Methods for treating pancreatic disorders

Abstract

Provided herein is a method of administering a therapeutic for a pancreatic disorder to a subject in need thereof, the method comprising (a) advancing an endoscope comprising a needle through the oropharynx and esophagus of the subject and into the stomach; (b) advancing the needle out of the stomach and into the retroperitoneal cavity of the subject; and (c) administering the therapeutic through the endoscope into the retroperitoneal cavity.

Description

Attorney Docket No. 1546.7. WOMETHODS FOR TREATING PANCREATIC DISORDERSRELATED APPLICATION

[0001] The present application claims priority from and the benefit of U.S. Provisional Patent Application No. 63 / 704,745 filed October 8, 2024, the disclosure of which is hereby incorporated herein by reference in full.FIELD OF THE INVENTION

[0002] This invention relates to methods of administering a therapeutic for the treatment of pancreatitis and other pancreatic disorders.BACKGROUND OF THE INVENTION

[0003] The pancreas produces enzymes that aid in digestion and absorption of food; one such enzyme is lipase, which digests fat. Certain individuals (e.g., obese individuals) have an increased risk of developing multisystem organ failure in acute inflammatory conditions such as severe burns, severe trauma, critical illness, and acute pancreatitis (AP). Pancreatitis is associated with the release of destructive digestive enzymes from pancreatic acinar cells into the pancreas itself. AP is described as a sudden inflammation of the pancreas, accompanied by severe abdominal pain, elevations of serum pancreatic enzymes, and often nausea and vomiting. This syndrome is usually a discrete episode, which may cause varying degrees of injury to the pancreas, and adjacent and distant organs. When AP is initiated, it can quickly become severe AP (SAP). This is a concern because SAP results in 30% or more mortality when complicated by infectious necrosis, acute renal failure, respiratory failure, hypocalcemia, and other manifestations of multisystem organ failure or by large areas of pancreatic necrosis.

[0004] Pancreatic lipase inhibitors have been hypothesized to possibly be effective therapeutics for AP. However, administration of these lipase inhibitors has proven difficult, as they are often poorly permeable and rapidly metabolized. Thus, systemic administration intravenously or subcutaneously or orally would not provide sufficient peripancreatic concentrations needed for lipase inhibition and efficacy. To inhibit lipases at the site of action, it is desirable to have alternative, direct administration methods for therapeutics that are used for treating AP and other pancreatic disorders.Attorney Docket No. 1546.7. WOSUMMARY OF THE INVENTION

[0005] The present invention is based on the finding that endoscopic ultrasound (EUS) guided peripancreatic injections of therapeutics is beneficial in treating pancreatic disorders.

[0006] Thus, one aspect of the invention provided herein is a method of administering a therapeutic for a pancreatic disorder to a subject in need thereof, the method comprising (a) advancing an endoscope comprising a needle through the oropharynx and esophagus of the subject and into the stomach; (b) advancing the needle out of the stomach and into the retroperitoneal cavity of the subject; and (c) administering the therapeutic through the endoscope into the retroperitoneal cavity. In some embodiments, the pancreatic disorder is acute pancreatitis, chronic pancreatitis, pancreatic cancer, post-operative pancreatic fistulas, pancreatic adhesions, pancreatic fibrosis, and / or cystic lesions of the pancreas. In some embodiments, the therapeutic is a pancreatic lipase inhibitor.

[0007] These and other aspects of the invention are set forth in more detail in the description of the invention below.BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Fig. 1 is a graph showing the mean compound 767 plasma concentration profiles over time in healthy human volunteers after receiving a 1-dose administration of compound 767 via EUS- guided percutaneous intraperitoneal injection. Cohort A (blue) received a 31.25 mg (25 mL of 1.25 mg / mL) dose of compound 767; Cohort B (red) received a 62.5 mg (25 mL of 2.5 mg / mL) dose of compound 767; Cohort C (green) received a 125 mg (25 mL of 5 mg / mL) dose of compound 767. N = 6 subjects in each cohort. Values that were below the quantitation limit (BQL) were treated as 0 ng / mL.

[0009] Fig. 2 is a schematic showing the study procedure and assessment schedule in participants receiving both RABI-767 and Standard of Care (SoC) and participants receiving SoC only.DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention is explained in greater detail below. This description is not intended to be a detailed catalog of all the different ways in which the invention may be implemented, or all the features that may be added to the instant invention. For example, features illustrated withAttorney Docket No. 1546.7. WO respect to one embodiment may be incorporated into other embodiments, and features illustrated with respect to a particular embodiment may be deleted from that embodiment. In addition, numerous variations and additions to the various embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure which do not depart from the instant invention. Hence, the following specification is intended to illustrate some particular embodiments of the invention, and not to exhaustively specify all permutations, combinations and variations thereof.

[0011] Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination.

[0012] 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 invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of a conflict in terminology, the present specification is controlling.

[0013] All publications, patent applications, patents, nucleotide sequences, amino acid sequences and other references mentioned herein are incorporated by reference in their entirety.Definitions

[0014] As used in the description of the invention and the appended claims, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0015] As used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).Attorney Docket No. 1546.7. WO

[0016] Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted.

[0017] Furthermore, the term “about,” as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of the specified amount.

[0018] As used herein, the transitional phrase “consisting essentially of’ is to be interpreted as encompassing the recited materials or steps and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. Thus, the term “consisting essentially of’ as used herein should not be interpreted as equivalent to “comprising.”

[0019] The term “enhance” or “increase” refers to an increase in the specified parameter of at least about 1.25-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 8-fold, 10-fold, twelve-fold, or even fifteen-fold.

[0020] The term “inhibit” or “reduce” or grammatical variations thereof as used herein refers to a decrease or diminishment in the specified level or activity of at least about 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95% or more. In particular embodiments, the inhibition or reduction results in little or essentially no detectible activity (at most, an insignificant amount, e.g., less than about 10% or even 5%).

[0021] A “therapeutically effective” or “treatment effective” amount as used herein is an amount that provides some improvement or benefit to the subject. Alternatively stated, a “therapeutically effective” or “treatment effective” amount is an amount that will provide some alleviation, mitigation, or decrease in at least one clinical symptom in the subject (e.g., in the case of treating pancreatitis a reduction in abdominal pain, pancreatic inflammation, pancreatic swelling, and / or serum pancreatic enzymes). Those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject.

[0022] By the term “treat,” “treating,” or “treatment of’ (or grammatically equivalent terms) is meant to reduce or to at least partially improve or ameliorate the severity of the subject’s condition and / or to alleviate, mitigate or decrease in at least one clinical symptom and / or to delay the progression of the condition.

[0023] As used herein, the term “prevent,” “prevents,” or “prevention” (and grammatical equivalents thereof) means to delay or inhibit the onset of a disease. The terms are not meant toAttorney Docket No. 1546.7. WO require complete abolition of disease, and encompass any type of prophylactic treatment to reduce the incidence of the condition or delay the onset of the condition.

[0024] A “prevention effective” amount as used herein is an amount that is sufficient to prevent and / or delay the onset or progression of a disease, disorder and / or clinical symptoms in a subject and / or to reduce and / or delay the severity of the onset of a disease, disorder and / or clinical symptoms in a subject relative to what would occur in the absence of the methods of the invention. Those skilled in the art will appreciate that the level of prevention need not be complete, as long as some benefit is provided to the subject.

[0025] As used herein, the terms “protein” and “polypeptide” are used interchangeably and encompass both peptides and proteins, unless indicated otherwise.

[0026] “Pharmaceutically acceptable,” as used herein, means a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual along with the compositions of this invention, without causing substantial deleterious biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. The material would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art (see, e.g., Remington's Pharmaceutical Science; 21sted. 2005). Exemplary pharmaceutically acceptable carriers for the compositions of this invention include, but are not limited to, phosphate buffered saline (PBS), sterile pyrogen-free water, and other sterile pyrogen- free physiological saline solutions.

[0027] As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present application include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether,Attorney Docket No. 1546.7. WO ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977). Conventional methods for preparing salt forms are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, 2002.

[0028] The term “administering” or “administration” of a compound and / or composition of the present invention to a subject includes any route of introducing or delivering to a subject a compound to perform its intended function (e.g., for treating pancreatitis).

[0029] A “subject” of the invention may include any animal in need thereof. In some embodiments, a subject may be, for example, a mammal, a reptile, a bird, an amphibian, or a fish. A mammalian subject may include, but is not limited to, a laboratory animal (e.g., a rat, mouse, guinea pig, rabbit, primate, etc.), a farm or commercial animal (e.g., cattle, pig, horse, goat, donkey, sheep, etc.), or a domestic animal (e.g., cat, dog, ferret, gerbil, hamster, etc.). In some embodiments, a mammalian subject may be a primate, or a non-human primate (e.g., a chimpanzee, baboon, macaque (e.g., rhesus macaque, crab-eating macaque, stump-tailed macaque, pig-tailed macaque), monkey (e.g., squirrel monkey, owl monkey, etc.), marmoset, gorilla, etc.). In some embodiments, a mammalian subject may be a human.

[0030] A “subject in need” of the methods of the invention can be any subject known or suspected of having a pancreatic disorder or having an increased risk of developing a pancreatic disorder to which administering a therapeutic may provide beneficial health effects.

[0031] A “sample”, “biological sample”, and / or “e vivo sample” of this invention can be any biological material, such as a biological fluid, an extract from a cell, an extracellular matrix isolated from a tissue, a cell (in solution or bound to a solid support), a tissue, a tissue homogenate, and the like as are well known in the art.Methods of Use

[0032] Provided herein is a method for administering a therapeutic for a pancreatic disorder to a subject in need thereof, wherein the method comprises: (a) advancing an endoscope (e.g., echoendoscope) comprising a needle through the oropharynx and esophagus of the subject and into the stomach; (b) advancing the needle out of the stomach and into the retroperitoneal cavity of the subject; and (c) administering the therapeutic through the endoscope into the retroperitonealAttorney Docket No. 1546.7. WO cavity (e.g., intraperitoneally; e.g., peripancreatic injection). In some embodiments, the needle is advanced under endoscopic ultrasound (EUS) guidance.

[0033] Also provided herein is a method for administering a therapeutic for a pancreatic disorder to a subject in need thereof, wherein the method comprises: advancing a needle through dorsal skin of the subject and into the retroperitoneal cavity of the subject; and administering the therapeutic through the needle into the retroperitoneal cavity (e.g., intraperitoneally; e.g., percutaneous injection). In some embodiments, the needle is advanced under imaging guidance (e.g., ultrasound, computed tomography (CT), and / or magnetic resonance imaging (MRI) guidance).

[0034] In some embodiments, the needle is contained inside of the endoscope and is advanced out of the endoscope, out of the stomach, and into the retroperitoneal cavity. In some embodiments, the needle is advanced into the retroperitoneal cavity to the left of the celiac trunk at the body-tail of the pancreas. The skilled artisan will recognize that any appropriate endoscope comprising a needle can be used. In some embodiments, the endoscope is a linear echoendoscope. In some embodiments, the needle has a gauge from about 14 gauge to about 25 gauge (e.g., about 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 gauge). In some embodiments, the needle is stainless-steel, cobalt chromium, or Nitinol (e.g., flexible Nitinol). In some embodiments, the needle is a fine- needle aspiration needle, a fine-needle biopsy needle, a fine-needle injection needle, an aspiration needle, a biopsy needle, or an injection needle.

[0035] In some embodiments, the endoscope further comprises a catheter. In some embodiments, the method for administering the therapeutic further comprises steps wherein the catheter is advanced over the needle into the retroperitoneal cavity; the needle is removed from the retroperitoneal cavity; and the therapeutic is administered into the retroperitoneal cavity through the catheter. In some embodiments, the method for administering the therapeutic further comprises steps wherein the catheter is advanced through the needle into the retroperitoneal cavity; the needle is removed from the retroperitoneal cavity; and the therapeutic is administered into the retroperitoneal cavity through the catheter. In some embodiments, the catheter further comprises an indwelling catheter that is surgically placed into the subject. In some embodiments, the indwelling catheter remains in the subject from about 1 week to about 12 weeks (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more weeks).Attorney Docket No. 1546.7. WO

[0036] In some embodiments, the endoscope further comprises a pump configured to move the therapeutic through the endoscope and into the retroperitoneal cavity. In some embodiments, the pump can be configured to control the infusion rate of the therapeutic; e.g., the pump can be configured to administer the therapeutic over a time frame from about 2 seconds to about 60 seconds (e.g., about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or about 60 seconds) or from about 1 minute to about 60 minutes (e.g., about 1, 2, 3, 4, 5, 10, 15, 20, 30, 35, 40, 45, 50, 55, or about 60 minutes). In some embodiments, the catheter is an indwelling catheter and further comprises the pump configured to move the therapeutic through the catheter and into the retroperitoneal cavity.

[0037] In some embodiments, the subject in need thereof is sedated during the administration. Any method of sedation known to those in the art can be used. In some embodiments, the method of sedation can be chosen by the individual clinician based on various factors including, but not limited to, the condition of subject (e.g., age, sex, weight, etc.), the progression and / or severity of the pancreatic disorder, known or suspected reactions of the subject to specific sedation techniques, and the like.

[0038] In some embodiments, the method further comprises administering one or more (e.g. , one, two, three, four, five or more) additional therapeutics used to treat the pancreatic disorder and / or performing therapies used to treat the pancreatic disorder. In some embodiments, the pancreatic disorder is pancreatitis and the additional therapeutics can include, without limitation, acetaminophen, ibuprofen, opioids (e.g., codeine and morphine), pancreatic enzymes, antiinflammatories, oxygen, intravenous fluids (e.g., lactated ringers and the like), steroids, and any combinations thereof In some embodiments, the pancreatic disorder is pancreatic cancer and the additional therapeutics can include, without limitation, chemotherapeutics or immunotherapeutics, e.g., gemcitabine, 5-fluorouracil (5-FU), oxaliplatin, albumin-bound paclitaxel, capecitabine, cisplatin, irinotecan, and any combinations thereof. In some embodiments, the pancreatic disorder is pancreatic fistulas and the additional therapeutics can include, without limitation, somatostatins, somatostatin analogues, and any combinations thereof. In cases where one or more pancreatic lipase inhibitors are used in combination with additional therapeutics used to treat one or more pancreatic disorders the one or more additional therapeutics can be administered at the same time (e.g., in a single composition containing both one or more pancreatic lipase inhibitors and the one or more additional therapeutics) or independently. For example, one or more pancreatic lipaseAttorney Docket No. 1546.7. WO inhibitors described herein can be administered first, and the one or more additional therapeutics administered second, or vice versa,

[0039] In some embodiments, the method further comprises a combination therapy used to treat the pancreatic disorder. In some embodiments, the combination therapy can include administering the therapeutic and performing one or more (e.g., one, two, three, four, five or more) additional therapies used to treat the pancreatic disorder. In some embodiments, the pancreatic disorder is pancreatitis and the additional therapies include, without limitation, endoscopic retrograde cholangiopancreatography, surgical removal of the gallbladder, surgical removal of pancreatic fluid, surgical removal of necrotic tissue (e.g., necrotic pancreatic tissue), and / or dialysis. In some embodiments, the pancreatic disorder is pancreatic cancer and the additional therapies include, without limitation, surgery, radiation therapy, surgery to remove one or more tumors within the pancreas, and / or surgical removal of all or part of the pancreas. In some embodiments, the pancreatic disorder is pancreatic fistulas and the additional therapies include, without limitation, total parenteral nutrition and / or fistulectomy. In some embodiments, the pancreatic disorder is pancreatic adhesions and the additional therapies include, without limitation, surgery (e.g., laparoscopic surgery) to remove the adhesions. In the embodiments where the therapeutic is used in combination with one or more additional therapies used to treat the pancreatic disorder, the one or more additional therapies can be performed at the same time or independently of the administration of the therapeutic. For example, the therapeutic can be administered before, during, or after the one or more additional therapies are performed.

[0040] In some embodiments, a course of treatment and the severity of one or more symptoms related to the condition being treated (e.g., the pancreatic disorder) can be monitored. Any appropriate method can be used to determine whether or not the severity of a symptom is reduced. For example, the severity of a symptom of the pancreatic disorder can be assessed using abdominal ultrasound, CT scan with or without contrast enhancement, MRI scan and / or blood tests (e.g., for an increase in amylase and / or lipase such as a level greater than about threefold the upper limit of normal) at different time points.

[0041] In some embodiments, the method further comprises administering an additional therapeutic to the subject in need thereof. In some embodiments, the additional therapeutic is an antibiotic (e.g., a prophylactic antibiotic). The antibiotic can be any antibiotic known to those in the art and can be chosen by the individual clinician based on various factors including, but notAttorney Docket No. 1546.7. WO limited to, availability of the antibiotics, known or suspected antibiotic allergies in the subject, efficacy of the antibiotics, the condition of subject (e.g., age, sex, weight, etc,), and the like. In some embodiments, the antibiotic can be administered through the endoscope comprising the needle and into the retroperitoneal cavity prior to administering the therapeutics. In some embodiments, the antibiotic can be administered prior to advancing the endoscope through the oropharynx and esophagus of the subject and into the stomach. In some embodiments, the antibiotic can be administered periprocedurally. In some embodiments, the antibiotic can be an oral antibiotic, an intravenous antibiotic injection, or an intramuscular antibiotic injection.

[0042] In some embodiments, the additional therapeutic is a local anesthetic. The local anesthetic can be any local anesthetic known to those in the art and can be chosen by the individual clinician based on various factors including, but not limited to, availability of the local anesthetic, known or suspected local anesthetic allergies or sensitivities in the subject, efficacy of the local anesthetic, the condition of subject (e.g., age, sex, weight, etc.), and the like. In some embodiments, the local anesthetic is bupivacaine, lidocaine, mepivacaine, prilocaine, etidocaine, ropivacaine, levobupivacaine, procaine, tetracaine, chloroprocaine, benzocaine, and the like. In some embodiments, the local anesthetic can be administered through the endoscope comprising the needle and into the retroperitoneal cavity prior to administering the first therapeutic. In some embodiments, the local anesthetic can be administered prior to advancing the endoscope through the oropharynx and esophagus of the subject and into the stomach.

[0043] In some embodiments, the methods provided herein can be useful in treating or reducing the severity of pancreatitis in the subject. In some embodiments, the methods provided herein can be useful to lower the risk of AP progressing to moderately severe and / or severe AP. In some embodiments, the methods are applied to subjects with AP that are predicted to progress to moderately severe and / or severe AP. In some embodiments, predicting the progression of acute pancreatitis from mild to moderately severe and / or from moderately severe to severe may comprises identifying clinical symptoms in the subject such as elevated levels of inflammatory markers (e.g., C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin, and the like); elevated hematocrit level (e.g., a hematocrit level greater than about 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50% or more); transient single or multiple organ failure (e.g., single or multiple organ failure that lasts 48 hours or less), such as transient pulmonary, renal, and or cardiovascular organ failure; the presence and / or extent of pancreatic and / or peripancreaticAttorney Docket No. 1546.7. WO necrosis; the presence and / or extent of peripancreatic fluid collections; and / or the presence of systemic inflammatory response syndrome (SIRS) (e.g., at least two of a heart rate greater than about 90 beats per minute; a core temperature between about 36 °C and about 38 °C; a white blood cell count between about 4,000 and about 12,000 mm3; and a respiratory rate of greater than about 20 breaths per minute or partial pressure of CO2 of less than about 4.3 kPa). In some embodiments, predicting the severity and or progression of severity of acute pancreatitis comprises analyzing the clinical symptoms of the subject using a scoring system including, but not limited to, Ranson's Criteria for Pancreatitis Mortality, Glasglow Scoring System, Pancreatitis Outcome Prediction (POP), Harmless Acute Pancreatitis Score (HAPS), Japanese Severity Score, PANC3, Bedside Index of Severity in Acute Pancreatitis (BISAP), Acute Physiology and Chronic Health Evaluation II (APACHE II), and / or Computed Tomography Severity Index (CTSI). In some embodiments, the methods provided herein can be useful in treating severe AP, e.g., downgrading a severe case of AP to a milder case of pancreatitis. The disclosure provides methods of treating one or more symptoms of pancreatitis in a subject in need thereof by administering a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, to treat one or more symptoms of AP.

[0044] In some embodiments, the methods provided herein can be useful in reducing the risk of secondary effects of AP in a subject in need thereof. For example, the risk of developing shock can be reduced. In some embodiments, the risk of developing renal failure is reduced. In some embodiments, the risk of developing pulmonary failure is reduced. In some embodiments, the risk of developing heart failure is reduced.

[0045] In some embodiments, the methods provided herein can be useful in reducing the risk of organ failure. Organs for which the risk of organ failure may be reduced include the kidney (where failure is referred to as renal failure), the lung (where failure is referred to as pulmonary failure), and the heart (where failure is referred to as cardiac failure). Ogan failure may be identified by, e.g., shock with low blood pressure or an increase in heart rate or the appearance of pulmonary edema (noted as crackles on auscultation, or CXR, or CT scan) as well as multisystem organ failure (e.g., multiple organ dysfunction syndrome involving at least these two organs). The status of these organs may be determined using clinical methods well known in the art. For example, and not by way of limitation, kidney function (and the development of renal failure) may be assessed via increased blood urea nitrogen levels, increased creatinine, decreased urine output, and / orAttorney Docket No. 1546.7. WO histologic findings; lung function and the development of pulmonary failure may be assessed using pulmonary function tests, blood gases (oxygen and carbon dioxide levels), oxygen supplementation requirements (e.g. nasal cannula or face mask or ventilator, with different percentages and flow rates of oxygen) and / or histologic findings; (for indices of organ failure, see J. Wallach, 1978, Interpretation of Diagnostic Tests, Third Edition, Little, Brown and Co., Boston, and / or J. Wallach, 2006, Interpretation of Diagnostic Tests, Eighth Edition, Lippincott Williams & Wilkins, both incorporated by reference in their entireties). Likewise, an index of systemic inflammation is an increase in levels of one or more inflammatory mediators, including but not limited to C-reactive protein (CRP), or parts of systemic inflammatory response syndrome (SIRS) criteria, tumor necrosis factor alpha, monocyte chemotactic protein 1 and / or interleukin 6.

[0046] In some embodiments, the therapeutic can be administered from within about 1 hour to about 48 hours (e.g., about 1, 2, 3, 4, 5, 6, 12, 18, 24, 30, 36, 42, or 48 hours) after the subject has been diagnosed with or suspected of having pancreatitis. The skilled artisan will appreciate that certain factors can influence the dosage and timing required to effectively treat a subject, including, but not limited to, the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a therapeutic can include a single treatment or a series of treatments. In some embodiments, the therapeutic is administered as a single dose. In some embodiments, the therapeutic is administered in more than one dose (e.g., about 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses). In some embodiments, the therapeutic can be administered to at least 2 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) injection sites in the subject such as in at least 2 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) administrations and / or doses in the retroperitoneal cavity. In some embodiments, the at least 2 injections are administered simultaneously. In some embodiments, the at least 2 injections are administered sequentially. In some embodiments, the therapeutic can be repeatedly administered from about 1 to about 12 times (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times) or more. In some embodiments, the therapeutic can be administered from once every 30 minutes to once every 360 minutes (e.g., once every 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180, 210, 240, 270, 300, 330, or 360 minutes). In some embodiments, the therapeutic can be administered from once every 6 hours to once every 24 hours (e.g., once every 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours). In some embodiments, the therapeutic can be administered from once every day to once every 7 days (e.g., once every 1, 2, 3, 4, 5, 6, or 7 day(s)).Attorney Docket No. 1546.7. WO

[0047] In some embodiments, the method further comprises collecting a biopsy from the subject, before, during, and / or after administering the therapeutic to the subject in need thereof. In some embodiments, the biopsy is a needle biopsy. In some embodiments, the biopsy is collected through the endoscope comprising a needle. In some embodiments, the biopsy is a blood biopsy and / or a tissue biopsy. In some embodiments, the biopsy is a pancreatic biopsy, a stomach biopsy, a liver biopsy, an intestine biopsy, a spleen biopsy, a gallbladder biopsy, a tumor biopsy, and the like. In some embodiments, the biopsy is a retroperitoneal percutaneous needle biopsy.Subjects

[0048] The methods of the present invention find use in both veterinary and medical applications. Suitable subjects include avians, reptiles, amphibians, fish, and mammals. The term “mammal” as used herein includes, but is not limited to, humans, primates, non-human primates (e.g., monkeys and baboons), cattle, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats, mice, hamsters, and the like), etc. Human subjects include neonates, infants, juveniles, and adults. Optionally, the subject is “in need of’ the methods of the present invention, e.g., because the subject is believed at risk of pancreatitis. As a further option, the subject can be a laboratory animal and / or an animal model of disease. Preferably, the subject is a human.

[0049] The methods provided herein can be used to treat any appropriate pancreatic disorder in the subject. Examples of pancreatic disorders that can be treated as described herein include, without limitation, acute pancreatitis, chronic pancreatitis, pancreatic cancer, post-operative pancreatic fistulas, pancreatic adhesions, pancreatic fibrosis, and cystic lesions of the pancreas. In some embodiments, the pancreatitis can be chronic pancreatitis. In some embodiments, the chronic pancreatitis can be due to heavy alcohol use and / or can develop from acute pancreatitis. In some embodiments, the pancreatic cancer can be any stage of pancreatic cancer. In some embodiments, when treating a pancreatic cancer, the pancreatic cancer can include fibrotic stroma. In some embodiments, the pancreatitis is AP. In some embodiments, the AP is severe pancreatitis. Exemplary symptoms of AP include acute severe abdominal pain, back pain, swollen abdomen, nausea, abdominal tenderness, diarrhea, fatty stool, indigestion, symptoms of malnutrition, jaundice, vomiting, fever, rapid pulse, shortness of breath, low body temperature and the like.Compounds and CompositionsAttorney Docket No. 1546.7. WO

[0050] A therapeutic useful to the present invention may be any compound that is capable of providing a therapeutic benefit to a subject who has or is suspected of having a pancreatic disorder. In some embodiments, the therapeutic is a pancreatic lipase inhibitor. The pancreatic lipase inhibitor can be any pancreatic lipase inhibitor known in the art. In some embodiments, the pancreatic lipase inhibitor inhibits pancreatic lipase related protein 2 (PLRP2). In some embodiments, the pancreatic lipase inhibitor can reduce or eliminate the ability of a pancreatic lipase to hydrolyze one or more lipids (e.g., linoleins, glyceryl trilinoleates, triglycerides, and / or neutral triglycerides). In some embodiments, the pancreatic lipase inhibitor can inhibit a pancreatic lipase that can hydrolyze any appropriate one or more lipids. In some embodiments, the pancreatic lipase inhibitor can inhibit pancreatic lipase polypeptide activity or pancreatic lipase polypeptide expression. Examples of compounds that can reduce or eliminate polypeptide expression of a pancreatic lipase include, without limitation, nucleic acid molecules designed to induce RNA interference of polypeptide expression of a pancreatic lipase (e.g., a siRNA molecule or a shRNA molecule), antisense molecules, and miRNAs. In some embodiments, the pancreatic lipase inhibitor is a small molecule. In some embodiments, the pancreatic lipase inhibitor is lipstatin and / or tetrahydrolipstatin (i.e., orlistat), or a pharmaceutically acceptable salt thereof. In some embodiments, the pancreatic lipase inhibitor comprises one or more compounds from Table 1 :Table 1.Attorney Docket No. 1546.7. WOAttorney Docket No. 1546.7. WOAttorney Docket No. 1546.7. WOAttorney Docket No. 1546.7. WOAttorney Docket No. 1546.7. WOAttorney Docket No. 1546.7. WOor a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, one or more (e.g., one, two, three, four, or more) therapeutics can be used with the methods as described herein. For example, one or more lipase inhibitors can be administered to a subject in need thereof.

[0052] Also provided are pharmaceutical compositions which contain, as the active ingredient, a compound as described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers (e.g., excipients). In making the pharmaceutical compositions provided herein, the active ingredient is typically mixed with an excipient, or diluted by an excipient. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be, for example, in the form of elixirs, suspensions, emulsions, solutions, and sterile injectable solutions. Some examples of suitable excipients include, without limitation, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. In some embodiments, the pharmaceutical compositions can additionally include, without limitation, alcohols (e.g., ethanol, methanol, and the like); lubricating agents such as polyethylene glycol (PEG; e.g., PEG-400), talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents (e.g., polysorbate 80 (PS80); e.g., Tween 80); preserving agents such as methyl- and propylhydroxy-benzoates; or combinations thereof.

[0053] In some embodiments, the pharmaceutical composition comprises the pancreatic lipase inhibitor, PEG-400, ethanol, and polysorbate 80 (e.g., 12.5% of the pancreatic lipase inhibitor by weight of the composition, 48.4% of PEG-400 by weight of the composition, 24.2% of ethanol byAttorney Docket No. 1546.7. WO weight of the composition, and 14.9% of polysorbate 80 by weight of the composition). In some embodiments, the pharmaceutical composition is diluted in water and / or saline prior to administration. In some embodiments, the pharmaceutical composition is diluted by about 1% to by about 95% (e.g, by about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 30%, 40%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%) in water prior to administration. In some embodiments, the pharmaceutical composition is diluted to a final volume of from about 5 mL to about 60 mL (e.g., about 5 mL, 10 mL, 15 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL, 45 mL, 50 mL, 55 mL, 60 mL or more). In some embodiments, the pharmaceutical composition may comprise between about 5% to about 25% (e.g., about 5%, 7%, 9%, 11%, 13%, 15%, 17%, 19%, 21%, 23%, or 25%) of the pancreatic lipase inhibitor by weight of the composition. In some embodiments, the pharmaceutical composition may comprise between about 25% to about 75% (e.g., about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%) of the PEG-400 by weight of the composition. In some embodiments, the pharmaceutical composition may comprise between about 10 to about 50% (e.g., about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%) of the ethanol by weight of the composition. In some embodiments, the pharmaceutical composition may comprise between about 5% to about 25% (e.g., about 5%, 7%, 9%, 11%, 13%, 15%, 17%, 19%, 21%, 23%, or 25%) of the Tween 80 by weight of the composition.

[0054] The therapeutics described herein can be effective over a wide dosage range and are generally administered in an effective amount. The amount of the therapeutics administered to a subject will vary from subject to subject, depending on the nature of the therapeutics, the species, gender, age, weight and general condition of the subject, and the like. Effective dosages and schedules for administering the therapeutics may be determined empirically, and making such determinations is within the skill in the art. The dosage ranges for the administration of the disclosed therapeutics are those large enough to produce the desired effect (e.g., to treat pancreatitis). The dosage should not be so large as to outweigh benefits by causing extensive or severe adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like, although some adverse side effects may be expected. The dosage can be adjusted by the individual clinician in the event of any counterindications. In some embodiments, the therapeutic is administered to the subject at a dosage from about 25 mg to about 500 mg (e.g., about 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 300, 350, 400, 450, or 500 mg); e.g.,Attorney Docket No. 1546.7. WO about 31.25 mg, 62.5 mg, or 125 mg. Dosages above or below the range cited above may be administered to the individual subject if desired.

[0055] Having described the present invention, the same will be explained in greater detail in the following examples, which are included herein for illustration purposes only, and which are not intended to be limiting to the invention.EXAMPLESExample 1

[0056] AP is becoming more common and is a leading cause of gastrointestinal (GI) emergency department visits and hospital admissions in the United States [Peery et al, 2019]. Each year, about 275,000 hospital stays for AP occur in the United States [Forsmark et al, 2016]. While many patients with AP will recover and be discharged within 1-2 weeks, a significant proportion (approximately 20-30%) will progress to develop SAP [van den Berg et al, 2020]. Persistent (> 48 hours) single or multiple organ failure (typically, respiratory, renal, and / or cardiovascular) signifies the development of SAP [Banks et al, 2013]. Patients with SAP will spend time in the hospital intensive care unit (ICU); and may be hospitalized for one or more months. These patients are also at significantly increased risk of death - mortality from AP is approximately 5% overall, but in patients with SAP, mortality rates of 30% or more have been reported. There is no treatment for AP other than supportive care. Those who survive SAP are at increased risk of recurrent attacks of acute disease, irreversible damage to vital organs (e.g., lungs, kidney, heart), and development of chronic pancreatitis, and diabetes mellitus [Boxhoorn et al, 2020 and Zhi et al, 2019].

[0057] Clinical studies have clearly demonstrated that disease severity and organ failure are not associated with the initial cause of AP. Clinical and animal model data are increasingly pointing to lipotoxicity as a critical determinant of disease severity and organ failure. Lipotoxicity is induced by the breakdown of triglycerides and production of non-esterified fatty acids (NEFAs) in the visceral adipose tissue. During an AP attack, pancreatic lipase is spilled from the inflamed pancreas into the surrounding adipocytes. Pancreatic lipase-mediated lipolysis results in the release of large quantities of NEFAs, which cause inflammation and elevated cytokines, thus worsening lung injury, kidney injury, and shock, culminating in multisystem organ failure and reduced survival. Moreover, lipotoxic NEFAs enriched in necrotic pancreatic fluid collections can cause mitochondrial damage, noted as swelling and disorganization of their ultrastructure. ClinicalAttorney Docket No. 1546.7. WO evidence for lipotoxicity in pancreatitis is threefold: 1) identification of toxic levels of NEFAs in peripancreatic fluid collections; 2) elevated triglyceride levels are a significant independent predictor of disease severity; and 3) the volume of visceral adipose tissue has been identified as a highly significant prognostic indicator in disease progression [de Oliveira et al, 2020].

[0058] As supported by two preclinical AP models, peripancreatic treatment with (5)-(S)-l- ((2S,3S -3-ethyl-4-oxooxetan-2-yl)tridecan-2-yl 2-formamidopropanoate (compound 767 or RABI-767), a small molecule lipase inhibitor, after the onset of AP prevents the cascading effect of adipose tissue decomposition and necrosis, preventing further tissue injury, systemic toxicity, organ failure and death. Because 767 is poorly permeable and rapidly metabolized, systemic administration intravenously or orally would not provide sufficient peripancreatic concentrations of 767 needed for lipase inhibition and efficacy. To inhibit lipases at the site of action, 767 is administered via EUS-guided peripancreatic injection in patients with AP predicted to become severe. Given lipotoxicity is likely a critical determinant of disease severity, coupled with the in vitro and in vivo efficacy data demonstrated with 767 in animal models of AP, the hypothesis that local lipase inhibition from peripancreatic injection of 767 may be an effective treatment for AP warranted clinical trial investigation.Study Design

[0059] Administration of therapeutics via EUS-guided fine-needle injection into the retroperitoneal cavity is a standard technique commonly utilized for celiac plexus block (CPB) or celiac plexus neurolysis (CPN) in patients with chronic pancreatitis and pancreatic cancer. Administration of therapeutics via this technique is considered generally safe, with a reported overall complication rate of about 2 to 3%, and a major complication rate of 0 to 0.5%. Further, a lower rate of complications has been reported with EUS-guided CPB and CPN than the percutaneous approach [O’Toole et al, 2009].

[0060] A first- in-human (FIH) single-ascending dose study of RABI-767 administered by ultrasound-guided percutaneous IP injection in healthy adult volunteers has been completed. The objective of the study was to evaluate the safety, tolerability, and pharmacokinetics (PK) of 767 in 18 healthy volunteers after injection into the IP cavity. 767 doses evaluated in this study were: 31.25 mg (25 mL of 1.25 mg / mL); 62.5 mg (25 mL of 2.5 mg / mL); and 125 mg (25 mL of 5 mg / mL). Overall, the PK data observed from this study confirmed limited to no systemicAttorney Docket No. 1546.7. WO bioavailability of 767 following IP injection of single doses ranging from 31.5 mg to 125 mg in healthy adult volunteers. The safety results from the study demonstrated that 767 was safe and well-tolerated in single doses up to 125 mg (25 mL of 5 mg / mL 767) when administered by ultrasound-guided percutaneous IP injection in healthy adult volunteers.

[0061] The study entailed the following three phases: 1) a screening phase of up to 28 days during which participants were evaluated for study eligibility; 2) a treatment phase during which participants were domiciled and study assessments were performed starting the day prior to study drug administration (Day -1) until at least 48 hours post-dose (Day 3); and 3) a follow-up phase during which participants returned to the clinic for an end-of study visit at 7 days (±1 day) post-dose. A total of 13 PK samples were collected per subject, at the following time points: predose (0 hours), 5 minutes and 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, and 24 hours post-dose.

[0062] Subjects in each cohort were randomized to receive either 767 or placebo. Each cohort was comprised of 8 subjects, with the first 2 subjects per cohort randomized 1 :1 (767:placebo) and dosed as sentinel subjects, and the next 6 subjects per cohort randomized 5:1 (767: placebo) for a total cohort randomization of 6:2 (767: placebo). Randomization was stratified by sex. Three subjects of each sex received active treatment per cohort, and 3 subjects of each sex received placebo overall.

[0063] Overall, 18 subjects (9 males and 9 females) received a single dose of 767, and 6 subjects (3 males and 3 females) received placebo. All subjects (100%) completed the study as planned. Subjects were primarily white and not Hispanic or Latino. The mean age (SD) was 43.5 (12.78) years, with a range of 20 to 60 years. The mean (SD) body mass index (BMI) was 25.92 (2.585) kg / m2, with a range of 19.0 to 31.4 kg / m2.ResultsSafety Data

[0064] There were no severe adverse events (AEs), serious adverse events (SAEs), deaths, or AEs leading to withdrawal in this study. All reported treatment emergent adverse events (TEAEs) were following 767 administration, with no TEAE reported after placebo. All TEAEs were mild in severity, except for 1 TEAE (headache in a participant receiving 767 125 mg) that was moderate in severity. The most commonly reported TEAEs, apart from a TEAE of headache (reported in 2 of the 18 767 participants overall), were local to the site of injection (i.e., injection site pain,Attorney Docket No. 1546.7. WO abdominal tenderness, abdominal discomfort, injection site bruising), and were resolved within 7 days post-dose, apart from 1 participant with mild injection site pain that resolved by 10 days postdose and 2 participants with mild injection site bruising that resolved by 11 days post-dose. There was a trend of increased leukocytes (driven by an increase in neutrophils) at 4 and 8 hours postdose in the 767 participants that returned to baseline levels by 48-hours post-dose. There were no individual participants with clinically significant laboratory, vital sign, or electrocardiogram (ECG) values. There was no notable 767 dose-dependent trend in TEAEs or safety assessments. A summary of all TEAEs by preferred term and dose group is provided in Table 1.Table 1.TEAEs coded to preferred term using the Medical Dictionary for Regulatory Activities (MedDRA), Version 25.0

[0065] Injection site related TEAEs, such as injection site pain, abdominal tenderness, abdominal discomfort, and bruising at the injection site, were all assessed as mild and were resolved within 7 days post-dose, apart from 1 subject (767 125 mg) with mild injection site pain that resolved by 10 days post-dose and 2 subjects (1 767 31.25 mg and 1 767 62.5 mg) with mild injection site bruising that resolved by 11 days post-dose. Physical examination findings of ecchymosis (bruising) at the injection site were observed for 2 subjects after administration of 767. Abdominal examination findings were observed for 12 subjects after administration of 767, which included mild tenderness, ecchymosis, needle mark, and mild injection site pain. Only 1 finding of needle mark was observed in 1 subject after placebo administration.Attorney Docket No. 1546.7. WO

[0066] Subjects were asked at multiple time points from Day 1 (pre-dose) to Day 8 (7 days postdose) to rate a series of potential injection site reaction (ISR) symptoms (i.e., abdominal discomfort, abdominal distention, abdominal pain, abdominal tenderness, general pain, injection site pain) on a scale of 0 to 10, with 0 = none / not present and 10 = worst imaginable; and to rate their general well-being on a scale of 0 to 10, with 0 = worst imaginable and 10 = feeling great. Conservatively, any injection site symptom rated by a subject as greater than zero on this assessment, was also reported as an AE. Most symptoms were rated greater than zero at one or more time points by subjects after 767 administration, whereas no subject rated these symptoms above zero after placebo administration. The highest / worst rating for each symptom was as follows:• Abdominal discomfort was rated as 5 by 1 subject (767 62.5 mg) at 1 hour post-dose and 1 subject (767 62.5 mg) at 12 hours post-dose. Abdominal discomfort was rated as 0 by all subjects by 48 hours post-dose.• Abdominal distention was rated as 0 by all subjects at all time points.• Abdominal pain was rated as 4 by 1 subject (76762.5 mg) at 4 hours post-dose. Abdominal pain was rated as 0 by all subjects by 12 hours post-dose.• Abdominal tenderness was rated as 4 by 1 subject (767 62.5 mg) at 4 hours post-dose; 1 subject (767 62.5 mg) at 8 hours post-dose; and 1 subject (767 62.5 mg) at 12 hours postdose.• Abdominal tenderness was rated as 0 to 2 by all subjects by 48 hours post-dose, and 0 by all subjects by Day 8.• General pain was rated as 1 by 1 subject (767 125 mg) at 4 hours post-dose and was rated 0 by all subjects at all other time points.• Injection site pain was rated as 4 by 2 subjects (767 62.5 mg) at 1 hour post-dose; 1 subject (767 62.5 mg) at 4 hours post-dose; 3 subjects (1 767 31.25 mg, 1 767 62.5 mg and 1 767 125 mg) at 8 hours post-dose; and 2 subjects (1 767 62.5 mg and 1 767 125 mg) at 12 hours post-dose. Injection site pain was rated as 0 to 1 by all subjects by Day 8.• Well-being was rated high (ratings of 7 to 10) in all subjects at all time points.

[0067] There were no subjects with clinically significant adverse laboratory values. There was a trend of increased leukocytes and neutrophils at 4 and 8 hours post-dose following administration of 767 across the 3 cohorts, while changes after placebo administration were minimal. As thereAttorney Docket No. 1546.7. WO were no changes in any other white blood cell counts, without wishing to be bound by any particular theory, the increase from baseline in overall leukocytes was considered likely to be driven by the increases in neutrophils.

[0068] Increasing neutrophils is the body’s first-line response to insult (e.g., direct needle injury to the skin), pain, infection, or inflammation [Peiseler et al, 2019]. In this case, without wishing to be bound by any particular theory, as the increase in neutrophils was specific to 767 administration, it may reflect inflammation in response to the 767 drug product (active ingredient and / or vehicle). Without wishing to be bound by any particular theory, the inflammation was likely local, as systemic exposure was minimal and there was no apparent relationship between PK and neutrophil increases. Without wishing to be bound by any particular theory, the source of potential inflammation was likely to be the peritoneal space and / or the area around the injection site, as evidenced by AEs of mild abdominal tenderness, discomfort, and injection site pain. The increase in neutrophil (and leukocyte) levels had returned to baseline by 48 hours post-dose, with no subsequent increases in other white cells, suggesting that any potential inflammation had resolved within 2 days post-dose. Further, the mean and median observed values for neutrophils and leukocytes across all 3 cohorts were within the laboratory normal range at all time points (i.e., neutrophil normal range: 1.4 to 6.3 10A9 / L; leukocyte normal range: 3.2 to 9.4 10A9 / L). For all other laboratory parameters, the changes from baseline for each laboratory value varied, and no significant difference was observed across treatments.

[0069] There were no subjects with clinically significant adverse vital signs or ECG values. The maximum Fridericia corrected QT (QTcF) interval at any post-dose time point was 444 msec (i.e., in 1 placebo subject at 24 hours post-dose). There were no apparent patterns of mean change from baseline in vital signs or ECG parameters to suggest any effect from 767.Pharmacokinetics (PK)

[0070] Systemic exposure to 767 was low following IP administration for all doses evaluated. The plasma samples of all 18 subjects in the PK population were assayed according to good laboratory practice (GLP) principles using a validated bioanalytical method (lower limit of quantification [LLOQ] = 1.0 ng / mL). A total of 7 subjects from the PK population had at least 3 quantifiable plasma concentrations and were included in the PK parameter population. Mean plasma concentration-time data for each of the 3 cohorts are plotted in FIG. 1. The results indicated thatAttorney Docket No. 1546.7. WO767 was poorly absorbed into the systemic circulation following IP administration in the 18 subjects who received an active dose. Eight of the 18 participants (2 to 4 participants per cohort) had no quantifiable 767 plasma concentrations at any sampling time, and of the 10 participants with a quantifiable concentration at one or more timepoints, low and variable plasma concentrations of 767 were observed.

[0071] At the low dose of 31.25 mg, only 3 measurable concentrations were reported following sample analysis. The range of concentrations was from 1.03 to 1.92 ng / mL, and there was insufficient data to conduct noncompartmental PK analysis. At the mid-dose of 62.5 mg, 4 of 6 subjects had measurable concentrations; therefore, it was possible to conduct PK analyses, and the derived PK parameters are summarized in Table 2. The median observed serum max (Cmax) was 3.60 ng / mL and the area under the plasma concentration vs time curve from time zero to the time of the first BQL sample (AUCall) was 6.07 h*ng / mL. Due to the low concentrations in all samples for these 4 subjects, it was only possible to estimate the half-life (t'A) (2.78 hours) in a single subject.Table 2.Notes: For all parameters, except the time to reach maximum concentration (Tmax), the values presented in the table are the median (%CV). For Tmax, values presented are the median (range). The t' / z of 767 could only be estimated for 1 subject (62.5 mg 767 group) in the study and could not be estimated for any other subjects in the study. AUCt = Area under the concentration-time curve from time zero until the last measurable concentration, estimated using the linear-up log-down trapezoidal method.

[0072] From the limited available data, 767 was absorbed quickly with a median Tmax of 3.87 hours and a median Cmax of 3.46 ng / mL for the 125 mg dose cohort. The highest 767 plasma concentration observed in any participant was 8.04 ng / mL at 4 hours after dosing at the highest dose level of 125 mg 767. Only 1 participant had sufficient data for an acceptable PK profile with a clear terminal phase (i.e., t / 2 = 2.78 hours based on data from 1 participant in the 62.5 mg dose group). The earliest 767 plasma concentration observed in any individual subject was 2.19 ng / mLAttorney Docket No. 1546.7. WO at 5 minutes post-dose at the mid-dose (62.5 mg 767). The latest 767 plasma concentrations observed were 1.46 ng / mL and 1.38 ng / mL at 8 hours post-dose in 1 subject at the mid-dose (62.5 mg 767) and 1 subject at the high-dose (125 mg 767), respectively. No quantifiable 767 plasma concentrations were observed in any individual subject at 12 hours and 24 hours post-dose (i.e., the last two PK sampling time points in the study).Example 2

[0073] The next clinical study of 767 is a pilot study to evaluate the safety and explore the efficacy of a single-dose of 767 in hospitalized patients with predicted SAP - i.e., patients exhibiting signs and symptoms shortly after hospital presentation that have been correlated with a higher risk of progressing to SAP than patients with AP overall. It is important to assess 767 in patients with predicted SAP, as the progression from AP to SAP is more likely to lead to significant extra morbidity and increased mortality.

[0074] A study of RABI-767 administered via EUS-guided fine-needle injection into the retroperitoneal cavity in adult subjects with acute pancreatitis has been completed. The 767 dose evaluated in this study is 125 mg (25 mL of 5 mg / mL) plus Standard of Care treatment. The safety and efficacy of 767 was evaluated against adult subjects with acute pancreatitis receiving only Standard of Care treatment.Study Design

[0075] The study entailed the following three phases: 1) a screening phase of up to 28 days during which participants were evaluated for study eligibility; 2) a treatment phase during which participants were assessed beginning on the day of drug administration until discharge; and 3) a follow-up phase during which participants returned to or called into the clinic for an end-of study visit at 35 days (±5 day) and 60 days (±7 day) post-dose (see FIG. 2).

[0076] Subjects were randomized (1 :1) to receive 767 or Standard of Care treatment (767:SoC).

[0077] Overall, 4 subjects (3 males and 1 female) received a single dose of 767 and Standard of Care treatment, and 5 subjects (3 males and 2 females) received only Standard of Care treatment. Subjects were primarily white and not Hispanic or Latino. The mean age (SD) was 56.89 (20.04) years, with a range of 23 to 79 years. The mean (SD) body mass index (BMI) was 31.28 (2.699) kg / m2, with a range of 26.6 to 35.5 kg / m2.Attorney Docket No. 1546.7. WO

[0078] Subjects of this study were diagnosed with acute pancreatitis and were predicted to progress to severe acute pancreatitis. This prediction is determined based on a lack of clinically meaningful improvement pre-treatment along with one or more of the following: (1) a bedside index of severity in acute pancreatitis (BISAP) score of 3 or higher; (2) a C-reactive protein (CRP) level of more than 150mg / L; or (3) meeting 3 or 4 of the systemic inflammatory response syndrome (SIRS) criteria or Persistent SIRS.ResultsSubject 06-01 ('RABI-767 + SoC)

[0079] A 62-y ear-old Hispanic male with a BMI of 33.1 kg / m2presented to the hospital with severe upper abdominal pain. He had no prior history of AP but had previously been diagnosed with diabetes and hypertension. He also had some existing bilateral paralysis as a result of a spinal cord injury 30 years previously. On presentation, his abdominal pain score was 10 / 10, and physical examination suggested a diagnosis of AP. No nausea, vomiting, diarrhea, or other symptoms were reported. He underwent MRI examination with contrast, which confirmed pancreatic inflammation without necrosis, likely of biliary origin. The patient had scores of: 3 on BISAP (driven by age, SIRS, and a pleural effusion); 2 on SIRS (driven by heart rate and WBC) which increased to a score of 3 (with additional respiratory rate increase) pre-dose; 3 on sequential organ failure assessment (SOFA) (driven by liver and respiratory issues); and 1 on Modified Marshall (for respiratory issues). He required 1-2 L / min of oxygen via nasal cannula. His Glasgow Coma Score (GCS) was 15. His lipase result was >6000 U / L (normal range: 13-60 U / L).

[0080] He was deemed eligible for the study and randomized to the 767 plus Standard of Care treatment arm. He received a single-dose of 25mL, 5 mg / mL(125mg) 767 on Study Day 1 via endoscopic ultrasound guided peripancreatic injection. The patient was sedated for the procedure, which took 12 minutes from scope-in to scope-out. Ultrasound images were captured at various stages. There were no procedural complications. He received a single dose of prophylactic antibiotic.

[0081] At screening, his alanine transaminase (ALT) was 225 which had decreased to 150 predose (normal range: 10-50 U / L). Day 1 post-dose it had decreased again to 109 and by Day 4 to 33. Days 5, 6, and 7 it had elevated slightly to 42, 57, and 54 respectively. At screening and Day 1 pre-dose and post-dose his albumin was within normal limits (WNL), but slightly below normalAttorney Docket No. 1546.7. WODays 3 to 7 (normal range: 3.5-5 g / dL). Alkaline Phosphatase (normal range: 40-129 U / L) was WNL until Days 6 and 7 when it was elevated to 225 and 202, respectively. Aspartate transferase (AST) (normal range: 10-50 U / L) was 64 pre-dose and WNL thereafter. Bilirubin (normal range: 0-1 mg / dL) was 2.5 at screen, 1.5 pre-dose, 1.4 post-dose, and WNL thereafter. Blood Urea Nitrogen (normal range: 8-22 mg / dL) was WNL at all time points, with the exception of being slightly low on Day 6. Creatinine (normal range: 0.5-1.3 mg / dL) was WNL at screening and Day 1 but slightly low Days 3-7. CRP was not measured. Glucose (normal range: 65-99 mg / dL) was high at all time points. Haematocrit (normal range: 40-49%) and haemoglobin (normal range: 13.5- 16.5 g / dL) were slightly low at all time points after screening. WBC (normal range: 4.5-10 xl03 / pL) was 12.1 at screen, 15.0 pre-dose, 16.6 post-dose, and remained high throughout.

[0082] Abdominal pain numeric rating scale (scale of 0 to 10, with 0 = no pain and 10 = worst imaginable pain) scores were 5 at pre-dose; 7 at post dose; 0 on Days 2, 3 and 4; 5 on Day 5 (1 day after laparoscopic cholecystectomy); 0 on Day 6; 4 on Day 7; and 0 on Day 9. He was receiving opioid analgesia at the time of the Day 5 abdominal pain assessment only. SIRS assessments showed 2 out of 4 criteria were met (heart rate and WBC) at each assessment time point through Day 7 and resolved by Day 8. SOFA scores were 1 (driven by respiratory dysfunction) at each assessment time point through Day 7. Modified Marshall scores were 1 (driven by respiratory dysfunction) at each assessment time point through Day 7. GCS was 15 (normal) throughout. By Day 4 (3 days post- 767 dose), he was sufficiently stable to undergo laparoscopic cholecystectomy. No AEs or SAEs were recorded during the period of observation.

[0083] Patient recovered and was discharged 7 days post-dose. On Day 35 follow-up phone call / visit patient reported being well; no re-hospitalizations or complications. At Day 60 / End-of Study phone follow-up patient was well.Subject 03-01 (RABI-767 + SoC)

[0084] A 69-year-old non-Hispanic, white male with a BMI of 29.7 kg / m2presented to the hospital experiencing acute pancreatitis. He had no prior history of AP but had previously been diagnosed with arthritis, diabetes, hypertension, hyperlipidemia, irritable bowel syndrome, insomnia, and sleep apnea. On presentation, his abdominal pain score was 10 / 10, and physical examination suggested a diagnosis of AP (idiopathic). The patient had scores of: 3 on BISAP (driven by age, SIRS, and blood urea nitrogen); and persistent SIRS (driven by elevated heart rate and WBC countAttorney Docket No. 1546.7. WO on 2 consecutive days). Patient also showed signs of early pancreatic necrosis in the tail of pancreas.

[0085] He was deemed eligible for the study and randomized to the 767 plus Standard of Care treatment arm. He received a single-dose of 25mL, 5 mg / mL (125mg) 767 on Study Day 1 via endoscopic ultrasound guided peripancreatic injection. There were no procedural complications.

[0086] SIRS criteria improved at 8 hrs. post dose and resolved at 16 hrs. post dose. At screening, WBC count was elevated (21.82 x 109 / L) and showed a sharp decline to WNL at 72 hrs. post dose. Through Day 4, WBC continued to decrease while remaining WNL.

[0087] Abdominal pain numeric rating scale scores were 7 / 10 at pre-dose; 6 / 10 at 12-24 hrs. post dose; 8 / 10 on Day 2 (increase attributed in-part to ongoing severe constipation); 5 / 10 on Day 3; and 4 / 10 on Day 4. No AEs or SAEs were recorded during the period of observation.

[0088] Patient recovered and was discharged 4 days post-dose. On Day 35 follow-up phone call / visit patient reported being well; no re-hospitalizations or complications. At Day 60 / End-of Study phone follow-up patient was well.Subject 05-01 (RABI-767 + SoC)

[0089] A 51 -year-old female with a BMI of 26.6 kg / m2presented to the hospital experiencing acute pancreatitis. She had no prior history of AP. On presentation, physical examination suggested a diagnosis of AP (hypertriglyceridemia). The patient had persistent SIRS (and worsening) for several days prior to dosing as well as very high CRP.

[0090] She initially did not qualify for this study due to ongoing C. Diff infection, symptomatic with diarrhea. Upon resolution, patient was deemed eligible for the study and randomized to the 767 plus Standard of Care treatment arm. She received a single-dose of 25mL, 5 mg / mL (125mg) 767 on Study Day 1 via endoscopic ultrasound guided peripancreatic injection. There were no procedural complications.

[0091] Patient’s condition began to improve shortly after dosing. SIRS resolved by 12 hrs. post dose. At screening, patient had an elevated WBC (13.1 x 103 / uL) but was WNL at 12 hrs. post dose. Patient’s elevated CRP (405 mg / L) also showed significant improvement (186 mg / L) at 48 hrs. post-dose. No AEs or SAEs were recorded during the period of observation.Attorney Docket No. 1546.7. WO

[0092] Patient recovered and was discharged 2 days post-dose. On Day 35 follow-up phone call / visit patient reported being well; no re-hospitalizations or complications. At Day 60 / End-of Study phone follow-up patient was well.Subject 03-02 (RABI-767 + SoC)

[0093] A 75-year-old non-Hispanic, white male with a BMI of 30.3 kg / m2presented to the hospital experiencing acute pancreatitis. Subject had previously been hospitalized for acute pancreatitis with no intervention beyond supportive care and had previously been diagnosed with CKD (stage 3), mixed hyperlipidemia, carotid artery disease, and coronary atherosclerosis. On presentation, his abdominal pain score was 5 / 10, and physical examination suggested a diagnosis of AP (biliary). The patient had scores of: 3 on BISAP (driven by age, SIRS, and pleural effusion); and persistent SIRS (driven by heart rate and WBC).]0094] He was deemed eligible for the study and randomized to the 767 plus Standard of Care treatment arm. He received a single-dose of 25mL, 5 mg / mL (125mg) 767 on Study Day 1 via endoscopic ultrasound guided peripancreatic injection. There were no procedural complications.

[0095] SIRS improved on Day 2 to a score of 1. At screening, WBC count was elevated (14.83 x 109 / L ) and showed a decline (11.46 x 109 / L) on Day 5. Patient also had an elevated CRP (279.7 mg / L) which showed significant improvement (89.2 mg / L) on Day 5

[0096] Abdominal pain numeric rating scale scores were 6 / 10 at pre-dose; 6 / 10 at 12-24 hrs. post dose; 8 / 10 on Day 2; 3 / 10 on Day 3; and 2 / 10 on Day 4. By Day 3 (2 days post-dose) he was sufficiently stable to undergo laparoscopic cholecystectomy. No AEs or SAEs were recorded during the period of observation.

[0097] Patient recovered and was discharged 4 days post-dose. On Day 35 follow-up phone call / visit patient reported being well; no re-hospitalizations or complications. At Day 60 / End-of Study phone follow-up patient was well.Subject 06-03 (SoC Only)

[0098] A 23-year-old, Hispanic / Latino male with a BMI of 35.5 kg / m2presented to the hospital experiencing acute pancreatitis. He had no prior history of AP but had previously been diagnosed with hyperlipidemia and pre-diabetes. The patient had persistent SIRS (driven by heart rate and WBC).Attorney Docket No. 1546.7. WO

[0099] He was deemed eligible for the study and randomized to the Standard of Care treatment arm. However, he was deemed a baseline failure due to clinical improvement (only 1 SIRS criteria met, WBC) and discharge by Study Day 2.Subject 08-01 (SoC Only)

[0100] A 79-year-old non-Hispanic, white female with a BMI of 30.9 kg / m2presented to the hospital experiencing acute pancreatitis. She had no prior history of AP but was recovering from a recent cholecystectomy. The patient had a score of 3 on BISAP (driven by age, blood urea nitrogen, and pleural effusion).

[0101] She was deemed eligible for the study and randomized to the Standard of Care treatment arm.

[0102] The patient’s condition showed signs of improvement shorty after an exploratory endoscopy and ductal stone removal on Day 1. However, on Day 4 the patient began to experience shortness of breath and suffered an SAE (pleural effusion exacerbation). On Day 5 and 6, patient had a score of 2 on SIRS (driven by heart rate and WBC). The patient was discharged to a Skilled Nursing Facility on Study Day 7. The patient subsequently reported several SAEs on Day 11 (pneumonia), Days 19-22 (sepsis and RSV infection) (readmitted to hospital), and Day 28 (portal vein thrombosis).

[0103] On Day 35 follow-up patient was still hospitalized;. At Day 60 / End-of Study phone followup patient was alive and still recovering from above SAEs.Subject 08-02 (SoC Only)

[0104] A 57-year-old non-Hispanic, white female with a BMI of 32.5 kg / m2presented to the hospital experiencing acute pancreatitis. She had no prior history of AP. Patient had persistent SIRS (driven by heart rate, respiratory rate, and WBC).

[0105] She was deemed eligible for the study and randomized to the Standard of Care treatment arm.

[0106] . Patient’s abdominal pain score remained at 4-5 throughout hospitalization. By Day 3, she was sufficiently stable to undergo laparoscopic cholecystectomy and had a score of 2 on SIRS (driven by heart rate and WBC) at discharge. No AEs or SAEs were recorded during the period of observation.Attorney Docket No. 1546.7. WO

[0107] Patient recovered and was discharged on Study Day 3. On Day 35 follow-up phone call / visit patient reported being well; no re-hospitalizations or complications. Day 60 / End-of Study phone follow-up is pending.Subject 10-01 (SoC Only)

[0108] A 69-year-old non-Hispanic, white male with a BMI of 33.7 kg / m2presented to the hospital experiencing acute pancreatitis. He had no prior history of AP. Patient had scores of: 4 on BISAP (driven by age, blood urea nitrogen, pleural effusion, and SIRS) and 3 on SIRS (driven by temperature, heart rate, and WBC).

[0109] He was deemed eligible for the study and randomized to the Standard of Care treatment arm.

[0110] By Day 3, he was sufficiently stable to undergo laparoscopic cholecystectomy. However, aspiration of gastric contents upon induction of anesthesia occurred, resulting in an SAE (aspiration pneumonitis). Patient had a score of 2-3 on SIRS on Days 1-7 and a score of 1 on SIRS on Day 9 (drawn to WBC).[oni] Patient recovered and was discharged on Study Day 10. Day 35 and Day 60 follow-ups are pending.Subject 03-03 (SoC Only)

[0112] A 27-year-old non-Hispanic, Asian male with a BMI of 29.2 kg / m2presented to the hospital experiencing acute pancreatitis. He had no prior history of AP. Patient had persistent SIRS (driven by heart rate and respiratory rate). A screening, patient had an abdominal pain score of 5 / 10.

[0113] He was deemed eligible for the study and randomized to the Standard of Care treatment arm.

[0114] On Day 4, patient had score of 3 on SIRS (driven by heart rate, WRC, and temperature). On Day 1 , patient had an abdominal pain score of 9 / 10. On Day 4, patient’s abdominal pain score was 3 / 10. No AEs or SAEs were recorded during the period of observation.

[0115] Patient recovered and was discharged on Study Day 4. Day 35 and Day 60 follow-ups are pending.Attorney Docket No. 1546.7. WOSummary

[0116] To date a total of 9 patients were enrolled in this study.

[0117] Four patients were randomized to 767 plus Standard of Care treatment arm. 767 dosing procedures were completed as planned with no complications in any patient doses to-date. All 4 patients showed clinical evidence of recovery shortly after dosing (e.g., resolution of SIRS, reduced WBC, etc.) and were all eligible for discharge for the hospital within 2-7 days post-dose. 2 patients were sufficiently recovered / stable within 2-3 days post-dose to undergo elective cholecystectomy during hospitalization. No safety signals, SAEs, or rehospitalization has occurred in these patients to-date.

[0118] Five patients were randomized to the Standard of Care treatment arm. 1 patient reported 4 SAEs (pleural effusions exacerbated, pneumonia, sepsis, portal vein thrombosis) and required prolonged hospitalization, discharge to a skilled nursing facility, and 2 subsequent rehospitalizations. 1 patient reported 1 SAE (aspiration pneumonitis). 1 patient was deemed a baseline failure. The remaining 2 patients have only recently been enrolled to this study, and safety / efficacy outcome date is still pending.

[0119] The foregoing examples are illustrative of the present invention, and are not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.

Claims

Attorney Docket No. 1546.

7. WOTHAT WHICH IS CLAIMED IS1. A method for administering a therapeutic for a pancreatic disorder to a subject in need thereof, wherein the method comprises:(a) advancing an endoscope comprising a needle through the oropharynx and esophagus of the subject and into the stomach;(b) advancing the needle out of the endoscope, through the stomach wall and into the retroperitoneal cavity of the subject; and(c) administering the therapeutic through the endoscope and needle into the retroperitoneal cavity.

2. The method of claim 1 , wherein the needle is advanced under endoscopic ultrasound (EUS) guidance.

3. The method of claim 1 or 2, wherein the pancreatic disorder is acute pancreatitis, chronic pancreatitis, pancreatic cancer, post-operative pancreatic fistulas, pancreatic adhesions, pancreatic fibrosis, and / or cystic lesions of the pancreas.

4. The method of claim 3, wherein the pancreatitis is acute pancreatitis.

5. The method of claim 4, wherein the acute pancreatitis is severe.

6. The method of claim 5, wherein the acute pancreatitis is downgraded from severe to mild following administration.

7. The method of claim 4, wherein the risk of progressing from mild acute pancreatitis to moderately severe acute pancreatitis is reduced following administration.

8. The method of claim 7, wherein the subject is predicted (e.g., predicted by a physician) to progress from mild acute pancreatitis to moderately severe acute pancreatitis prior to administration.Attorney Docket No. 1546.

7. WO9. The method of claim 4, wherein the risk of progressing from moderately severe acute pancreatitis to severe acute pancreatitis is reduced following administration.

10. The method of claim 7, wherein the subject in need thereof is predicted (e.g., predicted by a physician) to progress from moderately severe acute pancreatitis to severe acute pancreatitis prior to administration.

11. The method of any preceding claim, wherein the risk of developing shock, renal failure, cardiac failure, and / or pulmonary failure is reduced following administration.

12. The method of any preceding claim, wherein the subject is a human.

13. The method of any preceding claim, wherein the therapeutic is administered in an amount from about 25 mg to about 500 mg per dose.

14. The method of any preceding claim, wherein the therapeutic is a pancreatic lipase inhibitor.

15. The method of claim 14, wherein the pancreatic lipase inhibitor is lipstatin, tetrahydrolipstatin (i.e., orlistat)or a pharmaceutically acceptable salt thereof.

16. The method of claim 4, wherein the therapeutic is administered from within about 1 hour to about 48 hours after the subject has been diagnosed with pancreatitis.

17. The method of any preceding claim, wherein the therapeutic is repeatedly administered from about 1 to about 12 times.Attorney Docket No. 1546.

7. WO18. The method of claim 17, wherein the therapeutic is administered into two or more different areas of the retroperitoneal cavity of the subject.

19. The method of claim 17, wherein the therapeutic is repeatedly administered from about every 30 minutes to about every 360 minutes.

20. The method of any preceding claim, wherein the therapeutic is administered into the retroperitoneal cavity through the needle.

21. The method of any preceding claim, wherein the endoscope further comprises a catheter.

22. The method of claim 21, wherein: the catheter is advanced over the needle into the retroperitoneal cavity; the needle is removed from the retroperitoneal cavity; and the therapeutic is administered into the retroperitoneal cavity through the catheter.

23. The method of claim 21 , wherein: the catheter is advanced through the needle into the retroperitoneal cavity; the needle is removed from the retroperitoneal cavity; and the therapeutic is administered into the retroperitoneal cavity through the catheter.

24. The method of any preceding claim, wherein the endoscope further comprises a pump configured to move the therapeutic through the endoscope and into the retroperitoneal cavity.

25. The method of any preceding claim, wherein the subject is sedated during the administration.

26. The method of any preceding claim, wherein the method further comprises administering a prophylactic antibiotic.

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