BR112021007019A2 - use of reboxetine to treat narcolepsy - Google Patents

Abstract

described herein are methods of treating narcolepsy with cataplexy, comprising administering reboxetine to a human in need thereof. reboxetine can also be used in the manufacture of a drug for the treatment of narcolepsy with cataplexy. also described herein are kits comprising a pharmaceutical composition comprising reboxetine and instructions for using the pharmaceutical composition to treat narcolepsy with cataplexy in a human.

Description

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USE OF REBOXETINE TO TREAT NARCOLEPSY CROSS REFERENCE TO RELATED ORDERS

[001] This application claims the benefit of US Provisional Application No. 62/745,956, filed October 15, 2018, which is incorporated herein in its entirety by reference.

FUNDAMENTALS

[002] Narcolepsy is a serious and debilitating neurological condition that causes dysregulation of the sleep-wake cycle and is clinically distinguished by excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis, and fragmented nocturnal sleep. It is estimated that narcolepsy afflicts around 185,000 individuals in the US. Cataplexy is estimated to be seen in 70% of patients with narcolepsy and is a sudden reduction or loss of muscle tone while the patient is awake, typically 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 occupational or automobile accidents, and is associated with a 1.5-fold higher mortality rate. Depression is reported in up to 57% of patients. The debilitating effects of narcolepsy are far-reaching for the estimated 200,000 patients living with this disorder in the United States. Narcolepsy interferes with mental and social functioning, increases work-related and automobile accidents, and results in an almost twice as high mortality rate. Unfortunately, there are few currently approved treatments for this rare, underdiagnosed condition and are limited by patient-to-patient variability in effectiveness, tolerability issues, and the need to schedule an AED.

SUMMARY

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[003] Described herein are methods for treating narcolepsy with cataplexy, which comprises administering reboxetine to a human in need thereof.

[004] Some modalities include the use of reboxetine in the manufacture of a drug for the treatment of narcolepsy with cataplexy.

[005] Some embodiments include a kit comprising a pharmaceutical composition comprising reboxetine and instructions for using the pharmaceutical composition to treat narcolepsy with cataplexy in a human.

[006] In some embodiments, reboxetine is administered at least once daily for at least three weeks. In some modalities, three weeks from the start of treatment, the human experiences a reduction in the number of cataplexy attacks in one week, a reduction in the Epworth Sleepiness Scale score, or a reduction in the Maintenance of Wakefulness Test score. as a result of treatment.

DETAILED DESCRIPTION

[007] Reboxetine has the potential to treat the symptoms of narcolepsy without scheduling with the AED and would be of significant benefit to patients living with this condition.

[008] A person may have type 1 narcolepsy if criteria A and B have been met: A. the patient has daily periods of irrepressible need to sleep or daytime sleepiness occurring for at least 3 months B. the presence of one or both of the following :

1. cataplexy (as defined under Essential Features) and a mean sleep latency of <8 minutes and >2 episodes of early REM sleep (SOREMPs) on a mean sleep latency test (MSLT)

3 / 66 performed according to standard techniques. A SOREMP (within 15 minutes of sleep onset) on previous laboratory-based polysomnography (PSG) can replace one of the SOREMPs on the MSLT

2. CSF hypocretin-1 concentrations measured by immunoreactivity <110 pg/mL or <½ mean values obtained in normal subjects with the same assay

[009] In young children, narcolepsy can sometimes present as excessively long nighttime sleep or the resumption of a previously interrupted daytime nap. If there is strong clinical suspicion of type 1 narcolepsy but criteria B2 are not met, a possible strategy is to repeat the MSLT

[0010] Some patients treated with reboxetine may have, and/or may be selected for having, daily periods of irrepressible need to sleep or daytime naptime occurring for at least about 3 months, at least 4 months, at least about 5 months , at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 2 years, at least at least about 3 years, at least about 4 years, at least about 5 years, at least about 10 years, at least about 15 years, at least about 20 years, at least about 25 years, at least about 30 years old, at least about 40 years old, at least about 50 years old, at least about 60 years old, about 3-9 months, about 9-18 months, about 18 months, about 2 years, about 2-5 years, about 5-10 years, about 10-15 years, about 15-20 years, about 20 to 25 years, about 25 to 30 years, about 30 to 35 years, about 35 to 40 years, about 40-50 years, about 50 to 60 years, or more.

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[0011] Some patients treated with reboxetine may have, and/or may be selected to have, a mean sleep latency of less than about 1 minute, less than about 2 minutes, less than about 3 minutes, less than about 4 minutes, less than about 5 minutes, less than about 6 minutes, less than about 7 minutes, less than about 8 minutes, about 0.1 to 1 minute, about 1 to 2 minutes, about 2 to 3 minutes, about 3 to 4 minutes, about 4 to 5 minutes, about 5 to 6 minutes, about 6 to 7 minutes, about 7 to 8 minutes, about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, or about 8 minutes.

[0012] Some patients treated with reboxetine may have, and/or may be selected for, having at least 2, at least 3, or at least 4 SOREMPs on an MSLT (mean sleep latency test) performed according to standard techniques . A SOREMP within 15 minutes of sleep onset on the preceding nighttime PSG may replace one of the SOREMPs on the MSLT

[0013] Some patients treated with reboxetine may have, and/or may be selected to have, CSF hypocretin-1 concentrations measured by immunoreactivity that are less than about 40 pg/mL, less than about 50 pg/mL mL, less than about 60 pg/mL, less than about 70 pg/mL, less than about 80 pg/mL, less than about 90 pg/mL, less than about 100 pg/mL mL, less than about 110 pg/mL.

[0014] Some patients treated with reboxetine may have, and/or may be selected to have, CSF hypocretin-1 concentrations measured by immunoreactivity that are less than about 1/10, less than about 1/9, less than about 1/8, less than about 1/7, less than about 1/6, less than about 1/5, less than about 1/5

5 / 66 1/4, or less than about 1/3 of the mean values obtained in normal subjects with the same assay.

[0015] Some patients treated with reboxetine may be, and/or may be selected for, young children who have an excessively long night's sleep.

[0016] Some patients treated with reboxetine may be, and/or may be selected for being, young children who experience resumption of previously interrupted daytime napping.

[0017] Some patients treated with reboxetine may have, and/or may be selected to have, a cataplexy subscore on the Ullanlinna Narcolepsy Score (UNS) that is at least 1, at least about 2, at least about 3 , at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, about 11, about 1 to 2, about 2 to 3, about 3 to 4, about 4 to 5, about 5 to 6, about 6 to 7, about 7 to 8, about 8 to 9, about 9 to 10 , about 10 to 11, about 2 to 4, about 4 to 6, about 6 to 8, about 8 to 10, about 2 to 6, or about 6 to 10, or any number between 1 and 11.

[0018] Some patients treated with reboxetine may have, and/or may be selected for having, an Epworth Sleepiness Scale (ESS) score that is at least about 10, at least about 11, at least about 12 at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 20 at least about 21, at least about 22, at least about 23, at least about 24, about 10 to 11, about 11 to 12, about 12 to 13, about 13 to 14, about 14 to 15, about 15 to 16, about 16 to 17, about 17 to 18, about 18 to 19, about 19 to 20, about 20-21, about 21-22, about

6/66 of 22-23, about 23-24, about 10-13, about 13-16, about 16-19, about 19-22, or about 22-24.

[0019] Some patients treated with reboxetine may have, and/or may be selected for having, a Maintenance of Wakefulness Test (MWT) score that is less than about 1 minute, less than about 2 minutes, less less than about 3 minutes, less than about 4 minutes, less than about 5 minutes, less than about 6 minutes, less than about 7 minutes, less than about 8 minutes, less than about 9 minutes, less than about 10 minutes, less than about 11 minutes, less than about 12 minutes, less than about 13 minutes, less than about 14 minutes, less than about 14 minutes 15 minutes, less than about 16 minutes, less than about 17 minutes, less than about 18 minutes, less than about 19 minutes, less than about 20 minutes, about 0-1 minute, about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8 minutes about 8-9 minutes, about 9-10 minutes, about 10-11 minutes, about 11-12 minutes, about 12-13 minutes, about 13-14 minutes, about 14-15 minutes , about 15-16 minutes, about 16-17 minutes, about 17-18 minutes, about 18-19 minutes, about 19-20 minutes, about 0-4 minutes, about 4-8 minutes, about 8-12 minutes, about 12-16 minutes, about 16-20, or about 0-19 minutes.

[0020] In some embodiments, the patient has had, and/or may be selected to have had, symptoms of narcolepsy for about 1-5 years, about 5-10 years, about 10-15 years, about 15- 20 years old, about 20-25 years old, about 25-30 years old, about 30-35 years old, about 35-40 years old, about 40-45 years old, about 45-50 years old, about 50-55 years old years, about 55-60 years, about 60-65 years, about 65-70 years, about 70-75, or more than 75 years before receiving reboxetine for treatment.

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[0021] In some modalities, patient has, and/or may be selected for, an age of about 0-5 years, about 5-10 years, about 10-15 years, about 15-20 years, about 20-25 years old, about 25-30 years old, about 30-35 years old, about 35-40 years old, about 40-45 years old, about 45-50 years old, about 50-55 years old, about 55-60 years old, about 60-65 years old, about 65-70 years old, about 70-75 years old, or more than 75 years old before receiving reboxetine for treatment.

[0022] Some patients treated with reboxetine for narcolepsy (eg with cataplexy and/or EDS) may be and/or may be selected for being female.

[0023] Some patients treated with reboxetine for narcolepsy (eg with cataplexy and/or EDS) may be and/or may be selected for being male.

[0024] Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, any clinically significant conditions with the potential to cause EDS. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, any clinically significant mental disorders. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, any type of depression that was not caused by narcolepsy. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, any sleepiness caused by depression that was not caused by narcolepsy. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, an affective disorder. Some patients treated with reboxetine for narcolepsy

8 / 66 (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a mental disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a functional neurologic disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a movement disorder. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a dementia some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a motor neuron disease.

[0025] Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a neurodegenerative disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a seizure disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, headaches. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a depression. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, major depressive disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a treatment-resistant depression.

[0026] Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be

9/66 selected for not having treatment-resistant, bipolar depression. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, bipolar disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, cyclothymia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a seasonal affective disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a mood disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, chronic depression (eg, dysthymia). Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a psychotic depression.

[0027] Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a postpartum depression. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a premenstrual dysphoric disorder (PMDD). Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a situational depression. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, an atypical depression. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a mania.

10 / 66 Some patients treated with reboxetine for narcolepsy (eg with cataplexy and/or EDS) may not have, and/or may be selected for not having, an anxiety disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, attention deficit disorder (ADD).

[0028] Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, attention deficit hyperactivity disorder (ADDH). Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, attention deficit hyperactivity disorder (AD/H D). Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a manic condition. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, an obsessive-compulsive disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a bulimia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, obesity or weight gain. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a chronic fatigue syndrome.

[0029] Some patients treated with reboxetine for narcolepsy (eg with cataplexy and/or EDS) may not have, and/or may be selected for not having, a premenstrual syndrome. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or

11 / 66 EDS) may not have, and/or may be selected for not having, a substance abuse or addiction. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a nicotine addiction. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, psychogenic sexual dysfunction. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a pseudobulbar syndrome. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for, emotional lability.

[0030] Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, an anxiety disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a phobia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a generalized anxiety disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a social anxiety disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a panic disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, an agoraphobia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be

12/66 selected for not having an obsessive-compulsive disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, post-traumatic stress disorder (PTSD). Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a mania.

[0031] Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a manic-depressive illness. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a hypomania. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, unipolar depression. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a stress disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a somatoform disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a personality disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a psychosis.

[0032] Some patients treated with reboxetine for narcolepsy (eg with cataplexy and/or EDS) may not have, and/or may be selected for not having, schizophrenia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a delusional disorder.

13 / 66 Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a schizoaffective disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a schizotypy. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, aggression. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, aggression in Alzheimer's disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, agitation. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, agitation in Alzheimer's disease.

[0033] Some patients treated with reboxetine for narcolepsy (eg with cataplexy and/or EDS) may not have, and/or may be selected for not having, a chemical dependency. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, cocaine addiction. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, addiction to or dependence on a psychostimulant. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, crack addiction or dependence. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, cocaine addiction or dependence. Some patients treated with

14 / 66 reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, addiction to or dependence on a stimulant drug. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, methamphetamine addiction or dependence. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, nicotine addiction or dependence.

[0034] Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, alcohol addiction or dependence. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, an opioid addiction or dependence. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, addiction to or dependence on an anxiolytic and/or hypnotic drug. Some patients treated with reboxetine for narcolepsy (eg, with

[0035] cataplexy and/or EDS) may not have, and/or may be selected for not having, addiction to, or dependence on, cannabis (marijuana). Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, an amphetamine addiction or dependence. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, addiction to or dependence on a hallucinogen. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, an addiction to or dependence on phencyclidine.

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[0036] Some patients treated with reboxetine for narcolepsy (eg with cataplexy and/or EDS) may not have, and/or may be selected for not having, addition to or dependence on a volatile solvent. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, addiction to or dependence on a volatile nitrite. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, senile dementia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, Alzheimer's-type dementia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, memory loss. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, an amnesia/amnesiac syndrome. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, epilepsy. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, disturbances of consciousness.

[0037] Some patients treated with reboxetine for narcolepsy (eg with cataplexy and/or EDS) may not have, and/or may be selected for not having, a coma. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, impaired attention. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a speech disorder. Some patients treated

16 / 66 with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a vocal spasm. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, Parkinson's disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a Lennox-Gastaut syndrome.

[0038] Some patients treated with reboxetine for narcolepsy (eg with cataplexy and/or EDS) may not have, and/or may be selected for not having, autism. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a hyperkinetic syndrome. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, schizophrenia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have had, and/or may be selected for not having, a stroke. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a cerebral infarction. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a brain bleed. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, cerebral arteriosclerosis. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a cerebral venous thrombosis. Some patients treated with reboxetine for

17 / 66 narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a head injury.

[0039] Some patients treated with reboxetine for narcolepsy (eg with cataplexy and/or EDS) may not have, and/or may be selected for not having, an akinesia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, an athetosis. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, an ataxia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a ballismus. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a hemiballismus. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a bradykinesia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, cerebral palsy.

[0040] Some patients treated with reboxetine for narcolepsy (eg with cataplexy and/or EDS) may not have, and/or may be selected for not having, a chorea. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for, Huntington's disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a rheumatic chorea. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a Sydenham chorea. Some

18 / 66 patients treated with reboxetine for narcolepsy (eg with cataplexy and/or EDS) may not have, and/or may be selected for not having, dyskinesia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, tardive dyskinesia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a dystonia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a blepharospasm.

[0041] Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a spasmodic torticollis. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a dopamine-responsive dystonia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, restless legs syndrome (RLS). Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a tremor. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, an essential tremor. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, Tourette's syndrome. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, Wilson's disease.

19 / 66

[0042] Some patients treated with reboxetine for narcolepsy (eg with cataplexy and/or EDS) may not have, and/or may be selected for not having, a vascular dementia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a dementia with Lewy bodies. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be

[0043] selected for not having a mixed dementia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a frontotemporal dementia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, Creutzfeldt-Jakob disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a normal pressure hydrocephalus. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, Wernicke-Korsakoff syndrome.

[0044] Some patients treated with reboxetine for narcolepsy (eg with cataplexy and/or EDS) may not have, and/or may be selected for not having, Pick's disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a progressive bulbar palsy. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, primary lateral sclerosis (PLS). Some patients treated with reboxetine for narcolepsy (eg, with

20 / 66 cataplexy and/or EDS) may not have, and/or may be selected for not having, progressive muscle atrophy. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a post-polio syndrome (PPS). Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a spinal muscular atrophy (SMA).

[0045] Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a spinal motor atrophy. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, Tay-Sach disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a Sandhoff disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, hereditary spastic paraplegia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, Alzheimer's disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a prion disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a cerebellar ataxia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a spinocerebellar ataxia (SCA).

21 / 66

[0046] Some patients treated with reboxetine for narcolepsy (eg with cataplexy and/or EDS) may not have, and/or may be selected for not having, a spinal muscular atrophy (SMA). Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, bulbar muscular atrophy. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a Friedreich's ataxia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, Lewy body disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, multiple sclerosis (MS). Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, multisystem atrophy.

[0047] Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, Shy-Drager syndrome. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a corticobasal degeneration. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a progressive supranuclear palsy.

[0048] Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be

22/66 selected for not having Wilson's disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, Menkes disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, an adrenoleukodystrophy. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, an autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a muscular dystrophy.

[0049] Some patients treated with reboxetine for narcolepsy (eg with cataplexy and/or EDS) may not have, and/or may be selected for not having, a Charcot-Marie-Tooth (CMT) disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, hereditary spastic paraparesis. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a neurofibromatosis. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, an olivopontocerebellar atrophy or degeneration. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, striatonigral degeneration. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, Guillain-Barré syndrome. Some patients treated with reboxetine for narcolepsy (eg, with

23 / 66 cataplexy and/or EDS) may not have, and/or may be selected for not having, a spastic paraplesia.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, epileptic seizures.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, non-epileptic seizures.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, epilepsy.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, febrile seizures.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, partial seizures.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, simple partial seizures.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, Jacksonian seizures.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, complex partial seizures.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a continuous partial epilepsy.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, generalized seizures.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, generalized tonic-clonic seizures.

Some

24 / 66 patients treated with reboxetine for narcolepsy (eg with cataplexy and/or EDS) may not have, and/or may be selected for not having, an absence seizure.

[0050] Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, atonic seizures. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, myoclonic seizures. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, juvenile myoclonic seizures. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, infantile spasm. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, status epilepticus. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, Rett syndrome. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a tinnitus. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, disturbance of consciousness. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a sexual dysfunction. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a vocal disorder due to uncontrolled muscle spasms in the larynx. Some

25 / 66 patients treated with reboxetine for narcolepsy (eg with cataplexy and/or EDS) may not have, and/or may be selected for not having, abductor spasmodic dysphonia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, adductor spasmodic dysphonia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, muscle tension dysphonia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, a vocal tremor. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or

[0051] EDS) may not have, and/or may be selected for not having, a diabetic neuropathy. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, chemotherapy-induced neurotoxicity. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, methotrexate neurotoxicity. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, stress urinary incontinence. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, urge urinary incontinence. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for not having, fecal incontinence. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or

26 / 66 EDS) may not have, and/or may be selected for not having, erectile dysfunction.

[0052] Cataplexy includes a sudden reduction or loss of muscle tone while the patient is awake, which can affect specific parts of the body or the entire body, such as eyelids, head droop, facial sagging and/or twitching, slurred speech , jaw weakness, weakness in the arms, shoulders, or hands and/or bowing of the knees. Cataplexy may be pathognomonic of narcolepsy. Cataplexy can be triggered by strong emotions, such as laughter, jubilation, surprise, or anger. Cataplexy can be partial or localized (in about 75% of cases) and is usually short-lived. The frequency of cataplexy can vary widely. Narcolepsy with cataplexy can be socially disabling and isolating.

[0053] Some patients being treated with reboxetine may have, and/or may be selected for having, narcolepsy with cataplexy (type 1) which is an autoimmune disorder resulting in a loss of hypocretin (orexin) producing neurons in the CNS. Hypocretins (orexins) are hypothalamic-specific peptides with neuroexcitatory activity. A patient being treated with reboxetine for narcolepsy with cataplexy is, and may be selected for, a predisposed individual with specific genetic markers including human leukocyte antigen (H LA DQBl/06:02) and/or alpha T cell receptor variants Some patients being treated with reboxetine may not have, and may be selected for not having, narcolepsy associated with loss of hypocretin neurons. Some patients being treated with reboxetine may have, and may be selected for, narcolepsy precipitated by seasonal Streptococcus infections, H1N1 influenza, and/or H1N1 vaccination in genetically predisposed individuals.

[0054] Existing treatments for narcolepsy only address some of its symptoms, provide variable efficacy, and have side effects

27 / 66 significant. Additionally, all existing treatments are controlled substances.

[0055] According to the FDA, “there is an ongoing need for effective and tolerable treatment options for patients to improve their daily functioning.” (The Voice of the Patient, A series of reports from the U.S. Food and Drug Administration's (FDA's) Patient-Focused Drug Development Initiative, Narcolepsy, June 2014. pg. 25)

[0056] In some embodiments, administering reboxetine can reduce daytime sleepiness by at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 1-5%, about about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, for example , compared to baseline, placebo, or some other appropriate control (including an active control, such as a stimulant (eg, methylphenidate, an amphetamine), modafanil, armodaphanil, sodium oxybate, a tricyclic antidepressant, a selective inhibitor serotonin reuptake inhibitor (SSRI), or a selective norepinephrine reuptake inhibitor (SNRI) ).

[0057] In some embodiments, administering reboxetine can reduce cataplexy by at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 1-5%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70 -80%, about 80-90%, about 90-100%, about 1-25%, about

28 / 66 25-50%, about 50-75%, or about 75-100%, for example, compared to baseline, placebo, or some other appropriate control (including an active control, such as a stimulant (eg, methylphenidate, an amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SNRI).

[0058] In some embodiments, administering reboxetine can reduce the number of cataplexy attacks by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 40% 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20 %, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90% , about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, at least about 1 per week at least

[0059] About 2 a week, at least about 3 a week, at least about 4 a week, at least about 5 a week, at least about 6 a week, at least about 7 a week, at least at least about 8 a week, at least about 9 a week, at least about 10 a week, at least about 12 a week, at least about 14 a week, at least about 16 a week, at least about 18 a week, at least about 20 a week, at least about 22 a week, at least about 24 a week, at least about 26 a week, at least about 28 a week, at least about 30 a week, at least about 40 a week, at least about 50 a week, about 1-2 a week, about 2-3 a week, about 3-4 a week, about 4-5 a week , about 5-6 a week, about 6-7 a week, about 7-8 a week, about 8-9 a week, about 9-10 a week, about 10-11 a week, about from 11-12 a week a, about 12-

29 / 66 13 a week, about 13-14 a week, about 14-15 a week, about 15-16 a week, about 16-17 a week, about 17-18 a week, about 18 -19 a week, about 19-20 a week, about 1-10 a week, about 10-20 a week, about 20-30 a week, about 30-40 a week, about 40-50 per week, about 50-60 per week, or more, e.g. compared to baseline, placebo, or some other appropriate control (including an active control, such as a stimulant (e.g., methylphenidate, an amphetamine) , modafanil, armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SN RI).

[0060] In some embodiments, administering reboxetine can reduce the ESS score by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50% , at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, at least about 1, at least about 2, at least about 2 of 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11 , at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 17 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, about 24, about 1-2, about 2-3, about 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10, about 10-11, about 11- 12, about 12-13, about 13-14, about 14-15, about 15-16, about 16-17, about 17-18, about

30 / 66 18-19, about 19-20, about 20-21, about 21-22, about 22-23, about 23-24, about 1-4, about 4-8, about of 8-12, about 12-16, about 16-20, about 20-24, about 1-12, or about 12-24 for example, compared to baseline, placebo, or some other appropriate control (including a

[0061] active control, such as a stimulant (eg, methylphenidate, an amphetamine), modafanil, armodaphanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SN RI).

[0062] In some embodiments, administering reboxetine can reduce the MWT score by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50% , at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, at least about 1 minute, at least about 2 minutes, at least at least about 3 minutes, at least about 4 minutes, at least about 5 minutes, at least about 6 minutes, at least about 7 minutes, at least about 8 minutes, at least about 9 minutes, at least about 10 minutes, at least about 11 minutes, at least about 12 minutes, at least about 13 minutes, at least ce 14 minutes, at least about 15 minutes, at least about 16 minutes, at least about 17 minutes, at least about 18 minutes, at least about 19 minutes, at least about 20 minutes, about 1 -2 minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8 minutes, about 8- 9 minutes, about 9-10 minutes, about 10-11 minutes, about 11-12 minutes, about 12-13 minutes, about 13-14 minutes, about 14-15 minutes, about

31/66 15-16 minutes, about 16-17 minutes, about 17-18 minutes, about 18-19 minutes, about 19-20 minutes, about 20-21 minutes, about 21-22 minutes, about 22-23 minutes, about 23-24 minutes, about 24-26 minutes, about 1-4 minutes, about 4-8 minutes, about 8-12 minutes, about 12-16 minutes, about 16-20 minutes, about 1-10 minutes, or about 10-20 minutes, for example, compared to baseline, placebo, or some other appropriate control (including an active control, such as a stimulant (for (e.g., methylphenidate, an amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SN RI).

[0063] In some embodiments, administering reboxetine can reduce the UNS cataplexy score by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 40% 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20 %, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90% , about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, at least about 1, at least about 2, at least at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, about 11 , about 2-3, about 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10, about from 2-4, about 4-6, about 6-8, about of 8-10, about 10-11, about 2-6, or about 6-10, about 5-11, for example, compared to baseline, placebo, or some other appropriate control (including a active control, such as a stimulant (eg, methylphenidate, an amphetamine), modafanil, armodaphanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SN RI).

32 / 66

[0064] In some embodiments, administering reboxetine can increase sleep latency in the MSLT by at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100 %, about 50-75%, or about 75-100%, at least about 1 minute, at least about 2 minutes, at least about 3 minutes, at least about 4 minutes, at least about 5 minutes minutes, at least about 6 minutes, at least about 7 minutes, at least about 8 minutes, at least about 9 minutes, at least about 10 minutes, at least about 11 minutes, at least about 12 minutes , at least about 13 minutes, at least about 14 minutes, at least about 15 minutes, at least about 16 minutes, at least about 17 minutes, at least about 18 minutes, at least about 19 minutes, fur minus about 20 minutes, about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8 minutes, about 8-9 minutes, about 9-10 minutes, about 10-11 minutes, about 11-12 minutes, about 12-13 minutes, about 13-14 minutes, about 14 minutes -15 minutes, about 15-16 minutes, about 16-17 minutes, about 17-18 minutes, about 18-19 minutes, about 19-20 minutes, about 1-4 minutes, about 4- 8 minutes, about 8-12 minutes, about 12-16 minutes, about 16-20 minutes, about 1-10 minutes, or about 10-20 minutes, e.g. compared to baseline, placebo , or some other appropriate control (including an active control, such as a stimulant (e.g., methylphenidate, an amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SN RI).

[0065] In some modalities, administering reboxetine may reduce nightmares or unpleasant dreams (such as frequent nightmares and

33 / 66 frequent unpleasant dreams) by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, for example, compared to baseline, placebo, or some other control appropriate (including an active control, such as a stimulant (eg, methylphenidate, an amphetamine), modafanil, armodaphanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SN RI).

[0066] In some embodiments, administering reboxetine can reduce hallucinations by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 40%. at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80 -90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, for example, compared to baseline, placebo, or some other appropriate control (including an active control, such as a stimulant (e.g., methylphenidate, an amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SN RI).

[0067] In some embodiments, administering reboxetine can reduce sleep paralysis by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40% , at least about 50%, at least about 60%, at least about

34 / 66 of 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, for example, compared to baseline, placebo, or some other appropriate control (including an active control, such as a stimulant (e.g., methylphenidate, an amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SN RI).

[0068] In some embodiments, administering reboxetine can reduce fragmented nighttime sleep by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40% , at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about from 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, for example, compared to line base, placebo, or some other appropriate control (including an active control, such as a stimulant (e.g., methylphenidate, an amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SNRI).

[0069] In some modalities, administering reboxetine can reduce narcolepsy-related accidents by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40 %, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10% , about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about

35 / 66 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, e.g., compared to baseline, placebo, or some other appropriate control (including an active control, such as a stimulant (e.g., methylphenidate, an amphetamine), modafanil, armodaphanil, oxybate sodium, a tricyclic antidepressant, an SSRI, or an SN RI).

[0070] In some modalities, administering reboxetine can reduce narcolepsy-related lesions by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40 %, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10% , about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, for example, compared to line baseline, placebo, or some other appropriate control (including an active control, such as a stimulant (eg, methylphenidate, an amphetamine), modafanil, armodaphanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SN RI) .

[0071] In some modalities, administering reboxetine can reduce narcolepsy-related fatalities by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10 %, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80% , about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, for example, compared to baseline, placebo, or some other

36 / 66 appropriate control (including an active control, such as a stimulant (eg, methylphenidate, an amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SNRI).

[0072] Reboxetine (with the structure shown below) is a highly selective and potent norepinephrine reuptake inhibitor that has the potential to treat key symptoms of narcolepsy such as cataplexy or EDS. Unlike existing treatments for narcolepsy, reboxetine is not a controlled substance. Thus, reboxetine treatment would not be scheduled.

[0073] (reboxetine)

[0074] Unless otherwise indicated, any reference herein to a compound, such as reboxetine, by structure, name, or otherwise, includes pharmaceutically acceptable salts; free acids or bases; alternative solid forms such as polymorphs, solvates, hydrates, etc.; tautomers; enantiomers; deuterium-modified compounds, such as deuterium-modified reboxetine; or any chemical species that can readily convert to a compound described herein under conditions in which the compounds are used as described herein.

[0075] In some embodiments, reboxetine is in salt form, in free base form, or may contain an excess (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or at least 99%) (+)-reboxetine or an excess (e.g. at least 60%, at least 70%, at least 80%, at least 90%, at least at least 95%, at least 97%, or at least 99%) (-)-reboxetine.

[0076] For the treatment of narcolepsy, reboxetine may be administered in a manner that results in 1) a first local maximum in

37 / 66 plasma concentration of reboxetine and 2) a second local maximum in plasma concentration of reboxetine.

[0077] There are several possible ways in which reboxetine can be administered in a way that results in a first local maximum in plasma reboxetine concentration and a second local maximum in plasma reboxetine concentration. A local maximum described herein is a maximum of a plasma concentration over a period of interest in an individual patient, which is not necessarily the Cmax. The local maximum can be lower or the same as the C max. One possible way to administer reboxetine in a way that results in a first local maximum in plasma reboxetine concentration and a second local maximum in plasma reboxetine concentration is to administer a first reboxetine-containing dosage form and, at a later time, a second dosage form. dosage containing reboxetine. Doses are administered at times that result in a first local maximum in plasma reboxetine concentration and a second local maximum in

[0078] plasma concentration of reboxetine. For example, the second dosage form can be administered less than half a day after the first dosage form, for example about 1-8 hours, about 8-12 hours, about 2-6 hours, about 1- 2 hours, about 2-3 hours, about 3-4 hours, about 4-5 hours, about 5-6 hours, about 6-7 hours, about 7-8 hours, about 1-3 hours hours, about 2-4 hours, about 3-5 hours, about 4-6 hours, about 5-7 hours, about 6-8 hours, or about 7-10 hours after the first form of dosage, or any period within a range limited by any of these values.

[0079] Another method involves administering a single dosage form that comprises a first delivery component and a

38/66 second release component. Both the first release component and the second release component comprise reboxetine.

[0080] In some embodiments, the first dosage form administered in a day, the single dosage form administered during the day, or the first of two or more dosage forms administered during the day, is administered shortly after awakening, such as such as within about 3 hours, within about 2 hours, within about 1.5 hours, within about 1 hour, within about 30 minutes, or within about 15 minutes of waking up one night of sleep.

[0081] For a single dosage form comprising a first releasing component and a second releasing component that is administered in one day, the first releasing component may release reboxetine, it may begin releasing reboxetine, or it may result in a first local maximum in plasma reboxetine concentration, about 0-30 minutes, about 30-60 minutes, about 60-90 minutes, or about 90-120 minutes after the dosage form is administered orally, or any period in a range limited by any of these values. The second releasing component may release reboxetine after the first releasing component releases reboxetine, or it may cause an increase in plasma reboxetine concentration or a second local maximum in plasma reboxetine concentration, which is about 1-10 hours, about 2 - 6 hours, about 1-2 hours, about 2-3 hours, about 3-4 hours, about 4-5 hours, about 5-6 hours, about 6-7 hours, about 1- 3 hours, about 2-4 hours, about 3-5 hours, about 4-6 hours, about 5-7 hours, about 6-8 hours, or about 7-10 hours after reboxetine is released for the first time of the first component of release, or after the first local maximum in plasma reboxetine concentration, or at any time within a range limited by any of these values.

39 / 66

[0082] The first release component and the second release component may be incorporated into a single dosage form (such as a pill, tablet, capsule, caplet (long coated oval), or lozenge). In one embodiment, the first release component would be located in one of the outer layers of the dosage form and the second release component would be located in one of the inner layers of the same dosage form.

[0083] In another embodiment, the first release component is located in a first layer of the dosage form, and the second release component is located in a second layer of the same dosage form. The two layers are distinct and may or may not be in contact with each other. In some embodiments, the two layers are stacked on top of each other and physically bonded together in a bilayer structure (e.g., where the larger surfaces of the two layers come into contact with each other, or the layers are thin compared to each other. layer dimensions). In some embodiments, the two layers are positioned close together and physically linked in a bilayer structure (eg, where the layers are thicker than the other dimensions of the layers).

[0084] In another embodiment, the first release component and the second release component may be separately constructed into their own specific granules, particles, or the like, wherein the particles of the first release component are formulated to release reboxetine before wherein the second release component particles release reboxetine and wherein both the first release component particles and the second release component particles are combined into a single dosage form, such as a capsule, pill, tablet, caplet, lozenge or similar, and the

40 / 66 two release components may or may not be physically linked together.

[0085] In some embodiments, the first maximum local plasma concentration of reboxetine occurs about 1-30 minutes, about 30-60 minutes, about 1-2 hours, about 2-3 hours, or about 3-4 hours. hours after the single dosage form or the first dosage form is administered, or at any time within a range limited by either of these values. Generally, the second maximum local plasma concentration of reboxetine occurs less than half a day after the first maximum local plasma concentration of reboxetine, such as about 1-10 hours, about 1-2 hours, about 2-6 hours , about 2-3 hours, about 3-4 hours, about 4-5 hours, about 5-6 hours, about 6-7 hours, about 7-8 hours, about 1-3 hours, about 2-4 hours, about 3-5 hours, about 4-6 hours, about 5-7 hours, about 6-8 hours, or about 7-10 hours after the first maximum local plasma concentration of reboxetine, or any period in a range limited by any of these values.

[0086] For dosage forms containing a first releasing component and a second releasing component, the first releasing component is associated with the first local maximum in plasma concentration of reboxetine where the first releasing component releases the reboxetine which contributes with the first local maximum in plasma reboxetine concentration. For example, the first releasing component could release reboxetine faster or earlier than the second releasing component, so most of the reboxetine contributing to the first maximum local plasma concentration that was released from the first releasing component.

[0087] For dosage forms containing a first release component and a second release component, the second release component is associated with the second local maximum in concentration

41 / 66 plasma reboxetine in which the second releasing component releases reboxetine which contributes to the second local maximum in plasma reboxetine concentration. For example, the second releasing component could delay the release of its reboxetine so that, at a time when the plasma concentration of reboxetine is decreasing after the first local maximum, the second releasing component releases a sufficient amount of reboxetine to increase again the plasma concentration of reboxetine so that the second local maximum in plasma concentration of reboxetine is reached.

[0088] For dosage forms containing a first release component and a second release component, any suitable amount of reboxetine can be present in the first release component, such as about 1-10 mg, about 0.1-2 mg, about 0.5-1.5 mg, about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg, about 2.5-3.5 mg, about 3-4 mg, about 3.5-4.5 mg , about 4-5mg, about 4.5-5.5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 1-3 mg, about 2-4 mg, about 3-5 mg, about 4-6 mg, about 5-7 mg, about 7-10 mg, about 4 mg, about 5 mg, about

0.0003-0.006 mmol, about 0.006-0.009 mmol, about 0.009-0.012 mmol, about 0.012-0.015 mmol, about 0.015-0.018 mmol, about 0.018-0.021 mmol, about 0.021-0.024 mmol, about 0.024 -0.027 mmol, about

0.027-0.03 mmol, about 0.03-0.033 mmol, or any amount in a range limited by any of these values.

[0089] For dosage forms containing a first release component and a second release component, any suitable amount of reboxetine can be present in the second release component, such as about 0.1-2 mg, about 0.5-1.5 mg, about 1-3 mg, about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg, about 2.5-3.5 mg, about 3-4 mg, about 2-4 mg, about 3-5mg, about 3.5-4.5mg, about

42 / 66 from 4-5mg, about 4.5-5.5mg, about 5-6mg, about 4-6mg, about 6-7mg, about 7-8mg, about 8-9mg , about 9-10 mg, about 5-7 mg, about 7-10 mg, about 4 mg, about 5 mg, about 0.0003-0.006 mmol, about 0.006-0.009 mmol, about 0.009- 0.012 mmol, about 0.012-0.015 mmol, about 0.015-0.018 mmol, about 0.018-0.021 mmol, about

0.021-0.024 mmol, about 0.024-0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, or any amount in a range limited by any of these values.

[0090] The dose of reboxetine may increase gradually over time, such as over 1, 2, 3, 4, 5, 6, or 7 days, up to a maintenance dose, which is a total dose given each day (e.g. , a 10mg maintenance dose could be a 10mg daily dose, or 5mg given twice daily for a total of 10mg daily). In some embodiments, the maintenance dose may be 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 10-11 mg, about 11-12 mg, about 12-13 mg, about 13-14 mg, about 14-15 mg, about 15-16 mg, about 16-17 mg, about 2-5 mg, about 5-8 mg, about 8-11 mg, about 11-14 mg, about 14-17 mg, about 17-20 mg, about 0.006-0.009 mmol, about 0.009-0.012 mmol, about 0.012-0.015 mmol, about 0.015-0.018 mmol, about

0.018-0.021 mmol, about 0.021-0.024 mmol, about 0.024-0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, about 0.033-0.036 mmol, about 0.036-0.039 mmol, about 0.039 -0.042 mmol, about

0.042-0.045 mmol, about 0.045-0.048 mmol, about 0.048-0.051 mmol, about 0.051-0.054 mmol, about 0.054-0.057 mmol, about 0.057-0.06 mmol, about 0.06-0.063 mmol, about 0.063 -0.066 mmol, about

0.066-0.069 mmol, about 0.006-0.01 mmol, about 0.01-0.02 mmol, about 0.02-0.03 mmol, about 0.03-0.04 mmol, about 0.04-0.05 mmol, about 0.05-0.06 mmol, about 0.06 -0.07 mmol, or about 0.07-0.08

43 / 66 mmol. The maintenance dose can be administered for at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least 4 months, at least 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least 1.5 years, at least at least 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 10 years, at least about 20 years, or more.

[0091] In some embodiments, the first release component provides immediate release of reboxetine. In some embodiments, the first release component provides delayed release of reboxetine. In some embodiments, the first release component provides sustained release of reboxetine.

[0092] In some embodiments, the second release component provides immediate release of reboxetine. In some embodiments, the second release component provides delayed release of reboxetine. In some embodiments, the second release component provides sustained release of reboxetine.

[0093] In some embodiments, the first release component provides immediate release of reboxetine, and the second release component provides delayed release of reboxetine. In some embodiments, the first release component provides immediate release of reboxetine, and the second release component provides sustained release of reboxetine.

[0094] With respect to methods in which reboxetine is administered in a first dosage form containing reboxetine and a second

In the reboxetine-containing dosage form, any suitable amount of reboxetine may be present in the first dosage form, such as about 1-10 mg, about 0.1-1 mg, about 0.1-2 mg, about 0.5- 1.5mg, about 1-3mg, about 1-2mg, about 1.5-2.5mg, about 2-3mg, about

2.5-3.5mg, about 3-4mg, about 3.5-4.5mg, about 4-5mg, about

4.5-5.5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 2-4mg, about 3 -5mg, about 4-6mg, about 5-7mg, about 7-10mg, about 4mg, about 5mg, about

0.0003-0.006 mmol, about 0.006-0.009 mmol, about 0.009-0.012 mmol, about 0.012-0.015 mmol, about 0.015-0.018 mmol, about 0.018-0.021 mmol, about 0.021-0.024 mmol, about 0.024 -0.027 mmol, about

0.027-0.03 mmol, about 0.03-0.033 mmol, or any amount in a range limited by any of these values.

[0095] With respect to methods wherein reboxetine is administered in a first reboxetine-containing dosage form and a second reboxetine-containing dosage form, any suitable amount of reboxetine may be present in the second dosage form, such as about 0.1- 1 mg, about 0.1-2 mg, about 0.5-1.5 mg, about 1-3 mg, about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg, about 2.5-3.5 mg, about 3-4 mg, about 3.5-4.5 mg, about 4-5 mg, about 4.5-5.5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg , about 8-9 mg, about 9-10 mg, about 2-4 mg, about 3-5 mg, about 4-6 mg, about 5-7 mg, about 7-10 mg, about 4 mg, about 5 mg, about 0.0003-0.006 mmol, about 0.006-0.009 mmol, about 0.009-0.012 mmol, about 0.012-0.015 mmol, about 0.015-0.018 mmol, about 0.018-0.021 mmol, about

0.021-0.024 mmol, about 0.024-0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, or any amount in a range limited by any of these values.

45 / 66

[0096] In some embodiments, the first dosage form provides immediate release of reboxetine. In some embodiments, the first dosage form provides delayed release of reboxetine. In some embodiments, the first dosage form provides sustained release of reboxetine.

[0097] In some embodiments, the second dosage form provides immediate release of reboxetine. In some embodiments, the second dosage form provides delayed release of reboxetine. In some embodiments, the second dosage form provides sustained release of reboxetine.

[0098] With respect to single dosage forms containing both a first delivery component and a second delivery component, in some embodiments, the single dosage is administered within two hours of awakening from a night's sleep.

[0099] For some modalities where more than one dosage form is given, the first dosage form may be administered within two hours of awakening from a night's sleep.

[00100] There are many factors that can affect the overall time required for a pharmaceutical substance such as reboxetine to be completely absorbed and/or reach a maximum plasma concentration in a human. Some of these factors include a human patient's age, weight, gender, stress level, stomach contents, stomach pH level, and the presence of other medications. The time required to reach a maximum plasma concentration of the drug such as reboxetine may also be affected by the time of day that the drug such as reboxetine is taken and the physical activity level of the human patient. Another factor that may affect the time required to reach a maximum plasma concentration of a drug such as reboxetine is the presence

46 / 66 or absence of a controlled release coating on the drug such as reboxetine.

[00101] Controlled release includes: immediate release of the pharmaceutical substance such as reboxetine at a certain time or in a certain area of the body; delayed release of a pharmaceutical substance; sustained release of the pharmaceutical substance at a certain time or place in the body; or an extended release of a pharmaceutical substance such as reboxetine.

[00102] Reboxetine is normally rapidly absorbed in human patients, reaching a peak plasma concentration in about 2-4 hours. To achieve a delay in the time required to reach a maximum plasma concentration, a coating or controlled release mixture may be employed.

[00103] Delayed release is a general drug dispensing term that describes the form of an oral drug that does not immediately discharge its active pharmaceutical component into a patient's mouth or stomach. While there may be several ways to achieve delayed release, delayed release of reboxetine can be achieved by completely or partially wrapping the reboxetine, e.g., in the second delivery component, with a coating or layer (e.g., an inner release liner). controlled) that does not dissolve immediately when swallowed. For example, the material of the coating or layer may slowly dissolve in the stomach and/or slowly disintegrate by chemical reaction, such as hydrolysis, in the stomach until the layer can no longer prevent reboxetine from coming into contact with gastric juice.

[00104] In some embodiments, the delayed release coating ensures delivery through the stomach and into the intestines. Once in the duodenum, the lining can begin to decompose and begin to

47/66 release reboxetine. In some cases, reboxetine can be completely released into the duodenum. In some embodiments, reboxetine may be partially released into the duodenum and partially released into the jejunum. In some cases, reboxetine can be completely released into the jejunum. In some cases, reboxetine may be partially released in the jejunum and partially released in the ileum. In some cases, reboxetine can be completely released in the ileum. In some cases, reboxetine may be partially released into the duodenum, jejunum, and ileum. In some embodiments, reboxetine may be partially released in the ileum and partially released in the colon. In some cases, reboxetine can be completely released into the colon.

[00105] The time of delayed release, for example between the release of the first reboxetine component and the second reboxetine component, can be adjusted by using a material that dissolves or disintegrates more or less slowly in the digestive system, adjusting it whether the thickness of the coating layer or coating material (eg a thicker layer would provide a longer time) and/or using materials whose properties are pH sensitive. For example, materials that are less stable, or more soluble, at acidic pHs may dissolve or disintegrate more quickly in the stomach because the stomach pH is lower than the pH in the intestines. Conversely, materials that are stable at low pH but less stable at higher pH may later dissolve or disintegrate because of the time the dosage form takes to travel through the gastrointestinal tract.

[00106] A controlled release formulation containing reboxetine may be coated with one or more functional or non-functional coatings. Examples of functional coatings include polymeric controlled release coatings (i.e., release wraps

48 / 66), moisture barrier coatings, enteric polymeric coatings, and the like.

[00107] A controlled release polymer can be used for sustained release or for delayed release depending on the structure of the dosage form. For example, intercalating reboxetine throughout a controlled-release polymer can provide sustained release, as the drug will be released as long as the polymer is present in the gastrointestinal tract. Delayed release can be achieved by creating a barrier, such as a coating, that is intended to last for a short time (e.g. less than 12 hours, less than 10 hours, less than 6 hours, less than than 3 hours, etc.), so that when the barrier is penetrated, reboxetine is freely released. Barrier thickness can be used to control the lag time.

[00108] Any suitable controlled release polymer can be used, such as copolymers of acrylic acid and methacrylic acid and various esters thereof, e.g. methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer , poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polyacrylamide, poly(methacrylic acid anhydride) and methacrylate copolymers glycidyl.

[00109] Other suitable controlled release polymers include polymerizable quaternary ammonium compounds, for example, quaternized aminoalkyl esters and aminoalkyl amides of acrylic acid and methacrylic acid, for example, b-methacryloxyethyltrimethylammonium methosulfate, b-acryloxypropyltrimethylammonium chloride and methosulfate of trimethylaminomethylmethacrylamide. The quaternary ammonium atom may also be part of a heterocycle, as in methacryloxyethylmethylmorpholinium chloride or the corresponding piperidinium salt, or

49/66 may be attached to an acrylic acid group or a methacrylic acid group via a heteroatom-containing group, such as a polyglycol ether group. Other suitable polymerizable quaternary ammonium compounds include quaternized vinyl substituted nitrogen heterocycles such as methyl vinyl pyridinium salts, quaternized amino carboxylic acid vinyl esters, styryltrialkyl ammonium salts, and the like. Other polymerizable quaternary ammonium compounds include benzyldimethylammonioethyl methacrylate chloride, diethylmethylammonioethyl methacrylate and methacrylate methacrylate, N-trimethylammoniopropylmethacrylate chloride, and N-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride.

[00110] Delayed release can also be achieved using a controlled release polymer that targets a particular pH, with the understanding that, with proper fasting or feeding, the particular pH may correspond to a particular time after administration .

[00111] For some controlled release polymers, an acrylic or methacrylic polymer comprises one or more ammonium methacrylate copolymers. Ammonium methacrylate copolymers (such as those sold by Evonik under the EU DRAGIT® RS and RL trademarks) are fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. Ammonium groups are attached to the ester portion of the methacrylate (as 2-trimethylammonium-ethyl esters). The charged ammonium groups in these polymers make them insoluble and highly permeable with pH-independent swelling. These properties make these polymers useful for customized time-controlled release of the coated drug. In order to obtain a desirable dissolution profile for a given therapeutically active agent, such as reboxetine, two or more ammonium methacrylate copolymers with different physical properties can be incorporated. For example, it is known

50 / 66 that by changing the molar ratio of prepolymerized materials containing quaternary ammonium groups to prepolymerized materials containing uncharged neutral acrylic or methacrylic esters, the permeability properties of the resulting coating can be modified.

[00112] In other embodiments, the controlled release wrap additionally includes a polymer whose permeability is pH dependent, such as synthesized anionic polymers of methacrylic acid and methacrylic acid methyl ester. Such polymers are commercially available, for example, from Evonik under the tradenames EUDRAGIT® L and EUDRAGIT® S. The ratio of free carboxyl groups to esters is known to be 1:1 in EUDRAGIT® L and 1:2 in EUDRAGIT® S. EUDRAGIT® L is insoluble in acids and pure water, but becomes increasingly permeable above pH 5.0. This makes EUDRAGIT® L suitable for the targeted delivery of coated pharmaceutical substance such as coated reboxetine into the duodenum and jejunum of the small intestine. Thus, a EUDRAGIT® L coated drug substance can achieve a delay in peak plasma concentration, relative to an uncoated or immediate release drug substance (e.g. reboxetine in a first release component), from about 30 min to about 30 min. 1 hour, about 1-1.5 hours, about 1.5-2 hours, about 2-2.5 hours, about 2.5-3 hours, or about 3.5-4 hours.

[00113] EUDRAGIT® S is similar to EUDRAGIT® L, except that it becomes increasingly permeable above pH 7. This makes EUDRAGIT® S suitable for the targeted release of coated pharmaceutical substance such as coated reboxetine in the ileum of the small intestine and also in the colon. Thus, an EUDRAGIT® S coated drug substance can achieve a delay at maximum plasma concentration, relative to an uncoated or immediate release drug substance (e.g. reboxetine in a first component of

51/66 release), about 1-2 hours, about 2-3 hours, about 3-4 hours, about 4-5 hours, about 5-6 hours, about 6-7 hours, about 7-8 hours, about 8-9 hours, or about 9-10 hours.

[00114] A hydrophobic acrylic polymer coating may also include a polymer that is based on dimethylaminoethyl methacrylate and neutral methacrylic acid esters (such as EUDRAGIT® E, commercially available from Evonik). EUDRAGIT® E is not soluble in saliva (making it useful for taste and odor masking), but is soluble in gastric juice at pH 5 or less, which provides an immediate release of the pharmaceutical into the stomach. Reboxetine wrapped with an EUDRAGIT® E coating may release reboxetine, may begin to release reboxetine, or may reach a first local maximum in plasma reboxetine concentration, in a time of about 0-30 minutes, 30-60 minutes, 60- 90 minutes, or 90-120 minutes after the dosage form is administered orally, or any period within a range limited by any of these values.

[00115] A hydrophobic acrylic polymer coating may include a neutral copolymer based on a polymethacrylate, such as EUDRAGIT® N E (N E = neutral ester), commercially available from Evonik. EUDRAGIT® NE 30D Lacquer Films are insoluble in water and digestive fluids, yet permeable and swellable, providing another option for time-controlled release. EUDRAGIT® NE has a pH-independent sustained-release effect that can release a pharmaceutical substance such as reboxetine over a period of time, or it can delay the release for a period, where the time of release or delay is about 1-24 hours, about 1-18 hours, about 1-12 hours, about 1-8 hours, or about 1-6 hours.

[00116] In some embodiments, the controlled release wrap comprises a polymer comprising ethyl acrylate and methyl methacrylate.

52 / 66 methyl in a 2:1 ratio (KOLLICOAT® EMM 30 D, BASF). KOLLICOAT® EM M 30 D has a pH-independent sustained release effect that can release a pharmaceutical substance such as reboxetine over a period of time, or it can delay the release for a period, where the time of release or delay is about 1-24 hours, about 1-18 hours, about 1-12 hours, about 1-8 hours, or about 1-6 hours.

[00117] In some embodiments, the controlled release wrap comprises a polyvinyl acetate stabilized with polyvinylpyrrolidone and sodium lauryl sulfate such as KOLLICOAT® SR30D (BASF). The dissolution profile can be altered by changing the relative amounts of different acrylic resin lacquers included in the coating. Furthermore, by changing the molar ratio of the polymerizable permeability enhancing agent (eg, the quaternary ammonium compounds) to the neutral methacrylic esters, the permeability properties (which affect the dissolution profile) of the resulting coating can be modified. KOLLICOAT® SR30D is another coating with a pH-independent sustained release effect that can release a pharmaceutical substance such as reboxetine over a period of time, or it can delay the release for a period, where the time of release or delay is about 1-24 hours, about 1-18 hours, about 1-12 hours, about 1-8 hours, about 1-6 hours, about 1-4 hours, or about 1-2 hours.

[00118] In some embodiments, the controlled release wrapper comprises ethylcellulose, which can be used as a dry polymer (such as ETHOCELTM, Dow Chemical Company) solubilized in organic solvent prior to use, or as an aqueous dispersion. A suitable commercially available aqueous dispersion of ethylcellulose is Aquacoat® (Danisco). Aquacoat® ECD (Aqueous Dispersion of Ethyl Cellulose), Aquacoat® ARC (Aqueous Dispersion of Alcohol Resistant Ethyl Cellulose) and Aquacoat® CPD

53 / 66 (aqueous dispersion of cellulose acetate phthalate) are all commercially available controlled release coatings. Another suitable aqueous dispersion of ethylcellulose is commercially available as Surelease® (Colorcon, Inc.) This product can be prepared by incorporating plasticizer into the dispersion during the manufacturing process. A hot melt glue of a polymer, plasticizer (e.g. dibutyl sebacate), and stabilizer (e.g. oleic acid) can be mixed and prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion. which can be applied directly to substrates. These coatings have a pH-independent sustained-release effect that can release a pharmaceutical substance such as reboxetine over a period of time, or can delay the release for a period, where the release or delay time is about 1-24 hours. , about 1-18 hours, about 1-12 hours, about 1-8 hours, about 1-6 hours, about 1-4 hours, or about 1-2 hours.

[00119] Other examples of polymers that can be used in the controlled release wrap include cellulose acetate phthalate, cellulose acetate trimaleate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl alcohol phthalate, shellac, hydrogels and materials gel formers such as carboxyvinyl polymers, sodium alginate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, gelatin, starch, and cellulose-based crosslinked polymers in which the degree of crosslinking is low so as to facilitate water adsorption and expansion of the polymer matrix, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, cross-linked starch, microcrystalline cellulose, chitin, pullulan, collagen, casein, agar, gum arabic, sodium carboxymethylcellulose, (swellable hydrophilic polymers) poly( hydroxy methacrylate alkyl) (molecular weight 5k to 5,000

54 / 66 k), polyvinylpyrrolidone (molecular weight 10k to 360k), anionic and cationic hydrogels, zein, polyamides, polyvinyl alcohol with a low acetate residual, a swellable mixture of agar and carboxymethylcellulose, copolymers of maleic anhydride and styrene, ethylene , propylene or isobutylene, pectin (molecular weight 30k to 300k), polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar, polyacrylamides, polyethylene oxides POLYOX® (molecular weight 100k to 5000k, Dow), polymers of AQUA KEEP® acrylate (composed mainly of acrylic acid polymer, sodium salt), polyglucan diesters, cross-linked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, hydrophilic polymers such as polysaccharides, methyl cellulose, sodium or calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitrocellulose, carboxymethyl cellulose, cellulose ethers, methyl ethyl cellulose, ethyl hydroxyethyl cellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, starch, maltodextrin, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, fatty acid esters with glycerol, polyacrylamide, polyacrylic acid, natural gums, lecithins, pectin, alginates, ammonium alginate, sodium, calcium, potassium alginates, propylene glycol alginate, agar and gums such as arabic, karaya, locust bean, tragacanth, carrageenan, guar, xanthan, scleroglucan and mixtures and blends thereof.

[00120] In some embodiments, the reboxetine dosage forms are coated with polymers in order to facilitate mucoadhesion within the gastrointestinal tract. Non-limiting examples of polymers that can be used for mucoadhesion include carboxymethylcellulose, polyacrylic acid, Carbopol™ (Lubrizol), polycarbophil, gelatin and other natural or synthetic polymers.

[00121] The polymeric coatings of the present disclosure may be any of the described coatings or may be a combination of

55 / 66 two or more of the described coatings to achieve the desired release profiles of reboxetine release.

[00122] In addition to the modified release dosage forms described herein, other modified release technologies known to those skilled in the art can be used in order to achieve the modified release formulations of the present disclosure, i.e., formulations that provide a Tmax drug average and/or other pharmacokinetic parameters described herein when administered, for example, orally or by another mode of administration to human patients. Such formulations may be manufactured as a modified release oral formulation in a suitable tablet or a multiparticulate formulation known to those skilled in the art. In either case, the modified-release dosage form can optionally include a controlled-release carrier that is incorporated into a matrix along with the drug, or that is applied as a controlled-release coating.

[00123] Any dosage form that comprises an effective amount of reboxetine may additionally comprise a binder, a lubricant and other conventional inert excipients.

[00124] A binder (also sometimes called an adhesive) can be added to a drug-filler mixture to increase the mechanical strength of granules and tablets during formation. Binders can be added to the formulation in different ways: (1) as a dry powder, which is mixed with other ingredients before wet agglomeration, (2) as a solution, which is used as an agglomeration liquid during wet agglomeration and is called a binder solution, and (3) as a dry powder, which is mixed with the other ingredients before compaction. In this form the binder is called a dry binder. Binder solutions are a common way of incorporating a binder into granules. In certain embodiments, the binder used in the tablets is in the form of a binder solution. Examples

Non-limiting useful binders include hydrogenated vegetable oil, castor oil, paraffin, higher aliphatic alcohols, higher aliphatic acids, long chain fatty acids, fatty acid esters, waxy materials such as fatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol, hydrophobic and hydrophilic polymers with hydrocarbon backbones, and mixtures thereof. Specific examples of water-soluble polymer binders include modified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives (e.g., hydroxypropylmethylcellulose (H PMC) and hydroxypropylcellulose (HPC)), polyvinyl alcohol and mixtures thereof. Any suitable amount of binder can be present, such as about 0.5-5%, about 5-10%, about 10-15%, about 15-20%, about 20-25%, about 0.5- 25%, about 0.5-15%, about 1-6%, or about 3% by weight of the dry weight of the tablet. In some embodiments, the binder is polyvinyl alcohol.

[00125] Lubricants can be added to pharmaceutical formulations to lessen any friction that occurs between the solid and the matrix wall during tablet manufacture. High friction during compression can cause a number of problems, including poor tablet quality (lamination or even fragmentation of tablets during ejection and vertical scratches on the edges of tablets), and can even stop production. Consequently, lubricants may be added to tablet formulations. Non-limiting examples of useful lubricants include glyceryl behenate, stearic acid, hydrogenated vegetable oils (such as hydrogenated cottonseed oil (STEROTEX®, hydrogenated soybean oil (STEROTEX® HM) and hydrogenated soybean oil and hydrogenated castor wax ( STEROTEX® K), stearyl alcohol, leucine, polyethylene glycol (MW 1450, suitably 4000, and higher), magnesium stearate,

57 / 66 glyceryl, stearic acid, polyethylene glycol, ethylene oxide polymers (for example, available under the CARBOWAX® trademark from Union Carbide, Inc., Danbury, Conn.), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate sodium, sodium stearyl fumarate, DL-leucine, colloidal silica, mixtures thereof and others as known in the art. In some embodiments, the lubricant is glyceryl behenate (eg, COMPRITOL® 888). Any suitable amount of binder can be present, such as about 0.5-5%, about 5-10%, about 10-15%, about 15-20%, about 20-25%, about 0.5- 25%, about 0.5-15%, about 1-6%, or about 3% by weight of the dry weight of the tablet.

[00126] In some embodiments, reboxetine is given once daily or twice daily for at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 6 weeks. at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about of 12

[00127] months, at least 1.5 years, at least 2 years, at least about 3 years, at least about 4 years, at least about 5 years, about 0.1-5 years, about 5-10 years, at least about 10 years, about 10-15 years, at least about 15 years, about 15-20 years, at least about 20 years, or more.

[00128] An example, not as an attempt to limit the scope of disclosure, of a composition useful for a dosage form containing about 5-10 mg of reboxetine is shown in Table 1 below: Table 1. Example of a dosage form of reboxetine

58 / 66 Component Amount (w/w) reboxetine 30% to 70% lubricant 1% to 10% diluent 20% to 70% disintegrant 1% to 10%

[00129] Treatment of narcolepsy with cataplexy with reboxetine in the dosage forms described herein may not have significant side effects like existing treatment options. Treatment of narcolepsy with reboxetine cataplexy in the dosage forms described herein may be well tolerated in mammals such as humans.

[00130] 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 one unit of the dosage form comprises about 0.1-5 mg of reboxetine and instructions for using the pharmaceutical composition for treating narcolepsy with cataplexy in a human.

[00131] 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 one unit of the dosage form comprises about 5-10 mg of reboxetine and instructions for using the pharmaceutical composition for treating narcolepsy with cataplexy in a human.

[00132] Some embodiments include a kit comprising a pharmaceutical composition comprising one or more units of a

59 / 66 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 one unit of the dosage form comprises about 10-15 mg of reboxetine and instructions for using the pharmaceutical composition to treat narcolepsy with cataplexy in a human.

[00133] 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 one unit of the dosage form comprises about 15-20 mg of reboxetine and instructions for using the pharmaceutical composition for treating narcolepsy with cataplexy in a human.

[00134] 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 one unit of the dosage form comprises about 5-20 mg of reboxetine and instructions for using the pharmaceutical composition for treating narcolepsy with cataplexy in a human.

EXAMPLES Example 1

[00135] A 40-year-old man is diagnosed as suffering from narcolepsy with cataplexy. He is given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. The patient is evaluated before treatment and weekly to determine the number of cataplexy attacks, the ESS score, and the

60 / 66 MWT score. After one week of treatment, the number of cataplexy attacks decreased by 10-30%. Example 2

[00136] A 20-year-old woman is diagnosed as suffering from narcolepsy with cataplexy. She is given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. The patient is assessed before treatment and weekly to determine the number of cataplexy attacks, the ESS score, and the MWT score. After one week of treatment, the number of cataplexy attacks decreased by 30-60%. Example 3

[00137] A 60-year-old man is diagnosed as suffering from narcolepsy with cataplexy. He is given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. The patient is assessed before treatment and weekly to determine the number of cataplexy attacks, the ESS score, and the MWT score. After one week of treatment, the number of cataplexy attacks decreased by 60-100%. Example 4

[00138] A 50-year-old woman is diagnosed as suffering from narcolepsy with cataplexy. She is given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. The patient is assessed before treatment and weekly to determine the number of cataplexy attacks, the ESS score, and the MWT score. After one week of treatment, the ESS score decreased by 10-30%. Example 5

[00139] A 25-year-old man is diagnosed as suffering from narcolepsy with cataplexy. He is given reboxetine and instructed to

61/66 take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. The patient is assessed before treatment and weekly to determine the number of cataplexy attacks, the ESS score, and the MWT score. After one week of treatment, the ESS score decreased by 30-60%. Example 6

[00140] A 47-year-old woman is diagnosed as suffering from narcolepsy with cataplexy. She is given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. The patient is assessed before treatment and weekly to determine the number of cataplexy attacks, the ESS score, and the MWT score. After one week of treatment, the ESS score decreased by 60-100%. Example 7

[00141] A 19-year-old man is diagnosed as suffering from narcolepsy with cataplexy. He is given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. The patient is assessed before treatment and weekly to determine the number of cataplexy attacks, the ESS score, and the MWT score. After one week of treatment, the MWT score decreased by 10-30%. Example 8

[00142] A 42-year-old woman is diagnosed as suffering from narcolepsy with cataplexy. She is given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. The patient is assessed before treatment and weekly to determine the number of cataplexy attacks, the ESS score, and the MWT score. After one week of treatment, the MWT score decreased by 30-60%.

62 / 66 Example 9

[00143] A 33-year-old man is diagnosed as suffering from narcolepsy with cataplexy. He is given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. The patient is assessed before treatment and weekly to determine the number of cataplexy attacks, the ESS score, and the MWT score. After one week of treatment, the MWT score decreased by 60-100%. Example 10

[00144] A 54-year-old man is diagnosed as suffering from narcolepsy with cataplexy. He is given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. The patient is assessed before treatment and weekly to determine the number of cataplexy attacks, the ESS score, and the MWT score. After three weeks of treatment, the number of cataplexy attacks had decreased by 10-30%. Example 11

[00145] A 27-year-old woman is diagnosed as suffering from narcolepsy with cataplexy. She is given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. The patient is assessed before treatment and weekly to determine the number of cataplexy attacks, the ESS score, and the MWT score. After three weeks of treatment, the number of cataplexy attacks had decreased by 30-60%. Example 12

[00146] A 52-year-old man is diagnosed as suffering from narcolepsy with cataplexy. He is given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. The patient is evaluated before treatment and weekly for

63/66 determine the number of cataplexy attacks, the ESS score, and the MWT score. After three weeks of treatment, the number of cataplexy attacks had decreased by 60-100%. Example 13

[00147] A 66-year-old woman is diagnosed as suffering from narcolepsy with cataplexy. She is given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. The patient is assessed before treatment and weekly to determine the number of cataplexy attacks, the ESS score, and the MWT score. After three weeks of treatment, the ESS score decreased by 10-30%. Example 14

[00148] A 34-year-old man is diagnosed as suffering from narcolepsy with cataplexy. He is given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. The patient is assessed before treatment and weekly to determine the number of cataplexy attacks, the ESS score, and the MWT score. After three weeks of treatment, the ESS score decreased by 30-60%. Example 15

[00149] A 35-year-old woman is diagnosed as suffering from narcolepsy with cataplexy. She is given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. The patient is assessed before treatment and weekly to determine the number of cataplexy attacks, the ESS score, and the MWT score. After three weeks of treatment, the ESS score decreased by 60-100%. Example 16

64 / 66

[00150] A 19-year-old man is diagnosed as suffering from narcolepsy with cataplexy. He is given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. The patient is assessed before treatment and weekly to determine the number of cataplexy attacks, the ESS score, and the MWT score. After three weeks of treatment, the MWT score decreased by 10-30%. Example 17

[00151] A 70-year-old woman is diagnosed as suffering from narcolepsy with cataplexy. She is given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. The patient is assessed before treatment and weekly to determine the number of cataplexy attacks, the ESS score, and the MWT score. After three weeks of treatment, the MWT score decreased by 30-60%.

[00152] A 57-year-old man is diagnosed as suffering from narcolepsy with cataplexy. He is given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. The patient is assessed before treatment and weekly to determine the number of cataplexy attacks, the ESS score, and the MWT score. After three weeks of treatment, the MWT score decreased by 60-100%.

[00153] Unless otherwise stated, all numbers expressing ingredient amounts, properties such as amounts, percentage and so on used in the specification and claims are to be understood in all occurrences as indicating the exact values as shown and as being modified by the expression “about”. Consequently, unless otherwise indicated, the numerical parameters presented in the specification and in the attached claims

65 / 66 are approximations that may vary depending on the desired properties to be obtained. At the very least, and not in an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be interpreted in light of the number of significant figures reported and applying common rounding techniques.

[00154] The terms “a”, “an”, “the”, “the” and similar referents used in the context of describing modalities (especially in the context of the following claims) should be interpreted as covering both the singular and the plural , unless otherwise indicated in this document or clearly contradicted by the context. All methods described herein may be performed in any suitable order unless otherwise stated herein or otherwise clearly contradicted by the context. The use of any and all examples, or exemplary language (eg, "such as"), provided in this document is intended only to better illuminate the modalities and does not constitute a limitation on the scope of any claim. No language in the specification should be interpreted as indicating any element not claimed as essential to the practice of claims.

[00155] The groupings of elements or alternative modalities disclosed in this document should not be interpreted as limitations. Each group member may be referred to and claimed individually or in any combination with other group members or other elements found herein. It is envisaged that one or more members of a group may be added or deleted from a group for reasons of convenience and/or to speed up processing. When any such inclusion or deletion occurs, the descriptive report is

66/66 considered to contain the group as modified, thus fulfilling the written description of the Markush groups if used in the appended claims.

[00156] Certain embodiments are described herein, including the best method known to the inventors to carry out the claimed embodiments. Of course, variations on these described embodiments will become apparent to those skilled in the art upon reading the preceding description. The inventor expects those skilled in the art to employ such variations as appropriate, and the inventors intend that the claimed embodiments be practiced otherwise than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the matter mentioned in the claims as permitted by applicable law. Furthermore, any combination of the elements described above in all possible variations thereof is contemplated unless otherwise stated herein or otherwise clearly contradicted by the context.

[00157] In short, 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 way of example, but not limitation, alternative embodiments may be used in accordance with the teachings herein. Accordingly, the claims are not limited to the modalities exactly as shown and described.

Claims (20)

1. Use of reboxetine for the treatment of narcolepsy with cataplexy, characterized in that it comprises the administration of reboxetine to a human being in need thereof, wherein reboxetine is administered at least once a day for at least three weeks , in which, two weeks from the start of treatment, the human experiences a reduction in the number of cataplexy attacks in one week, a reduction in the Epworth Sleepiness Scale score, a decrease in the cataplexy subscore on the Narcolepsy Scale Ullanlinna Test (UNS), or a reduction in the Maintenance of Awake Test score as a result of treatment. 2. Use of reboxetine characterized by the fact that it is in the manufacture of a drug for the treatment of narcolepsy with cataplexy, in which reboxetine is administered at least once a day for at least three weeks, in which, two weeks from the beginning of treatment, the human experiences a reduction in the number of cataplexy attacks in one week, a reduction in the Epworth Sleepiness Scale score, a decrease in the cataplexy subscore on the Ullanlinna Narcolepsy Scale (UNS), or a reduction in Maintenance of Awake Test score as a result of treatment. 3. Kit, characterized in that it comprises a pharmaceutical composition comprising reboxetine and instructions for using the pharmaceutical composition to treat narcolepsy with cataplexy in a human, wherein reboxetine is administered at least once a day for at least three weeks. . 4. Use or kit according to any one of claims 1 to 3, characterized in that reboxetine is administered twice a day, wherein a first dosage form is administered in the morning and a second dosage form is administered. about 2 hours to about 6 hours later. 5. Use or kit according to any one of claims 1 to 3, characterized in that the reboxetine is in a dosage form that is administered daily, wherein the dosage form contains a first release component comprising reboxetine and a second release component comprising reboxetine, wherein the first release component provides a first maximum site in plasma reboxetine concentration and the second release component provides a second maximum site in plasma reboxetine concentration, wherein the first site maximum in plasma concentration of reboxetine occurs about 2 to about 6 hours before the second site maximum in plasma concentration of reboxetine. 6. Use or kit, according to claim 5, characterized by the fact that the second maximum site in the plasma concentration of reboxetine occurs about 4 to about 6 hours after the first maximum site in the plasma concentration of reboxetine. 7. Use or kit, according to any one of claims 1 to 3, characterized by the fact that the human being is selected not to suffer from depression. 8. Use or kit according to any one of claims 1 to 3, characterized in that the dose amount of reboxetine is increased for 1 to 7 days, and then kept constant at a total daily dose of about 0.006 mmol to about 0.08 mmol. 9. Use or kit according to any one of claims 1 to 3, characterized in that the reboxetine is in a dosage form and the dosage form contains about 5 mg of reboxetine. 10. Use or kit according to any one of claims 1 to 3, characterized in that the reboxetine is in a dosage form and the dosage form contains about 10 mg of reboxetine. 11. Use or kit according to claim 9, characterized in that the dosage form is administered once a day or twice a day for at least three weeks. 12. Use or kit according to claim 10, characterized in that the dosage form is administered once a day or twice a day for at least three weeks. 13. Use or kit, according to any one of claims 1 to 3, characterized in that the human being experiences an increase in sleep latency in the multiple sleep latency test (MSLT). 14. Use or kit, according to claim 13, characterized in that the human being experiences an increase of at least 10% in sleep latency in the MSLT. 15. Use or kit, according to claim 13, characterized in that the human being experiences an increase of at least 20% in sleep latency in the MSLT. 16. Use or kit, according to claim 13, characterized in that the human being experiences an increase of about 30% to about 60% in sleep latency in the MSLT. 17. Use or kit according to any one of claims 1 to 3, characterized by the fact that the human being experiences a decrease of at least 15% in the cataplexy subscore in the UNS. 18. Use or kit, according to claim 17, characterized by the fact that the human being experiences a decrease of at least 30% in the cataplexy subscore in the UNS. 19. Use or kit, according to claim 17, characterized in that the human being experiences a decrease of about 20% to about 70% in the cataplexy subscore in the UNS. 20. Use or kit according to claim 17, characterized in that the human being has a cataplexy subscore of about 0 after administration of reboxetine.