Use of reboxetine to treat narcolepsy

Abstract

Described herein are methods of treating narcolepsy with cataplexy, comprising administering reboxetine, or a pharmaceutically acceptable salt thereof, to a human being in need thereof. Reboxetine, or a pharmaceutically acceptable salt thereof, may also be used in the manufacture of a medicament for the treatment of narcolepsy with cataplexy. Also disclosed herein are kits comprising a pharmaceutical composition comprising reboxetine, or a pharmaceutically acceptable salt thereof, and instructions to use the pharmaceutical composition to treat narcolepsy with cataplexy in a patient.

Description

[0001] PCT Patent Application 134057-00001032_12T20-W0

[0002] USE OF REBOXETINE TO TREAT NARCOLEPSY

[0003] Inventor: Herriot Tabuteau

[0004] CROSS-REFERENCE TO RELATED APPLICATIONS

[0005] This application claims the benefit of the following United States Provisional Applications: Serial No. 63 / 696,325, filed September 18, 2024; Serial No. 63 / 725,385, filed November 26, 2024; Serial No. 63 / 735,287, filed December 17, 2024; Serial No. 63 / 775,236, filed March 20, 2025; Serial No. 63 / 810,696, filed May 22, 2025; Serial No. 63 / 816,529, filed June 02, 2025; and Serial No. 63 / 848,145, filed July 21, 2025, all of which are incorporated by reference herein in their entireties.

[0006] FIELD

[0007] Described herein are methods of providing clinically safe and clinically proven effective treatment of narcolepsy, particularly ty pe 1 narcolepsy in patients whose clinical response is measured weekly.

[0008] BACKGROUND

[0009] Narcolepsy is a serious and debilitating neurological condition that causes dysregulation of the sleep-wake cycle and is characterized clinically by excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis, and disrupted nocturnal sleep. Narcolepsy is estimated to afflict an estimated 185,000 individuals in the U.S. Cataplexy is seen in an estimated 70% of narcolepsy patients and is a sudden reduction or loss of muscle tone while a patient is awake, ty pically triggered by strong emotions such as laughter, fear, anger, stress, or excitement. Type 1 narcolepsy includes cataplexy, while Type 2 narcolepsy does not include cataplexy. Narcolepsy interferes with cognitive, psychological, and social functioning, increases the risk of work- and driving-related accidents, and is associated with a 1.5 fold higher mortality7rate. Other comorbidities such as depression and anxiety reported are commonly reported in patients with narcolepsy type 1.

[0010] Yet, currently approved treatments are few for this under-diagnosed orphan condition and are limited by variability7in efficacy from patient to patient, tolerability issues and the need for Drug Enforcement Administration (DEA) scheduling. Accordingly, there is an unmet need for new7treatments for narcolepsy (e.g., narcolepsy with cataplexy). PCT Patent Application

[0011] 134057-00001032_12T20-W0

[0012] SUMMARY

[0013] The present application describes clinically proven safe and clinically proven effective methods and compositions for treatment of Type 1 narcolepsy by administration of a therapeutically effective amount of reboxetine, or a pharmaceutically acceptable salt thereof (e.g., reboxetine mesylate) to patients in need thereof and measuring indicators of clinical response (efficacy) weekly (e.g., at week 1 through week 24). Indicators of clinical response described herein include, for example, achieving at least one of the following: cataplexy remission, reduction in the number of cataplexy attacks in a week, a reduction in the Epworth Sleepiness Scale (ESS) score, a reduction in the weekly frequency of inadvertent naps, a reduction in the Maintenance of Wakefulness Test (MWT) score, a reduction in the Narcolepsy Symptom Assessment Score (NSAQ), a reduction in the Patient Global Impression of Severity (PGI-S) score, a reduction in the Hamilton Depression Rating Scale (HAM-D), a score below 4 in the Patient Global Impression of Change (PGI-C), improvement in excessive daytime sleepiness (EDS), improvement in sleep quality, night awakenings, sleep paralysis episodes, and / or hypnagogic hallucinations, improvement in the ability to concentrate (e.g. on the NSAQ), and improvement in EQ-5D-5L Anxiety / Depression Dimension Score.

[0014] In some embodiments, as a result of treatment with a therapeutically effective amount of reboxetine, or a pharmaceutically acceptable salt thereof (e.g., reboxetine mesylate), the patient experiences a reduction in the number of cataplexy attacks in a week, a reduction in the Epworth Sleepiness Scale (ESS) score, a reduction in the weekly frequency of inadvertent naps, a reduction in the Maintenance of Wakefulness Test (MWT) score, a reduction in the Narcolepsy Symptom Assessment Score (NSAQ), a reduction in the Patient Global Impression of Severity (PGI-S) score, a reduction in the Hamilton Depression Rating Scale (HAM-D), a score below 4 in the Patient Global Impression of Change (PGI-C), improvement in excessive daytime sleepiness (EDS), improvement in sleep quality, night awakenings, sleep paralysis episodes, and / or hypnagogic hallucinations, improvement in the ability' to concentrate (e.g. on the NSAQ), and / or improvement in EQ-5D-5L Anxiety / Depression Dimension Score. In some embodiments, the patient experiences cataplexy remission.

[0015] Some embodiments include a method of rapidly reducing the number of cataplexy attacks in a patient having narcolepsy with cataplexy, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof (e.g., reboxetine mesylate), at least once-daily for the first for at least one week. In some embodiments, the 8 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, is administered PCT Patent Application

[0016] 134057-00001032 12T20-WO at least once-daily for at least two weeks to a patient in need thereof, wherein one week after the start of the treatment, the patient has less cataplexy attacks (e.g., at least 30% fewer cataplexy attacks) as compared to baseline and the reduction in the number of cataplexy attacks is statistically significant as compared to administering a placebo with p<0.01. In some embodiments, the reduction in the number of cataplexy attacks is statistically significant as compared to administering a placebo with p<0.001. In some embodiments, the patient experiences cataplexy remission. In some embodiments, the reboxetine is administered as a pharmaceutically acceptable salt. In some embodiments, the reboxetine is reboxetine mesylate.

[0017] Some embodiments include a method of improving the ability to concentrate in a human being having narcolepsy with cataplexy, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof (e.g., reboxetine mesylate), daily for at least one week (e.g., one week, two weeks, three weeks) to a patient in need thereof, wherein, prior to the start of treatment, the human being has an ability to concentrate that is “average,” “poor,” or “very poor,” and at least one week (e.g., one week, two weeks, three weeks) after the start of the treatment, the human being has an ability to concentrate that is “good” or “very good,” as determined by the Ability to Concentrate Item of the Narcolepsy Symptom Assessment Questionnaire. In some embodiments, the reboxetine is administered as a pharmaceutically acceptable salt. In some embodiments, the reboxetine is reboxetine mesylate.

[0018] Some embodiments include a method of reducing the number of inadvertent naps in a patient having narcolepsy with cataplexy, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof (e.g.. reboxetine mesylate), daily for at least one week (e.g., one week, two weeks, three weeks) to a patient in need thereof, wherein at least one week (e.g., one week, two weeks, three weeks) after the start of the treatment, the patient has few er inadvertent naps per w eek (e.g., at least 20% fewer inadvertent naps per week) as compared to the week before the patient first receives reboxetine. or a pharmaceutically acceptable salt thereof. In some embodiments, the reboxetine is administered as a pharmaceutically acceptable salt. In some embodiments, the reboxetine is reboxetine mesylate.

[0019] Some embodiments include a method of improving sleep quality in a human being having narcolepsy with cataplexy, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof (e.g., reboxetine mesylate), daily for at least one week (e.g., one w eek, two weeks, three w eeks) to a patient in need thereof, wherein PCT Patent Application 134057-00001032_12T20-W0 at least one week (e.g., one week, two weeks, three weeks) after the start of the treatment, the patient reports having improved sleep quality as compared to the week before the patient first receives reboxetine, or a pharmaceutically acceptable salt thereof. In some embodiments, the reboxetine is administered as a pharmaceutically acceptable salt. In some embodiments, the reboxetine is reboxetine mesylate.

[0020] Some embodiments include a method of reducing night awakenings in a human being having narcolepsy with cataplexy, comprising administering about 5 mg to about 10 mg of reboxetine. or a pharmaceutically acceptable salt thereof (e.g.. reboxetine mesylate), at least once daily for at least one week (e.g., one week, two weeks, three weeks) to a patient in need thereof, wherein at least one week (e.g., one week, two weeks, three weeks) after the start of the treatment, the patient reports having fewer night awakenings as compared to the week before the patient first receives reboxetine, or a pharmaceutically acceptable salt thereof. In some embodiments, the reboxetine is administered as a pharmaceutically acceptable salt (e.g., mesylate). In some embodiments, the reboxetine is reboxetine mesylate.

[0021] Some embodiments include a method of reducing sleep paralysis in a human being having narcolepsy with cataplexy, comprising administering about 5 mg to about 10 mg of reboxetine. or a pharmaceutically acceptable salt thereof (e.g.. reboxetine mesylate), at least once daily for at least one week (e.g., one week, two weeks, three weeks) to a patient in need thereof, wherein at least one week (e.g., one week, two weeks, three weeks) after the start of the treatment, the human being reports having fewer sleep paralysis episodes as compared to the week before the patient first receives reboxetine. In some embodiments, the reboxetine is administered as a pharmaceutically acceptable salt. In some embodiments, the reboxetine is reboxetine mesylate.

[0022] Some embodiments include a method of reducing hypnagogic hallucinations in a human being having narcolepsy with cataplexy, comprising administering about 5 mg to about 10 mg of reboxetine. or a pharmaceutically acceptable salt thereof (e.g., reboxetine mesylate), at least once daily for at least one week (e.g., one week, two weeks, three weeks) to a patient in need thereof, wherein at least one week (e.g., one week, two weeks, three weeks) after the start of the treatment, the patient reports having fewer hypnagogic hallucinations as compared to the week before the patient first receives reboxetine. or a pharmaceutically acceptable salt thereof. In some embodiments, the reboxetine is administered as a pharmaceutically acceptable salt. In some embodiments, the reboxetine is reboxetine mesylate. PCT Patent Application

[0023] 134057-00001032 12T20-WO

[0024] Some embodiments include a method of improving the ability to concentrate in a patient suffering from narcolepsy, comprising administering reboxetine, or a pharmaceutically acceptable salt thereof (e.g., reboxetine mesylate), to a patient in need thereof. In some embodiments, the reboxetine is administered as a pharmaceutically acceptable salt. In some embodiments, the reboxetine is reboxetine mesylate.

[0025] Some embodiments include a method of treating narcolepsy with cataplexy, comprising administering reboxetine, or a pharmaceutically acceptable salt thereof (e.g., reboxetine mesylate), to a patient in need thereof, wherein reboxetine, or a pharmaceutically acceptable salt thereof, is administered at least once daily for more than two weeks, wherein, two weeks after the beginning of treatment, the patient experiences a reduction in the number of cataplexy attacks in a week, a reduction in the Epworth Sleepiness Scale score, a decrease in the cataplexy subscore on the Ullanlinna Narcolepsy Scale (NUS), or a reduction in the Maintenance of Wakefulness Test score as a result of the treatment.

[0026] Some embodiments include use of reboxetine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of narcolepsy with cataplexy, wherein reboxetine is administered at least once daily for at least three weeks. In some embodiments, the reboxetine is administered as a pharmaceutically acceptable salt (e.g., mesylate). In some embodiments, the reboxetine is reboxetine mesylate.

[0027] Some embodiments include a kit comprising a pharmaceutical composition comprising reboxetine (or as a pharmaceutically acceptable salt thereof) and instructions to use the pharmaceutical composition to treat narcolepsy with cataplexy in patient, wherein reboxetine, or a pharmaceutically acceptable salt thereof, is administered at least once daily for at least three weeks. In some embodiments, the reboxetine is administered as a pharmaceutically acceptable salt (e.g., mesylate). In some embodiments, the reboxetine is reboxetine mesylate.

[0028] BRIEF DESCRIPTION OF THE FIGURES

[0029] FIG. 1 depicts a novel pharmacological approach for the treatment of narcolepsy through synergistic Norepinephrine-dependent Dopamine (‘"NE / DA”) effects.

[0030] FIG. 2 depicts efficacy of reboxetine across the three placebo-controlled clinical trials, CONCERT (Phase 2), SYMPHONY (Phase 3), and ENCORE (Phase 3).

[0031] FIG. 3A depicts the change in weekly cataplexy attacks for patients who received reboxetine or placebo and as described in Example 1. PCT Patent Application 134057-00001032_12T20-W0

[0032] FIG. 3B depicts the change in weekly cataplexy attacks for patients who received reboxetine or placebo and as described in Example 2.

[0033] FIG. 4A depicts the number of patients with a 50% or greater reduction in weekly cataplexy attacks, where the patients received reboxetine or placebo and as described in Example 1.

[0034] FIG. 4B depicts the percentage of subjects achieving cataplexy remission for patients who received reboxetine or placebo as described in Example 2.

[0035] FIG. 5 depicts the number of patients with a 75% or greater reduction in weekly cataplexy attacks, where the patients received reboxetine or placebo as described in Example 1.

[0036] FIG. 6A depicts the change in Epworth Sleepiness Scale (“ESS”) Score for patients who received reboxetine or placebo as described in Example 1.

[0037] FIG. 6B depicts the reduction in the weekly frequency of inadvertent naps for patients who received reboxetine or placebo as described in Example 1.

[0038] FIG. 7 depicts the number of patients with a 50% or greater reduction in inadvertent naps, where the patients received reboxetine or placebo as described in Example 1.

[0039] FIG. 8A depicts the improvement in the ability to concentrate score for patients who received reboxetine or placebo as described in Example 1.

[0040] FIG. 8B depicts the number of patients with a “very good” or “good” ability' to concentrate, where the patients received reboxetine or placebo as described in Example 1.

[0041] FIG. 9 depicts the proportion of patients demonstrating improvement in sleep quality, night awakenings, sleep paralysis episodes, and hypnagogic hallucinations as described in Example 1 .

[0042] FIG. 10 depicts the baseline characteristics for study subjects of the phase 3, multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy, safety', and tolerability of reboxetine in patients with narcolepsy as described in Example 2.

[0043] FIG. 11A depicts the CGI-S for EDS change from baseline for patients who received reboxetine or placebo as described in Example 2.

[0044] FIG. 11B depicts the proportion of patients demonstrating both improved EDS and cataplexy as compared to placebo as described in Example 2.

[0045] FIG. 12A depicts the FOSQ-IO cognitive function items improvement from baseline for patients who received reboxetine or placebo as described in Example 2. PCT Patent Application 134057-00001032_12T20-W0

[0046] FIG. 12B depicts the percentage of concurrent cataplexy and cognitive responders for patients who received reboxetine or placebo as described in Example 2.

[0047] FIG. 13A depicts the CGI-S total score change from baseline for patients who received reboxetine or placebo as described in Example 2.

[0048] FIG. 13B depicts the percentage of patients with improvement from baseline in the EQ- 5D-5L anxiety / depression dimension score as described in Example 2.

[0049] FIG. 14 depicts the Phase 3, multicenter trial that was carried out for 24-weeks to evaluate the efficacy and long-term safety of reboxetine (i.e.. reboxetine mesylate) in participants with narcolepsy as described in Example 3.

[0050] FIG. 15A depicts the change in weekly cataplexy attacks for patients who received reboxetine or placebo and as described in Example 3.

[0051] FIG. 15B depicts the percentage of patients on placebo who experienced worsening on the NSAQ Ability' to Concentrate as compared to patients on reboxetine as described in Example 3.

[0052] FIG. 16 depicts the percentage of patients on placebo who experienced worsening in narcolepsy overall as compared to patients on reboxetine as described in Example 3.

[0053] FIG. 17A depicts the current treatment types used by narcolepsy type 1 patients as described in Example 4.

[0054] FIG. 17B depicts the survey results as described in Example 4.

[0055] FIG. 18 depicts the percentage of patients with persistent symptoms while on treatment as described in Example 4.

[0056] FIG. 19 depicts the impact of cataplexy on daily life as described in Example 4.

[0057] FIG. 20 depicts the complications of human patients with narcolepsy type 1 as described in Example 4.

[0058] FIG. 21 depicts the percentage of patients with improvement from baseline in the NASQ score as described in Example 2.

[0059] FIG. 22 depicts the percentage of patients with improvement from baseline in the CGI- S score as described in Example 2.

[0060] FIG. 23 depicts the percentage of patients with improvement from baseline in the FOSQ-IO score for individual subscales as described in Example 2. PCT Patent Application 134057-00001032_12T20-W0

[0061] FIG. 24 depicts the baseline clinical and sociodemographic characteristics for participants in the study described in Example 2.

[0062] FIG. 25 depicts the baseline clinical and sociodemographic characteristics for participants in the study described in Example 3.

[0063] FIG. 26 depicts the percentage of patients with improvement from OLE baseline in the frequency of cataplexy attacks as described in Example 3.

[0064] FIG. 27 depicts the percentage of patients with improvement from OLE baseline in the frequency of cataplexy attacks over six months as described in Example 3.

[0065] FIG. 28 depicts the percentage of cataplexy free days per week improvement for patients in the study as described in Example 3.

[0066] DETAILED DESCRIPTION

[0067] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification. All patents, published patent applications and publications cited herein are incorporated by reference as if set forth fully herein.

[0068] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as amounts, percentage, and so forth used in the specification and claims are to be understood in all instances as indicating both the exact values as shown and as being modified by the term “about.” Accordingly, unless indicated to the contrary7, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0069] The terms “a,” “an,” “the” and similar referents used in the context of describing the embodiments (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. By way of example, "an element" means one element or more than one element. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate PCT Patent Application 134057-00001032_12T20-W0 the embodiments and does not pose a limitation on the scope of any claim. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the claims.

[0070] As used herein in the specification and in the claims, the phrase "and / or.” should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and / or" clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B,” when used in conjunction with open-ended language such as "comprising" can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0071] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of,” or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of."

[0072] In the claims, as well as in the specification above, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of' and "consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively.

[0073] Wherever the phrase “for example,” “such as,” “including,” and the like are used herein, the phrase “and without limitation” is understood to follow unless explicitly stated otherwise. Similarly, “an example,” “exemplary,” and the like are understood to be non-limiting. PCT Patent Application 134057-00001032_12T20-W0

[0074] As used herein, “patient ” or “ subject ” means any animal, preferably a mammal, most preferably a human, whom will be or has been treated by a method according to an embodiment of the invention.

[0075] As used herein, reboxetine (CAS. No. 71620-89-8) is a highly selective and potent norepinephrine reuptake inhibitor and cortical dopamine modulator that has the potential to address the key symptoms of narcolepsy, such as cataplexy or EDS. Unlike existing treatments for narcolepsy, reboxetine is not a controlled substance. Thus, the treatment with reboxetine would not be scheduled. The chemical name for reboxetine is 2-[(2-ethoxyphenoxy)- phenylmethyl]morphohne and the structural formula is below. Reboxetine can be administered as a pharmaceutically acceptable salt, such as reboxetine mesylate (CAS 98769-84-7). As used herein, “AXS-12” refers to reboxetine, which can be administered as a pharmaceutically acceptable salt (reboxetine mesylate).

[0076] Unless otherwise indicated, any reference to a compound herein, such as reboxetine, by structure, name, or any other means, includes pharmaceutically acceptable salts; free acids or bases; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; enantiomers; deuterium modified compounds, such as deuterium modified reboxetine; or any chemical species that may rapidly convert to a compound described herein under conditions in w hich the compounds are used as described herein.

[0077] The following is a list of abbreviations and acronyms used throughout the application: PCT Patent Application

[0078] 134057-00001032 12T20-WO

[0079] Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or to expedite prosecution. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups if used in the appended claims.

[0080] Certain embodiments are described herein, including the best mode known to the inventors for carry ing out the claimed embodiments. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the claimed embodiments to be practiced otherwise than specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

[0081] Reboxetine Tablet Dosage Forms

[0082] The dosage form, such as a tablet, may contain reboxetine free base, such as about 4-6 mg, about 4.5-5.5 mg, or about 5 mg of reboxetine free base, or a molar equivalent amount of a salt form of reboxetine, such as about 5.5-7.5 mg, about 6-7 mg, or about 6.5 mg of reboxetine mesylate. 6.5 mg reboxetine mesylate is equivalent to 5 mg reboxetine free base.

[0083] The dosage form, such as a tablet, may contain multiple layers, such as about 1 to 4 layers, about 1 to 3 layers, or about 2 layers. In some embodiments, the tablet may contain an intra granular component and an extra granular component. For example, the intra granular component may comprise an active pharmaceutical ingredient (API), a diluent, a binder, and / or a disintegrant. For example, the extra granular component may comprise a glidant, a PCT Patent Application 134057-00001032_12T20-W0 disintegrant, and / or a lubricant. In some embodiments, the intra granular component may be about 90-100%, about 93-97%, about 95-96%, or about 96.9% of the weight of the dosage form. In some embodiments, the extra granular component may be about 1-10%, about 2.5- 5%, about 3-4%. or about 3. 1% of the weight of the dosage form.

[0084] The dosage form, such as a tablet, may contain a diluent (such as microcrystalline cellulose and / or calcium phosphate), such as about 50-99%, about 75-95%, about 80-90%, or about 85-86% diluent by weight.

[0085] The dosage form, such as a tablet, may contain microcrystalline cellulose, as a binder and / or a diluent, such as about 50-80%, about 60-70%. about 63-66%, or about 64.6% microcrystalline cellulose by weight. In some embodiments, the microcrystalline cellulose is microcrystalline cellulose PH102.

[0086] The dosage form, such as a tablet, may contain calcium phosphate, such as calcium phosphate dibasic dihydrate. In some embodiments, the tablet contains about 10-30%, about 15-25%, about 20-22%, or about 21.5% of calcium phosphate dibasic dihydrate by weight.

[0087] The dosage form, such as a tablet, may contain a binder (such as microcrystalline cellulose and / or hydroxypropyl methylcellulose), such as about 2.5-10%, about 2.5-7%, about 4-7.5%, about 5%, about 60-80%, or about 65-75% binder by weight.

[0088] The dosage form, such as a tablet, may contain hydroxypropyl methylcellulose (HPMC), also referred to as Hypromellose, such as about 2.5-10%, about 2.5-7%, about 4- 7.5%, or about 5% hydroxypropyl methylcellulose by weight. In some embodiments, the hydroxypropyl methylcellulose is Hypromellose 2910-5.

[0089] The dosage form, such as a tablet, may contain polyvinylpolypyrrolidone, also referred to as Crospovidone, such as about 1 -10%, about 2-10%, about 1 -5%, about 2-5%, or about 2.5% polyvinylpolypyrrolidone by weight. In some embodiments, the polyvinylpolypyrrolidone is Crospovidone Ultra 10.

[0090] The dosage form, such as a tablet, may contain silicone dioxide colloidal, such as about 0.01-1%, about 0.05-0.5%, or about 0.1% by weight.

[0091] The dosage form, such as a tablet, may contain magnesium stearate such as about 0.1- 5%, about 0.5-2.5%, or about 0.5% by weight. In some embodiments, the magnesium stearate is Magnesium Stearate 5712.

[0092] The dosage form, such as a tablet, may be coated, e.g., with a film coating. For example, a film coating may comprise a polymer, a plasticizer, and / or a pigment. The film coating may PCT Patent Application 134057-00001032 12T20-WO be, e.g., about 1-10%, about 4-6%, about 2-5%, or about 3.5% of the weight of the dosage form or tablet. In some embodiments, the film coating may be Opadry II Pink 85F140228-CN.

[0093] Additional examples of suitable dosage form compositions are listed in Table 1 below.

[0094] Table 1

[0095] Table 2 PCT Patent Application 134057-00001032 12T20-WO

[0096] Table 3

[0097] Unless otherwise indicated, any reference to a compound herein, such as reboxetine, by structure, name, or any other means, includes pharmaceutically acceptable salts; alternate solid forms, such as tautomers, polymorphs, solvates, hydrates, etc.

[0098] Some embodiments include a kit comprising a pharmaceutical composition comprising one or more units of a dosage form (e g. about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720 units of a dosage form), wherein a unit of the dosage form comprises a therapeutically effective amount of reboxetine free base, or a molar equivalent amount of a salt form of reboxetine, such as reboxetine mesylate and instructions to use the pharmaceutical composition to treat narcolepsy with cataplexy in a human being.

[0099] Some embodiments include a kit comprising a pharmaceutical composition comprising one or more units of a dosage form (e.g. about 1-30, about 30-60, about 60-90, about 90-120, about 120-180. about 180-360, or about 360-720 units of a dosage form), wherein a unit of the dosage form comprises about 4.5-5.5 mg, or about 5 mg of reboxetine free base, or a molar equivalent amount of a salt form of reboxetine, such as about 5.5-7.5 mg, about 6-7 mg, or about 6.5 mg of reboxetine mesylate and instructions to use the pharmaceutical composition to treat narcolepsy with cataplexy in a human being. PCT Patent Application 134057-00001032_12T20-W0

[0100] Methods of Treatment

[0101] Disclosed herein are methods of treating narcolepsy (e.g., narcolepsy with cataplexy ), in a patient in need thereof, comprising administering a therapeutically effective amount of reboxetine, or a pharmaceutically acceptable salt thereof, to a patient in need thereof and measuring at least one indicator of clinical response (efficacy). In some embodiments, disclosed herein are methods of treating narcolepsy (e.g., narcolepsy with cataplexy), in a patient in need thereof, comprising administering a therapeutically effective amount of reboxetine. or a pharmaceutically acceptable salt thereof, to a patient in need thereof wherein the patient achieves at least one indicator of clinical response such as a reduction in the number of cataplexy attacks.

[0102] In some embodiments, a human patient is treated with a dosage form or composition described herein, such as a dosage form of Table 1, Table 2, or Table 3, e.g., containing about 6-7 mg or about 6.5 mg of reboxetine mesylate, or a molar equivalent of another salt form, or a molar equivalent amount of the free base form (e g., 5 mg of reboxetine free base), e.g., once daily or twice daily to treat narcolepsy, such as Type I narcolepsy, or narcolepsy with cataplexy.

[0103] A person may have Type 1 narcolepsy if Criteria A and B are met:

[0104] A. The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least 3 months

[0105] B. The presence of one or both of the following:

[0106] 1. Cataplexy (as defined under Essential Features) and a mean sleep latency of <8 minutes and >2 Sleep-Onset REM Periods (SOREMPs) on a Mean Sleep Latency Test (MSLT) performed according to standard techniques. A SOREMP (within 15 minutes of sleep onset) on the preceding laboratorybased polysomnography (PSG) may replace one of the SOREMPs on the MSLT

[0107] 2. CSF hypocretin- 1 concentrations measured by immunoreactivity either <110 pg / mL or <!4 of mean values obtained in normal subjects with the same assay

[0108] In some embodiments, a patient has a diagnosis of narcolepsy with cataplexy that meets International Classification of Sleep Disorders, Third Edition criteria.

[0109] In young children, narcolepsy may sometimes present as excessively long night sleep or by resumption of previously discontinued daytime napping. If narcolepsy Type 1 is strongly suspected clinically but criteria B2 are not met, a possible strategy is to repeat the MSLT. PCT Patent Application 134057-00001032_12T20-W0

[0110] The following embodiments are specifically contemplated.

[0111] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy, in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, wherein the patient treated experiences a reduction in the number of cataplexy attacks. In some embodiments, the patient experiences a reduction in the number of cataplexy attacks after at least one week of treatment. In some embodiments, the patient experiences a reduction in the number of cataplexy attacks after at least two weeks of treatment. In some embodiments, the patient experiences a reduction in the number of cataplexy attacks after 3 weeks of treatment. In some embodiments, the patient has at least 7 cataplexy attacks per week prior to receiving reboxetine, or a pharmaceutically acceptable salt thereof. In some embodiments, reboxetine is administered as free base to the patient once daily or twice daily. In some embodiments, 5 mg of reboxetine free base is administered to the patient once daily or twice daily. In some embodiments, reboxetine is administered to the patient as a pharmaceutically acceptable salt, such as reboxetine mesylate. In some embodiments, 6.5 mg of reboxetine mesylate is administered to the patient once daily or twice daily.

[0112] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine. or a pharmaceutically acceptable salt thereof, wherein the patient treated experiences at least 50% reduction from baseline in mean weekly cataplexy attacks at 1 month of treatment. In some embodiments, the patient experiences at least 65% reduction from baseline in mean weekly cataplexy attacks at 1 month of treatment. In some embodiments, the patient experiences at least 70% reduction (e.g., about 71-72%, about 71- 75%, about 71-77%, etc.) from baseline in mean weekly cataplexy attacks at 1 month of treatment. In some embodiments, the patient experiences about 71% reduction from baseline in mean weekly cataplexy attacks at 1 month of treatment. In some embodiments, the patient experiences about 72% reduction from baseline in mean weekly cataplexy attacks at 1 month of treatment In some embodiments, the patient has at least 7 cataplexy attacks per week prior to receiving reboxetine, or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine. or a pharmaceutically acceptable salt thereof, wherein the patient experiences at least 60% reduction from baseline in mean weekly cataplexy attacks at 6 months of PCT Patent Application 134057-00001032_12T20-W0 treatment. In some embodiments, the patient experiences at least 70% reduction (e.g., about 71-72%, about 71-75%, about 71-77%, etc.) from baseline in mean weekly cataplexy attacks at 6 months of treatment. In some embodiments, the patient experiences about 77% reduction from baseline in mean weekly cataplexy attacks at 6 months of treatment. In some embodiments, the patient experiences at least 80% reduction (e.g., about 80-82%, about 83- 85%, etc.) from baseline in mean weekly cataplexy attacks at 6 months of treatment. In some embodiments, the patient experiences about 82% reduction from baseline in mean weeklycataplexy attacks at 6 months of treatment. In some embodiments, the patient has at least 7 cataplexy attacks per week prior to receiving reboxetine. or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine. or a pharmaceutically acceptable salt thereof, wherein the patient experiences at least 70% reduction (e.g., about 71-72%, about 71-75%, about 71-77%, etc.) from baseline in mean weekly cataplexy attacks at 1 month of treatment and at least 60% reduction from baseline in mean weekly cataplexy attacks at 6 months of treatment. In some embodiments, the patient experiences at least 70% reduction from baseline in mean weekly cataplexy attacks at 1 month of treatment and at least 70% reduction from baseline in mean weekly cataplexy attacks at 6 months of treatment. In some embodiments, the patient experiences about 71% reduction from baseline in mean weekly cataplexy attacks at 1 month of treatment and about 75% reduction from baseline in mean weekly cataplexy attacks at 6 months of treatment. In some embodiments, the patient experiences about 71% reduction from baseline in mean weekly cataplexy attacks at 1 month of treatment and about 77% reduction from baseline in mean weekly cataplexy attacks at 6 months of treatment. In some embodiments, the patient has at least 7 cataplexy attacks per week prior to receiving reboxetine, or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments disclosed herein the patient experiences remission in weekly cataplexy attacks. In some embodiments, patients treated with reboxetine, or a pharmaceutically acceptable salt thereof, experience remission in weekly cataplexy attacks after about 1 week of treatment as compared with placebo. In some embodiments, at least 20% of the patients treated with reboxetine, or a pharmaceutically acceptable salt thereof, experience remission in weekly cataplexy attacks after about 2 weeks of treatment as compared with placebo. In some embodiments, at least 30% of the patients treated w ith PCT Patent Application 134057-00001032_12T20-W0 reboxetine, or a pharmaceutically acceptable salt thereof, experience remission in weekly cataplexy attacks after about 4 weeks of treatment as compared with placebo. In some embodiments, at least 30% of the patients treated with reboxetine, or a pharmaceutically acceptable salt thereof, experience remission in weekly cataplexy attacks after about 5 weeks of treatment as compared with placebo. In some embodiments, the patient has at least 7 cataplexy attacks per week prior to receiving reboxetine, or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, wherein the patient experiences an increased percentage of cataplexy-free days (days with zero cataplexy attacks) per week. In some embodiments, the patient experiences an increased percentage of cataplexy -free days per week from about 14% at baseline to about 60% at 1 month. In some embodiments, the patient experiences an increased percentage of cataplexy-free days per week from about 14% at baseline to about 70% at 6 months. In some embodiments, the patient experiences an increased percentage of cataplexy-free days per week from about 14% at baseline to about 60% at 1 month and about 70% at 6 months. In some embodiments, the patient experiences an increased percentage of cataplexy -free days per week from about 14.3% at baseline to about 61% at 1 month and about 70% at 6 months.

[0117] In some embodiments disclosed herein, compared with patients taking reboxetine, pharmaceutically acceptable salt thereof, patients not taking reboxetine (e.g., patients taking placebo) experience a worsening in the average weekly number of cataplexy attacks. In some embodiments, the patients not taking reboxetine (e g., patients taking placebo) experience an increase of about 10 attacks per week as compared to about 1 or 2 attacks per week for patients taking reboxetine at 3 weeks. In some embodiments, patients not taking reboxetine (e.g.. patients taking placebo) experience an increase of 10.29 attacks per week as compared to 1.32 attacks per week for patients taking reboxetine at 3 weeks ( =0.017).

[0118] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, wherein the patient treated experiences an improvement in cognition as compared to placebo, wherein the improvement in cognition is assessed by the Narcolepsy Symptom Assessment Questionnaire (NSAQ). In some embodiments, the patient has a reduction in the Ability to Concentrate item of the PCT Patent Application 134057-00001032_12T20-W0

[0119] NSAQ that is at least about 0.1 prior to treatment with reboxetine, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient achieves an improvement in cognition at 1 month of treatment. In some embodiments, the patient achieves an improvement in cognition at 6 months of treatment.

[0120] In some embodiments, improvement in cognition as assessed by the NSAQ Ability to Concentrate item, is reported by at least 50% of patients atl month of treatment. In some embodiments, improvement in cognition as assessed by the NSAQ Ability to Concentrate item, is reported by at least 50% of patients at 6 months treatment. In some embodiments, improvement in cognition, assessed by the NSAQ Ability to Concentrate item, was reported by about 50% of patients at 1 month and about 50% at 6 months with reboxetine treatment. In some embodiments, improvement in cognition, assessed by the NSAQ Ability to Concentrate item, was reported by about 55% of patients at 1 month and about 59% at 6 months with reboxetine treatment.

[0121] In some embodiments, a greater proportion of patients not taking reboxetine, or a pharmaceutically acceptable salt thereof, after reboxetine treatment, experience a worsening on the NSAQ Ability to Concentrate item compared with those on reboxetine treatment. In some embodiments, a greater proportion of patients switched to placebo after treatment with reboxetine, or a pharmaceutically acceptable salt thereof, experienced a worsening on the NSAQ Ability’ to Concentrate item compared with those on reboxetine treatment (52.6% vs 14.3%) at 3 weeks ( =0.011).

[0122] In some embodiments, the proportion of patients who report improvement in the ability to concentrate on the PGI-C scale is about 65% at 1 month. In some embodiments, the proportion of patients who report improvement in the ability to concentrate on the PGI-C scale is about 67% at 1 month. In some embodiments, the proportion of patients who report improvement in the ability to concentrate on the PGI-C scale is about 65% at 6 months reboxetine treatment. In some embodiments, the proportion of patients who report improvement in the ability to concentrate on the PGI-C scale is about 70% at 6 months reboxetine treatment. In some embodiments, the proportion of patients who report improvement in the ability to concentrate on the PGI-C scale is about 67% at 1 month, and 70% at 6 months with reboxetine treatment.

[0123] In some embodiments, a greater proportion of patients not taking reboxetine. or a pharmaceutically acceptable salt thereof, after reboxetine treatment, experience a worsening on the Patient Global Impression of Change (PGI-C) scale compared with those on PCT Patent Application 134057-00001032_12T20-W0 reboxetine treatment. In some embodiments, a greater proportion of patients switched to placebo after treatment with reboxetine, or a pharmaceutically acceptable salt thereof, experienced a worsening on the in their ability to concentrate, as assessed by the PGI-C, compared to those continuing on reboxetine (57.9% vs 22.2%) at 3 weeks (T^O.029).

[0124] In some embodiments disclosed herein is a method of improving the ability to concentrate in a patient suffering from narcolepsy with cataplexy, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has difficulty concentrating or is in need of improvement in ability to concentrate. In some embodiments, the patient has an improvement in the Ability to Concentrate item of the NSAQ that is at least about -0.1.

[0125] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine. or a pharmaceutically acceptable salt thereof, wherein the patient treated experiences an improvement in excessive daytime sleepiness (EDS) as assessed using the Epworth Sleepiness Scale (ESS). In some embodiments, the patient has an Epworth Sleepiness Scale score that is greater than 10 prior to treatment with reboxetine, or a pharmaceutically acceptable salt thereof. In some embodiments, the mean Epworth Sleepiness Scale scores are reduced by at least 3 points at 1 month of treatment. In some embodiments, the mean Epworth Sleepiness Scale scores are reduced by at least 5 points at 1 month of treatment. In some embodiments, the mean Epworth Sleepiness Scale scores are reduced by 5.6 points at 1 month of treatment. In some embodiments, the mean Epworth Sleepiness Scale scores are reduced by at least 5 points at 6 months of treatment. In some embodiments, the mean Epworth Sleepiness Scale scores are reduced by at least 7 points at 6 months of treatment. In some embodiments, the mean Epworth Sleepiness Scale scores are reduced by 7.3 points at 6 months of treatment. In some embodiments, the mean Epworth Sleepiness Scale scores are reduced by at least 5 points at 1 month of treatment and at least 5 points at 6 months of treatment. In some embodiments, the mean Epworth Sleepiness Scale scores are reduced by at least 5 points at 1 month of treatment and at least 7 points at 6 months of treatment. In some embodiments, the mean Epworth Sleepiness Scale scores are reduced by 5.6 points at 1 month of treatment and 7.3 points at 6 months of treatment.

[0126] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, wherein the patient treated PCT Patent Application 134057-00001032_12T20-W0 experiences an improvement in excessive daytime sleepiness as assessed using the Clinician Global Impression of Change scale. In some embodiments, at least 70% of patients are reported to have an improvement in excessive daytime sleepiness at 1 month of treatment. In some embodiments, at least 80% of patients are reported to have an improvement in excessive daytime sleepiness at 1 month of treatment. In some embodiments, 84% of patients are reported to have an improvement in excessive daytime sleepiness at 1 month of treatment. In some embodiments, at least 70% of patients are reported to have an improvement in excessive daytime sleepiness at 6 months of treatment. In some embodiments, at least 75% of patients are reported to have an improvement in excessive daytime sleepiness at 6 months of treatment. In some embodiments, 78% of patients are reported to have an improvement in excessive daytime sleepiness at 6 months of treatment.

[0127] In some embodiments, at least 70% of patients are reported to have an improvement in excessive daytime sleepiness at 1 month of treatment and at least 70% of patients are reported to have an improvement in excessive daytime sleepiness at 6 months of treatment. In some embodiments, at least 80% of patients are reported to have an improvement in excessive daytime sleepiness at 1 month of treatment and at least 70% of patients are reported to have an improvement in excessive daytime sleepiness at 6 months of treatment. In some embodiments, 84% of patients are reported to have an improvement in excessive daytime sleepiness at 1 month of treatment and 78% of patients are reported to have an improvement in excessive daytime sleepiness at 6 months of treatment.

[0128] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, wherein the patient treated experiences an improvement in narcolepsy overall as assessed using the Patient Global Impression of Change (PGI-C). In some embodiments, at least 80% of patients are reported to have an overall improvement in narcolepsy at one month of treatment. In some embodiments, 90% of patients are reported to have an overall improvement in narcolepsy at one month of treatment. In some embodiments, at least 80% of patients are reported to have an overall improvement in narcolepsy at six months of treatment. In some embodiments, at least 90% of patients are reported to have an overall improvement in narcolepsy at six months of treatment.

[0129] In some embodiments, at least 80% of patients are reported to have an overall improvement in narcolepsy at one month of treatment and at least 80% of patients are PCT Patent Application 134057-00001032_12T20-W0 reported to have an overall improvement in narcolepsy at six months of treatment. In some embodiments, 90% of patients are reported to have an overall improvement in narcolepsy at one month of treatment and 90% of patients are reported to have an overall improvement in narcolepsy at six months of treatment.

[0130] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering a therapeutically effective amount of reboxetine, or a pharmaceutically acceptable salt thereof, wherein the patient treated experiences an improvement in narcolepsy overall as assessed using the Patient Global Impression of Change scale. In some embodiments, at least 70% of patients experience an overall improvement in narcolepsy at one month of treatment. In some embodiments, about 78% of patients experience an overall improvement in narcolepsy at one month of treatment. In some embodiments, at least 75% of patients experience an overall improvement in narcolepsy at six months of treatment. In some embodiments, about 80% of patients experience an overall improvement in narcolepsy at six months of treatment. In some embodiments, at least 70% of patients experience an overall improvement in narcolepsy at one month of treatment and at least 75% of patients experience an overall improvement in narcolepsy at six months of treatment. In some embodiments, about 78% of patients experience an overall improvement in narcolepsy at one month of treatment and about 80% of patients experience an overall improvement in narcolepsy at six months of treatment.

[0131] In some embodiments disclosed herein, a significantly greater proportion of patients randomized to switch to placebo reported worsening of their narcolepsy overall, as assessed by the Patient Global Impression of Change (PGI-C), compared with those on reboxetine (52.6% vs 16.7%) at 3 weeks (P=0.024).

[0132] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, wherein the patient experiences a decrease in time impaired due to narcolepsy while working as assessed by Work Productivity and Activity Impairment (WPAI) Questionnaire. In some embodiments, the patient is at least 50% at baseline and 30-35% at 1 month of treatment. In some embodiments, the patient is about 53% at baseline and about 34% at 1 month of treatment. In some embodiments, the patient is at least 50% at baseline and 20-30% at 6 months of treatment. In some embodiments, the patient is about 53% at baseline and about 24% at 6 months of treatment. PCT Patent Application 134057-00001032_12T20-W0

[0133] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, to the patient, wherein the reboxetine. or a pharmaceutically acceptable salt thereof, is administered to the patient once daily for the first week of treatment.

[0134] In some embodiments, disclosed herein is a method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg of reboxetine to the patient, wherein the reboxetine is administered to the patient once daily for the first week of treatment. In some embodiments, disclosed herein is a method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 6.5 mg of reboxetine mesylate to the patient, wherein the reboxetine mesylate is administered to the patient once daily for the first week of treatment.

[0135] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, to the patient, wherein the reboxetine, or a pharmaceutically acceptable salt thereof, is administered to the patient once daily for the first week of treatment and is subsequently administered to the patient twice daily.

[0136] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, to the patient, wherein the reboxetine. or a pharmaceutically acceptable salt thereof, is administered to the patient once daily for the first week of treatment and is subsequently administered to the patient twice daily for at least 3 weeks. In some embodiments, about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, is administered to the patient once daily for the first week of treatment and is subsequently administered to the patient twice daily for at least 7 weeks. In some embodiments, about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, is administered to the patient once daily for the first week of treatment and is subsequently administered to the patient twice daily for at least 23 weeks.

[0137] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg of reboxetine, or a molar equivalent amount of a salt form of reboxetine, to the patient, wherein the reboxetine, PCT Patent Application 134057-00001032_12T20-W0 or molar equivalent amount of a salt form of reboxetine, is administered to the patient once daily for the first week of treatment and is subsequently administered to the patient twice daily. In some embodiments, about 5 mg of reboxetine, or a molar equivalent amount of a salt form of reboxetine, is administered to the patient once daily for the first week of treatment and is subsequently administered to the patient twice daily for at least 3 weeks. In some embodiments, about 5 mg of reboxetine, or a molar equivalent amount of a salt form of reboxetine, is administered to the patient once daily for the first w eek of treatment and is subsequently administered to the patient twice daily for at least 7 weeks. In some embodiments, about 5 mg of reboxetine, or a molar equivalent amount of a salt form of reboxetine, is administered to the patient once daily for the first week of treatment and is subsequently administered to the patient twice daily for at least 23 weeks.

[0138] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 6.5 mg of reboxetine mesylate to the patient, wherein the reboxetine mesylate is administered to the patient once daily for the first w eek of treatment and is subsequently administered to the patient twice daily. In some embodiments, about 6.5 mg of reboxetine mesylate is administered to the patient once daily for the first week of treatment and is subsequently administered to the patient twice daily for at least 3 weeks. In some embodiments, about 6.5 mg of reboxetine mesylate is administered to the patient once daily for the first week of treatment and is subsequently administered to the patient twice daily for at least 7 weeks. In some embodiments, about 6.5 mg of reboxetine mesylate is administered to the patient once daily for the first week of treatment and is subsequently administered to the patient twice daily for at least 23 weeks.

[0139] In some embodiments disclosed herein is a method of reducing sleep paralysis in a patient having narcolepsy with cataplexy, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, daily for at least two weeks to the patient, wherein two weeks after the start of the treatment, the patient reports having fewer sleep paralysis episodes as compared to the week before the patient first receives reboxetine, or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments disclosed herein is a method of reducing hypnagogic hallucinations in a patient having narcolepsy with cataplexy, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, daily for at least tw o weeks to the patient, wherein two w eeks after the start of the treatment, the patient PCT Patent Application 134057-00001032_12T20-W0 reports having fewer hypnagogic hallucinations as compared to the week before the patient first receives reboxetine, or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy, comprising administering reboxetine, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein reboxetine, or a pharmaceutically acceptable salt thereof, is administered at least once daily for more than two weeks, wherein, two weeks from the beginning of treatment, the patient experiences a reduction in the number of cataplexy attacks in a week, a reduction in the Epworth Sleepiness Scale score, a decrease in the cataplexy subscore on the Ullanlinna Narcolepsy Scale (NUS), or a reduction in the Maintenance of Wakefulness Test score as a result of the treatment.

[0142] In some embodiments disclosed herein is use of reboxetine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of narcolepsy with cataplexy, wherein reboxetine, or a pharmaceutically acceptable salt thereof, is administered at least once daily for at least one week. In some embodiments, the medicament is for at least two weeks. In some embodiments, the medicament is for at least three weeks.

[0143] In some embodiments disclosed herein is a kit comprising a pharmaceutical composition comprising reboxetine, or a pharmaceutically acceptable salt thereof, and instructions to use the pharmaceutical composition to treat narcolepsy with cataplexy in a patient, wherein reboxetine, or a pharmaceutically acceptable salt thereof, is administered at least once daily for at least one week. In some embodiments, reboxetine, or a pharmaceutically acceptable salt thereof, is administered for at least two weeks. In some embodiments, reboxetine, or a pharmaceutically acceptable salt thereof, is administered for at least three weeks.

[0144] In some embodiments disclosed herein is a kit comprising a pharmaceutical composition comprising reboxetine, or a pharmaceutically acceptable salt thereof, and instructions to use the pharmaceutical composition to treat narcolepsy with cataplexy in a patient, wherein reboxetine, or a pharmaceutically acceptable salt thereof, is administered twice daily for at least one week. In some embodiments, reboxetine, or a pharmaceutically acceptable salt thereof, is administered twice daily for at least two weeks. In some embodiments, reboxetine, or a pharmaceutically acceptable salt thereof, is administered for at least twice daily weeks. In some embodiments, a first dosage form is administered in the morning and a second dosage form is administered about 2 hours to about 6 hours later. In some embodiments, the second dosage form is administered about 2 hours to about 3 hours PCT Patent Application 134057-00001032_12T20-W0 after the first dosage form. In some embodiments, the second dose is administered about 3 hours to about 4 hours after the first dosage form. In some embodiments, the second dosage form is administered about 4 hours to about 5 hours after the first dosage form. In some embodiments, the second dosage form is administered about 5 hours to about 6 hours after the first dosage form.

[0145] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy comprising administering reboxetine, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the patient does not suffer from depression or anxiety.

[0146] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy comprising administering reboxetine, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the patient suffers from depression.

[0147] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy comprising administering reboxetine, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the patient suffers from anxiety.

[0148] In some embodiments disclosed herein is a method of treating narcolepsy with cataplexy comprising administering reboxetine, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the patient suffers from depression and anxiety.

[0149] EXAMPLES

[0150] As shown in FIG. 2 and described herein, reboxetine has demonstrated robust efficacy across three placebo-controlled trials: CONCERT (the Phase 2 clinical trial described in Example 1), SYMPHONY (the Phase 3 clinical trial described in Example 2), and ENCORE (the Phase 3 clinical trial described in Example 3). In these trials, patients were treated with reboxetine, which can be administered as reboxetine free base, or as a pharmaceutically acceptable salt of reboxetine, such as reboxetine mesylate. As used herein, AXS-12 is used interchangeably with reboxetine, including pharmaceutically acceptable salts thereof (e.g. reboxetine mesylate).

[0151] Example 1; A Phase 2 Study: Clinical Outcomes in Narcolepsy and Cataplexy: An Evaluation of Reboxetine Treatment (CONCERT)

[0152] A Phase 2, double-blind, randomized, placebo-controlled, crossover, multicenter trial of reboxetine was carried out in patients with narcolepsy. A total of 21 patients with a diagnosis of narcolepsy with cataplexy were treated for 2 weeks with reboxetine (i.e., reboxetine PCT Patent Application 134057-00001032_12T20-W0 mesylate) or with placebo, followed by a crossover to the other treatment after a 1-week downtitration and washout period. Reboxetine was administered orally twice daily, with a total daily dose of 8 mg for Week 1 which was escalated to 10 mg for Week 2. Patients were randomized in a 1 : 1 ratio either to treatment with reboxetine followed by placebo (sequence 1), or to treatment with placebo followed by reboxetine (sequence 2). The average number of cataplexy attacks at baseline was 30. Key assessments were made daily using an electronic diary. The prespecified primary endpoint was the change in the weekly number of cataplexy attacks, averaged over the 2-week treatment period (overall treatment effect). Secondary endpoints included changes in the number of inadvertent naps, cognition, and Epworth Sleepiness Scale. Cognition was assessed using the Ability to Concentrate item of the Narcolepsy Symptom Assessment Questionnaire, a patient reported outcome measure. This item is rated on 5-point scale (l=very good to 5=very poor). All analyses were conducted on an intent-to-treat basis.

[0153] As shown in FIG. 3A, Reboxetine met the prespecified primary endpoint by demonstrating a highly statistically significant reduction from baseline in the mean weekly number of cataplexy attacks, averaged for the 2-week treatment period (overall treatment effect), as compared to placebo (p<0.001). At Week 2, reboxetine demonstrated a mean reduction of 14.6 cataplexy attacks per week compared to a reduction of 2.6 attacks per week for placebo (p=0.002), representing mean reductions of 48.7% and 8.7% from baseline, respectively (FIG. 3A). Furthermore, Reboxetine treatment resulted in rapid reduction in the cataplexy attacks. After 1-week treatment, reboxetine demonstrated a mean reduction of 13.0 cataplexy attacks compared to a reduction of 0.3 attacks for placebo (p<0.001), representing mean reductions of 43.3% and 1.0% from baseline, respectively (FIG. 3A). The proportion of patients achieving a 50% or greater reduction in the weekly number of cataplexy attacks was 76.2% for reboxetine, compared to 30.0% for placebo (p=0.003) at Week 2 (FIG. 4A). The proportion of patients achieving a 75% or greater reduction in the weekly number of cataplexy attacks was 42.9% for reboxetine, compared to 10.0% for placebo (p=0.018) at Week 2 (FIG. 5). The improvement in cataplexy was rapid with reboxetine demonstrating significant benefit over placebo as early as Week 1 (p<0.001).

[0154] Reboxetine significantly improved EDS (excessive daytime sleepiness) symptoms compared to placebo, as measured by the Epworth Sleepiness Scale (ESS) and by the frequency of inadvertent naps. As shown in FIG. 6A, the improvement on the ESS with reboxetine treatment was twice that observed with placebo, with reductions in the ESS score from baseline of 6.0 and 3.1, respectively for reboxetine and placebo (p=0.003). Reboxetine treatment PCT Patent Application 134057-00001032_12T20-W0 resulted in a 31.8% mean reduction from baseline in the average weekly number of inadvertent naps versus a 5.3% mean reduction for placebo (p<0.001) at Week 2 (FIG. 6B). As shown in FIG. 7. reboxetine treatment resulted in a greater number of patients with 50% or greater reduction in inadvertent naps (38.1%) as compared to placebo (10.0%) (p=0.036). The improvement in frequency of inadvertent naps was rapid with reboxetine demonstrating significant benefit over placebo as early as Week 1.

[0155] Reboxetine significantly improved cognitive function compared to placebo over the 2- week treatment period as measured by the Ability to Concentrate item of the Narcolepsy Symptom Assessment Questionnaire (NSAQ), which was assessed daily (p<0.01) (FIGs. SA- 813). For this assessment, patients rated their ability to concentrate on a 5-point scale (l=very good, 2=good, 3=average, 4=poor, and 5=very poor). At the end of the 2-week treatment period, 42.9% of patients had an ability to concentrate that was “good’' to “very good’' with reboxetine treatment, compared to 25.0% of patients with placebo, and 0% of patients at baseline. The improvement in the ability to concentrate was rapid with reboxetine demonstrating significant improvement over placebo (38.1% vs 15.0%) as early as Week 1 (p=0.007).

[0156] Reboxetine significantly improved sleep quality, as measured by overall improvement and by number of awakenings at night, and reduced sleep-related symptoms, as compared to placebo. As shown in FIG. 9, reboxetine treatment resulted in 45.0% of patients reporting improved sleep quality7versus 5.3% of patients with placebo (p=0.007). Reboxetine treatment resulted in 30.0% of patients reporting a reduction in the number of awakenings at night versus 5.3% of patients with placebo (p=0.044). Reboxetine treatment also resulted in greater proportion of patients with reductions in sleep paralysis episodes, and in hypnagogic hallucinations, as compared to placebo.

[0157] Reboxetine w as safe and well tolerated. There were no serious adverse events reported in the trial, and no discontinuations due to adverse events. The overall percentage of patients experiencing adverse events was 42.9% with reboxetine and 40.0% with placebo, with the most commonly reported adverse events with reboxetine treatment being anxiety', constipation, and insomnia. The completion rate was 91% for patients randomized to treatment sequence 1 (reboxetine followed by placebo) and 100% for those randomized to sequence 2 (placebo followed by reboxetine). PCT Patent Application 134057-00001032_12T20-W0

[0158] Example 2; A Phase 3 Study to Assess the Efficacy and Safety of Reboxetine in Patients with Narcolepsy (SYMPHONY)

[0159] A Phase 3, multicenter, randomized, double-blind, placebo-controlled trial was carried out to assess the efficacy, safety, and tolerability of reboxetine (i.e., reboxetine mesylate) in patients with narcolepsy type 1. Key inclusion criteria for the study were patients aged 15-75 years old who were diagnosed with narcolepsy type 1 with >7 cataplexy attacks per week or >14 cataplexy attacks across two weeks. Key exclusion criteria for the study was the diagnosis of another clinically significant condition potentially causing EDS.

[0160] A total of 90 patients, aged 15-75 years with a diagnosis of narcolepsy with cataplexy w ere treated for 5 weeks with reboxetine or placebo. Reboxetine 5 mg was administered orally once daily during week 1 followed by twice daily dosing during weeks 2-5. Patients were randomized in a 1 :1 ratio to either treatment with reboxetine or placebo for 5 weeks. Stable / concurrent modafinil / armodafinil use was allowed if the dose w as stable for at least 3 weeks before trial treatment and maintained through the trial duration. Diagnosis of another clinically significant condition potentially causing EDS was exclusionary. Concurrent rates of modafinil / armodafinil use w ere 32.6% in the reboxetine group and 29.5% in the placebo group (FIG. 10). Baseline sociodemographic and clinical characteristics were similar across both treatment groups. The mean time since diagnosis was about 7.9 years for the reboxetine group and 6.3 years for the placebo group.

[0161] Mean weekly cataplexy attacks at baseline were 27.7 for the reboxetine group and 35.4 for the placebo group. In SYMPHONY, baseline mean weekly frequency of cataplexy attacks was 31.5. The median number of cataplexy attacks at baseline was 20 (19.3 for the reboxetine group and 21.6 in the placebo group) and the Epworth Sleep Scores were 17.8 at baseline (18.3 in the reboxetine group and 17.3 in the placebo group). The mean CGI-S for narcolepsy score for the reboxetine arm was 5.2 and 4.9 in the placebo arm of the study. At baseline, mean FOSQ-IO total score was 11.1 (3.1) in the AXS-12 arm and 11.6 (3.2) in the placebo arm. At baseline, 47.8% of participants in the AXS-12 arm and 45.5% in the placebo arm reported anxiety / depression (EQ-5D-5L).

[0162] The prespecified primary endpoint was the change in frequency of weekly cataplexy attacks. Secondary endpoints included effect on excessive daytime sleepiness, effect on cognitive function, effect on narcolepsy overall, function and quality of life, anxiety / depression comorbidity, as well as safety and tolerability were assessed throughout the study. PCT Patent Application 134057-00001032_12T20-W0

[0163] As shown in FIG. 3B, Reboxetine met the prespecified primary endpoint by demonstrating a substantial and statistically significant reduction from baseline in weekly cataplexy attacks compared to placebo at Week 5, with reductions of 83% for reboxetine and 66% for placebo (rate ratio=0.49) (p=0.018). Reboxetine demonstrated a statistically significant reduction from baseline in weekly cataplexy attacks compared to placebo at Week 1, with reductions of 56% for reboxetine and 31% for placebo (rate ratio=0.65) (p=0.007). Moreover, as described in FIG. 3B, rate ratio analysis further supports that reboxetine significantly reduced risk of cataplexyattacks as compared to placebo. Here, for both the placebo and reboxetine groups, the ratio of the weekly frequency of cataplexy attacks post-treatment to baseline was taken; the ratio of these values is the rate ratio. A rate ratio less than 1 indicates fewer attacks with reboxetine compared to placebo. As can be seen in FIG. 3B, greater reductions in weekly cataplexy attacks were observed as early as Week 1.

[0164] As shown in FIG. 4B. Reboxetine induced remission of cataplexy and increased cataplexy- free days compared to placebo. Remission of cataplexy, defined as a 100% reduction from baseline, was achieved at Week 5 by 33% of reboxetine treated patients compared to 9.5% of placebo patients (p=0.008). Achievement of remission was rapid, being experienced at Week 2 by 24% of reboxetine treated patients compared to 4.5% of placebo patients (p=0.008). Reboxetine increased the percentage of cataplexy-free days per week, defined as days with zero cataplexy attacks, to 84.5% for reboxetine at Week 5 compared to 22.6% for placebo (p=0.014).

[0165] As shown in FIG. 11 A, Reboxetine significantly reduced excessive daytime sleepiness (EDS) severity, assessed by the Clinician Global Impression of Severity (CGI-S) scale for EDS, compared to placebo at Week 5 with mean reductions of -1.8 points for reboxetine compared to - 0.9 points for placebo (p=0.027). Rapid improvement on the CGI-S for EDS was seen as early as Week 1 compared to placebo (p=0.006). Reboxetine concurrently improved EDS and cataplexy as compared to placebo (see FIG. 11B). Concurrent EDS and cataplexy- response was achieved at Week 5 by 57% of patients treated with reboxetine compared to 33% of placebo patients (p=0.029). Concurrent EDS and cataplexy response w as defined as a >30% reduction in inadvertent naps (EDS response), and a >50% reduction in cataplexy attacks (cataplexy response). The baseline CGI-S for EDS, mean was 5.3 for the reboxetine group and 5.1 for the placebo group. Reboxetine led to a significant reduction versus placebo in CGI-S for narcolepsy at Week 5 (LS mean difference [95% CI]=0.72 [0.29, 1.16]; p=0.001).

[0166] A decrease in the number of inadvertent naps was experienced by 54% of reboxetine patients at Week 5 compared to 28% of placebo patients (p=0.016), assessed by the Narcolepsy PCT Patent Application 134057-00001032_12T20-W0

[0167] Symptom Assessment Questionnaire (NSAQ). Reduction in inadvertent naps at week 1 were 56% for reboxetine and 31% for placebo (rate ratio=0.65; nominal p=007). By week 5, the number of participants with a reduction from the baseline in naps / sleep attacks was up 53.5% for those taking reboxetine and 27.9% for those on the placebo. (p=0.016) Improvement on the Epworth Sleepiness Scale (ESS) was numerically greater for reboxetine than for placebo, with mean reductions from baseline on the ESS of 4.7 points for reboxetine compared to 3.4 points for placebo. A >3-point improvement from baseline on the ESS was achieved by 60% of reboxetine patients who had a cataplexy response.

[0168] Reboxetine significantly improved concentration and memory as measured by the Cognitive Function Items of the Functional Outcomes of Sleep Questionnaire (FOSQ-IO) at Week 5, with 1.6 points in the reboxetine group compared with 0.7 points in the placebo group (p=0.004) (FIG. 12A). The LS mean change in FOSQ-IO total score from the baseline to Week 5 was 3.50 for those taking reboxetine and 1.84 for those taking the placebo (p=0.005). Reboxetine concurrently improved cognition and cataplexy as compared to placebo. Concurrent cognitive and cataplexy response was achieved at Week 5 by 41% of patients treated with reboxetine compared to 17% of placebo patients (p=0.016) (FIG. 12B). Response was defined by an increase in days patients rated their Ability to Concentrate as very good or good (cognitive response), and a >50% reduction in cataplexy attacks (cataplexy response). General productivity had a LS mean change in FOSQ-IO subscales from the baseline to Week 5 by 0.8 for those taking reboxetine and 0.35 for those on the placebo. Activity level had a LS mean change in FOSQ-IO subscales from the baseline to Week 5 by 0.83 for those taking reboxetine and 0.58 for those on the placebo. Vigilance had a LS mean change in FOSQ-IO subscales from the baseline to Week 5 by 0.62 for those taking reboxetine and 0.27 for those on the placebo. Social outcomes had a LS mean change in FOSQ-IO subscales from the baseline to Week 5 by 0.44 for those taking reboxetine and 0.29 for those on the placebo. Intimacy and sexual relationships had a LS mean change in FOSQ-IO subscales from the baseline to Week 5 by 0.45 for those taking reboxetine and 0.24 for those on the placebo. Reboxetine led to a statistically significant improvement from baseline to Week 5 in FOSQ-IO total scores compared to placebo (1.66 [0.51, 2.82], p=0.005).

[0169] Reboxetine improved narcolepsy overall disease condition, and patient function and quality of life (see, e.g.. FIG. 13A). Clinicians reported a rapid and significant reduction in overall narcolepsy severity (CGI-S for narcolepsy overall) for patients treated with reboxetine compared to placebo at Week 5 (p=0.007), with improvements observed as early as Week 1 PCT Patent Application 134057-00001032_12T20-W0

[0170] (p<0.001). The LS mean change in CGI-S total score from the baseline to Week 5 was 1.6 for the reboxetine group and 0.87 for the placebo group (p=0.001). Reboxetine demonstrated significant improvement in overall patient function and quality of life as measured by the FOSQ-IO total score as compared to placebo at Week 5 (p=0.005).

[0171] Anxiety and depression, known common narcolepsy co-morbidities, was reported by 45% of study participants at baseline, as assessed by the EuroQol (EQ-5D-5L). Improvement from baseline in the Anxiety / Depression domain of the EQ-5D-5L was achieved by 55% of patients treated with reboxetine compared to 32% of placebo patients (p=0.146) (FIG. 13B).

[0172] Reboxetine was well tolerated in the trial. No new safety signals were observed. The most commonly reported adverse events in the reboxetine arm (>5%) were dry mouth (n=6; 13.0%), nausea (n=6; 13.0%), decreased appetite (n=3; 6.5%), and constipation (n=4; 8.7%), which were overall mild to moderate. The rates of discontinuation due to adverse events was low (n=l in each of reboxetine [2.2%] and placebo [2.3%] arms). There were no serious adverse events in the trial.

[0173] Example 3; A Phase 3 Study to Assess the Long-term Efficacy and Safety of Reboxetine in Subjects with Narcolepsy (ENCORE; Evaluating Continued Treatment with Reboxetine)

[0174] A multicenter, two-period Phase 3 trial consisted of a 24-week open-label period followed by a 3-week, double-blind, randomized withdrawal period was carried out to evaluate the efficacy and long-term safety of reboxetine (i.e., reboxetine mesylate) in participants with narcolepsy with cataplexy (FIG. 14). This study consisted of a 6-month open-label reboxetine treatment period, followed by a 3-week double-blind, placebo-controlled, randomized withdrawal period. To this end, investigators evaluated 68 participants who rolled over from the SYMPHONY phase 3 trial of reboxetine (described in Example 2), then enrolled into the open-label period and were treated with reboxetine (5 mg) once-daily for the first week, followed by twice daily dosing for the next 23 weeks. The participants who completed the open-label treatment period (n=42) were then randomized in a 1 : 1 ratio to continue on reboxetine (n=22) or to switch to placebo (n=20). At baseline, the mean number of weekly cataplexy attacks w as 31.3 and the mean ESS w as 18. The mean number of cataplexy attacks at randomization was 4.2 (reboxetine) and 6.9 (placebo). The prespecified primary efficacy endpoint was the change in frequency of weekly cataplexy attacks from baseline at randomization to week 3 of the double-blind period. Other symptoms of narcolepsy as w ell as safety and tolerability were assessed throughout the study. PCT Patent Application 134057-00001032_12T20-W0

[0175] Reboxetine met the primary endpoint of the change from randomization in the frequency of cataplexy attacks as compared with placebo at week 3 of the double-blind period (see FIG. 15 A). Compared with participants taking reboxetine, patients who were randomized to switch to placebo experienced a statistically significant worsening in the average weekly number of cataplexy attacks, seeing an increase of 10.29 attacks per w eek with placebo vs 1.32 with reboxetine, at 3 weeks ( =0.017).

[0176] Reboxetine also show ed improvement in participants across a range of other measures. For example, reboxetine resulted in statistically significant benefit in cognition compared with placebo. Investigators assessed cognition using the Narcolepsy Symptom Assessment Questionnaire (NSAQ) and the Patient Global Impression of Change (PGI-C). A significantly greater proportion of patients randomized to switch to placebo experienced worsening on the NSAQ Ability to Concentrate item compared with those on reboxetine (52.6% vs 14.3%) at 3 weeks (P=0.011) (see FIG. 15B), and a worsening in their ability to concentrate, as assessed by the PGI-C, compared to those continuing on reboxetine (57.9% vs 22.2%) at 3 weeks ( =0.029). Additionally, as seen in FIG. 16, a significantly greater proportion of patients randomized to switch to placebo reported worsening of their narcolepsy overall, as assessed by the PGI-C, compared with those on reboxetine (52.6% vs 16.7%) at 3 weeks (7J=0.024).

[0177] Treating patients with reboxetine resulted in statistically significant benefit in narcolepsy overall compared to placebo, as assessed by the PGI-C. A significantly greater proportion of patients randomized to sw itch to placebo reported w orsening of their narcolepsy, as assessed by the PGI-C, compared to those continuing on reboxetine (52.6% versus 16.7%) at 3 weeks (p=0.024).

[0178] During the long-term open-label treatment portion of the trial, patients experienced substantial and sustained improvement of cataplexy with reboxetine treatment. Treatment with reboxetine resulted in a mean reduction from baseline of 22.3 cataplexy attacks per week at 1 month, corresponding to a decrease of 71%. The improvement in cataplexy was maintained with long-term reboxetine treatment, resulting in a mean reduction of 24. 1 cataplexy attacks per week at 6 months, corresponding to a decrease of 77%. Cataplexy response, defined as >50% reduction from baseline in w eekly frequency of cataplexy attacks, was achieved by 72% of patients at 1 month, and by 82% of patients at 6 months with reboxetine treatment. Treatment with reboxetine also substantially increased the percentage of cataplexy-free days (days with zero cataplexy attacks) per week from 14.3% at baseline to 61% at 1 month and 70% at 6 months. PCT Patent Application 134057-00001032_12T20-W0

[0179] Long-term open-label treatment with reboxetine resulted in substantial improvements in excessive daytime sleepiness (EDS), assessed using the Epworth Sleepiness Scale (ESS) and the Clinician Global Impression of Change (CGI-C) scale. Mean ESS scores were reduced by 5.6 points at 1 month. This improvement was maintained with long-term treatment resulting in a mean reduction of 7.3 points at 6 months. Clinicians reported improvement in EDS in a substantial proportion of patients on the CGI-C scale, with 84% of patients achieving EDS improvement at 1 month, and 78% of patients at 6 months with reboxetine treatment.

[0180] A substantial proportion of patients reported improvement in cognition with reboxetine which was sustained with long-term open-label treatment. Improvement in cognition, assessed by the NSAQ Abili ty to Concentrate item, was reported by 55% of patients at 1 month and 59% at 6 months with reboxetine treatment. Change in the abi 1 i ty to concentrate was also assessed using the PGI-C scale. The proportion of patients reporting improvement in the ability to concentrate on the PGI-C was 67% at 1 month and 70% at 6 months with reboxetine treatment.

[0181] Long-term open-label treatment with reboxetine was also associated with improvement in overall narcolepsy status and patient functioning, assessed using the CGI-C. the PGI-C, and the Work Productivity and Activity Impairment Questionnaire (WPAI). On the CGI-C, clinicians reported overall improvement in narcolepsy in 90% of patients at 1 month, and 90% of patients at 6 months with reboxetine treatment. Results were similar with the patient-reported PGI-C. For example, reboxetine treatment was associated with an improvement in narcolepsy overall, assessed by the PGI-C. with 78% of patients reporting improvement at 1 month, and 80% reporting improvement at 6 months. Impairment due to narcolepsy while working was assessed after treatment with reboxetine using the WPAI. Reboxetine treatment was associated with improved patient function by substantially decreasing the time impaired due to narcolepsy while working, assessed by the WPAI. from 53% at baseline to 34% at 1 month and 24% at 6 months.

[0182] Reboxetine was well tolerated with long-term dosing. The safety profile with longterm dosing was consistent with prior trials of reboxetine with no new safety signals identified. During the 6-month open-label treatment period, the most common adverse events (>5%) were nausea (5.9%) and tachycardia (5.9%). Over the 6-month treatment period, 17.6% of patients discontinued due to adverse events, with no individual adverse event leading to discontinuation by more than 1 patient. Treatment-related adverse events during PCT Patent Application 134057-00001032_12T20-W0 the double-blind period were reported in 4.5% of patients in the reboxetine group and 15% of patients in the placebo group. Rates of discontinuation due to adverse events in the doubleblind period were 0% and 5% (i.e., 1 patient) in the reboxetine and placebo groups, respectively.

[0183] Accordingly, the results described in Example 3 demonstrate the efficacy of reboxetine in patients with narcolepsy with cataplexy and indicate that the potential benefits of reboxetine are substantial and sustained with long-term treatment. The results, moreover, also show improvements in excessive daytime sleepiness and cognition reported by a majority of patients in the trial with long-term reboxetine treatment. Importantly, these improvements were accompanied by a favorable long-term safety and tolerability profile.

[0184] Example 4; A survey was conducted among adult patients who were currently undergoing treatment for narcolepsy type 1 (NT1). The survey included 203 adult patients, aged 18-82 years (mean 41 years) with a diagnosis of narcolepsy Type 1, all of whom had experience with FDA-approved treatments for their narcolepsy.

[0185] Survey respondents collectively have more than 2600 years of lived experience with the sleep disorder. The survey was conducted to understand respondents’ experience and journey, to measure disease symptoms including cognitive impairment while on treatment, and to assess burden of illness, comorbidities, and unmet needs and challenges patients face. To quantify key elements of the narcolepsy patient experience, the study utilized patient reported measures, and validated scales including the Epworth Sleepiness Scale (ESS) to assess excessive daytime sleepiness (EDS), and the British Columbia Cognitive Complaints Inventory (BC-CCI) to assess cognitive function.

[0186] Survey respondents w ere receiving pharmacotherapy for narcolepsy. As shown in FIG. 17A, the most common treatments used by NT1 patients were w ake promoting agents (about 53% of surveyed patients), oxy bates (47%). and stimulants (42%). Thirty-seven percent (37%) of survey participants w ere diagnosed with depression, of which 80% were taking medication to manage their depression (FIG. 17B). Thirty-seven percent (37%) of survey participants were diagnosed with anxiety, of which 72% were taking medication to manage their anxiety (FIG. 17B). Thirty-seven percent (38%) of survey participants were taking antidepressants for narcolepsy (FIG. 17 A). Ten percent (10%) reported taking an “other” nighttime medication and 7% of survey participants were taking an “other” daytime medication. Despite receiving treatment, the majority of narcolepsy PCT Patent Application 134057-00001032_12T20-W0 patients continued to experience symptoms. Accordingly, these high rates of patient dissatisfaction and polypharmacy underscore unmet need for new treatment options for this patient population.

[0187] As shown in FIG. 18, NT1 patients experience high rates of symptoms despite current treatments. Cataplexy was reported by 77% of patients while on their current treatment regimen. EDS, assessed using the ESS (scores > 10), was observed in 64% of patients despite receiving current treatments. Cognitive impairment, assessed using the BC-CCI (scores >5), was observed in 74% of patients on treatment. Disrupted nighttime sleep was reported in 77% of patients on treatment. 68% of survey participants rated their ability to concentrate as poor, very poor, or average. Depression and anxiety were experienced by about 45% and 57% of patients respectively.

[0188] The impact of cataplexy on daily life was surveyed among participants. As shown in FIG. 19, 65% of participants currently experiencing cataplexy reported that cataplexy burdens their professional life (e.g. career, school), despite treatment. 60% of participants currently experiencing cataplexy reported that cataplexy burdens their social life, despite treatment. 50% of patients currently experiencing cataplexy reported that cataplexy burdens their day-to-day life, despite treatment. 64% and 68% of patients experiencing cataplexy reported being embarrassed by falling down and slurred speech, respectively, despite treatment. 77% of patients on current treatments continue to experience cataplexy. Cataplexy poses a significant patient burden.

[0189] Narcolepsy is associated with significant morbidity, mortality, and healthcare utilization (FIG. 20). People with narcolepsy have two times the hospital and physician visits, two times the medication use, two times the healthcare use and costs, six times the motor vehicle accident injuries, and one and a half times the mortality rate according to multiple sources. Narcolepsy leads to impaired psychosocial development, education, and employment, and often results in permanent disability and increased mortality.

[0190] In closing, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by w ay of example, but not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to embodiments precisely as shown and described.

Claims

1. PCT Patent Application 134057-00001032_12T20-W0CLAIMS1. A method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof wherein the patient treated experiences a reduction in the number of cataplexy attacks.

2. The method of claim 1 , wherein about 5 mg of reboxetine free base, or a molar equivalent amount of a salt form of reboxetine, is administered to the patient.

3. The method of claim 1 or claim 2, wherein about 6.5 mg of reboxetine mesylate is administered to the patient.

4. The method of any one of the preceding claims, wherein the patient experiences at least 50% reduction from baseline in mean weekly cataplexy attacks at 1 month of treatment.

5. The method of any one of the preceding claims, wherein the patient experiences at least 65% reduction from baseline in mean weekly cataplexy attacks at 1 month of treatment.

6. The method of any one of the preceding claims, wherein the patient experiences at least 70% reduction from baseline in mean weekly cataplexy attacks at 1 month of treatment.

7. The method of any one of the preceding claims, wherein the patient experiences at least 60% reduction from baseline in mean weekly cataplexy attacks at 6 months of treatment.

8. The method of any one of the preceding claims, wherein the patient experiences at least 70% reduction from baseline in mean weekly cataplexy attacks at 6 months of treatment.

9. The method of any one of the preceding claims, wherein at least 30% of the patients treated with reboxetine, or a pharmaceutically acceptable salt thereof, experience remission in w eekly cataplexy attacks after 5 weeks of treatment as compared with placebo.

10. A method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, wherein the patient treated experiences an improvement in cognitionPCT Patent Application 134057-00001032_12T20-W0 as compared to placebo, wherein the improvement in cognition is assessed by the Narcolepsy Symptom Assessment Questionnaire.

11. The method of claim 10, wherein the patient treated experiences an improvement in cognition as assessed by the Narcolepsy Symptom Assessment Questionnaire at 1 month of treatment.

12. The method of claims 10 or claim 11, wherein the patient treated experiences an improvement in cognition as assessed by the Narcolepsy Symptom Assessment Questionnaire at 6 months of treatment.

13. A method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, wherein the patient treated experiences an improvement in excessive daytime sleepiness as assessed using the Epworth Sleepiness Scale.

14. The method of claim 13, wherein mean Epworth Sleepiness Scale scores are reduced by at least 3 points at 1 month of treatment.

15. The method of claim 13 or claim 14. wherein mean Epworth Sleepiness Scale scores are reduced by at least 5 points at 1 month of treatment.

16. The method of any one of claims 13 to 15. wherein mean Epworth Sleepiness Scale scores are reduced by at least 5 points at 6 months of treatment.

17. The method of any one of claims 13 to 16, wherein mean Epworth Sleepiness Scale scores are reduced by at least 7 points at 6 months of treatment.

18. A method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, wherein the patient treated experiences an improvement in excessive daytime sleepiness as assessed using the Clinician Global Impression of Change scale.

19. The method of claim 18. wherein at least 70% of patients are reported to have an improvement in excessive daytime sleepiness at 1 month of treatment.PCT Patent Application 134057-00001032_12T20-W020. The method of claim 18 or claim 19, wherein about 80% of patients are reported to have an improvement in excessive daytime sleepiness at 1 month of treatment.

21. The method of any one of claims 18-20, wherein at least 70% of patients are reported to have an improvement in excessive daytime sleepiness at 6 months of treatment.

22. The method of any one of claims 18-21, wherein at least 75% of patients are reported to have an improvement in excessive daytime sleepiness at 6 months of treatment.

23. A method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, wherein the patient treated experiences an improvement in narcolepsy overall as assessed using the Clinician Global Impression of Change scale.

24. The method of claim 23, wherein at least 80% of patients are reported to have an overall improvement in narcolepsy at one month of treatment.

25. The method of claim 23 or claim 24, wherein 90% of patients are reported to have an overall improvement in narcolepsy at one month of treatment.

26. The method of any one of claims 23-25, wherein at least 80% of patients are reported to have an overall improvement in narcolepsy at six months of treatment.

27. The method of any one of claims 23-26, wherein at least 90% of patients are reported to have an overall improvement in narcolepsy at six months of treatment.

28. A method of treating narcolepsy with cataplexy in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof wherein the patient treated experiences an improvement in narcolepsy overall as assessed using the Patient Global Impression of Change scale.

29. The method of claim 28, wherein at least 70% of patients experience an overall improvement in narcolepsy at one month of treatment.

30. The method of claim 28 or claim 29, wherein about 78% of patients experience an overall improvement in narcolepsy at one month of treatment.PCT Patent Application 134057-00001032_12T20-W031. The method of any one of claims 28-30, wherein at least 75% of patients experience an overall improvement in narcolepsy at six months of treatment.

32. The method of any one of claims 28-31, wherein about 80% of patients experience an overall improvement in narcolepsy at six months of treatment.

33. A method of treating narcolepsy with cataplexy, in a patient in need thereof, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, wherein the patient experiences a decrease in time impaired due to narcolepsy while working as assessed by Work Productivity and Activity Impairment Questionnaire.

34. The method of claim 33, wherein the patient is at least 50% at baseline and 30-35% at 1 month of treatment.

35. The method of claim 33 or claim 34, wherein the wherein the patient is about 53% at baseline and about 34% at 1 month of treatment.

36. The method of any one of claims 33-35, wherein the patient is at least 50% at baseline and 20-30% at 6 months of treatment.

37. The method of any one of claims 33-36, wherein the patient is about 53% at baseline and about 24% at 6 months of treatment.

38. The method of any one of the preceding claims, wherein the reboxetine, or a pharmaceutically acceptable salt thereof, is administered to the patient once daily for the first week of treatment.

39. The method of claim of any one of the preceding claims, wherein the reboxetine, or a pharmaceutically acceptable salt thereof, is administered to the patient once daily for the first week of treatment and is subsequently administered to the patient twice daily.

40. The method of claim 39, wherein after the first week of treatment, the reboxetine, or a pharmaceutically acceptable salt thereof, is administered to the patient twice daily for at least 3 weeks.PCT Patent Application 134057-00001032_12T20-W041. The method of claim 39 or claim 40, wherein after the first week of treatment, the reboxetine, or a pharmaceutically acceptable salt thereof, is administered to the patient twice daily for at least 7 weeks.

42. The method of any one of claims 39-41, wherein after the first week of treatment, the reboxetine, or a pharmaceutically acceptable salt thereof, is administered to the patient twice daily for at least 23 weeks.

43. A method of reducing sleep paralysis in a patient having narcolepsy with cataplexy, comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, daily for at least two weeks to the patient, wherein two weeks after the start of the treatment, the patient reports having fewer sleep paralysis episodes as compared to the week before the patient first receives reboxetine, or a pharmaceutically acceptable salt thereof.

44. A method of reducing hypnagogic hallucinations in a patient having narcolepsy with cataplexy , comprising administering about 5 mg to about 10 mg of reboxetine, or a pharmaceutically acceptable salt thereof, daily for at least two weeks to the patient, wherein two weeks after the start of the treatment, the patient reports having fewer hypnagogic hallucinations as compared to the week before the patient first receives reboxetine, or a pharmaceutically acceptable salt thereof.

45. The method of any one of the preceding claims, wherein the patient has a reduction in the Ability to Concentrate item of the NSAQ that is at least about 0. 1 prior to treatment with reboxetine, or a pharmaceutically acceptable salt thereof.

46. The method of any one of the preceding claims, wherein the patient has an Epworth Sleepiness Scale score that is greater than 10 prior to treatment with reboxetine, or a pharmaceutically acceptable salt thereof.

47. The method of any one of the preceding claims, wherein the patient has a diagnosis of narcolepsy with cataplexy that meets International Classification of Sleep Disorders, Third Edition criteria.PCT Patent Application 134057-00001032_12T20-W048. The method of any one of the preceding claims, wherein the patient has at least 7 cataplexy attacks per week prior to receiving reboxetine, or a pharmaceutically acceptable salt thereof.

49. The method of any one of claims 10-37 or claims 43-44, wherein about 5 mg of reboxetine free base, or a molar equivalent amount of a salt form of reboxetine, is administered to the patient.

50. The method of any one of claims 10-37 or claims 43-44, wherein about 6.5 mg of reboxetine mesylate is administered to the patient.

51. A method for the long-term treatment of narcolepsy type 1, comprising administering a tablet to a patient suffering from narcolepsy type 1 once daily for one week, followed by administering the tablet twice daily to the patient for at least 26 weeks, wherein the tablet contains about 6.5 mg of reboxetine mesylate.

52. The method of any preceding claim, wherein the patient has about 31.3 cataplexy attacks per week prior to receiving the tablet.

53. The method of any preceding claim, wherein the patient has an Epworth Sleepiness Scale (ESS) score of about 18 prior to receiving the tablet.

54. The method of any preceding claim, wherein the patient experiences a reduction from baseline of about 22.3 cataplexy attacks per week at one month after receiving the first tablet.

55. The method of any preceding claim, wherein the patient experiences about a 71% reduction from baseline in the number of cataplexy attacks per week at one month after receiving the first tablet.

56. The method of any preceding claim, wherein the patient experiences about 71% fewer cataplexy attacks per week at one month after receiving the first tablet.

57. The method of any preceding claim, wherein the patient is one of about 72% of patients who experience at least a 50% reduction from baseline in frequency of cataplexy attacks at one month after receiving the first tablet.PCT Patent Application 134057-00001032_12T20-W058. The method of any preceding claim, wherein the patient is one of about 84% of patients who experience an improvement from baseline in excessive daytime sleepiness (EDS) on the Clinician Global Impression of Change (CGI-C) scale one month after receiving the first tablet.

59. The method of any preceding claim, wherein the patient experiences about a 5.6 point reduction in the ESS score from baseline at one month after receiving the first tablet.

60. The method of any preceding claim, wherein the patient is one of about 55% of patients who experience an improvement in cognition, as assessed by the Narcolepsy Symptom Assessment Questionnaire (NSAQ) Ability to Concentrate item, at one month after receiving the first tablet.

61. The method of any preceding claim, wherein the patient is one of about 67% of patients who experience an improvement in ability- to concentrate, as assessed by the ability- to concentrate on the PGI-C. at one month after receiving the first tablet.

62. The method of any preceding claim, wherein the patient is one of about 90% of patients who experience overall improvement in narcolepsy, as assessed by the CGI-C, at one month after receiving the first tablet.

63. The method of any preceding claim, wherein the patient is one of about 78% of patients who experience overall improvement in narcolepsy, as assessed by the CGI-C, at one month after receiving the first tablet.

64. The method of any preceding claim, wherein the patient experiences a reduction from baseline of about 53% in time impaired due to narcolepsy while working at one month after receiving the first tablet.

65. The method of any preceding claim, wherein after the patient receives the tablet once daily for one week and then receives the tablet twice daily for 23 weeks, the patient has about 4 to about 7 cataplexy attacks per week, and wherein after the patient receives the tablet twice daily for 26 weeks, the patient experiences about 9 fewer cataplexy attacks per week than the patient would have experienced if the patient had received the tablet once daily for one week, and then received the tablet twice daily for 23 weeks, and then received a placebo twice daily for three weeks.PCT Patent Application 134057-00001032_12T20-W066. The method of any preceding claim, wherein the patient experiences about 24. 1 fewer cataplexy attacks per week at 6 months after receiving the first tablet.

67. The method of any preceding claim, wherein the patient experiences about 77% fewer cataplexy attacks per week at 6 months after receiving the first tablet.

68. The method of any preceding claim, wherein the patient is one of about 72% of patients who experience at least a 50% reduction from baseline in frequency of cataplexy attacks at 6 months after receiving the first tablet.

69. The method of any preceding claim, wherein the patient experiences about a 7.3 point reduction in the ESS score from baseline at 6 months after receiving the first tablet.

70. The method of any preceding claim, wherein the patient is one of about 78% of patients who experience an improvement from baseline in EDS on the CGI-C scale at 6 months after receiving the first tablet.

71. The method of any preceding claim, wherein the patient is one of about 59% of patients who experience an improvement in cognition, as assessed by the NSAQ Ability to Concentrate item, at 6 months after receiving the first tablet.

72. The method of any preceding claim, wherein the patient is one of about 70% of patients who experience an improvement in abi li ty to concentrate, as assessed by the ability- to concentrate on the PGI-C. at 6 months after receiving the first tablet.

73. The method of any preceding claim, wherein the patient is one of about 90% of patients who experience overall improvement in narcolepsy, as assessed by the CGI-C, at 6 months after receiving the first tablet.

74. The method of any preceding claim, wherein the patient is one of about 80% of patients who experience overall improvement in narcolepsy, as assessed by the PGI-C, at 6 months after receiving the first tablet.

75. The method of any preceding claim, wherein the patient experiences a reduction from baseline of about 34% in time impaired due to narcolepsy while working at 6 months after receiving the first tablet.PCT Patent Application 134057-00001032_12T20-W076. The method of any preceding claim, wherein the patient is not one of about 5.9% of patients who experience nausea during 6 months of treatment.

77. The method of any preceding claim, wherein the patient is not one of about 5.9% of patients who experience tachycardia during 6 months of treatment.

78. The method of any preceding claim, wherein the patient is not one of about 1.6% of patients who discontinue treatment prior to 6 months of treatment.

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