500,000, 2,000,000, 2,500,000, 3,000,000, 3,500,000, 4,000,000, 4,500,000, 5,000,000, 5,500,000, 6,000,000, 6,500,000, 7.000,000, 7,500,000, 8,000,000, 8,500,000, 9,000,000, 9,500,000, 10,000,000, 10,500,000, 11,000,000, 11,500,000, 12,000,000, 12,500,000, 13,000,000, 13,500,000, 14,000,000, 14,500,000, or about 15,000,0000 U. S.P. Units / per dose, along with all values in-between; a lipase activity level of about 190 to 2,900,000 U. S.P Units / dose including about 10,000, about 100,000, about 200,000, about 300,000, about 400,000, about 500,000, about 600,000, about 700,000, about 800,000, about 900.000, about 1,000,000, 1,100,000, about 1,200,000, about 1,300,000, about 1,400,000, about 1,500,000, about 1,600,000, about 1,700,000, about 1,800,000, about 1,900.000, about 2,000,000, about 2,100,000, about 2,200,000, about 2,300,000, about 2,400,000, about 2,500,000, about 2,600,000, about 2,700,000, about 2,800,000, about 2,900.000 along with all values in-between; and an amylase activity level of about 15,000 to 22,450,000 U. S.P Units / dose including: about 50,000, about 100,000, about 150,000, about 200 000, about 250,000, about 300,000, about 350,000, about 400,000, about 450,000, about 500,000, about 550,000, about 600,000, about 650,000, about 700,000, about 750,000, about 800,000, about 850,000, about 900,000, about 950,000, about 1,000,000, about 1,250,000, about 1,500,000, about 2,000,000, about 2,500,000, about 3,000,000, about 3,500,000, about 4,000,000, about 4,500,000, about 5,000,000, about 5,500,000, about 6,000,000, about 6,500,000, about 7,000,000, about 7,500,000, about 8,000,000, about 8,500,000, about 9,000,000, about 9,500,000, about 10,000,000, about 10,500,000, about 11,000,000, about 11,500,000, about 12,000,000, about 12,500,000, about 13,000,000, about 13,500,000, about 14,000,000, about 14,500,000, about 15,000,0000, about 16,000,000, about 16,500,000, about 17.000,000, about 17,500,000, about 18,000,000, about 18,500,000, about 19,000,000, about 19,500,000, about 20,000,000, about 20,500,000, about 21,000,000, about 21, 500, 000, about 22,000,000, about 22,500,000 U.S.P. Units / dose along with all values in-between.

[0186] In some embodiments the lipase activity level is designed not to exceed 10,000 U. S.P units of lipase per day per kilogram of a patient’ s body weight. In some embodiments the titration activity level is designed not to exceed and 2,500 U.S.P units per meal per kilogram of a patient’s body weight.

[0187] In some embodiments the digestive enzyme will include only proteases or proteases and amylases. An added benefit is of a protease-only or a protease and amylase-only formulation is for very young infants who are not able to tolerate lipase activity.WSGR Docket No. 41012-760.601

[0188] A pharmaceutical composition described herein, in one instance, comprises coated particles that contain (a) a core and (b) a coating. In some embodiments, a coated enzyme preparation is in the form of coated particles, which coated particles comprise: (a) a core comprising digestive enzymes present in the coated particles in an amount of from about 5% to 99% by weight and (b) a coating. In one aspect, this disclosure relates to an enzyme delivery system comprising a coated enzyme preparation in the form of coated particles, which coated particles comprise: (a) a core comprising digestive enzymes present in the coated particles in an amount of from about 50% to about 95% by weight; and (b) a coating. In yet another aspect, this disclosure relates to an enzyme delivery system comprising a coated enzyme preparation having coated particles, which coated particles comprise: (a) a core comprising digestive enzymes present in the coated particles in an amount of from about 70% to about 90% by weight; and (b) a coating. In yet another aspect, this disclosure relates to an enzyme delivery system comprising a coated enzyme preparation having coated particles, which coated particles comprise: (a) a core comprising digestive enzymes present in the coated particles an amount of from about 75% to about 85% by weight; and (b) a coating. The coated particles may be non-aerosolizable. In certain instances, the coating masks the taste and / or smell of the pharmaceutical composition, which renders it more palatable to autistic subjects to be treated.

[0189] The minimum amount of digestive enzymes present in the coated particles is about 5% active enzymes by weight. The maximum amount of digestive enzymes present in the coated particles is about 99% by weight, and in other embodiments at most about 90%, 85%, 80%, 75% or 70% of the coated enzyme preparation. In other embodiments, the amount of digestive enzymes present in the coated particles is about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 35%, 40%, 45%, 55%, 60%, 61 %, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 92.5%, 95%, or 99% by weight or anywhere in between. In other embodiments, the amount of digestive enzymes present in the coated particles is about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% by weight or anywhere in between. In other embodiments, the amount of digestive enzymes present in the coated particles is about 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, or 87% by weight or anywhere in between. At least about or at most about a % of enzyme may include equal to or about that % of enzyme.

[0190] In one aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of about 146,700 U.S.P. units / dose or about 163,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 244,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of about 31,000 U. S.P. units / dose. In one instance, the protease is present in the coated particles in an amount of about 146,700 U.S.P. units / dose. Alternatively, in another instance, the protease is present in the coated particles in an amount of about 163,000 U. S.P. units / dose. In another aspect, provided hereinWSGR Docket No. 41012-760.601 is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of from about 98, 100 to about 193,500 U. S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U. S.P. units / dose. Alternatively, in another aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the digestive enzyme preparation comprises from about 400 to about 800 mg of the digestive enzyme and from about 100 to about 500 mg of the lipid. Alternatively, in another aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the digestive enzyme preparation comprises from about 500 to about 800 mg of the digestive enzymes and from about 100 to about 400 mg of the lipid. Alternatively, in another aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the digestive enzyme preparation comprises from about 600 to about 800 mg of the digestive enzymes and from about 100 to about 200 mg of the lipid. Alternatively, in another aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the digestive enzyme preparation comprises from about 780 to about 800 mg of the digestive enzymes and from about 100 to about 120 mg of the lipid. Alternatively, in another aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the digestive enzyme preparation comprises about 780 to mg of the digestive enzymes and about 120 mg of the lipid. Alternatively, in another aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the digestive enzyme preparation comprises about 720 to mg of the digestive enzymes and about 180 mg of the lipid. In one instance, the digestive enzyme preparation comprises about 700±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 710±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprisesWSGR Docket No. 41012-760.601 about 720±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 730±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 740±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 750±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 760±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 770±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 780±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 790±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 800±2 mg of the digestive enzymes. In one instance, the digestive enzyme preparation comprises about 440±5 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 440±4 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 440±3 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 440±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 615±5 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 615±4 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 615±3 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises about 615±2 mg of the digestive enzymes. In other instances, the digestive enzyme preparation comprises from about 109 to about 215 U.S.P units / mg of the protease, from about 154 to about 575 U.S.P. units / mg of the amylase, and from about 10 to about 48 U. S.P. units / mg of the lipase. In other instances, the digestive enzyme preparation comprises about 165 U.S.P units / mg of the protease, about 245 U.S.P. units / mg of the amylase, and about 31 U.S.P. units / mg of the lipase. In other instances, the digestive enzyme preparation comprises about 195 U.S.P units / mg of the protease, about 390 U.S.P. units / mg of the amylase, and about 30 U.S.P. units / mg of the lipase.

[0191] In one embodiment, the protease is present in the coated particles in an amount of from about 98,100 to about 193,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U.S.P. units / dose. In one embodiment, the protease is present in the coated particles in an amount of from about 165,000 to about 190,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 340,000 to about 360,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 22,000 to about 35,000 U. S.P. units / dose. In one embodiment, the protease is present in the coated particles in an amount of from about 170,000 to about 180,000 U. S.P. units / dose, the amylase is present in the coated particles in an amount of from about 345,000 to about 355,000 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 24,000 to about 30,000 U.S.P. units / dose. In one embodiment, the protease is present in the coated particles in an amount of from about 175,000 to about 176,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 350,000 to about 352,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 26,000 to about 28,000 U. S.P. units / dose. In one embodiment, the protease is present in theWSGR Docket No. 41012-760.601 coated particles in an amount of about 175,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 351,000 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of about 27,000 U.S.P. units / dose. In one embodiment, the protease is present in the coated particles in an amount of from about 109,000 to about 215,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 154,000 to about 575,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 10,000 to about 48,000 U. S.P. units / dose. In another embodiment, the protease is present in the coated particles in an amount of from about 138,000 to about 215,500 U. S.P. units / dose, the amylase is present in the coated particles in an amount of from about 154,000 to about 575,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 10,000 to about 48,000 U.S.P. units / dose. In another embodiment, the protease is present in the coated particles in an amount of about 146,700 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 219,600 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of about 27,900 U.S.P. units / dose.

[0192] In certain instances, the amount of the lipase does not exceed 2,500 lipase units / kg / dose. In other instances, the amount of the lipase does not exceed 10,000 lipase units / kg / day.

[0193] The minimum amount of digestive enzymes present in the coated particles is at least about 5% by weight. The digestive enzymes can be present in the coated particles may be present in the coated particles in an amount of from about 5% to about 99% by weight. In one embodiment, the minimum amount of digestive enzymes present in the coated particles is at least about 30%, about 35%, about 40%, or about 50% by weight. The maximum amount of digestive enzymes present in the coated particles is about 99% by weight. For example, the amount of digestive enzymes present in the coated particles is at most 99%, about 98%, about 95%, about 90%, about 87.5%, about 85%, about 82.5%, about 80%, about 77.5%, about 75%, about 72.5%, or about 70% by weight. In one instance, the amount of digestive enzymes present in the coated particles is about 5%, 10%, 15%, 20%, 25%, 35%, 40%, 45%, 55%, 60%, 61 %, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 92.5%, or 95% by weight, or any integer in-between. In certain embodiments, the digestive enzymes are present in the coated particles in an amount of from about 70% to about 90% by weight. In other embodiments, the digestive enzymes are present in the coated particles in an amount of from about 75% to about 87% by weight. In other embodiments, the digestive enzymes are present in the coated particles in an amount of from about 77.5% to about 82.5% by weight. In other embodiments, the digestive enzymes are present in the coated particles in an amount of from about 82.5% to about 87.5% by weight. In other embodiments, the digestive enzymes are present in the coated particles in an amount of from about 84% to about 88% by weight. In other embodiments, the digestive enzymes are present in the coated particles in an amount of from about 86% to about 87%. "At least about" or "at most about" a percentage (%) of enzyme may include equal to or about that % of enzyme.

[0194] The coating can be present in coated digestive enzyme particles in an amount of from about 1 % to about 50%, from about 1 % to about 30%, or about 20%. The coating can be present in coatedWSGR Docket No. 41012-760.601 digestive enzyme particles in an amount of about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11 %, about 12%, about 13%, about 14%, about 15%, about 16%, about 16.5%, about 17%, about 17.5%, about 18%, about 18.5%, about 19%, about 19.5%, about 20%, about 20.5%, or about 21 %, about 21.5%, about 22%, about 22.5%, about 23%, about 23.5%, about 24%, about 24.5%, about 25%, about 25.5%, about 26%, about 26.5%, about 27%, about 27.5%, about 28%, about 28.5%, about 29%, about 29.5%, about 30%, about 30.5%, about 31%, about 31.5%, about 32%, about 32.5%, about 33%, about 33.5%, about 34%, about 34.5%, about 35%, about 35.5%, about 36%, about 36.5%, about 37%, about 37.5%, about 38%, about 38.5%, about 39%, about 39.5%, about 40%, about 40.5%, about 41%, about 41.5%, about 42%, about 42.5%, about 43%, about 43.5%, about 44%, about 44.5%, about 45%, about 45.5%, about 46%, about 46.5%, about 47%, about 47.5%, about 48%, about 48.5%, about 49%, about 49.5%, or about 50%, by weight. In some instances, the coating can be present in coated digestive enzyme particles in an amount of from about 10% to about 30% by weight. In some instances, the coating can be present in coated digestive enzyme particles in an amount of from about 15% to about 25% by weight. In some instances, the coating can be present in coated digestive enzyme particles in an amount of about 13% by weight. In some instances, the coating can be present in coated digestive enzyme particles in an amount of about 14% by weight. In some instances, the coating can be present in coated digestive enzyme particles in an amount of about 15% by weight. In some instances, the coating can be present in coated digestive enzyme particles in an amount of about 16% by weight. In some instances, the coating can be present in coated digestive enzyme particles in an amount of about 17% by weight. In some instances, the coating can be present in coated digestive enzyme particles in an amount of about 18% by weight. In some instances, the coating can be present in coated digestive enzyme particles in an amount of about 19% by weight. In some instances, the coating can be present in coated digestive enzyme particles in an amount of about 20% by weight.

[0195] In another embodiment enzyme preparations are utilized with lipid coating of enzymes. The method of making the preparations comprises providing a crystallizable lipid (e.g, hydrogenated soy oil), and coating size-specific digestive enzyme particles as described herein with the crystallizable lipid (e.g. , hydrogenated soy oil). The digestive enzymes may be present in the coated particles in an amount of from about 5% to about 95% by weight, including, but not limited to, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69% 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 92.5%, or 95% along with all values in-between. The digestive enzymes may be present in the coated particles in an amount of from about 70% to about 90% by weight. The digestive enzymes may be present in the coated particles in an amount of from about 72.5% to about 87.5% by weight. The digestive enzymes may be present in the coated particles in an amount of from about 75% to about 85% by weight. The digestive enzymes may be present in the coated particles in an amount of from about 77.5% to about 82.5% by weight. The digestive enzymes may be present in the coated particles in an amount of about 80%. The digestive enzymes may be present in the coated particles in an amount ofWSGR Docket No. 41012-760.601 about 79%. The digestive enzymes may be present in the coated particles in an amount of about 80%. The digestive enzymes may be present in the coated particles in an amount of about 81%. The digestive enzymes may be present in the coated particles in an amount of about 82%. The digestive enzymes may be present in the coated particles in an amount of about 83%. The digestive enzymes may be present in the coated particles in an amount of about 84%. The digestive enzymes may be present in the coated particles in an amount of about 85%. The digestive enzymes may be present in the coated particles in an amount of about 86%. The digestive enzymes may be present in the coated particles in an amount of about 87%.

[0196] In one aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of about 146,700 U.S.P. units / dose or about 163,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 244,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of about 31,000 U. S.P. units / dose. In one instance, the protease is present in the coated particles in an amount of about 146,700 U.S.P. units / dose. Alternatively, in another instance, the protease is present in the coated particles in an amount of about 163,000 U.S.P. units / dose.

[0197] In one aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a hydrogenated soy oil, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of about 146,700 U.S.P. units / dose or about 163,000 U. S.P. units / dose, the amylase is present in the coated particles in an amount of about 244,000 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of about 31,000 U.S.P. units / dose. In one instance, the protease is present in the coated particles in an amount of about 146,700 U. S.P. units / dose. Alternatively, in another instance, the protease is present in the coated particles in an amount of about 163,000 U. S.P. units / dose.

[0198] In another aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of from about 98, 100 to about 193,500 U. S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U.S.P. units / dose.

[0199] In another aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a hydrogenated soy oil, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of from about 98, 100 to about 193,500 U. S.P. units / dose, the amylase is present in the coated particles in anWSGR Docket No. 41012-760.601 amount of from about 138,600 to about 517,500 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U.S.P. units / dose.

[0200] In another aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the digestive enzyme preparation comprises from about 400 to about 800 mg of the digestive enzyme and from about 100 to about 500 mg of the lipid. Alternatively, or in addition, in another aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the digestive enzyme preparation comprises from about 760 to about 800 mg of the digestive enzyme and from about 100 to about 120 mg of the lipid. In one embodiment, the unit dose comprises from about 500 to about 800 mg of the digestive enzymes and from about 100 to about 400 mg of the lipid. In another embodiment, the unit dose comprises from about 600 to about 800 mg of the digestive enzymes and from about 100 to about 300 mg of the lipid. In another embodiment, the unit dose comprises from about 780 to about 800 mg of the digestive enzymes and from about 100 to about 120 mg of the lipid. In another embodiment, the unit dose comprises about 780 mg of the digestive enzymes and about 120 mg of the lipid. In another embodiment, the unit dose comprises about 720 mg of the digestive enzymes and about 180 mg of the lipid. In another embodiment, the unit dose comprises about 440±5 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 440±4 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 440±3 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 440±2 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 615±5 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 615±4 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 615±3 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 615±2 mg of the digestive enzymes. In another embodiment, the unit dose comprises from about 109 to about 215 U. S.P units / mg of the protease, from about 154 to about 575 U.S.P. units / mg of the amylase, and from about 10 to about 48 U.S.P. units / mg of the lipase. In another embodiment, the unit dose comprises about 165 U.S.P units / mg of the protease, about 245 U.S.P. units / mg of the amylase, and about 31 U.S.P. units / mg of the lipase. In another embodiment, the unit dose comprises about 195 U. S.P units / mg of the protease, about 390 U.S.P. units / mg of the amylase, and about 30 U. S.P. units / mg of the lipase.

[0201] In another aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a hydrogenated soy oil, wherein the coating coats the core; wherein the digestive enzyme preparation comprises from about 400 to about 800 mg of the digestive enzyme and from about 100 to about 500 mg of the lipid. Alternatively, or in addition, in another aspect, provided herein is a digestive enzyme preparation comprising coatedWSGR Docket No. 41012-760.601 particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a hydrogenated soy oil, wherein the coating coats the core; wherein the digestive enzyme preparation comprises from about 760 to about 800 mg of the digestive enzyme and from about 100 to about 140 mg of the lipid. In one embodiment, the unit dose comprises from about 400 to about 800 mg of the digestive enzymes and from about 100 to about 500 mg of the lipid. In another embodiment, the unit dose comprises from about 600 to about 800 mg of the digestive enzymes and from about 100 to about 300 mg of the lipid. In another embodiment, the unit dose comprises from about 780 to about 800 mg of the digestive enzymes and from about 100 to about 120 mg of the lipid. In another embodiment, the unit dose comprises about 780 mg of the digestive enzymes and about 120 mg of the lipid. In another embodiment, the unit dose comprises about 720 mg of the digestive enzymes and about 180 mg of the lipid. In another embodiment, the unit dose comprises about 440±5 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 440±4 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 440±3 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 440±2 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 615±5 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 615±4 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 615±3 mg of the digestive enzymes. In another embodiment, the unit dose comprises about 615±2 mg of the digestive enzymes. In another embodiment, the unit dose comprises from about 109 to about 215 U. S.P units / mg of the protease, from about 154 to about 575 U.S.P. units / mg of the amylase, and from about 10 to about 48 U.S.P. units / mg of the lipase. In another embodiment, the unit dose comprises about 165 U.S.P units / mg of the protease, about 245 U.S.P. units / mg of the amylase, and about 31 U. S.P. units / mg of the lipase. In another embodiment, the unit dose comprises about 195 U.S.P units / mg of the protease, about 390 U.S.P. units / mg of the amylase, and about 30 U.S.P. units / mg of the lipase.

[0202] In one embodiment, the protease is present in the coated particles in an amount of from about 98,100 to about 193,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 138,600 to about 517,500 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 9,000 to about 48,000 U.S.P. units / dose. In one embodiment, the protease is present in the coated particles in an amount of from about 165,000 to about 190,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 340,000 to about 360,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 22,000 to about 35,000 U. S.P. units / dose. In one embodiment, the protease is present in the coated particles in an amount of from about 170,000 to about 180,000 U. S.P. units / dose, the amylase is present in the coated particles in an amount of from about 345,000 to about 355,000 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 24,000 to about 30,000 U.S.P. units / dose. In one embodiment, the protease is present in the coated particles in an amount of from about 175,000 to about 176,000 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 350,000 to about 352,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amountWSGR Docket No. 41012-760.601 of from about 26,000 to about 28,000 U. S.P. units / dose. In one embodiment, the protease is present in the coated particles in an amount of about 175,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 351,000 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of about 27,000 U.S.P. units / dose. In one embodiment, the protease is present in the coated particles in an amount of from about 109,000 to about 215,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of from about 154,000 to about 575,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 10,000 to about 48,000 U. S.P. units / dose. In another embodiment, the protease is present in the coated particles in an amount of from about 138,000 to about 215,500 U. S.P. units / dose, the amylase is present in the coated particles in an amount of from about 154,000 to about 575,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of from about 10,000 to about 48,000 U.S.P. units / dose. In another embodiment, the protease is present in the coated particles in an amount of about 146,700 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 219,600 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of about 27,900 U.S.P. units / dose.

[0203] In certain instances, the amount of the lipase does not exceed 2,500 lipase units / kg / dose. In other instances, the amount of the lipase does not exceed 10,000 lipase units / kg / day.Coatings

[0204] The nature of the human digestive tract creates challenge for the delivery of digestive enzymes to subjects. Multiple temperature and pH changes over the course of the digestive tract make specific delivery a challenge but a necessity. For instance, a pH as low as 1 is encountered in the stomach, but rapidly increases to a more basic pH of 5-6 in the proximal small intestine. For example, he pH in the stomach, duodenumjejunum, proximal ileum and the distal ileum are approximately 1.2, 5.0-6.0, 6.8, 7.2 and 7.5 respectively. The low pH in the stomach that changes rapidly to a more basic pH of 5-6 in the proximal small intestines calls for a specific delivery method depending upon where the enzyme is to be delivered.

[0205] In one example, the release of digestive enzymes is timed to release specific percentages of enzymes in specific portions of the gastrointestinal tract by use of coating technologies. Administration of the digestive enzymes described herein via any available route increases a concentration of the digestive enzymes in the subject such that they are available to, for example, cleave one or more protein(s).

[0206] Delivery of digestive enzymes can also be challenging due to the rapid degradation and denaturing of enzymes at ambient room temperature, as well as the enhanced degradation and denaturing that can occur with high temperature, pressure, humidity and / or exposure to light. Moisture and heat together can quickly destabilize enzymes, reducing their effectiveness, and shortening shelf life, leading to inaccurate dosing. Denaturization or destabilization of the digestive enzymes can reduce their effectiveness by reducing the dose of active enzymes to less than the amount needed for effective treatment. Coatings can be used to help mitigate these factors. In one embodiment, coating of a digestive enzyme preparation is used to obtain release at selected transit times or in selected locations of theWSGR Docket No. 41012-760.601 gastrointestinal tract of humans. In one aspect, this relates to controlled-release enzyme preparations administered to a subject with Autism Spectrum Disorder. In another aspect, one or more coatings are utilized to target delivery to the small intestines. Coated digestive enzyme preparations undergo less hydrolysis as a result of protection from moisture in the environment by the lipid coating. As a result, digestive enzymes are provided which can tolerate storage conditions (e.g. , moisture, heat, oxygen, etc.) for long periods of time, thus, enabling extended shelf life. The coating protects the digestive enzymes from an environment and can provide, in some instances, emulsification in a solvent without detracting from the abrasion resistance of the coating. The coated digestive enzyme preparations, therefore, reduce overfilling of the digestive enzyme dosage and enhance delivery of more accurate doses of the digestive enzymes.

[0207] In some instances, coating may be used to obtain release of digestive enzymes from a pharmaceutical composition or formulation at selected transit times or in selected locations of the gastrointestinal tract of humans. In one aspect, this disclosure relates to controlled-release enzyme preparations administered to a subject with Autism Spectrum Disorder. In another aspect of the present invention, one or more coating(s) are utilized to target delivery to the small intestines.

[0208] Some embodiments utilize stable enzyme preparations protected against the environment to reduce, degradation and / or denaturation of the enzymes. This permits delivery of more accurate doses of the digestive enzymes to subjects needing treatment. The coating can also, in some aspects, provide emulsification when the enzyme preparations are contacted with appropriate solvents, while also surprisingly providing for a controlled release of the enzyme in the GI system. The emulsification properties of the coating in a solvent allows for controlled release of the digestive enzymes at, for example, in selected locations in the GI tract or in the mucosa of a subject.

[0209] Pharmaceutical compositions (preparations) comprising uncoated or coated digestive enzymes may be manufactured using any appropriate technology including, but not limited to, polymer enteric coating, lipid encapsulation, lipid coating, wax coating, direct compression, dry granulation, wet granulation, and any combination thereof. In one embodiment, one or more digestive enzyme(s) are utilized with one or more existing, emergent, or future coating technologies. Coating technology selection is based upon one or more desired parameters including, but not limited to, desired release kinetics, duration, control of peak concentration, pharmacokinetics, and dose.

[0210] The property of physical and chemical methods may be used to combine the digestive enzymes with a coating material such as coacervation, emulsions, meltable dispersion, spray drying, pan coating, and fluidized bed granulations. In this manner, coatings and digestive enzymes can be combined to control the kinetics, time and location of enzyme release in the body. In one non-limiting instance, about 80% of the digestive enzymes are released by about 30 minutes after the coated digestive enzyme particles reach the small intestine.

[0211] As described herein, suitable digestive enzymes and optional suitable coatings may be used in the compositions and methods of this invention. The choice of suitable digestive enzymes and of suitableWSGR Docket No. 41012-760.601 coatings, including choice of the type or the amounts of digestive enzymes and / or coating, are guided by the specific digestive enzyme needs of the subject, and the selected diseases to be treated.

[0212] In addition, a coating can provide controlled release of digestive enzymes in some instances. For example, the emulsification properties of a coating in a solvent allows for controlled release of the enzyme in the gastrointestinal system, such as the region of the GI tract where the digestive enzymes are to be utilized after administration. The coating protects the enzyme from the environment and provides emulsification in a solvent (e. g. , a biological fluid) without detracting from the abrasion resistance of the coating. For example, the release of the protease from a pharmaceutical composition may occur in the proximal small intestine, and the coating has a dissolution profile between 30-90 minutes with 80% or greater release. Lower levels of release are still beneficial and may be utilized in some embodiments. The dissolution profile may also be about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 minutes. Dissolution profiles may be obtained using methods and conditions known to those in the art. F or example, dissolution profiles can be determined at various pHs, including pHs 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. Shorter dissolution profiles of about 10, 15, 20, or 25 minutes, or any values in between, may be advantageous for subjects with faster transit times such as, but not limited to, subjects with dumping syndrome.

[0213] "Encapsulate" as used herein means that the coating completely surrounds the digestive enzyme. In the manufacture of pharmaceutical compositions, encapsulation refers to a range of techniques used to enclose medicines in a relatively stable shell known as a capsule, allowing them to, for example, be taken orally or be used as suppositories.

[0214] Lipid Coatings

[0215] Lipid coating or encapsulation may reduce aerosolization of digestive enzymes, which may be caustic to a subject if inhaled. For example, lipid encapsulation reduces aerosolization and the potential for caustic bum, aspiration, and / or aspiration pneumonias in subjects to be treated and administrators of the pharmaceutical composition, thereby reducing the potential for illness in subjects, thereby leading to safer administration.

[0216] "Lipids", as used herein, refers to lipids which contain at least one hydrophilic group and at least one hydrophobic group, and have a structure capable of forming a hydrophilic and hydrophobic interface. These chemical and / or physical properties, mentioned above, of a lipid permit emulsification. Examples of interfaces include, for example, micelles and bilayers. The hydrophilic group can be a polar group and can be charged or uncharged.

[0217] Digestive enzymes may possess a significant odor. For example, digestive enzymes obtained from a pig pancreas can possess a significant odor and / or taste similar to cured or smoked pork. This taste and smell can be strong and offensive to some subjects, such as children, and especially in some children with ASD. In one embodiment, the addition of a lipid coating significantly masks odor and taste of digestive enzymes enzyme, which allows for the tolerance of taste as the lipid coating is odorless and tasteless. The coated digestive enzyme compositions described herein may have improved taste and odor compared to non-coated digestive enzymes.WSGR Docket No. 41012-760.601

[0218] The lipid may be any lipid, lipid mixture, or blend of lipid of lipid with emulsifiers which emulsifies when exposed to a solvent and has a melting point which allows the lipid to be a solid at typical storage temperatures and / or additives. In some embodiments, the lipid consists essentially of or comprises one or more monoglycerides, diglycerides or triglycerides, or other components including, for example, emulsifiers found in hydrogenated vegetable oils. In another embodiment, the lipid is a nonpolar lipid. Examples of lipids include, but are not limited to, monoglycerides, diglycerides, triglyceride^ fatty acids, esters of fatty acids, phospholipids, salts thereof, and combinations thereof. In one non- limiting instance, the lipid coating comprises monoglycerides, diglycerides, triglycerides, or a combination thereof. In another non-limiting instance, the lipid coating comprises monoglycerides, diglycerides, or triglycerides. In another non-limiting instance, the lipid coating comprises a combination of monoglycerides and diglycerides. In another nonlimiting instance, the lipid coating comprises a combination of diglycerides and triglycerides. In another non-limiting instance, the lipid coating comprises a combination of monoglycerides, diglycerides, and triglycerides.

[0219] In another embodiment with respect to coated particles which contain a core and a coating, the enzymatic core containing comprised of one or more of a protease, a lipase, and an amylase, is coated by an inert lipid that allows for safe delivery of the enzymatic core through the oropharynx and into the stomach where it is quickly and efficiently released in the stomach and duodenum.

[0220] The lipid can be a vegetable-derived lipid or an animal derived lipid. As used herein, animal lipids and / or vegetable lipids include, but are not limited to, fats and oils originating from plant sources, animal sources and / or tissues, and / or synthetically produced based on the structures of fats and oils originating from plant or animal sources. Lipid material may be refined, extracted or purified by known chemical or mechanical processes. Certain fatty acids present in lipids, termed essential fatty acids, must be present in the mammalian diet. The lipid may, in some embodiments, comprise a Type I US Pharmacopeia (U. S.P.) National Formulary vegetable oil. The lipid can be derived from animal origins or vegetable origins, such as, for example, palm kernel oil, soybean oil, cottonseed oil, canola oil, or poultry fat, including hydrogenated type I vegetable oils. In some embodiments, the lipid is hydrogenated. The lipid can also be saturated or partially saturated. In certain embodiments, the lipid is a hydrogenated soy oil.

[0221] The rate of release of the digestive enzyme from a pharmaceutical composition upon exposure to a solvent (e.g. , stomach acid) may be controlled by coating digestive enzymes with a lipid to form coated particles that comprise a core (which contains the digestive enzymes), and a coating which contains the lipid. Alternatively, the rate of release of the digestive enzyme from a pharmaceutical composition upon exposure to a solvent (e.g. , stomach acid) may be controlled by (i) blending a lipid with an amount of one or more additives to obtain a lipid blend; and (ii) coating digestive enzymes with the lipid blend to form coated particles that comprise a core (which contains the digestive enzymes), and a coating which contains the lipid blend. In one instance, the coating comprises a lipid blend where the lipid and additive are not the same, and the rate of release of the digestive enzymes from the coated particles upon exposure to a solvent is decreased as the amount of additive is increased. In the alternative, the rate of release ofWSGR Docket No. 41012-760.601 the digestive enzymes from the coated particles upon exposure to a solvent is increased as the amount of additive is increased.

[0222] The lipid coating surprisingly does not appear to be reduced or destroyed by hydrochloric acid (HC1) present in the stomach, thereby protecting the digestive enzymes from degradation following administration until the digestive enzymes reach their target region in the proximal GI tract. Further, a lipid coating may reduce the exposure of the digestive enzymes to attack by water, thereby reducing hydrolysis, and further protecting the digestive enzymes from degradation In addition, the inventors have found that a coating containing only lipid can be used to coat digestive enzymes that only contain one or more lipase(s).

[0223] Because, in some embodiments, a lipid coating does not require the digestive enzymes to be treated with solvents extenders and excipients to facilitate flow or improve stability, a lipid coating described herein includes a "clean" preparation of GRAS (generally regarded as safe) substances to be administered. The reduction in the use of solvents, extenders, excipients and other additives permitted by the methods described herein reduces the exposure of the individuals taking the digestive enzymes to potential allergens, thereby producing a hypoallergenic enzyme preparation that further enhances its potential uses in the treatment of individuals who might otherwise develop an allergic response to treatment. Administration of the coated digestive enzyme compositions described herein can thus reduce exposure to potentially toxic substances and will also reduce the possibility of allergy formation. Accordingly, in some embodiments, the pharmaceutical composition is hypoallergenic.

[0224] The lipid may be, in some instances, a "food grade lipid". Examples of food grade lipids include, but are not limited to, a sorbitan monostearates, sorbitan tristearates, and calcium stearoyl lactylates. Other examples of food grade fatty acid esters which are lipids include acetic acid esters of mono and diglycerides, citric acid esters of mono- and di-glycerides, lactic acid esters of mono- and di-glycerides, poly glycerol esters of fatty acids, propylene glycol esters of fatty acids, and diacetyl tartaric acid esters of mono- and diglycerides.

[0225] The lipid may also be, in some instances, a "pharmaceutical grade lipid". Pharmaceutical grade lipids include, but are not limited to, highly purified lipid from which all protein antigens have been removed. Such lipids are beneficial in that they do not induce allergic responses and do not include cis or trans fatty acids. One non-limiting example of a pharmaceutical grade lipid comprises a soybean oil that is fully hydrogenated. One non-limiting example of a pharmaceutical grade lipid consists of a soybean oil that is fully hydrogenated. In some instances, a lipid coating will produce non-agglomerating, nonaerosolizing coated digestive enzyme particles.

[0226] The inclusion of one or more additives with a lipid can be used to control emulsification or dissolution of the coating and release of the digestive enzymes. For example, a triglyceride can be blended with a monoglyceride to control emulsification or dissolution of the coating and thus control (e.g , decrease) the rate of release of the digestive enzymes from the coated particles. As a further example, a diglyceride and a triglyceride can be blended with a monoglyceride to control the rate ofWSGR Docket No. 41012-760.601 release of the digestive enzymes. Hydrogenated vegetable oils may contain emulsifying agents, such as soy lecithin or other components.

[0227] Properties including mechanical strength, melting point, and hydrophobicity can be considered when choosing a suitable lipid coating for the digestive enzymes. Lipids having lower melting points or more polar, hydrophilic properties are generally less suitable for the coating because they may result in a product that would cake under accelerated storage stability conditions. Coated digestive enzyme particles made using, for example, hydrogenated soy oil (e g. , partially or fully hydrogenated), which demonstrated good pouring and no caking.

[0228] In some embodiments a coated digestive enzyme preparation comprises coated particles, where the coated particles comprise (a) a core containing digestive enzymes; and (b) a coating comprising one or more lipids; where the digestive enzymes are present in the coated particles in an amount of from about 5% to about 95% by weight, including, but not limited to, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 61 %, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, and 95% by weight, along with all values / integers in-between. In some embodiments the coating is one or more of a lipid blend, a generally uniform coating to provide for controlled release of the digestive enzymes, the coating comprising a crystahizable lipid (e.g. , a hydrogenated soy oil).

[0229] The methods of this disclosure can be used to produce coated digestive enzyme preparations comprising digestive enzymes coated with a crystallizable lipid alone, or with a lipid blend to achieve a controlled rate of enzyme release, with increased release of the digestive enzyme upon exposure of the coated preparation to a suitable solvent. Coated digestive enzyme preparations having a coating comprising one or more monoglycerides exhibit increased release of the digestive enzyme upon exposure of the coated composite to a solvent, such as water, while protecting against release in 0. 1 N HC1.

[0230] In some embodiments, the compositions according to this disclosure produce enzyme preparations, including coated enzyme preparations, characterized, for example, by controlled rates of release, reduction in aerosolization and safer administration, ability to be administered by a sprinkle / sachet delivery method, improved flow characteristics, enhanced shelf life and storage capacity, and other properties described herein. In other aspects, the coated enzyme preparation has improved pour properties which facilitate manufacturing and packaging processes, for example packaging in pouches and sachet.

[0231] In some aspects, coated digestive enzyme preparations are prepared to obtain specific delivery times or specific regions within the GI tract. In some embodiments, the crystahizable lipid composition comprises, consists essentially of, or consists of, a hydrogenated soybean oil, but may be any suitable crystahizable lipid or lipid blend. Lipid coating or encapsulation reduces aerosolization of the digestive enzymes that may be caustic to a subject if inhaled through the lungs or the nose. In another embodiment, delivery of digestive enzymes with improved safety of administration can be achieved by reducing the amount of aerosolization of the enzyme. The lipid coating or encapsulation reduces aerosolization and the potential for caustic bum, aspiration, and / or aspiration pneumonias in subjects and administrators ofWSGR Docket No. 41012-760.601 the enzyme preparation, thereby reducing the potential for illness in Children with ASD, thereby leading to safer administration.

[0232] In one instance, the coated digestive enzyme particles have enhanced flow properties and are useful in the treatment of subjects with a coronavirus infection, the method comprising: a) blending a lipid with one or more additives to obtain a lipid blend; and b) coating screened digestive enzyme with the lipid blend to form the coated digestive enzyme particles containing a core which contains the digestive enzymes and a coating which contains the lipid blend.

[0233] In another embodiment with respect to coated particles which contain a core and a coating, the enzymatic core containing comprised of one or more of a protease, a lipase, and an amylase, is coated by a lipid coating, a wax coating, a polymer enteric coating, a cellulose acetate phthalate (CAP) coating, a cellulose acetate trimellitate (CAT) coating, a hydroxyl propyl methyl cellulose phthalate (HPMCP) coating, a hydroxyl propyl methyl cellulose acetate succinate (HPMCAS) coating, a polyvinyl acetate phthalate (PVAP) coating, a methacrylic acid copolymer coating, a shellac coating, a zein coating, or an ethylcellulose coating, nano-crystal API carrier suspensions, matrices, other available coatings with appropriate release properties, or any combination thereof.

[0234] Waxes

[0235] In some embodiments a wax may be utilized for coating the digestive enzymes. In one embodiment an unreactive wax is utilized. The wax can be paraffin wax; a petroleum wax; a mineral wax such as ozokerite, ceresin, or Montan wax; a vegetable wax such as, for example, carnauba wax, bayberry wax or flax wax; an animal wax such as, for example, spermaceti; or an insect wax such as beeswax. Additionally, the wax material can be an ester of a fatty acid having 12 to 31 carbon atoms and a fatty alcohol having 12 to 31 carbon atoms, the ester having from a carbon atom content of from 24 to 62, or a mixture thereof. Examples of waxes include, but are not limited to, myricyl palmitate, cetyl palmitate, myricyl cerotate, cetyl myristate, cetyl palmitate, cetyl certate, myricyl myristate, stearyl palmitate, stearyl myristate, and lauryl laurate. Digestive enzyme pharmaceutical compositions made using, for example, hydrogenated castor wax or carnauba wax may demonstrate good pouring and no caking.

[0236] Polymer Enteric Coatings

[0237] In another aspect, digestive enzymes may be coated with a polymeric coating. The same principles of controlled dissolution still apply but access to a variety of materials expands options for control of both the location and rate of release. In one embodiment, one or more hydrophobic or hydrophilic polymers are used separately or in combination. Polymer enteric coatings for use in a composition described herein include, but are not limited to, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxyl propyl methyl cellulose phthalate (HPMCP), hydroxyl propyl methyl cellulose acetate succinate (HPMCAS), ethyl cellulose (EC), polyvinyl acetate phthalate (PVAP), a methacrylic acid copolymer, a shellac (esters of aleurtic acid), Zein, ethylcellulose, gelatins, polyvinyl alcohol, styrene maleic anhydride, or a combination thereof. It should be noted that certain coatings which utilize cellulose (e.g. , HPMC / HPEC, EUDRAGET®, etc. ) may be hydrophilic and, as such, absorbWSGR Docket No. 41012-760.601 moisture which degrades the activity of digestive enzymes (e.g. , pancreatin, etc.) utilized in various embodiments described herein.

[0238] In some embodiments, a pharmaceutical dosage form comprises a population of extended-release beads, wherein said extended-release beads comprise: an active- containing core particle comprising digestive enzymes as the active agent; and an extended-release coating comprising a water insoluble polymer membrane surrounding said core, wherein said water-insoluble polymer membrane comprises a polymer selected from the group consisting of ethers of cellulose, esters of cellulose, cellulose acetate, ethyl cellulose, polyvinyl acetate, neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, pH -insensitive ammonio methacrylic acid copolymers, and mixtures thereof; wherein the total amount of digestive enzymes in the pharmaceutical dosage form contain from about 15,000 U. S.P. Units protease to about 1.5 million U. S.P. Units protease per dose and where the ratio of protease to lipase is such that the amount of lipase is never more than 0. 188 times the amount of protease and where the ratio of protease activity to amylase activity is between 1 :0. 1 and 1: 10.

[0239] In some embodiments, an extended-release coating further comprises a water-soluble polymer selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyethylene glycol, polyvinylpyrrolidone, and mixtures thereof.

[0240] Cellulose Acetate Phthalate (CAP)

[0241] In some embodiments, cellulose acetate phthalate, also known as cellacefate (a synthetic enteric coating polymer), may be utilized for coating of the digestive enzymes. Because the degree of substitution can lead to changes in CAP properties, specifications for CAP composition have been established to ensure more uniform performance from batch to batch. According to United State Pharmacopoeia (U. S.P.) specifications, CAP should contain from about 21.5% to about 26.0% w / w acetyl content and from about 30.0% to about 10 36.0% w / w phthalyl groups on the cellulose backbone as calculated on an anhydrous basis. CAP exhibits rapid dissolution at apH>6 and is relatively permeable to moisture and gastric juices. Due to its high moisture permeability, CAP is susceptible to hydrolytic decomposition. Phthalic 15 and acetic acid molecules may hydrolyze during storage and significantly compromise the degree of enteric protection that the film coating provides. The addition of a plasticizing agent can improve the water-resistance of CAP films. CAP is compatible with most water-soluble and insoluble plasticizers with diethyl phthalate (DEP), tributyl citrate (TBC), triethyl citrate (TEC), tributyrin, and triacetin being the most commonly used, typically, in the range of from about 25% to about 35% by weight of dry polymer. CAP is commercially available as a white powder from, for example, Eastman Chemical Co. A 30% solids latex dispersion version of CAP (AQUACOAT® CPD) is available for aqueous enteric coating of tablets, beads, and both hard and soft gelatin capsules.

[0242] Cellulose Acetate Trimellitate (CAT)

[0243] In some embodiments, chemically cellulose acetate trimellitate (CAT), may be utilized for coating of the digestive enzymes. CAT bears a strong resemblance to CAP. It is formed by the same synthesis process as CAP with trimellitic anhydride as the substituent group in place of phthalicWSGR Docket No. 41012-760.601 anhydride. Typical values for timellityl and acetyl substitution are 29.0% and 22.4%, respectively. Trimellitic anhydride contains an additional free carboxyl group over that of phthalic anhydride, and hence CAT contains a greater concentration of acidic groups for a given degree of substitution than CAP rendering it more soluble in aqueous media. Also, the pKa of CAT is between 4. 1 and 4.3 which is slightly lower than CAP. With a relatively low pKa value and greater functional group concentration, CAT is the most soluble enteric cellulose derivative with the onset of dissolution occurring at pH 4.7-5.0. This useful property makes CAT ideal for targeted rug release to the proximal regions of the small intestine. CAT is commercially available as a white powder from Eastman Chemical Co. To obtain the best enteric coating results from aqueous processing, ammoniacal solutions of CAT in water are recommended. Plasticizer considerations for CAT are identical to that of CAP.

[0244] Hydroxyl Propyl Methyl Cellulose Phthalate (HPMCP)

[0245] In some embodiments HPMCP may be utilized for coating of the digestive enzymes. HPMCP is a white to slightly off-white, free-flowing flakes or granular powder with a slightly acidic odor and a barely detectable taste. It is a derivative of hydroxypropyl methylcellulose that is produced by the transesterification of hydroxypropyl methylcellulose with phthalic acid and is a cellulose derivative for enteric coating. HPMCP has been admitted in the European and Japanese pharmacopoeias and included in the USP / NF under the name hypromellose phthalate. Depending on the degree of phthalyl substitution, HPMCP is soluble in aqueous media in a pH range of from about 5.0 to about 5.5. HPMCP is characteristically insoluble in gastric fluids but swellable and rapidly soluble in the upper intestine. It may be plasticized with di ethylphthalate, acetylated mono glyceride or triacetin. Mechanically, HPMCP is a more flexible polymer and on a weight basis and will not require as much plasticizer as CAP or CAT. Solvent mixtures can be effectively prepared for commercial spray-drying by using proper spray-drying optimization.

[0246] Hydroxyl Propyl Methyl Cellulose Acetate Succinate (HPMCAS)

[0247] In some embodiments HPMCAS, also known as hypromellose acetate succinate, may be utilized for coating of the digestive enzymes. HPMCAS is a white to off-white powder or granules derived from HPMC by the esterification of free hydroxyl groups on the polymer backbone with acetic anhydride and succinic anhydride. It is commercially available in three grades (L, M & 10 H), which correspond to pH- dependent release profiles of low pH (5.0), medium (5.5), and high (6.5) pH. HPMCAS is soluble in neutral pH according to ionization of free carboxyl groups on the polymer backbone.

[0248] Polyvinyl Acetate Phthalate (PVAP)

[0249] In some embodiments polyvinyl acetate phthalate (PVAP) may be utilized for coating of the digestive enzymes. PVAP is a free-flowing white to off-white powder with a slight odor of acetic acid. The onset of aqueous dissolution of PVAP begins at a pH of about 5.0, allowing for enteric release as well as targeted drug release in the proximal small intestine. Although structurally similar to CAP (containing the dicarboxylic phthalic acid in a partially esterified form), PVAP is relatively more stable to hydrolysis than CAP due to its lower moisture permeability. It is compatible with plasticizers such as, for example, glyceryl triacetate, Triethyl citrate (TEC), acetyl triethylcitrate, Diethyl phthalate (DEP),WSGR Docket No. 41012-760.601 and polyethylene glycol (PEG) 400. PVAP (SURETERIC®) is commercially avail-able from COLORCON® as a complete preformulated coating system consisting of a powder blend of PVAP, plasticizers, and other functional ingredients intended for reconstitution in water for rapid coating dispersion production.

[0250] Methacrylic Acid Copolymers (MACP)

[0251] In some embodiments methacrylic acid copolymers (MACP) (for example EUDRAGIT®) may be utilized for coating of the digestive enzymes. MACP are widely used for enteric coating applications as they contain free 35 carboxylic acid groups that are ionized whenever the pH of the environment exceeds 5.5. Several different types of EUDRAGIT® polymers with enteric release capabilities are commercially available in a wide range of different physical forms (aqueous dispersion, organic solution, granules and powders). Methacrylic acid methylmethacrylate copolymers (EUDRAGIT® Land S), and methacrylic acid ethyl acrylate copolymer (EUDRAGIT® L30D) are coating polymers for enteric formulations which allow targeting of specific areas of the intestine.

[0252] Shellac

[0253] In some embodiments edible shellac may be utilized for coating of the digestive enzymes. Shellac may be employed as a glazing agent on a pharmaceutical composition that comprises a pill. Because of its acidic properties (resisting stomach acids), shellac-coated pills may be used for a timed enteric or colonic release. Shellac provides an excellent barrier against water vapor penetration.

[0254] Zein

[0255] In some embodiments Zein may be utilized for coating of the digestive enzymes. Zein is a class of prolamine protein found in maize (corn) that is usually manufactured as a powder from corn gluten meal. Pure zein is clear, odorless, tasteless, hard, water-insoluble, and edible. Zein's properties make it usable in pharmaceutical compositions and may be used as a coating the digestive enzymes described herein. It is classified as Generally Recognized as Safe (GRAS) by the U.S. Food and Drug Administration. For use as a pharmaceutical coating, zein is all natural and requires less testing per the U.S.P. monographs.

[0256] Ethylcellulose

[0257] In some embodiments ethyl cellulose (ethylcellulose) be utilized for coating of the digestive enzymes. Ethylcellulose is a derivative of cellulose in which some of the hydroxyl groups on the repeating glucose units are converted into ethyl ether groups and which may be used as a thin-film coating material for coating a pharmaceutical composition described herein. Food grade ethyl cellulose is a non-toxic film and thickener which is not water soluble.

[0258] API Carrier Suspensions

[0259] Utilization of nano-crystal API carrier suspensions utilizing compounds such as Hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), lecithin, and docusate sodium to create nanoparticles and other dispersions for improved solubility and interaction with target molecules. Nanocrystals are small particles of the API combined with an excipient "carrier" for dispersion.Typically, particles are from about 0.1 nm to about 1 nm (e.g. , about 0.5 nm) in size. These are createdWSGR Docket No. 41012-760.601 using dissolution of the fine API particles in a carrier and subsequent utilization of precipitation and emulsification or the use of high-pressure homogenization, sonication and micro-fluidization.

[0260] Carriers used for dispersion include, but are not limited to, HPMC, HPC, and decussate sodium. Docusate sodium (bis(2-ethylhexyl) sulfosuccinate), also commonly called dioctyl sulfosuccinate (DOSS) is a long chain carbon polymer with the formula C2oH37NaO?S. Lecithin refers to a group of animal-derived fat like substances. Chemically, they are composed of mixtures of glycerophospholipids, phosphatidylcholine, phosphatidylethanolamine, phosphati-dylinositol, and phosphatidylserine.

[0261] Matrices

[0262] A pharmaceutical composition may be prepared in which an excipient provides a matrix to capture and protect the digestive enzymes before delivery. Pharmaceutical compositions may be prepared whereby the subject who takes the composition has a reduction in the number of capsules / tablets per dosage; for example, the preparation is stabilized and may contain a therapeutically effective amount of a protease, an amylase, and / or a lipase. Compositions may include, for example, a stabilizing matrix consisting essentially of a solidified microcrystaHine cellulose which captures and protects therapeutically effective amounts of digestive enzyme particles within the stabilizing matrix. This can be done, for example, through the use of what is known in the art as PROSOLV® technology.

[0263] PROSOLV® is a combination of excipients which allow for optimized flow, compaction and product uniformity. This technology allows for uniformity in this combination, as well as manufacturing a very small tablet which would be amenable for children. With PROSOLV® technology, the ingredients are not just blended, but are co-processed, which assures that equal particles are uniformly distributed, and these results are easily reproducible. This allows for stability and superb product quality.

[0264] Whether utilizing the PROSOLV® method or other methodology, the one or more digestive enzyme(s) will be formulated and manufactured such that the particles will be uniformly distributed and there will be no overage with respect to the amount of enzyme found in the preparation. Said new drug formulation can be found in, but is not limited to, formulations which include digestive enzymes with and without the utilization of the PROSOLV® technology.

[0265] Digestive enzymes may be combined with one of the patented PROSOLV® technologies, e.g. : PROSOLV® SMCC 50 or PROSOLV® SMCC 90, or other PROSOLV® technologies. When employing the PROSOLV® method, the silicified microcrystalline cellulose (SMCC) used in a pharmaceutical composition described herein may be any commercially available combination of microcrystaHine cellulose granulated with colloidal silicon dioxide. The SMCC generally will be as described in Sherwood et al., Pharm. Tech., October 1998, 78-88 and U. S. Pat. No. 5,585, 115, which are incorporated herein by reference with respect to PROSOLV® technology. SMCC can be obtained commercially from Edward Mendell Company, Inc., a subsidiary of Penwest Ltd., under the name PROSOLV® SMCC. There are different grades of SMCC available, with particle size being the differentiating property among the grades. For example, PROSOLV® SMCC 90 has a median particle size by sieve analysis, in the region of 90 micrometers. PRO-SOLV® SMCC 50 has a median particle size, by sieve analysis, in the region of from about 40 to about 50 micrometers.WSGR Docket No. 41012-760.601

[0266] Other Coatings

[0267] The embodiments described herein are not limited to the aforementioned coatings. By way of example, other hydrophobic polymers that can be used as coatings include, but are not limited to, various forms of acrylics, amides / imides, olefins, styrenes, vinyl acetates / vinyl esters, or a combination thereof. Any existing, emergent, or yet to be developed coating which meets the appropriate safety and applicable regulatory requirements while delivering the active ingredients to the appropriate place in the gastrointestinal tract may be utilized.Optional Components of Coatings

[0268] Coatings are often utilized with a variety of excipients including, but not limited to, one or more plasticizers, colorants (e.g, dyes), solvents, flavors (e.g., sweeteners), surfactants, disintegrants, lubricants, preservatives, anti-microbials, or a combination thereof.

[0269] Plasticizers are relatively low molecular weight materials which may be added to film-coating formulations to modify the physical properties of polymers. Some film-coating polymers are amorphous, and as such, exhibit a reasonably well-defined glass transition temperature, Tg (a fundamental characteristic of polymers that has an effect on polymer properties that can also influence film formation, especially when using aqueous polymer dispersions). Common effects of plasticizers on the properties of thin film coatings include: reducing tensile strength, reducing elastic modulus, altering film adhesion (including increasing under optimal use conditions), increasing the viscosity of coating liquid (effect is greater as plasticizer molecular weight is increased), altering film permeability (depends of physiochemical; properties of plasticizer), and / or reducing the glass transition temperature Tg of film (magnitude of effect influenced by compatibility with polymer). Non-limiting examples of plasticizers used in film coating processes include: a. Polyols, such as glycerol (glycerin), polyethylene glycols (PEG 200-6000 grades) and propylene glycol; b. Organic esters, such as Diethyl phthalate (DEP), Dibutyl phthalate (DBP), Dibutyl sebacate (DBS), Triethyl citrate (TEC), Acetyltriethyl citrate (ATEC), Acetyltributyl citrate (ATBC), Tributyl citrate (TBC), and Triacetin (glyceryl triacetate; TA); c. Oils / glycerides, such as fractionated coconut oil, castor oil, and distilled acetylated monoglycerides (AMG); or d. a combination thereof. In some embodiments, an extended-release coating further comprises a plasticizer selected from the group consisting of triacetin, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil, acetylated mono- and diglycerides, and mixtures thereof.

[0270] Colorants are included in many film-coating formulations to: a. improve product appearance and / or enable product identification; b. modify the gas permeability of a film; c. decrease the risk of counterfeiting the product; d. protect the active ingredient against light by optimizing the opacifying properties of pigments; or e. a combination thereof.

[0271] Either water-soluble colorants (known as dyes) or water-insoluble colorants (known as pigments) may be utilized. Water-insoluble colorants may be utilized in film-coating formulations based on exhibition of: a. better light stability; b. better opacity and covering power; c. optimizing moisture barrier properties of the applied film coatings; and / or d. do not suffer from the disadvantageous phenomenon ofWSGR Docket No. 41012-760.601 motling (caused by solute migration) that can be observed with water-soluble colorants. The effects of colorants on thin films include, but again are not limited to: reducing tensile strength (effect may be minimized by effective pigment dispersion in film); increasing the elastic modulus; slightly increasing the viscosity of the coating liquid, reducing film permeability (unless critical pigment volume concentration CPCV is exceeded); and increasing hiding power (effect is dependent upon refractive index and light absorption char-acteristics of pigment). Colorants typically utilized in thin film coatings include, but are not limited to Water-soluble dyes (e.g. , FD&C Yellow #5, FD&C Blue #2, etc. ); FD&C Lakes such as FD&C Yellow #5 Lake, FD&C Blue #2 Lake, etc.); D&C Lakes (e.g, D&C Yellow #10 Lake, D&C Red #30 lake, etc.), Inorganic Pigments (e.g , Titanium Dioxide, Iron Oxides, etc.) and Natural Colorants (e.g, Riboflavin, Beta- carotene, Carmine lake, etc.), or a combination thereof.

[0272] Solvents may be used to dissolve or disperse coating materials and convey them to the surface of the tablet core. Common solvents used in film coating include, but are not limited to Water, Ketones such as Acetone; Alcohols such as Methanol, Ethanol, and Isopropanol; Esters such as Ethyl acetate and Ethyl lactate; and Chlorinated Hydrocarbons such as Methylene Chloride, 1:1: 1: Trichloroethane, and Chloroform.

[0273] While polymers, plasticizers, colorants, and solvents constitute the major ingredients in filmcoating formulations, other materials might be used occasionally in low concentrations for specific formulations. Flavors and sweeteners may be added to mask unpleasant odor of the digestive enzymes or to make them more, palatable. Surfactants or dissolution enhancers such as polyoxyethylene sorbitan derivatives may be added to emulsify water-insoluble plasticizers; ii. improve substrate wetability and enhance spreadability of the film during application; iii. stabilize suspensions; or iv. a combination thereof.

[0274] Additionally, some film coatings may also contain pre-servative / antimicrobials (e.g, carbamate^ alkylisothiazolinone, benzothiazoles, etc. ), adhesion enhancers (such as poly dextrose, maltodextrin, and lactose), antifoaming agents (e.g. , dimethylpolysiloxane), antioxidants (e.g, oximes, phenols, etc.), poreforming agents (e.g., sucrose or sodium chloride with ethylcellulose-coated salicylic acid tablets) and waxes. In rare instances, the film coat itself may contain active drug substance. When used, all ingredients used in film-coating formulations will comply with relevant regulatory and pharmacopoeia requirements.

[0275] Suitable disintegrants include, for example, sodium starch glycolate, other starches such as pregelatinized starch, and celluloses. Suitable lubricants may be provided such as, for example, magnesium stearate, calcium stearate, talc, stearic acid, etc.

[0276] In any of such embodiments, the lipid can be a food grade lipid (e.g. , a high-grade lipid that is suitable for administration to a human subject, a GMP-grade lipid, etc.). Food-grade lipid coatings include, but are not limited to, monoglycerides, diglycerides, triglycerides, a combination of monoglycerides and diglycerides, a combination of monoglycerides and triglycerides, a combination of diglycerides and triglycerides, or a combination of monoglycerides, diglycerides, and triglycerides. In one non-limiting embodiment, the lipid coating comprises a soy oil such as, for example, a crystatiizableWSGR Docket No. 41012-760.601 lipid (e.g. , a hydrogenated soy oil). Some coated digestive enzyme preparations which comprise a coating of a crystallizable lipid and a digestive enzyme core have favorable release and activity profiles and permit site time specific and / or location specific targeted release along the GI tract. In some aspects, the coated digestive enzyme preparations are prepared to obtain specific delivery times or specific regions within the human GI tract. In some embodiments, the crystahizable lipid composition is hydrogenated soybean oil, but may be any suitable crystahizable lipid or lipid blend. Additionally, the coating of the coated digestive enzyme preparations may be tailored for optimal targeted release of the enzyme(s) to achieve maximal combined efficacy of the digestive enzymes when used in conjunction with an acid reducer.

[0277] In another example, the coatings and digestive enzymes are concentrically nested to allow timed release of the digestive enzymes in more than one portion of the gastrointestinal tract for prophylaxis or to treat an ASD. In another example, the coatings and digestive enzymes are concentrically nested to allow timed release of the digestive enzymes in the proximal small intestines.

[0278] In one aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of about 175,500 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 351,000 U.S.P. units / dose, and the lipase is present in the coated particles in an amount of about 27,000 U.S.P. units / dose.

[0279] In one aspect, provided herein is a digestive enzyme preparation comprising coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wherein the coating coats the core; wherein the protease is present in the coated particles in an amount of about 146,700 U.S.P. units / dose, the amylase is present in the coated particles in an amount of about 219,600 U. S.P. units / dose, and the lipase is present in the coated particles in an amount of about 27,900 U.S.P. units / dose.

[0280] In some embodiments, a pharmaceutical composition comprises a coated particles which comprise: (a) a core comprising digestive enzymes present in an amount of from about 5% to about 99% by weight of the coated particles, including 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 92.5%, 95%%, or 99% by weight along with all values in-between; and (b) a coating, the coating comprising a lipid.

[0281] In some embodiments, a pharmaceutical composition comprises a coated particles which comprise: (a) a core comprising digestive enzymes present in an amount of from about 70% to about 90% by weight of the coated particles, including 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% by weight along with all valuesWSGR Docket No. 41012-760.601 in between; and (b) a coating, the coating comprising a lipid. In some embodiments, a pharmaceutical composition comprises a coated particles which comprise: (a) a core comprising digestive enzymes present in an amount of from about 75% to about 90% by weight of the coated particles, including 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% by weight along with all values in-between; and (b) a coating, the coating comprising a lipid. In some embodiments, a pharmaceutical composition comprises a coated particles which comprise: (a) a core comprising digestive enzymes present in an amount of from about 83% to about 88%% by weight of the coated particles, including 83%, 84%, 85%, 86%, 87%, or 88% by weight along with all values in-between; and (b) a coating, the coating comprising a lipid. In some embodiments, a pharmaceutical composition comprises a coated particles which comprise: (a) a core comprising digestive enzymes present in an amount of from about 85% to about 87% by weight of the coated particles, including 85%, 86%, or 87%by weight along with all values in-between; and (b) a coating, the coating comprising a lipid. In some embodiments, a pharmaceutical composition comprises a coated particles which comprise: (a) a core comprising digestive enzymes present in an amount of from about 86% to about 87%% by weight of the coated particles, including 86.0%, 86.1%, 86.2%, 86.3%, 86.4%, 86.5%, 86.0%, 86.7%, 86.8%, 86.9%, or 87.0% by weight along with all values in-between; and (b) a coating, the coating comprising a lipid. In some embodiments, the coated enzyme preparation particles of the enzyme delivery system are non- aerosolizable. In some instances, the coating is generally uniform and provides for controlled-release of the digestive enzymes when administered to a subject.

[0282] Any suitable coating for use in the pharmaceutical compositions described herein includes, but is not limited to, a lipid, a mixture of lipids, a lipid blend, or a polymer enteric coating as described in more detail below. In one nonlimiting aspect, coatings in pharmaceutical compositions create a barrier to degradation and denaturation and allow more accurate levels of active enzymes to reach the treated subjects. In any of such embodiments, the lipid can be a food grade lipid (e.g. , a high-grade lipid that is suitable for administration to a human subject, a GMP-grade lipid, etc.). Food-grade lipid coatings include, but are not limited to, monoglycerides, diglycerides, triglycerides, a combination of monoglycerides and diglycerides, a combination of monoglycerides and triglycerides, a combination of diglycerides and triglycerides, or a combination of monoglycerides, diglycerides, and triglycerides. In one non-limiting embodiment, the lipid coating comprises a soy oil such as, for example, a hydrogenated soy oil. In one non-limiting embodiment, the hydrogenated soy oil comprises a crystatiizable lipid.

[0283] In another aspect, provided herein is a sachet comprising a digestive enzyme preparation as describe above. Sachets may, in certain embodiments, be stored in a trilaminar foil pouch. Sachet pharmaceutical packaging is a small, sealed pouch used to package single doses of pharmaceutical products such as described herein. Alternatively, or in addition, provided herein is a digestive enzyme preparation is in the form of a sprinkle. Sprinkle formulations are drug-containing pellets or granules that can be mixed with soft food before administration. These formulations provide similar dosing flexibility and ease of ingestion as liquid formulations when sprinkled on liquid or semi -solid vehicles, such as, forWSGR Docket No. 41012-760.601 example, applesauce, pudding or yogurt. The food taken together with the drug may also mask the unpleasant taste and smell of the drug substance, which potentially improves patient compliance.

[0284] A pharmaceutical composition described herein may be prepared using a direct compression method, a dry granulation method, or by wet granulation. Preferably, the digestive enzyme preparation may be prepared using a direct compression process. This preferred process consists of two main steps: blending and compression. The blending step is composed of an active blend, color blend, pre-blend, and final blend (lubrication). A formulation may include a number of other ingredients for optimal characteristics of the pharmaceutical composition.

[0285] The digestive enzymes can be used in cores of coated particles where about 90% of the coated particles are from about #40 to about #140 USS S mesh in size, or from about 105 to about 425 pm in size (diameter). Alternatively, the digestive enzyme particles used in cores of coated particles where about 75% of the particles are from about #40 to about #80 USSS mesh, or from about 180 to about 425 pm in size (diameter). Particles fromabout #40 to about #140 USSS mesh in size pass through #40 USSS mesh but do not pass through #140 USSS mesh. The coated digestive enzymes, in one embodiment, may comprise less than about 35%, 30%, 25%, 20%, 15%, or 10% of coated particles which can be sieved through #100 USSS mesh (150 pm). In some embodiments, the term "non-aerosolizable" refers to a digestive enzyme preparation where less than about 20% of the coated particles can be sieved through #100 USSS mesh (150 pm). In some embodiments, the term "non-aerosolizable" refers to a digestive enzyme preparation where less than about 15% of the coated particles can be sieved through #100 USSS mesh (150 pm). The digestive enzyme preparation can be an encapsulated digestive enzyme composite where the digestive enzyme particles can contain one, two, three, four, five, six, seven, eight, nine, ten, or more digestive enzymes.

[0286] Coated particles may be sieved to obtain coated particles of a suitable size or more uniform size range. The coated particles may be sieved through #40 USSS mesh and through USSS #140 USSS mesh. Coated particles that pass through the #40 USSS mesh but are retained by the #140 USSS mesh are of an appropriate size range. In some instances, the particles may also be screened to obtain particles of a suitable size for encapsulation by removing particles that are too fine or too large. For example, the coated particles may be sieved to obtain coated particles of a suitable size or more uniform size range for encapsulation. As a further example, the coated particles may be sieved through #40 USSS mesh and through USSS #140 USSS mesh. Coated particles that pass through the #40 USSS mesh but are retained by the #140 USSS mesh are of an appropriate size range for coating or encapsulation. Particles may also be screened by sieving through USSS #140, #120, #100, 55 #80, #70, #60, #50, #45, or #40 USSS mesh, or any combination thereof.Pharmaceutical Compositions

[0287] The compositions described herein can be administered either alone or in combination with one or more of a conventional pharmaceutical carrier, buffer, stabilizer, surfactant, filler, binder, sweetener, or the like. The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent orWSGR Docket No. 41012-760.601 encapsulating material, involved in carrying or transporting the subject compounds from the administration site to a portion of the body. Each carrier is acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to a subject to whom it is administered. Nor should an acceptable carrier alter the specific activity of the subject compounds.

[0288] Other acceptable carriers, excipients, or stabilizers are those that are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose; mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; and / or non-ionic surfactants such as TWEEN®, PLURONICS®, or polyethylene glycol (PEG). Such other ingredients and the amounts to be used are within the knowledge of one in the art and are known in the pharmaceutical arts. In one embodiment, a digestive enzyme composition is prepared without the use of extenders colorants, dyes, flow enhancers and other additives to reduce the potential for allergens and other sensitivity reactions.Methods of Treatment

[0289] In one aspect, provided herein is a method of treating a neurological disease in a subject in need thereof, comprising administering a pharmaceutical composition comprising coated digestive enzyme particles to the subject daily, wherein per day: A first dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition ingested with food; a second dose comprises from about 700 mg to about 1100 mg of the pharmaceutical composition ingested with food; and a third dose comprises from about 700 mg to about 1100 mg of the pharmaceutical composition ingested with food.

[0290] In one embodiment, the method further comprising administering a fourth dose comprising from about 800 mg to about 1000 mg of the pharmaceutical composition ingested with food. In another embodiment, the method further comprising administering a fifth dose comprising from about 800 mg to about 1000 mg of the pharmaceutical composition ingested with food. In another embodiment, the method further comprising administering a sixth dose comprising from about 800 mg to about 1000 mg of the pharmaceutical composition ingested with food. In one embodiment, the first dose comprises about 1800 mg of the pharmaceutical composition. In one embodiment, the second and third dose each comprise about 900 mg of the pharmaceutical composition. In one embodiment, the fourth, fifth, or sixth dose each comprise about 900 mg of the pharmaceutical composition.

[0291] In another aspect, provided herein is a method of treating a neurological disease in a subject in need thereof, comprising administering a pharmaceutical composition comprising coated digestive enzyme particles to the subject daily, wherein per day: a first dose comprises from about 1600 mg toWSGR Docket No. 41012-760.601 about 2000 mg of the pharmaceutical composition ingested with food; a second dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition ingested with food; and a third dose comprises from about 700 mg to about 1100 mg of the pharmaceutical composition ingested with food.

[0292] In one embodiment, the method further comprising administering a fourth dose comprising from about 800 mg to about 1000 mg of the pharmaceutical composition ingested with food. In another embodiment, the method further comprising administering a fifth dose comprising from about 800 mg to about 1000 mg of the pharmaceutical composition ingested with food. In another embodiment, the method further comprising administering a sixth dose comprising from about 800 mg to about 1000 mg of the pharmaceutical composition ingested with food. In one embodiment, the first and second dose each comprise about 1800 mg of the pharmaceutical composition. In one embodiment, the third dose comprises about 900 mg of the pharmaceutical composition. In one embodiment, the fourth, fifth, or sixth dose each comprise about 900 mg of the pharmaceutical composition.

[0293] In another aspect, provided herein is a method of treating a neurological disease in a subject in need thereof, comprising administering a pharmaceutical composition comprising coated digestive enzyme particles to the subject daily, wherein per day: a first dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition ingested with food; a second dose of two sachets comprising lipid composition 1 ingested with a food; and a third dose of one sachet comprising lipid composition 1 ingested with a food; and optionally, a fourth dose of one sachet comprising lipid composition 1 ingested with a food; wherein a total amount of lipase administered to the subject does not exceed 10,000 U / kg / day or wherein a total amount of lipase does not exceed 2,500 lipase units / kg / dose, whereby autism is treated. In one embodiment, the method further comprises administering the fourth dose of lipid composition 1 ingested with a food. In another embodiment, the method further comprising administering a fifth dose of lipid composition 1 ingested with a food. In another embodiment, the method further comprising administering a sixth dose of lipid composition 1 ingested with a food.

[0294] In any of such methods, each sachet can comprise from about 700 mg to about 1100 mg of lipid composition 1. In another embodiment, each sachet comprises about 800 mg to about 1000 mg of lipid composition 1. In another embodiment, each sachet comprises about 900 of lipid composition 1.

[0295] In another aspect, provided herein is a method of treating a level 1 autism, a level 2 autism, or a level 3 autism in a human subject of about 18 years of age or older, comprising orally administering to the human subject a pharmaceutical composition comprising lipid composition 1 daily, wherein the subject is administered per day: A first dose of two sachets comprising lipid composition 1 ingested with a food; a second dose of two sachets comprising lipid composition 1 ingested with a food; and a third dose of two sachets comprising lipid composition 1 ingested with a food; and a fourth dose of two sachets comprising lipid composition 1 ingested with a food; wherein a total amount of lipase administered to the subject does not exceed 10,000 U / kg / day or wherein a total amount of lipase does not exceed 2,500 lipase units / kg / dose, whereby autism is treated. In one embodiment, the lipid composition 1 comprises coated digestive enzyme particles, each particle comprising a core and a coating. The core comprises digestive enzymes formulated as pancreatin with a protease activity of not less than 156 U. S.P.WSGR Docket No. 41012-760.601 units / mg, an amylase activity of not less than 25 U. S.P. units / mg, and a lipase activity of not less than 2 U.S.P. units / mg. The coating comprises a pharmaceutical grade hydrogenated soy oil or food grade hydrogenated soy oil. The digestive enzymes are present in the composition in an amount of 80%±2.0 by weight. At least 90% of the coated digestive enzyme particles are from about 180 to about 425 pm in diameter. The lipid composition 1 comprises no more than (NMT) about 6% fat, no more than (NMT) about 5% loss on drying, and is substantially negative (less than 1%) for bacterial species such as Escherichia coli and Salmonella species.

[0296] In one embodiment, the method further comprising administering a fifth dose of two sachets comprising lipid composition 1 ingested with a food. In another embodiment, the method further comprising administering a sixth dose of two sachets comprising lipid composition 1 ingested with a food.

[0297] In one embodiment, each sachet comprises from about 700 mg to about 1100 mg of lipid composition 1. In another embodiment, each sachet comprises about 800 mg to about 1000 mg of lipid composition 1. In another embodiment, each sachet comprises about 900 of lipid composition 1.

[0298] In any of such methods, the subject exhibits about a 2.5%, 5%, 10%, 15%, 20%, 25%, 25%, 30%, or 35%, or more, improvement in irritability, agitation, hyperactivity, lethargy, stereotypy, communication, a repetitive behavior, anxiety, attention, noncompliance or a combination thereof, following about 12 weeks of treatment or longer compared to a placebo or compared to the subject prior to treatment.

[0299] In any of such methods, the subject exhibits about a 2.5%, 5%, 10%, 15%, 20%, 25%, 25%, 30%, or 35%, or more, improvement in irritability, agitation, hyperactivity, lethargy, stereotypy, communication, a repetitive behavior, anxiety, attention, noncompliance or a combination thereof, following about 24 weeks of treatment or longer compared to a placebo or compared to the subject prior to treatment.

[0300] In any of such methods, the subject exhibits about a 2.5%, 5%, 10%, 15%, 20%, 25%, 25%, 30%, or 35%, or more, improvement in irritability, agitation, hyperactivity, lethargy, stereotypy, communication, a repetitive behavior, anxiety, attention, noncompliance or a combination thereof, following about 36 weeks of treatment or longer compared to a placebo or compared to the subject prior to treatment.

[0301] In any of such methods, the subject exhibits about a 2.5%, 5%, 10%, 15%, 20%, 25%, 25%, 30%, or 35%, or more, improvement in irritability, agitation, hyperactivity, lethargy, stereotypy, communication, a repetitive behavior, anxiety, attention, noncompliance or a combination thereof, following about 48 weeks of treatment or longer compared to a placebo or compared to the subject prior to treatment.

[0302] In any of such methods, the subject exhibits about a 2.5%, 5%, 10%, 15%, 20%, 25%, 25%, 30%, or 35%, or more, improvement in irritability, agitation, hyperactivity, lethargy, stereotypy, communication, a repetitive behavior, anxiety, attention, noncompliance or a combination thereof,WSGR Docket No. 41012-760.601 following about 1 year of treatment or longer compared to a placebo or compared to the subject prior to treatment.

[0303] In any of such methods, the subject exhibits about a 2.5%, 5%, 10%, 15%, 20%, 25%, 25%, 30%, or 35%, or more, improvement in irritability, agitation, hyperactivity, lethargy, stereotypy, communication, a repetitive behavior, anxiety, attention, noncompliance or a combination thereof, following about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 years, or more of treatment compared to a placebo or compared to the subject prior to treatment.

[0304] In any of such methods, the subject exhibits an improvement of about a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 in irritability, agitation, hyperactivity, lethargy, stereotypy, communication, a repetitive behavior, anxiety, attention, noncompliance or a combination thereof, on the ABC scale following about 12 weeks or more of treatment compared to a placebo or compared to the subj ect prior to treatment.

[0305] In any of such methods, the neurological disease or autism is modified following treatment compared to a placebo or compared to the subject prior to treatment. In any of such methods, the neurological disease or autism is modified for about 2 months or more following treatment compared to a placebo or compared to the subject prior to treatment. In any of such methods, the neurological disease or autism is modified for about 6 months or more following treatment compared to a placebo or compared to the subject prior to treatment. In any of such methods, the neurological disease or autism is modified for about 1 year or more following treatment compared to a placebo or compared to the subject prior to treatment. In any of such methods, the neurological disease or autism is modified for about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years or more following treatment compared to a placebo or compared to the subject prior to treatment.

[0306] In any of such methods, a co-morbidity associated with the neurological disease or autism is treated. Co-morbidities include, but are not limited to, a sleep disorder, a mood disorder, an immune dysfunction, or a gastrointestinal disorder.

[0307] In any of such methods, the method can further comprise administering at least one additional therapy to the subject. Additional therapies include, but are not limited to, behavioral therapy, dietary therapy, a methylphenidate, an amphetamine, atomoxetine (Strattera), viloxazine (Qelbree), guanfacine (Intuniv), clonidine (OnydaXR), risperidone, aripiprazole, or a combination thereof. In one embodiment, the at least one additional therapy comprises the methylphenidate and the methylphenidate comprises Ritalin, Biphentin, Concerti, or Aptensio XR. Alternatively, or in addition, the at least one additional therapy comprises the amphetamine and the amphetamine comprises Adderall, Dexedrine, or Vyvanse.

[0308] Provided herein are methods of treating a symptom of a disease or condition in a human subject in need thereof, comprising administering to the human subject a composition comprising high-protease pancreatic replacement (CM- AT), whereby the symptom of the disease or condition is improved in the human subject, and wherein the disease or condition is an autism spectrum disorder.

[0309] Any of the compositions provided herein may be administered to a subject. “Subject” may be used interchangeably with “individual” or “patient.” By way of example only, a subject includes, but isWSGR Docket No. 41012-760.601 not limited to, a mammal, including, but not limited to, a human or a non -human mammal, such as a nonhuman primate, bovine, equine, canine, ovine, feline, etc. In some embodiments, the individual is a human. In some embodiments, the individual is a human child.

[0310] In one aspect, provided herein is a method of treating an Autism Spectrum Disorder (ASD) in a subject in need thereof, comprising administering to the subject about 900 mg of a digestive enzyme preparation three times per day with a food; wherein the subject is from about 3 to about 8 years of age or from about 3 to about 6 years of age at commencement of treatment, wherein the digestive enzyme preparation comprises coated particles, each coated particle comprising: (a) a core containing digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase, and a lipase, and (b) a coating comprising a lipid, wh...

Claims

WSGR Docket No. 41012-760.601CLAIMSWhat is claimed:

1. A method of treating a neurological disease in a subject in need thereof, comprising administering a pharmaceutical composition comprising coated digestive enzyme particles to the subject daily for at least 12 weeks, wherein per day: a first dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition within about 2-3 hours of waking; a second dose comprises from about 700 mg to about 1100 mg of the pharmaceutical composition about mid-day; and a third dose comprises from about 700 mg to about 1100 mg of the pharmaceutical composition in the evening; wherein the subject is from about 9 to about 12 years of age; wherein the pharmaceutical composition is administered to the subject orally, via a gastrointestinal tube (G-tube), or a nasal gastrointestinal tube (NG-tube); and wherein the method improves irritability, agitation, hyperactivity, stereotypy, communication, or a combination thereof by at least 5% on an Aberrant Behavioral Checklist (ABC) score compared to a placebo or compared to the subject prior to treatment; whereby the neurological disease is treated.

2. The method of claim 1 , wherein the method further comprising administering a fourth dose, fifth does or sixth dose comprising from about 800 mg to about 1000 mg of the pharmaceutical composition.

3. The method of any one of claims 1-2, wherein the method each dose of the pharmaceutical composition is ingested with food.

4. The method of any one of claims 1-3, wherein a total amount of lipase administered to the subject does not exceed 2,500 lipase units / kg / dose.

5. The method of any one of claims 1 -4, wherein the first dose comprises about 1800 mg of the pharmaceutical composition.

6. The method of any one of claims 1-5, wherein the second dose and third dose each comprise about 900 mg of the pharmaceutical composition.

7. The method of any one of claims 2-6, wherein the fourth, the fifth, or the sixth dose each comprise about 900 mg of the pharmaceutical composition.

8. A method of treating a neurological disease in a subject in need thereof, comprising administering a pharmaceutical composition comprising coated digestive enzyme particles to the subject daily for at least 12 weeks, wherein per day: a first dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition within about 2-3 hours of waking; a second dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition about mid-day; andWSGR Docket No. 41012-760.601 a third dose comprises from about 700 mg to about 1100 mg of the pharmaceutical composition in the evening; wherein the subject is from about 13 to about 17 years of age; wherein the pharmaceutical composition is administered to the subject orally, via a gastrointestinal tube (G-tube), or a nasal gastrointestinal tube (NG-tube); and wherein the method improves irritability, agitation, hyperactivity, stereotypy, communication, or a combination thereof by at least 5% on an Aberrant Behavioral Checklist (ABC) score compared to a placebo or compared to the subject prior to treatment; whereby the neurological disease is treated.

9. The method of claim 8, wherein the method further comprising administering a fourth dose, a fifth dose, or a sixth dose comprising from about 800 mg to about 1000 mg of the pharmaceutical composition ingested with food.

10. The method of any one of claims 8-9, wherein each dose of the pharmaceutical composition is ingested with food.

11. The method of claim 10, wherein a total amount of lipase administered to the subject does not exceed 2,500 lipase units / kg / dose.

12. The method of any one of claims 8-11, wherein the first dose and the second dose each comprise about 1800 mg of the pharmaceutical composition.

13. The method of any one of claims 8-12, wherein the third dose comprises about 900 mg of the pharmaceutical composition.

14. The method of any one of claims 9-13, wherein the fourth dose, the fifth dose, or the sixth dose each comprise about 900 mg of the pharmaceutical composition.

15. A method of treating a neurological disease in a subject in need thereof, comprising administering a pharmaceutical composition comprising coated digestive enzyme particles to the subject daily for at least 12 weeks, wherein per day: a first dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition within about 2-3 hours of waking; a second dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition about mid-day; and a third dose comprises from about 1600 mg to about 2000 mg of the pharmaceutical composition in the evening; wherein the subject is about 18 years of age or older; wherein the pharmaceutical composition is administered to the subject orally, via a gastrointestinal tube (G-tube), or a nasal gastrointestinal tube (NG-tube); and wherein the method improves irritability, agitation, hyperactivity, stereotypy, communication, or a combination thereof by at least 5% on an Aberrant Behavioral Checklist (ABC) score compared to a placebo or compared to the subject prior to treatment; whereby the neurological disease is treated.WSGR Docket No. 41012-760.60116. The method of claim 15, wherein the method further comprising administering a fourth dose, a fifth dose, or a sixth comprising from about 1600 mg to about 2000 mg of the pharmaceutical composition ingested with food.

17. The method of any one of claims 15-16, wherein each does of the pharmaceutical composition is ingested with food.

18. The method of any one of claims 15-17, wherein a total amount of lipase administered to the subject does not exceed 2,500 lipase units / kg / dose.

19. The method of any one of claims 15-18, wherein each dose comprises about 1800 mg of the pharmaceutical composition.

20. A method of treating a neurological disease in a subject in need thereof, comprising administering to the subject a dose of from about 700 mg to about 2000 mg of a pharmaceutical composition comprising coated digestive enzyme particles at least 4 times per day with a food for at least 12 weeks; wherein the subject is about 18 months of age or older; wherein the pharmaceutical composition is administered to the subject orally, via a gastrointestinal tube (G-tube), or a nasal gastrointestinal tube (NG-tube); wherein a first dose is administered within about 2-3 hours of waking, a second dose is administered from about 2 to about 4 hours after the first dose, a third dose is administered from about 2 to about 4 hours after the second dose, and wherein a fourth dose is administered from about 2 to about 4 hours after the third dose; wherein a total amount of a lipase administered to the subject does not exceed 2,500 lipase units / kg / dose; and wherein the method improves irritability, agitation, hyperactivity, stereotypy, communication, or a combination thereof by at least 5% on an Aberrant Behavioral Checklist (ABC) score compared to a placebo or compared to the subject prior to treatment; whereby the neurological disease is treated.

21. The method of claim 20, wherein the method further comprises administering to the subject a fifth dose of from about 2 to about 4 hours after the fourth dose.

22. The method of claim 21, wherein the method further comprises administering to the subject a sixth dose of from about 2 to about 4 hours after the fifth dose.

23. The method of any one of claims 20-22, wherein each dose is from about 1600 mg to about 2000 mg.

24. The method of any one of claims 20-23, wherein each dose is from about 1700 mg to about 1900 mg.

25. The method of any one of claims 20-24, wherein each dose is from about 1750 mg to about 1850 mg.

26. The method of any one of claims 20-25, wherein each dose is about 1800 mg.WSGR Docket No. 41012-760.60127. The method of any one of claims 20-22, wherein each dose is from about 700 mg to about 1100 mg.

28. The method of claim 20, 22, or 27, wherein each dose is from about 800 mg to about 1000 mg.

29. The method of claim 20, 22, 27, or 28, wherein each dose is from about 850 mg to about 950 mg.

30. The method of claim 20, 22, 27, 28, or 29, wherein each dose is about 900 mg.

31. The method of any one of claims 20-30, wherein the subject is about 9 of age or older.

32. The method of any one of claims 20-31, wherein the subject is about 13 years of age, at least 17 years of age, or older.

33. The method of any one of claims 20-30, wherein the subject is 12 years of age or younger.

34. The method of any one of claims 20-30, wherein the subject is from about 18 months to about 72 months of age, from about 3 to about 6 years of age, from about 3 to about 8 years of age, from about 3 to about 9 years of age, from about 9 to about 12 years of age. , from about 13 to about 17 years of age, from about 5 to about 16 years of age or from about 6 to about 17 years of age.

35. The method of any one of claims 1-34, wherein the subject is a human subject.

36. The method of any one of claims 1-35, wherein the subject is biologically a male.

37. The method of any one of claims 1-35, wherein the subject is biologically a female.

38. The method of any one of claims 1-37, wherein the coated digestive particles each comprise a core and a coating.

39. The method of claim 38, wherein the core comprises digestive enzymes.

40. The method of claim 39, wherein the digestive enzymes comprise a protease, an amylase, and a lipase.

41. The method of claim 39 or 40, wherein the digestive enzymes comprise in each mg of the pharmaceutical composition not less than 25 U.S.P. units of amylase activity, not less than 2 U.S.P. units of lipase activity, and not less than 25 U.S.P. units of protease activity.

42. The method of any one of claims 39-41, wherein the digestive enzymes comprise of the pharmaceutical composition: a protease activity of not less than 156 U.S.P. units / mg, an amylase activity of not less than 25 U. S.P. units / mg, and a lipase activity of not less than 2 U.S.P. units / mg.

43. The method of any one of claims 1-42, wherein the pharmaceutical composition comprises no more than (NMT) about 6% fat.

44. The method of any one of claims 1-43, wherein the pharmaceutical composition comprises no more than (NMT) about 5% loss on drying.

45. The method of any one of claims 1-44, wherein the pharmaceutical composition is substantially negative for bacterial species.

46. The method of claim 45, wherein the pharmaceutical composition is substantially negative for Escherichia coli and Salmonella species.WSGR Docket No. 41012-760.60147. The method of any one of claims 39-46, wherein the digestive enzymes are formulated as pancreatin.

48. The method of any one of claims 1-47, wherein a total amount of lipase administered to the subject does not exceed 10,000 U / kg / day.

49. The method of any one of claims 1-48, wherein digestive enzymes are present in the pharmaceutical composition in an amount of from about 70% to about 90% by weight.

50. The method of any one of claims 1-49, wherein digestive enzymes are present in the pharmaceutical composition in an amount of from about 75% to about 85% by weight.

51. The method of any one of claims 1-50, wherein digestive enzymes are present in the coated particles in an amount of from about 78±2% to about 83±2% by weight.

52. The method of any one of claims 1-51, wherein digestive enzymes are present in the coated particles in an amount of about 78±1%, 79±1%, 80±l%, 81±1%, 82±1%, or 83±1.

53. The method of any one of claims 1-52, wherein the digestive enzymes are present in the composition in an amount of about 80% by weight.

54. The method of any one of claims 1-53, wherein the coated digestive enzyme particles have a size range of from about 105 to about 425 pm in diameter.

55. The method of any one of claims 1-54, wherein at least 75% of the particles are from about 180 to about 425 pm in diameter.

56. The method of any one of claims 1-55, wherein about 90% of the particles are from about 180 to about 425 pm in diameter.

57. The method of any one of claims 1-56, wherein the coating comprises a lipid, a wax, a polymer enteric coating, a cellulose acetate phthalate (CAP), a cellulose acetate trimellitate (CAT), a hydroxyl propyl methyl cellulose phthalate (HPMCP), a hydroxyl propyl methyl cellulose acetate succinate (HPMCAS), a polyvinyl acetate phthalate (PVAP), a methacrylic acid copolymer, a shellac, a zein, an ethylcellulose, a nano-crystal API carrier suspension, a matrix, or any combination thereof.

58. The method of claim 57, wherein the coating comprises the lipid.

59. The method of claim 58, wherein the lipid comprises a food grade lipid.

60. The method of claim 57 or 58, wherein the lipid comprises a pharmaceutical grade lipid.

61. The method of any one of claims 58-60, wherein the lipid comprises monoglycerides, diglycerides, triglycerides, or a combination thereof.

62. The method of any one of claims 58-61, wherein the lipid comprises monoglycerides, diglycerides and triglycerides.

63. The method of any one of claims 1-62, wherein the coating comprises a soy oil.

64. The method of any one of claims 58-63, wherein the lipid comprises a hydrogenated soy oil.

65. The method of any one of claims 1-64, wherein the subject has been diagnosed with an Autism Spectrum Disorder (ASD), attention deficit disorder (ADD), attention deficit hyperactivityWSGR Docket No. 41012-760.601 disorder (ADHD), oppositional defiant disorder (ODD), obsessive compulsive disorder (OCD), schizophrenia, Alzheimer’s disease, bipolar disorder, or a pervasive dysautonomic disorder (PDD).

66. The method of any one of claims 1-65, wherein the subject has been diagnosed with the ASD.

67. The method of claim 66, wherein the ASD comprises autism.

68. The method of claim 78, wherein the subject has been diagnosed as having a level 1 autism, level 2 autism or level 3 autism.

69. The method of any one of claims 1-68, wherein the subject has a baseline ABC- irritability (ABC-I) score of about 8.0 or higher prior to treatment, about 9.0 or higher prior to treatment, about 10.0 or higher prior to treatment or about 11.0 or higher prior to treatment.

70. The method of any one of claims 1-69, wherein the subject exhibits an improvement of at least about 10%, 15%, 20%, 25%, or 30%, or more in irritability following treatment with the pharmaceutical composition.

71. The method of any one of claims 1-70, wherein the subject has been diagnosed with ADD or ADHD.

72. The method of any one of claims 1-70, wherein the pharmaceutical composition is administered for about 12 weeks, about 24 weeks, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 110 weeks, about 120 weeks, about 130 weeks, about 140 weeks, about 150 weeks, about 160 weeks, about 170 weeks, about 180 weeks, about 190 weeks, about 200 weeks, about 210 weeks, about 220 weeks, about 230 weeks, or more.

73. The method of claim 72, wherein the pharmaceutical composition is administered for about 110 weeks±2 weeks.

74. The method of any one of claims 1-73, wherein the pharmaceutical composition is administered for about 1 year, about 2 years, about 3 years, about 4 years, or about 5 years, or more.

75. The method of any one of claims 1-74, wherein the pharmaceutical composition is administered to the subject approximately every 2-4 hours during waking hours of the subject’s day.

76. The method of any one of claims 1-75, wherein the pharmaceutical composition is hypoallergenic.

77. The method of any one of claims 1-76, wherein the coating masks the taste or the smell of the digestive enzymes.

78. The method of any one of claims 1-77, wherein the pharmaceutical composition is administered to the subject orally.

79. The method of any one of claims 1-77, wherein the pharmaceutical composition is administered to the subject via a gastrointestinal tube (G-tube).

80. The method of any one of claims 1-77, wherein the pharmaceutical composition is administered to the subject via a nasal gastrointestinal tube (NG-tube).WSGR Docket No. 41012-760.60181. A method of treating a level 1 autism, a level 2 autism, or a level 3 autism in a human subject of under 12 years of age, comprising administering to the human subject a pharmaceutical composition comprising lipid composition 1 daily, wherein the subject is administered per day: a first dose of two sachets comprising lipid composition 1 ingested with a food within about 2-3 hours of waking; a second dose of one or two sachets comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the first dose; and a third dose of one sachet comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the second dose; and optionally, a fourth dose of one sachet comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the third dose; wherein the lipid composition 1 is administered to the subject orally, via a gastrointestinal tube (G-tube), or a nasal gastrointestinal tube (NG-tube); wherein the pharmaceutical composition is administered to the subject orally, via a gastrointestinal tube (G-tube), or a nasal gastrointestinal tube (NG-tube); wherein a total amount of a lipase administered to the subject does not exceed 2,500 lipase units / kg / dose; and wherein the method improves irritability, agitation, hyperactivity, stereotypy, communication, or a combination thereof by at least 5% on an Aberrant Behavioral Checklist (ABC) score compared to a placebo or compared to the subject prior to treatment; wherein a total amount of lipase administered to the subject does not exceed 10,000 U / kg / day or wherein a total amount of lipase does not exceed 2,500 lipase units / kg / dose, whereby autism is treated.

82. The method of claim 81, wherein the method further comprises administering the fourth dose of lipid composition 1 ingested with a food from about 2 to about 4 hours after the third dose.

83. The method of claim 82, wherein the method further comprising administering a fifth dose of lipid composition 1 ingested with a food from about 2 to about 4 hours after the fourth dose.

84. The method of claim 83, wherein the method further comprising administering a sixth dose of lipid composition 1 ingested with a food from about 2 to about 4 hours after the fifth dose.

85. The method of any one of claims 81-84, wherein each sachet comprises from about 700 mg to about 1100 mg of lipid composition 1.

86. The method of any one of claims 81-85, wherein each sachet comprises about 800 mg to about 1000 mg of lipid composition 1.

87. The method of any one of claims 81-86, wherein each sachet comprises about 900 of lipid composition 1.

88. The method of any one of claims 81-87, wherein the human subject is from about 18 to about 72 months of age.WSGR Docket No. 41012-760.60189. The method of any one of claims 81-87, wherein the human subject is from about 3 to about 6 years of age.

90. The method of any one of claims 1-87, wherein the human subject is from about 3 to about 8 years of age.

91. The method of any one of claims 81-87, wherein the human subject is from about 9 to about 12 years of age.

92. A method of treating a level 1 autism, a level 2 autism, or a level 3 autism in a human subject of from about 13 to about 17 years of age, comprising administering to the human subject a pharmaceutical composition comprising lipid composition 1 daily, wherein the subject is administered per day: a first dose of two sachets comprising lipid composition 1 ingested with a food within about 2-3 hours of waking; a second dose of two sachets comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the first dose; and a third dose of one sachet comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the second dose; and optionally, a fourth dose of one sachet comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the third dose; wherein the lipid composition 1 is administered to the subject orally, via a gastrointestinal tube (G-tube), or a nasal gastrointestinal tube (NG-tube); wherein the method improves irritability, agitation, hyperactivity, stereotypy, communication, or a combination thereof by at least 5% on an Aberrant Behavioral Checklist (ABC) score compared to a placebo or compared to the subject prior to treatment; and wherein a total amount of lipase administered to the subject does not exceed 10,000 U / kg / day or wherein a total amount of lipase does not exceed 2,500 lipase units / kg / dose, whereby autism is treated.

93. The method of claim 92, wherein the method further comprises administering the fourth dose of lipid composition 1 ingested with a food from about 2 to about 4 hours after the third dose.

94. The method of claim 93, wherein the method further comprising administering a fifth dose of lipid composition 1 ingested with a food from about 2 to about 4 hours after the fourth dose.

95. The method of claim 94, wherein the method further comprising administering a sixth dose of lipid composition 1 ingested with a food from about 2 to about 4 hours after the fifth dose.

96. The method of any one of claims 92-95, wherein each sachet comprises from about 700 mg to about 1100 mg of lipid composition 1.

97. The method of any one of claims 92-96, wherein each sachet comprises about 800 mg to about 1000 mg of lipid composition 1.

98. The method of any one of claims 92-97, wherein each sachet comprises about 900 of lipid composition 1.WSGR Docket No. 41012-760.60199. A method of treating a level 1 autism, a level 2 autism, or a level 3 autism in a human subject of about 18 years of age or older, comprising administering to the human subject a pharmaceutical composition comprising lipid composition 1 daily, wherein the subject is administered per day: a first dose of two sachets comprising lipid composition 1 ingested with a food within about 2-3 hours of waking; a second dose of two sachets comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the first dose; and a third dose of two sachets comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the second dose; and a fourth dose of two sachets comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the third dose; wherein the lipid composition 1 is administered to the subject orally, via a gastrointestinal tube (G-tube), or a nasal gastrointestinal tube (NG-tube); wherein the method improves irritability, agitation, hyperactivity, stereotypy, communication, or a combination thereof by at least 5% on an Aberrant Behavioral Checklist (ABC) score compared to a placebo or compared to the subject prior to treatment; and wherein a total amount of lipase administered to the subject does not exceed 10,000 U / kg / day or wherein a total amount of lipase does not exceed 2,500 lipase units / kg / dose, whereby autism is treated.

100. The method of claim 99, wherein the method further comprising administering a fifth dose of two sachets comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the fourth dose.

101. The method of claim 100, wherein the method further comprising administering a sixth dose of two sachets comprising lipid composition 1 ingested with a food from about 2 to about 4 hours after the fifth dose.

102. The method of any one of claims 99-101, wherein each sachet comprises from about 700 mg to about 1100 mg of lipid composition 1.

103. The method of any one of claims 99-102, wherein each sachet comprises about 800 mg to about 1000 mg of lipid composition 1.

104. The method of any one of claims 99-103, wherein each sachet comprises about 900 of lipid composition 1.

105. The method of any one of claims 1-104, wherein the subject exhibits about a 2.5%, 5%, 10%, 15%, 20%, 25%, 25%, 30%, or 35%, or more, improvement in irritability, agitation, hyperactivity, lethargy, stereotypy, communication, a repetitive behavior, anxiety, attention, noncompliance, or a combination thereof, following about 12, 24, 36, or 48 weeks of treatment or longer compared to a placebo or compared to the subject prior to treatment.WSGR Docket No. 41012-760.601106. The method of any one of claims 1-105, wherein the subject exhibits about a 2.5%, 5%, 10%, 15%, 20%, 25%, 25%, 30%, or 35%, or more, improvement in irritability, agitation, hyperactivity, lethargy, stereotypy, communication, a repetitive behavior, anxiety, attention, noncompliance, or a combination thereof, following about 1 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 years, or more years of treatment or longer compared to a placebo or compared to the subject prior to treatment.

107. The method of any one of claims 1-106, wherein the neurological disease or autism is modified following treatment compared to a placebo or compared to the subject prior to treatment.

108. The method of claim 1-107, wherein the neurological disease or autism is modified for about 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 months, or more following treatment compared to a placebo or compared to the subject prior to treatment.

109. The method of any one of claims 1-108, wherein the neurological disease or autism is modified for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years or more following treatment compared to a placebo or compared to the subject prior to treatment.

110. The method of any one of claims 1-109, wherein a co-morbidity associated with the neurological disease or autism is treated.

111. The method of claim 110, wherein the co-morbidity comprises a sleep disorder, a mood disorder, an immune dysfunction, or a gastrointestinal disorder.

112. The method of any one of claims 1-111, further comprising administering at least one additional therapy to the subject.

113. The method of claim 112, wherein the at least one additional therapy comprises behavioral therapy, dietary therapy, a methylphenidate, an amphetamine, atomoxetine (Strattera), viloxazine (Qelbree), guanfacine (Intuniv), clonidine (Onyda XR), risperidone, aripiprazole, or a combination thereof.

114. The method of claim 113, wherein the at least one additional therapy comprises the methylphenidate and the methylphenidate comprises Ritalin, Biphentin, Concerti, or Aptensio XR.

115. The method of claim 113, wherein the at least one additional therapy comprises the amphetamine and the amphetamine comprises Adderall, Dexedrine, or Vyvanse.

116. The method of any one of claims 1-115, wherein the subject does not have (exhibit) any severe adverse events during or following treatment.

117. The method of any one of claims 1-116, wherein the subject does not have (exhibit) any adverse events during or following treatment related to treatment.

118. The method of any one of claims 1-117, wherein the subject does not have (exhibit) any severe adverse events during or following treatment related to treatment.

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