Method of providing ecopipam therapy to a patient

Abstract

Methods for decreasing adverse events associated with administering ecopipam. The methods include dosing by particular weight ranges, and related dose escalation regimens, and further descending dosage regimens for ecopipam discontinuation.

Description

METHOD OF PROVIDING ECOPIPAM THERAPY TO A PATIENT CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 424,084, filed November 9, 2022, is claimed and the disclosure thereof is incorporated by reference herein in its entirety for all purposes. BACKGROUND Field of the Invention

[0002] The invention relates to methods for decreasing adverse events associated with administration of ecopipam ((6aS,13bR)-11-chloro-7-methyl-5,6,6a,8,9,13b- hexahydronaphtho[1,2-a][3]benzazepin-12-ol) and pharmaceutically acceptable salts thereof, e.g. ecopipam HCl. Description of the Related Art

[0003] Ecopipam is small drug molecule whose chemical name is (6aS,13bR)-11-chloro-7- methyl-5,6,6a,8,9,13b-hexahydronaphtho[1,2-a][3]benzazepin-12-ol. Ecopipam is a benzazepine derivative that is a selective antagonist of the dopamine D1 family of receptors. Ecopipam (known under development codes EBS-101, PSYRX-101, and SCH-39166; C19H20NOCl as the hydrochloride salt), and its structure and synthesis are known. Ecopipam is being evaluated clinically in patients having Tourette Syndrome (a.k.a. Tourette’s Disorder), Childhood Onset Fluency Disorder (i.e., patients who stutter or have been diagnosed as having a stuttering disorder), and in Restless Legs Syndrome.

[0004] Karlsson et al., “Evaluation of SCH 39166 at PET ligand for central D1 dopamine receptor binding and occupancy in man,” Psychopharmacology 121:300-308 (1995), reported on oral administration of ecopipam in single oral doses to each of three healthy subjects, at doses of 25 mg, 100 mg, and 400 mg. After 25 mg dosing, all three subjects reported tiredness as the only side-effect. After 100 mg dosing, all three subjects reported tiredness and two subjects reported restlessness. After 400 mg dosing, restless and sedation was reported by all three subjects, while irritation was reported by two subjects.

[0005] De Beaurepaire et al., "An Open Trial of the D1 Antagonist SCH 39166 in Six Cases of Acute Psychotic States," Psychopharmacology, 121:323-327 (1995) reported on administration of ecopipam to six adult, psychotic patients in a four-week study. The dose wasPATENT Attorney Docket No. 33087 / 54179 progressively increased every three days initially from 50 mg / day to 200 mg / day, followed by a 400 mg / day dose on days 10-17 and a 600 mg / day dose being administered on days 18-28. There was an improvement in extrapyramidal symptoms in three patients (no. 1, 2, 5), but a marked induction of extrapyramidal symptoms in one patient (no. 4) (Table 4). Other reported side effects were nausea and vomiting (three patients), hypotension, dizziness, and headache (one patient each).

[0006] Den Boer et al. "Differential Effects of the D1-DA Receptor Antagonist SCH39166 on Positive and Negative Symptoms of Schizophrenia," Psychopharmacology, 121:317-322 (1995), reported on the use of ecopipam in a 3-week study in patients having schizophrenia. Ecopipam was given orally according to a fixed dosage schedule of: day 1:25 mg b.i.d, day 4:50 mg b.i.d., day 7:100 mg b.i.d., day 18:200 mg b.i.d., day 21: 225 mg b.i.d.. Patients remained on the 225 mg b.i.d. dose until the end of the study on day 28. Seven patients completed 2 weeks, and five patients completed the study. The reason for premature withdrawal was lack of efficacy or refusal to take ecopipam. The most frequent side effect was dizziness which was reported by four patients. Other side effects which were considered to be probably or possibly related to treatment according to the investigator were: hypokinesia, cogwheeling, nausea, anxiety insomnia and somnolence.

[0007] Karlsson et al, “Lack of apparent antipsychotic effect of the D1-dopamine receptor antagonist SCH39166 in acutely ill schizophrenic patients,” Psychopharmacology 121:309-316 (1995) reported on oral administration of ecopipam to 17 schizophrenic patients in a 4-week study. Doses were given in the morning, starting at 10 mg b.i.d. for days 1-3, 25 mg b.i.d. for days 4-6, 50 mg b.i.d. for days 7-9, 75 mg b.i.d. for days 10-17, and 100 mg b.i.d. for days 18- 28. Dose reduction was permitted on the occurrence of an adverse event that was not tolerable or acceptable to the patient. Seven patients completed the 4-week study, another four participated for 10 days or more, and four patients participated for 4 days or less. The reasons for early withdrawal were refusal to take the drug (8 patients) and deterioration (2 patients). The most common adverse events were agitation, anxiety, and restlessness.

[0008] Haney et al. “Effects of ecopipam, a selective dopamine D1 antagonist, on smoked cocaine self-administration by humans,” Psychopharmacology 155:330-337 (2001), reported on the use of ecopipam in 10 non-treatment-seeking cocaine smokers. Ecopipam was administered at night for 8 consecutive days at a dose of 100mg. Seven of the ten participants experienced atPATENT Attorney Docket No. 33087 / 54179 least one adverse event, but their occurrence did not vary as a function of maintenance condition. Headaches were reported six times during placebo maintenance and five times during ecopipam maintenance, while gastrointestinal upset (constipation, stomachache) occurred twice during placebo maintenance and twice during ecopipam maintenance.

[0009] Astrup et al., "Randomized Controlled Trials of the D1 / D5 Antagonist Ecopipam for Weight Loss in Obese Subjects," OBESITY, 15(7):1717-1731 (2007) reported on a 12-week Phase 2 placebo-controlled study of patients receiving 10, 30, or 100 mg ecopipam daily, and a Phase 3 placebo-controlled studies of ecopipam in obese adult patients receiving 50 or 100mg daily for a duration of 52 weeks. The weight range of patients was 60 kg to 172 kg, and a mean weight of 100kg. The studies included a dose of 50 mg / day (one study) or 100 mg / day (three studies). For the 50 mg dose, the average dose based on the mean subject weight was 0.5 mg / kg, with a range of 0.29 to 0.83 mg / kg. For the 100 mg dose, the average dose based on the mean subject weight was 1 mg / kg, with a range of 0.58 to 1.66 mg / kg. For 100mg dose, 85-92% of subjects experienced a treatment-related adverse event (TEAE), 6-9% more than placebo. In the 100 mg dose, the most frequent adverse events were insomnia (8-11% more than placebo), depression (8-13% more than placebo), fatigue (7-13% more than placebo), anxiety (8-11% more than placebo), and somnolence (6-14% more than placebo).

[0010] Gilbert et al., "A D1 Receptor Antagonist, Ecopipam, for Treatment of Tics in Tourette Syndrome," Clinical Neuropharmacology, 37(1):26-30 (2014) reported on a trial of ecopipam in eighteen adults with TS. The doses were administered orally before bedtime, and were 50 mg / day for 2 weeks, followed by 100 mg / day for six weeks. 100% of the patients experienced adverse events. The %incidence of the most common adverse events was generally higher than in Astrup et al. 2007. Two subjects discontinued participation early.

[0011] International Patent Application Publication WO 2014 / 012063 A1 suggested a pharmaceutical dosage form having a controlled release component to reduce or eliminate adverse side effects of ecopipam administration, stating that previous studies have shown that the peak adverse sedative effects of ecopipam occur within several hours of dosing and these sedative effects may be related to the high plasma levels at those times since the effects peak at roughly 2-4 hours post dose and dissipate by 6-8 hours thereafter. The ‘063 publication also suggested a dosing regimen where frequent doses may be required, such three or four times a day.PATENT Attorney Docket No. 33087 / 54179

[0012] Khasnavis et al., “A double-blind, placebo-controlled, crossover trial of the selective dopamine D1 receptor antagonist ecopipam in patients with Lesch-Nyhan disease,” Mol. Genet. Metab., 118:160-6 (2016) reported on use of ecopipam in subjects aged 6-22 years with Lesch- Nyhan disease. The study was terminated early due to side effects. The majority of subjects had a weight below 30 kg; the subjects received doses in a range of 1.81 mg / kg / day to 4.65 mg / kg / day.

[0013] Gilbert et al., “Ecopipam, a D1 Receptor Antagonist, for Treatment of Tourette Syndrome in Children: A Randomized, Placebo-controlled Crossover Study,” Movement Disorders, Vol. 33, Issue 8, p. 1272-80, (August 2018), reported on a 4-week, placebo- controlled, Phase 2b trial of ecopipam in subjects aged 7-17 years (PSY302). The full dose was 50 mg / day if the subject weight was ≤34kg, 100 mg / day for subjects >34kg. The minimum subject weight was 20kg. The mean weight was 56.6 kg. For the 50 mg dose, the possible dose range was 1.47 mg / kg to 2.5 mg / kg, and for the 100 mg dose, the possible range was bounded on the upper end by about 2.86mg / kg (i.e. based on a 35 kg patient). 50 mg dosing started with 12.5 mg / day for days 1-3, then 25 mg / day for days 4-7, then 50 mg / day onward for the final three weeks. 100 mg dosing started with 25 mg / day for days 1-7, 50 mg / day for days 8-14, then 100 mg / day onward for the final two weeks. The total incidence of adverse events was not reported. Two subjects discontinued participation in the study associated with adverse events, both while taking ecopipam during a second phase of the crossover study: one from rash in the upper arms, believed likely to be urticarial and possibly unrelated as it was present prior to study onset; one from worsening tic severity. Incidence of TEAS was reported in Table 3. SUMMARY

[0014] Provided herein are methods of administering ecopipam. One aspect is method of orally administering ecopipam or a pharmaceutically acceptable salt thereof to a patient in need thereof including: providing a first daily dosage of ecopipam to the patient in a first daily dosage amount for a first period of time of at least 5 days, e.g. seven days; providing a second daily dosage of ecopipam to the patient in a second daily dosage amount, greater than the first dosage amount, for a second period of time following the first period, wherein the second period of time is at least 5 days, e.g. seven days; and providing a third daily dosage of ecopipam to the patient in a third daily dosage amount, greater than the second dosage amount, for a third period of time following the second period, wherein (a) the third period of time is greater than seven days andPATENT Attorney Docket No. 33087 / 54179 one or more of the following three conditions is met (1) the ecopipam daily dosage amount administered in the third period of time is 37.5 mg; (2) the first daily dosage amount is 1 / 3 the amount of the third daily dosage amount and the second daily dosage amount is 2 / 3 the amount of the third daily dosage amount; and (3) the patient has a weight of ≥18 kg to ≤23 kg; or (b) the third period of time is seven days and the method further comprises providing a fourth daily dosage of ecopipam to the patient in a fourth daily dosage amount greater than the third daily dosage amount, for a fourth period of time following the third period, wherein the fourth daily dosage amount is 2.41 mg / kg or less.

[0015] Another aspect is a method of orally administering ecopipam or a pharmaceutically acceptable salt thereof to a patient in need thereof including: providing a first daily dosage of ecopipam to the patient in a first daily dosage amount for a first period of time of about seven days; providing a second daily dosage of ecopipam to the patient in a second daily dosage amount, greater than the first daily dosage amount, for a second period of time following the first period, wherein the second period of time is about seven days; and providing a third daily dosage of ecopipam to the patient in a third daily dosage amount, greater than the second daily dosage amount, for a third period of time following the second period, wherein the third period of time is at least seven days; and optionally providing a fourth daily dosage of ecopipam to the patient in a fourth daily dosage amount, greater than the third daily dosage amount, for a fourth period of time following the third period; wherein (a) the third period of time is greater than seven days when the patient has a weight of ≥18 kg to ≤23 kg and one or more of the following two conditions is met (1) the daily ecopipam dose administered in the third period of time is 37.5 mg; and (2) the first daily dosage amount is 1 / 3 the amount of the third daily dosage amount and the second daily dosage amount is 2 / 3 the amount of the third daily dosage amount; and (b) the third period of time is seven days and the method further comprises providing a fourth daily dosage of ecopipam to the patient in a fourth daily dosage amount greater than the third daily dosage amount, wherein the dosage amount is 2.41 mg / kg or less; and wherein when the patient has a weight of >23 kg to ≤34 kg then the first daily dosage amount is 12.5 mg, the second daily dosage amount is 25 mg, the third daily dosage amount is 37.5 mg, and the fourth daily dosage amount is 50 mg; and when the patient has a weight of >34 kg to ≤44 kg then the first daily dosage amount is 12.5 mg, the second daily dosage amount is 25 mg, the third daily dosage amount is 50 mg, and the fourth daily dosage amount is 75 mg; and when the patient has a weight of >44 kg to ≤68 kg then the first daily dosage amount is 25 mg, the second daily dosagePATENT Attorney Docket No. 33087 / 54179 amount is 50 mg, the third daily dosage amount is 75 mg, and the fourth daily dosage amount is 100 mg; and when the patient has a weight of >68 kg to ≤83 kg then the first daily dosage amount is 25 mg, the second daily dosage amount is 50 mg, the third daily dosage amount is 100 mg, and the fourth daily dosage amount is 150 mg; and when the patient has a weight of >83 kg then the first daily dosage amount is 25 mg, the second daily dosage amount is 50 mg, the third daily dosage amount is 100 mg, and the fourth daily dosage amount is 200 mg.

[0016] Another aspect is a method of withdrawing pharmaceutical therapy from a patient receiving ecopipam or a pharmaceutically acceptable salt thereof according to a method described herein, the method of withdrawing including: following administration of a previous dosage of ecopipam or a pharmaceutically acceptable salt thereof to the patient, (a) providing a decreased daily dosage of ecopipam or a pharmaceutically acceptable salt thereof to the patient in an amount in a range of about 20 mg to 30 mg less than the patient was administered in the previous dosage; and (b) repeating step (a) until the decreased daily dosage of ecopipam or a pharmaceutically acceptable salt thereof is 0 mg; and then (c) terminating administration of ecopipam or a pharmaceutically acceptable salt thereof.

[0017] For the compositions and methods described herein, optional features, including but not limited to components, compositional ranges thereof, substituents, conditions, and steps, are contemplated to be selected from the various aspects, embodiments, and Examples provided herein.

[0018] Further aspects and advantages will be apparent to those of ordinary skill in the art from a review of the following detailed description, taken in conjunction with the drawings. While the methods are susceptible of embodiments in various forms, the description hereafter includes specific embodiments with the understanding that the disclosure is illustrative, and is not intended to limit the invention to the specific embodiments described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] For further facilitating the understanding of the present invention, drawing figures are appended hereto with detailed information on adverse events and other safety parameters associated with Example 1. DETAILED DESCRIPTIONPATENT Attorney Docket No. 33087 / 54179

[0020] As an investigational drug, ecopipam is provided in tablet and capsule forms principally for oral administration. Tablet formulations have been used clinical trials. Common adverse reactions or events associated with ecopipam therapy have previously been reported as insomnia, depression, somnolence, fatigue, and anxiety. Adverse events can interfere with everyday activities and quality of life, and if serious enough can lead to discontinuation of therapy. These effects of administering ecopipam appear to be dose related.

[0021] The present inventors made several determinations from unpublished results derived from the PSY302 study described in Gilbert 2018. First, the safety analysis set incidence of adverse events in the ecopipam groups was 80% overall, which was 15% more than placebo subjects. Second, that subjects taking doses lower than 1.4 mg / kg / day (correlated to the 25thpercentile in that study) would be unlikely to have substantial efficacy. Thus, the present methods optionally and preferably have a minimum full dose after titration of at least 1.4 mg / kg / day, or greater than 1.4 mg / kg / day. Third, that subjects taking doses substantially higher than 2 mg / kg, e.g. greater than about 2.4 mg / kg, may not be well tolerated.

[0022] Additional results of the PSY302 study will now be described.

[0023] Adverse events are summarized by treatment group in the table below. Thirty-five subjects (87.5%) reported at least one adverse event during the study. A total of 149 adverse events were reported, 80 while subjects were taking ecopipam and 69 while subjects were taking placebo. One SAE occurred in the placebo group and one adverse event in the ecopipam group led to premature discontinuation. There were no fatal adverse events. Twenty subjects (50.0%) reported a study drug-related adverse event while taking ecopipam and 10 subjects (25.0%) reported a study drug-related adverse event while taking placebo. Adverse events by treatment group are summarized in Table 14-20-2 of the Figures. Table of Overview of Adverse Events Ecopipam Placebo TotalPATENT Attorney Docket No. 33087 / 54179 Ecopipam Placebo Total N=40 N=40 N=40 i h AE 1 2 1 2 in.

[0025] The most frequently reported adverse events (≥ 5% of subjects) are shown in the table below Table of Adverse Events Reported in ≥ 5% of Subjects in Either Treatment Group Treatment (Safety Analysis Set, all subjects to took at least 1 dose of study drug) System Organ Class Ecopipam Placebo Preferred Term N=40 N=40

[0026] e seve y o a ve se eve s as assesse y e ves ga o s su a ed in the table below. Most adverse events (144 / 149, 96.6%) were assessed by the investigator as mild or moderate in severity. Five subjects (12.5%) experienced adverse events that were assessed as severe, 2 subjects (5.0%) while taking ecopipam and 3 (7.5%) while taking placebo. One of the severe adverse events during ecopipam treatment (insomnia) was considered almost certainly related to study drug. The severe adverse events did not cause discontinuations and resolved without consequence. Table of Severity of Adverse EventsPATENT Attorney Docket No. 33087 / 54179 Ecopipam Placebo N=40 N=40 f TEAE

[0027] Adverse events considered by the investigator to be possibly, probably, or almost certainly related to study drug are summarized in the table below. The most frequently reported adverse events (≥ 7.5%) considered related to study drug in subjects taking ecopipam were nausea (10.0%), somnolence (10.0%), abdominal pain upper, decreased appetite, fatigue, headache, and sedation (all 7.5%). Table of Adverse Events Possibly, Probably, or Almost Certainly Related to Study Drug System Organ Class Ecopipam Placebo N=40 N=40PATENT Attorney Docket No. 33087 / 54179 System Organ Class Ecopipam Placebo Preferred Term N=40 N=40 % %

[0028] No deaths occurred in the study. One subject experienced an SAE of psychotic disorder, 10 days after the final study visit but within the 30-day post-treatment observation phase (approximately 55 days after the last dose of ecopipam). One subject prematurely discontinued from the study due to an adverse event of rash. One subject required a dose reduction due to an adverse event of fatigue.

[0029] Furthermore, there was an Open Label Extension study using the dosing method described in Gilbert et al. 2018 (PSY302 OLE). Because subjects had stopped taking ecopipam by the time they had enrolled in the open label extension study, subjects had to re-titrate to full dose, using the same method as described above in Gilbert et al. 2018. Twenty-six subjects enrolled in the study, and all subjects received at least one dose of study drug. Overall, 10 subjects (38.5%) completed the study and 16 subjects (61.5%) prematurely discontinued, including four subjects (15.4%) who discontinued due to adverse events. Overall, 14 subjects (53.8%) had at least 12 months of exposure to study drug, 7 subjects (26.9%) had > 12 months, and 1 subject (3.8%) took study drug for 24 months. The median number of treatment days was 374.5, ranging from 1 to 752 days.

[0030] In the PSY302 OLE study, a TEAE was defined as any adverse event occurring after the first dose of study drug. Twenty-five subjects (96.2%) reported a total of 84 adverse events during the study; 6 of the reported adverse events were non-treatment emergent and 78 were TEAEs. One subject (3.8%) had 15 TEAEs, while the number of adverse events reported for other subjects ranged from one to 7. The most frequently reported TEAEs (> 3 subjects) were upper respiratory tract infection (5 subjects, 19.2%), anxiety (3 subjects, 11.5%), cerebral congestion (verbatim term `head congestion'; 3 subjects, 11.5%), and suicidal ideation (3 subjects, 11.5%). One subject (3.8%) experienced an SAE that was not considered related toPATENT Attorney Docket No. 33087 / 54179 study drug; there were no fatal adverse events. Twenty-three subjects (88.5%) experienced TEAEs classified as mild or moderate in severity. Seven severe TEAEs were reported by 2 subjects (7.7%), one of which was an SAE (anxiety). None of the severe events were considered related to study drug. TEAES considered related to study drug were reported for 13 subjects (50.0%), 9 subjects (34.6%) with events moderate in severity and 4 subjects (15.4%) with events mild in severity. Four subjects (15.4%) experienced one or more TEAEs that led to study drug discontinuation (suicidal ideation [n=3], depressed mood [n=2], and intrusive thoughts [n=1]). One of the TEAEs of depressed mood that led to discontinuation was ongoing at the end of the study; the remainder resolved. In all 4 cases (100%) the events were considered possibly related to study drug. Three subjects (11.5%) experienced an adverse event of special interest (AESI); all 3 were events of moderate suicidal ideation that led to study drug discontinuation. All AESI (100%) were considered possibly related to study drug and resolved.

[0031] Tables providing Overall Summary of TEAEs, Safety Population (Table 14.3.1.1), Summary of TEAEs by System Organ Class (SOC) and Preferred Term (PT), Safety Population (Table 14.3.1.2), Summary of TEAEs by SOC, PT, and Severity, Safety Population (Table 14.3.1.3), Summary of TEAEs by SOC, PT, and Relationship to Study Drug, Safety Population (Table 14.3.1.4), Summary of Treatment-Emergent AESI by SOC and PT, Safety Population (Table 14.3.1.5), Summary of Serious TEAEs by SOC and PT, Safety Population (Table 14.3.1.6) and Summary of TEAEs Leading to Study Drug Discontinuation by SOC and PT, Safety Population (Table 14.3.1.7) are provided in the Figures.

[0032] TEAEs are summarized in the table belowPATENT Attorney Docket No. 33087 / 54179tly reported TEAEs (> 3 subjects) were upper respiratory tract infection (5 subjects, 19.2%), anxiety (3 subjects, 11.5%), cerebral congestion (3 subjects, 11.5%), and suicidal ideation (3 subjects, 11.5%).PATENT Attorney Docket No. 33087 / 54179 [y g , , . investigators assessed 71 / 78 TEAEs (91.0%) as mild or moderate in severity, and 7 / 78 TEAEs (9.0%) were rated as severe. The 7 severe events occurred in 2 subjects (7.7%), as summarized in the table below.PATENT Attorney Docket No. 33087 / 54179. related to study drug. Nine subjects (34.6%) had related events moderate in severity and 4 subjects (15.4%) had related events mild in severity. Related TEAEs experienced by 2 or more subjects are summarized in the table below.PATENT Attorney Docket No. 33087 / 54179

[0036] There were no deaths in the study. One subject (3.8%) experienced an SAE of severe anxiety requiring hospitalization. The SAE was not considered related to study drug.

[0037] Four subjects in the safety population (15.4%) experienced one or more TEAEs that led to discontinuation of study drug. All events (100%) were in the Psychiatric Disorders system organ class and all events (100%) were considered possibly related to study drug. One TEAE that led to discontinuation was ongoing at the end of the study (depressed mood); the remainder resolved. Subjects with TEAEs that led to premature discontinuation are summarized in the table below. The protocol required study drug discontinuation if subjects experienced persistent symptoms of depression or suicidality.PATENT Attorney Docket No. 33087 / 54179experienced moderate TEAEs of suicidal ideation. All 3 subjects (100%) prematurely discontinued study drug due to these events, as required by the protocol. All 3 events (100%) were considered related to study drug and resolved.

[0039] One subject (3.8%) experienced an SAE of severe anxiety which was assessed by the investigator as being not related to study drug. The SAE resolved. Four subjects (15.4%) experienced one or more TEAEs that led to study drug discontinuation (suicidal ideation [n=3], depressed mood [n=2], and intrusive thoughts [n=1]). One of the TEAEs of depressed mood that led to discontinuation was ongoing at the end of the study; the remainder resolved. Three subjects (11.3%) experienced an AESI; all 3 were events of moderate suicidal ideation that led to study drug discontinuation. All AESI (100%) were considered possibly related to study drug and all events (100%) resolved.PATENT Attorney Docket No. 33087 / 54179

[0040] It was discovered that adverse events associated with ecopipam administration can be reduced by an initial dose titration method as further described below. As a point of contrast, a study was conducted in healthy adults with repeat oral doses of about 2 mg / kg ecopipam HCl wherein the dose was not titrated up, but given as full dose from the start. Two cohorts of 12 and 18 subjects were administered multiple daily doses of ecopipam HCl; 19 of the 30 subjects (63.3%) experienced more than one treatment-emergent adverse event (TEAE), withdrew consent, and underwent early termination procedures.

[0041] Provided herein are methods of providing ecopipam therapy or administering ecopipam to a patient in need of ecopipam with an escalating initial dosage regimen. The method can mitigate one or more adverse events associated with the introduction of ecopipam and / or the introduction and continued use of ecopipam. The escalating dosage regimen is believed to better match the development of tolerance to ecopipam with increases in the dosage. The methods are also effective in treating patients in need of ecopipam, e.g. patients with TS, including children and adolescents with TS.

[0042] The dosing methods are contemplated to include embodiments including any combination of one or more of the additional optional elements, features, and steps further described below (including those shown in the figures and Examples), unless stated otherwise.

[0043] In jurisdictions that forbid the patenting of methods that are practiced on the human body, the meaning of “administering” of a composition to a human subject shall be restricted to prescribing a controlled substance that a human subject will self-administer by any technique (e.g., orally, inhalation, topical application, injection, insertion, etc.). The related invention would be understood in view of the disclosure herein as a method of use of ecopipam or a pharmaceutically acceptable salt thereof, or the use of ecopipam or a pharmaceutically acceptable salt thereof for manufacture of a medicament for use as described herein. The broadest reasonable interpretation that is consistent with laws or regulations defining patentable subject matter is intended. In jurisdictions that do not forbid the patenting of methods that are practiced on the human body, the “administering” of compositions includes both methods practiced on the human body and also the foregoing activities.

[0044] As used herein, the term “comprising” indicates the potential inclusion of other agents, elements, steps, or features, in addition to those specified.PATENT Attorney Docket No. 33087 / 54179

[0045] A study of pharmacokinetics from oral administration of ecopipam HCl was conducted, using a single oral dose of 200 mg ecopipam HCl administered to healthy volunteers. A noncompartmental PK analysis showed that the half-life of ecopipam was 15.8 hours, and that of the active metabolite N-desmethylecopipam was 24.0 hours. The calculated average time to steady state plasma concentration of ecopipam is ~80 hours, or about 3.3 days, and a range of about 3 to 5 days taking into account variability between subjects. Thus, one aspect of the method herein provides a method of orally administering ecopipam or a pharmaceutically acceptable salt thereof with an increasing-dose titration schedule wherein the time between dose increases is at least 5 days, or greater than 5 days, or 6 days, for example 7 days.

[0046] The amount of ecopipam administered to a patient in need of ecopipam or provided to a patient herein can be determined by the weight of the patient. In general, the larger the weight of the patient, the larger the full dosage amount (absolute amount) for that patient can be. For example, the dose escalation regimens described herein can be designed to escalate to final daily dosing amounts in a range of about 37 mg / day to about 200 mg / day.

[0047] The number of dose increases from the first increase to the final, full dose can also be different depending on the patient’s weight. For a patient having a weight of at least about 15 kg and about 30 kg or less, or at least 18 kg and 23 kg or less, the number of dose increases until full dose can be 2 or 3, for example 2. Each dose increase can be after a period of at least 5 days on the previous daily dose, or 6 days, or 7 days. For a patient having a weight at least about 20 kg, or of greater than 23 kg, the number of dose increases until full dose can be 3 or 4, for example 3. Each dose increase can be after a period of at least 5 days on the previous daily dose, or 6 days, or 7 days. In one type of method, each dose increase for any patient will be after 7 days on the previous daily dose.

[0048] The amount of ecopipam administered to a patient in need of ecopipam or provided to a patient herein can be more strictly tied to the weight of the patient than in prior known methods. For example, the maximum amount of ecopipam administered can be about 2.4 mg / kg / day or 2.41 mg / kg / day. In patients having a weight of 18 kg or more and 23 kg or less, the maximum dose can be 2.08 mg / kg / day, or in a range of 1.67 to 2.08 mg / kg / day. In patients having a weight of greater than 23 kg and 34 kg or less, the maximum dose can be 2.17 mg / kg / day, in a range of 1.47 to 2.17 mg / kg / day. In patients having a weight of greater than 34 kg and 44 kg or less, the maximum dose can be 2.21 mg / kg / day, in a range of 1.70 to 2.21PATENT Attorney Docket No. 33087 / 54179 mg / kg / day. In patients having a weight of greater than 44 kg and 68 kg or less, the maximum dose can be 2.27 mg / kg / day, in a range of 1.47 to 2.27 mg / kg / day. In patients having a weight of greater than 68 kg and 83 kg or less, the maximum dose can be 2.21 mg / kg / day, in a range of 1.81 to 2.21 mg / kg / day. In patients having a weight of greater than 83 kg, the maximum dose can be 2.41 mg / kg / day.

[0049] The amount of dose administered as a first dose, and the amount of each increase in dose, can also be relative to the patient’s weight. For example, the absolute daily dose administered as a first dose can be in a range of about 10 mg to about 35 mg, or about 12.5mg to about 25 mg. The first daily dose can be about 10 mg to about 15 mg, or about 12.5 mg in patients having a weight of at least 18 kg and 44 kg or less. The amount of increase in daily dose at each dose increase interval (e.g. every 5 days, or every 6 days, or every 7 days), for patients having a weight of at least 18 kg and 44 kg or less, can be in a range of about 10 mg to about 15 mg, or about 12.5mg. The first daily dose can be in a range of about 20 mg to about 40 mg, or about 25 mg, in patients having a weight of greater than 44 kg. In patients having a weight of greater than 44 kg, the amount of increase in daily dose at the first dose increase interval (e.g. after 5 days, or 6 days, or 7 days of the first daily dose), can be in a range of about 20 mg to about 40 mg, or about 25 mg. In patients having a weight of greater than 44 kg, the amount of increase in daily dose at the second dose increase interval can be in a range of about 20 mg to about 60 mg, or about 25 mg, or about 50 mg, for example about 25 mg in patients having a weight of greater than 44 kg to 68 kg or less, and about 50 mg in patients having a weight of greater than 68 kg. In patients having a weight of greater than 44 kg, the amount of increase in daily dose at the third dose increase interval can be in a range of about 20 mg to about 125 mg, or about 25 mg, or about 50 mg, or about 100 mg, for example 25 mg in patients having a weight of greater than 44 kg to 68 kg or less, about 50 mg in patients having a weight of greater than 68 kg and 83 kg or less, and 100 mg in patients having a weight of greater than 83 kg.

[0050] In addition to or independent of the absolute dose amounts provided above, the initial dose and dose increase can also be characterized by the fraction of the full dose. For example, the initial dose can be in a range of about 1 / 8 to about 1 / 3 of the full dose, e.g. 1 / 8, 1 / 6, 1 / 4, or 1 / 3 of the full dose. The initial daily dose can be about 1 / 3 of the full daily dose in patients having a weight of at least 18 kg and 23 kg or less. The amount of increase in daily dose at each dose increase interval (e.g. every 5 days, or every 6 days, or every 7 days), for patients having a weight of at least 18 kg and 23 kg or less, can be about 1 / 3. The first daily dose can be aboutPATENT Attorney Docket No. 33087 / 54179 1 / 4 or less of the full daily dose, in patients having a weight of greater than 23 kg, for example 1 / 6 or 1 / 8 of the full daily dose. The first daily dose can be about 1 / 4 to about 1 / 6 of the full daily dose, in patients having a weight of greater than 23 kg and 83kg or less, for example 1 / 4 or 1 / 6 of the full daily dose. The first daily dose can be about 1 / 8 or less of the full daily dose, in patients having a weight of greater than 83 kg, for example 1 / 8 of the full daily dose. In patients having a weight of greater than 23 kg, the amount of increase in daily dose at the first dose increase interval (e.g. after 5 days, or 6 days, or 7 days of the first daily dose), can be in a range of about 1 / 8 to about 1 / 4. In patients having a weight of greater than 23 kg, the amount of increase in daily dose at the second dose increase interval can be in a range of about 1 / 6 to about 1 / 3, for example 1 / 6 or 1 / 4 or 1 / 3. In patients having a weight of greater than 23 kg, the amount of increase in daily dose at the third dose increase interval can be in a range of about 1 / 4 to about 1 / 2, for example about 1 / 3, or about 1 / 4, or about 1 / 2.

[0051] In various embodiments, ecopipam or ecopipam therapy can be used interchangeably with a pharmaceutically acceptable salt of ecopipam, e.g. ecopipam HCl. Reference to ecopipam or ecopipam therapy herein shall be understood to apply to ecopipam and pharmaceutically acceptable salts and constitute explicit disclosure of ecopipam pharmaceutically acceptable salts, e.g. ecopipam HCl, in each instance.

[0052] In one aspect, provided herein is a method of orally administering ecopipam or a pharmaceutically acceptable salt thereof to a patient in need thereof including providing a first daily dosage of ecopipam to the patient in a first daily dosage amount for a first period of time of seven days; providing a second daily dosage of ecopipam to the patient in a second daily dosage amount, greater than the first dosage amount, for a second period of time following the first period, wherein the second period of time is seven days; providing a third daily dosage of ecopipam to the patient in a third daily dosage amount, greater than the second dosage amount, for a third period of time following the second period, wherein (a) the third period of time is greater than seven days and one or more of the following three conditions is met (1) the ecopipam daily dosage amount administered in the third period of time is 37.5 mg; (2) the first daily dosage amount is 1 / 3 the amount of the third daily dosage amount and the second daily dosage amount is 2 / 3 the amount of the third daily dosage amount; and (3) the patient has a weight of ≥18 kg to ≤23 kg; or (b) the third period of time is seven days and the method further includes providing a fourth daily dosage of ecopipam to the patient in a fourth daily dosagePATENT Attorney Docket No. 33087 / 54179 amount greater than the third daily dosage amount, for a fourth period of time following the third period, wherein the fourth daily dosage amount is 2.41 mg / kg or less.

[0053] In such a method, the third period of time can be greater than seven days and the daily ecopipam dose administered in the third period of time can be 37.5 mg. In addition or in the alternative, the third period of time can be greater than seven days and the first daily dosage amount can be 1 / 3 the amount of the third daily dosage amount and the second daily dosage amount can be 2 / 3 the amount of the third daily dosage amount. In addition or in the alternative, the patient can have a weight of ≥18 kg to ≤23 kg.

[0054] In such a method when the third period of time is seven days and the method further includes providing a fourth daily dosage of ecopipam to the patient in a fourth daily dosage amount greater than the third daily dosage amount, and the fourth daily dosage amount is 2.41 mg / kg or less, the first daily dosage amount can be 1 / 4 the amount of the fourth daily dosage amount, the second daily dosage amount can be 1 / 2 the amount of the fourth daily dosage amount, and the third daily dosage amount can be 3 / 4 the amount of the fourth daily dosage amount. In such a method, the patient optionally can have a weight of >23 kg to ≤34 kg and the fourth daily dosage amount is 50 mg, and / or the patient can have a weight of >44 kg to ≤68 kg and the fourth daily dosage amount is 100 mg.

[0055] In such a method when the third period of time is seven days and the method further includes providing a fourth daily dosage of ecopipam to the patient in a fourth daily dosage amount greater than the third daily dosage amount, and the fourth daily dosage amount is 2.41 mg / kg or less, the first daily dosage amount can be 1 / 6 the amount of the fourth daily dosage amount, the second daily dosage amount can be 1 / 3 the amount of the fourth daily dosage amount, and the third daily dosage amount can be 2 / 3 the amount of the fourth daily dosage amount. In such a method, the patient optionally can have a weight of >34 kg to ≤44 kg and the fourth dosage amount is 75 mg, and / or the patient can have a weight of >68 kg to ≤83 kg and the fourth dosage amount is 150 mg.

[0056] In such a method when the third period of time is seven days and the method further includes providing a fourth daily dosage of ecopipam to the patient in a fourth daily dosage amount greater than the third daily dosage amount, and the fourth daily dosage amount is 2.41 mg / kg or less, the first daily dosage amount can be 1 / 8 the amount of the fourth daily dosage amount, the second daily dosage amount can be 1 / 4 the amount of the fourth daily dosagePATENT Attorney Docket No. 33087 / 54179 amount, and the third daily dosage amount can be 1 / 2 the amount of the fourth daily dosage amount. In such a method, the patient optionally can have a weight of >83 kg and the fourth dosage amount is 200 mg.

[0057] In such a method when the third period of time is seven days and the method further includes providing a fourth daily dosage of ecopipam to the patient in a fourth daily dosage amount greater than the third daily dosage amount, and the fourth daily dosage amount is 2.41 mg / kg or less, a specific 6-weight band method can be applied, wherein when the patient has a weight of >23 kg to ≤34 kg then the first daily dosage amount is 12.5 mg, the second daily dosage amount is 25 mg, the third daily dosage amount is 37.5 mg, and the fourth daily dosage amount is 50 mg; and when the patient has a weight of >34 kg to ≤44 kg then the first daily dosage amount is 12.5 mg, the second daily dosage amount is 25 mg, the third daily dosage amount is 50 mg, and the fourth daily dosage amount is 75 mg; and when the patient has a weight of >44 kg to ≤68 kg then the first daily dosage amount is 25 mg, the second daily dosage amount is 50 mg, the third daily dosage amount is 75 mg, and the fourth daily dosage amount is 100 mg; and when the patient has a weight of >68 kg to ≤83 kg then the first daily dosage amount is 25 mg, the second daily dosage amount is 50 mg, the third daily dosage amount is 100 mg, and the fourth daily dosage amount is 150 mg.

[0058] A more specific method contemplated is a method of orally administering ecopipam or a pharmaceutically acceptable salt thereof to a patient in need thereof including: providing a first daily dosage of ecopipam to the patient in a first daily dosage amount for a first period of time of about seven days; providing a second daily dosage of ecopipam to the patient in a second daily dosage amount, greater than the first daily dosage amount, for a second period of time following the first period, wherein the second period of time is about seven days; providing a third daily dosage of ecopipam to the patient in a third daily dosage amount, greater than the second daily dosage amount, for a third period of time following the second period, wherein the third period of time is at least seven days; optionally providing a fourth daily dosage of ecopipam to the patient in a fourth daily dosage amount, greater than the third daily dosage amount, for a fourth period of time following the third period;PATENT Attorney Docket No. 33087 / 54179 wherein (a) the third period of time is greater than seven days when the patient has a weight of ≥18 kg to ≤23 kg and one or more of the following two conditions is met (1) the daily ecopipam dose administered in the third period of time is 37.5 mg; (2) the first daily dosage amount is 1 / 3 the amount of the third daily dosage amount and the second daily dosage amount is 2 / 3 the amount of the third daily dosage amount; (b) the third period of time is seven days and the method further comprises providing a fourth daily dosage of ecopipam to the patient in a fourth daily dosage amount greater than the third daily dosage amount, wherein the dosage amount is 2.41 mg / kg or less; and wherein when the patient has a weight of >23 kg to ≤34 kg then the first daily dosage amount is 12.5 mg, the second daily dosage amount is 25 mg, the third daily dosage amount is 37.5 mg, and the fourth daily dosage amount is 50 mg; and when the patient has a weight of >34 kg to ≤44 kg then the first daily dosage amount is 12.5 mg, the second daily dosage amount is 25 mg, the third daily dosage amount is 50 mg, and the fourth daily dosage amount is 75 mg; and when the patient has a weight of >44 kg to ≤68 kg then the first daily dosage amount is 25 mg, the second daily dosage amount is 50 mg, the third daily dosage amount is 75 mg, and the fourth daily dosage amount is 100 mg; and when the patient has a weight of >68 kg to ≤83 kg then the first daily dosage amount is 25 mg, the second daily dosage amount is 50 mg, the third daily dosage amount is 100 mg, and the fourth daily dosage amount is 150 mg; and when the patient has a weight of >83 kg then the first daily dosage amount is 25 mg, the second daily dosage amount is 50 mg, the third daily dosage amount is 100 mg, and the fourth daily dosage amount is 200 mg.

[0059] In any of the methods described herein, the fourth period can be in a range of about 1 day to an unlimited number of days. For example, the fourth and / or final period of time can be at least one day, or at least two days, or at least 1 week, or greater than 1 week, or at least 2 weeks, or at least 1 month, or at least 3 months, or at least 1 year, or more. The fourth period can be at least two days. The fourth period can be more than one week

[0060] In any of the methods described herein, the patient can have an age of ≥6 years to <18 years. In any of the methods described herein, the patient can have an age of ≥6 years to any age. In any of the methods described herein, the patient can have an age of ≥18 years.PATENT Attorney Docket No. 33087 / 54179

[0061] In any of the methods described herein, the ecopipam administration can be for the treatment of a patient in need thereof, or a patient in need of a dopamine D1 antagonist. The ecopipam administration can be for the treatment of a patient in need of a selective dopamine D1 antagonist. The ecopipam administration can be for the treatment of a tic disorder or movement disorder. The tic disorder can be Tourette Syndrome, a pediatric autoimmune disorder associated with streptococcal infection (PANDAS), a transient tic disorder, a chronic tic disorder, or a Tic Disorder Not Otherwise Specified (NOS). The subject can exhibit a motor tic (e.g., a complex motor tic), a vocal tic (e.g., a complex vocal tic), or a combination thereof. The ecopipam administration can be for the treatment of Childhood Onset Fluency Disorder (stuttering). The ecopipam administration can be for the treatment of Restless Legs Syndrome, Restless Legs Syndrome with Augmentation, or for Augmentation associated with Restless Legs Syndrome. The ecopipam administration can be for the treatment of obesity, including type 2 diabetic subjects.

[0062] Specific contemplated dosing methods are described in the table below. In parentheticals, the table includes optional combinations of dosage form amounts of 12.5mg, 50mg, 75mg, and 100mg per dosage form, e.g. tablets or capsules, to reach the target dose amount. The methods per weight band can be used individually, or in combinations of one or more thereof as desired. Weight Daily dose (mg) Daily dose (mg) Daily dose (mg) Daily dose (mg) (k ) W k #1 W k #2 W k #3 W k #4 n rd

[0063] Further provided herein is a method of administering ecopipam to a patient with a descending dosage regimen to mitigate adverse events associated with a withdrawal of ecopipam from the patient’s body, wherein the patient has been receiving ecopipam therapy as described herein, e.g. in amounts of about 2 mg / kg / day, or in doses greater than 100 mg / day, or in doses greater than 150 mg / day. In one embodiment of the present disclosure is a method ofPATENT Attorney Docket No. 33087 / 54179 administering ecopipam to a patient receiving ecopipam comprising, following the administration of a previous dosage of ecopipam or a pharmaceutically acceptable salt thereof to the patient, (a) providing a decreased daily dosage of ecopipam or pharmaceutically acceptable salt thereof to the patient in an amount in a range of about 20 mg to 30 mg less than the patient was administered in the previous dosage, and (b) repeating step (a) until the decreased daily dosage of ecopipam is 0 mg (calculated non-negative doses being equivalent to zero), and then (c) terminating ecopipam administration. In embodiments, the decreased daily dosage of ecopipam to the patient can be an amount of about 25 mg less per day than the patient was administered in the previous dosage. Optionally, the decreased daily dosage of ecopipam to the patient can be an amount of about 1 / 16 or less, or 1 / 8 or less, or 1 / 4 less per day than the patient was administered in the previous dosage. In embodiments, the decreased daily dosage of ecopipam to the patient can be an amount of about 1 / 4 less per day than the patient was administered in the previous dosage. In embodiments, step (b) can be carried out on a frequency of daily, or every other day, or every third day, or every fourth day, or every fifth day, or every sixth day, or weekly. A frequency of daily or every other day is particularly contemplated. For example, the patient can be administered a decreased daily dosage of ecopipam (compared to the previous dose before the start of decreased dosing) for up to 7 days, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days, or 14 days, or 21 days, or 28 days. The withdrawal method can be applied to any type of patient, including children and adolescents of at least six years of age and less than 18 years of age, and adults, and patients with TS, and patients with other disease states described herein, or any combination thereof.

[0064] In any method described herein, the doses of ecopipam can be taken in the fasted state. In any method described herein, the doses of ecopipam can be taken with water. In any method described herein, the doses of ecopipam can be taken at bedtime. In any method described herein, the patient can be instructed to, or provided with instructions to, take the doses as described herein.

[0065] In any of the ascending or dosage regimens and / or descending dosage regimens described herein, the daily dosing can be divided into one or more dosages, e.g. a dose of 25 mg / day can be divided into two 12.5mg doses taken separately in the same day (i.e. b.i.d.). It is specifically contemplated that in any of the ascending or dosage regimens and / or descending dosage regimens described herein, the daily dosing is as a single dosing event, i.e. once per day. The dosing, such as the single dosing event, can be in the evening.PATENT Attorney Docket No. 33087 / 54179

[0066] A dose escalation described herein can provide a reduced incidence of adverse events compared to prior known dosing methods.

[0067] In embodiments, the dose escalation described herein can reduce incidence of one or more treatment-related adverse event(s) compared to alternative dosing regimens using the same full, final dose. For example, it was determined in the study of Example 1 that the overall incidence of TEAEs using a method of the invention was 61.8%, 12.4% higher than the placebo arm, which demonstrated a reduced incidence of adverse events compared to the method described in Gilbert et al. 2018 described above. The incidence of Cmax related GI side effects was reduced, e.g. nausea, vomiting, diarrhea, abdominal pain. The incidence of Cmax related CNS side effects was also reduced, e.g. sedation and somnolence. The incidence of decreased appetite and rash was also reduced compared to the method described in Gilbert et al. 2018. In addition or in the alternative, the incidence of discontinuation of ecopipam due to adverse events can be reduced compared to alternative dosing regimens using the same full, final dose by a different method, e.g. one using a titration regiment that reaches an equivalent full dose more quickly and / or one which reaches a higher full dose in the same or shorter period of time. Optionally the comparison can be made within the same patient population e.g., having the same disorder (e.g. Tourette’s disorder or stuttering disorder), the same weight range, or the same age group, or any combination thereof.

[0068] A descending dosage regimen as described herein can mitigate adverse events associated with withdrawal of ecopipam. Such adverse events can be one or more of those described above. For example, the adverse events can be one or more in the group of insomnia, depression, dyspepsia, somnolence, fatigue, anxiety, headache, vomiting, nausea, abdominal pain. The adverse events reduced can be one or more in the group of nausea, diaphoresis, tachycardia, lightheadedness, headaches, tremors, and anxiety. In embodiments, the adverse events, particularly associated with the administration of ecopipam in children / adolescents, can be one or more of headache, abdominal pain upper, insomnia, somnolence, nausea, and vomiting. In embodiments, the adverse events, particularly associated with the administration of ecopipam in adults, can be one or more of sedation, insomnia, fatigue, somnolence, headache, muscle twitching and anxiety. In one type of embodiment, the type of adverse event reduced is a central nervous system related event (e.g. sedation, insomnia, somnolence, or headache). In one type of embodiment, the type of adverse event reduced is insomnia. In another type of embodiment, the type of adverse event reduced is sedation. In another type of embodiment, thePATENT Attorney Docket No. 33087 / 54179 type of adverse event reduced is somnolence. In another type of embodiment, the type of adverse event reduced is headache. Optionally the comparison can be made within the same patient population e.g., having the same disorder (e.g. Tourette’s disorder or stuttering disorder), the same weight range, or the same age group, or any combination thereof. Example 1

[0069] This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase 2b study in pediatric subjects (aged ≥6 to <18 years) with Tourette Syndrome. A total of 150 subjects were planned to participate in the study. A total of 154 subjects were enrolled and 153 subjects were randomized; 1 enrolled subject was not randomized, did not receive study drug, and was not included in an analysis set. Following a screening period of up to 28 days and after all pre-dose baseline visit assessments had been completed, eligible subjects were randomized 1:1 to receive either a target steady-state dose of 2 mg / kg / day ecopipam HCl or matching placebo, for a titration period as described in the table below, followed by an 8-week treatment period. Randomization assignment was stratified by weight. Weight Dose (mg) Dose (mg) Dose (mg) Dose (mg) (kg) Week #1 Week #2 Week #3 Week #4 onward

[0070] Subjects who could not tolerate the dose were withdrawn from the study. Weight band assignments were not changed during the study.

[0071] Subjects must have had a minimum score of 20 on the YGTSS-TTS at Screening and Base-line visits with tic symptoms in the investigator’s judgment causing: subjective discomfort (eg, pain or injury), sustained social problems (e.g., social isolation or bullying), social and emotional problems, or functional interference (e.g., impairment of academic achievements). Subjects must not have been taking any medications used to treat motor or vocal tics for at least 14 days prior to baseline.PATENT Attorney Docket No. 33087 / 54179

[0072] Subjects were randomized 1:1 to receive either a target full (steady-state) dose of 2 mg / kg / day ecopipam HCl tablets or matching placebo tablets. All doses were to be administered by mouth once daily in the evening.

[0073] Subjects who had changes in weight during the study were not to have their doses adjusted for the duration of the study. At the end of the 8-week treatment period, subjects titrated off therapy by receiving ecopipam HCl doses or matching placebo that were reduced by 25 mg / day until off of study drug. Subjects who did not tolerate the dose titration up to the full designated dose for their weight stratum were to be discontinued from the study. These subjects were also to be tapered off their current dose of study drug according to their weight stratum.

[0074] Efficacy assessments used are described below.

[0075] The YGTSS is a clinician-completed rating scale used to quantify overall tic severity as well as specific subdomains of tic number, frequency, intensity, complexity, and interference. Each of these subdomains is scored, on a 5-point scale, separately for motor and vocal tics and then summed across both motor and vocal tics to yield a YGTSS total tic score (TTS) ranging from 0 to 50. The YGTSS also provides for an overall impairment rating (0 = ‘‘none’’ to 50 = ‘‘severe’’). The YGTSS-Global Score (GS) is the sum of the motor, vocal, and impairment scores. The YGTSS has demonstrated acceptable internal consistency, good interrater reliability, and acceptable convergent and divergent validity. The YGTSS was assessed at Screening, Baseline and at Weeks 4, 6, 8 and 12.

[0076] The Clinical Global Impression (CGI) scale consists of 2 reliable and valid 7-item Likert scales used to assess severity and change in clinical symptoms. The CGI severity scale ranges from 1 = “normal, not ill at all” to 7 = “extremely ill.” The CGI improvement scale ranges from 1 = “very much improved” to 7 = very much worse.” The CGI severity and CGI improvement scales were administered at specific visits.

[0077] The Caregiver Global Impression of Change (CaGI-C) scale is a 7-item Likert scale that asks the caregiver the following question: Overall, how have the patient’s symptoms changed (if at all) since the beginning of the study (before starting treatment)? The CaGI-C is rated as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse).PATENT Attorney Docket No. 33087 / 54179

[0078] The Gilles de la Tourette Syndrome – Quality of Life Scale for Children and Adolescents (C&A-GTS-QOL) is a patient-reported health-related quality of life measure developed for children and adolescents. The C&A-GTS-QOL is a 27-item questionnaire specific to TS that asks the subject to assess the extent to which their quality of life is impacted by their symptoms. The C&A-GTS-QOL contains 6 subscales (cognitive, coprophenomena, psychological, physical, obsessive-compulsive, and ADL) and uses a 5-point Likert scale ranging from 0 = “never” to 4 = “always”. Subjects were also asked how satisfied they felt overall with their life at that moment by using a visual analog scale (VAS) scale between 0 and 100.5The following questions are assessed in each C&A-GTS-QOL subscale: • Cognitive (Questions 11, 12, 13, 14, 18, 20, 21, 23) (range: 0 – 32) • Psychological (Questions 15, 16, 17, 19, 25, 27) (range: 0 – 24) • Obsessive-compulsive (Questions 7, 8, 9, 10) (range: 0 – 16) • Physical (Questions 1, 3, 4) (range: 0 – 12) • Coprophenomena (Questions 5, 6, 22) (range: 0 – 12) • ADL (Questions 2, 24, 26) (range: 0 – 12)

[0079] Scores for the 6 subscales are generated by summing items and, for ease of interpretation, transformed to a range of 0 to 100. The total score, resulting from the sum of the subscale scores, is also normalized to a 0 to 100 range.

[0080] An Adverse Event (AE )was defined as any untoward medical occurrence in a subject administered a study drug and which does not necessarily have a causal relationship with the treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not related to the study drug.

[0081] An abnormality identified during a medical test (eg, laboratory parameter, vital sign, ECG data, physical exam) was to be defined as an AE only if the abnormality met 1 of the following criteria: • Induced clinical signs or symptoms • Required active intervention • Required interruption or discontinuation of study drug • Was clinically significant in the opinion of the investigatorPATENT Attorney Docket No. 33087 / 54179

[0082] A Serious Adverse Event (SAE) was defined as an AE occurring during any study phase (i.e., baseline, treatment, washout, or follow-up), and at any dose of the investigational product, comparator or placebo, that fulfilled 1 or more of the following: • Resulted in death • Was immediately life-threatening • Required in-subject hospitalization or prolongation of existing hospitalization • Resulted in persistent or significant disability or incapacity • Resulted in a congenital abnormality or birth defect • Was an important medical event that may have jeopardized the subject or may have required medical intervention to prevent 1 of the outcomes listed above

[0083] The investigator was to decide whether, in his or her medical judgment, there was a reasonable possibility that the AE may have been caused by the investigational product. If no valid reason existed for suggesting a relationship, then the AE was to be classified as “unrelated.” If there was any valid reason, even if undetermined, for suspecting a possible cause- and-effect relationship between the investigational product and the occurrence of the AE, then the AE was to be considered “related.” If the relationship between the AE / SAE and the investigational product was determined to be “possible” or “probable”, the event was considered related to the investigational product for the purposes of expedited regulatory reporting.

[0084] Intensity of AEs was assessed according to the following scale: • Mild (awareness of sign or symptom, but easily tolerated) • Moderate (discomfort sufficient to cause interference with normal activities) • Severe (incapacitating, with inability to perform normal activities)

[0085] The Columbia-Suicide Severity Rating Scale (C-SSRS) was assessed at all visits except for the 30-day Follow-Up visit. The C-SSRS is a low burden (approximately 5 minutes for completion) instrument to assess both suicidal behavior and ideation. The scale is appropriate for subjects from age 6 through to an elderly population.

[0086] Additional safety outcomes assessed at Baseline and Weeks 4, 6, 8, and 12 included the following scales:

[0087] Abnormal Involuntary Movement Scale (AIMS): This scale records the occurrences of tar-dive dyskinesia in subjects receiving neuroleptic medications. The test is used to detect tardive dyskinesia and to follow the severity over time. It consists of rating the presence andPATENT Attorney Docket No. 33087 / 54179 severity of movement disorders involving the face, mouth, extremities, and trunk as well as 3 items of global judgment from a scale of 0 (none) to 4 (severe).

[0088] Barnes Akathisia Rating Scale (BARS) scale: This scale assesses the severity of drug- induced akathisia. Objective and subjective items in the scale measure the level of subject’s restlessness, ranging from 0 (normal) to 3 (most severe). The BARS also includes a global assessment of akathisia, ranging from 0 (absent) to 5 (severe).

[0089] Swanson, Nolan and Pelham (SNAP-IV) Questionnaire: This measure is designed to assess ADHD and oppositional defiant disorder (ODD) symptoms in children and adolescents. The SNAP-IV is based on a 0 to 3 rating scale: Not at All = 0, Just A Little = 1, Quite A Bit = 2, and Very Much = 3. Subscale scores on the SNAP-IV are calculated by summing the scores on the items in the subset and dividing by the number of items in the subset. The score for any subset is expressed as the Average Rating-Per-Item.

[0090] Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS): This assessment is a reliable and valid scale to both determine severity of OCD and to monitor improvement during treatment. The scale is a clinician-rated, 10-item scale that includes questions about the amount of time spent on obsessions / compulsions, level of impairment or distress, and how much resistance and control subjects have over these thoughts. Severity of compulsions and obsessions are rated on a 5-point scale from 0 to 4. The CY-BOCS total score is computed as the sum of the 10 items, ranging from 0 to 40, with higher scores indicating more severe compulsions and obsessions.

[0091] Children's Depression Rating Scale-Revised (CDRS-R): This assessment is a clinically validated rating scale designed to assess psychiatric signs and symptoms of depressions. Fourteen signs and symptoms are rated from 1 (normal) to 7 (most severe), and 3 signs and symptoms are rated from 1 (normal) to 5 (most severe). The raw summary score is the sum of all 17 items, ranging from 17 to 113.

[0092] Pediatric Anxiety Rating Scale (PARS): This scale is a clinician-rated instrument for assessing the severity of anxiety symptoms associated with common anxiety disorders and generalized anxiety in children and adolescents. The PARS has 2 sections: the symptom checklist and the severity items. The symptom checklist is used to determine the child’s repertoire of symptoms during the past week. The 7 severity items are used to determine severity of symptoms and the PARS total score. Each severity item is coded from 0 (none) to 5 (mostPATENT Attorney Docket No. 33087 / 54179 extreme). Not applicable is coded to 8, and does not know is coded to 9. The total score for the PARS is total of the 7 severity items. The total score ranges from 0 to 35. Codes “8” and “9” are not included in the summation.

[0093] The primary efficacy endpoint was the change in the YGTSS-TTS from Baseline to end of therapy at Week 12 compared to the placebo group. The YGTSS-TSS ranges from 0 to 50, with higher scores indicating more severe symptoms.

[0094] A summary of observed YGTSS-TTS scores and changes from Baseline at each time point for the modified intent-to-treat (mITT) set is presented in Table 9. The mITT set was all children and adolescent subjects with TS who were randomized, received at least 1 dose of study drug, and had at least 1 post-Baseline scoring of the YGTSS. Mean YGTSS-TTS scores decreased in both treatment groups over the study, with larger decreases observed in the ecopipam group compared to the placebo group. Table 1. Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS): Summary (mITT Set) Placebo (N=75) Ecopipam (N=74) m ) )PATENT Attorney Docket No. 33087 / 54179 Placebo (N=75) Ecopipam (N=74) Visit Change from Change fromNote: Baseline is defined as the last measurement taken before the first dose of double-blind treatment on Day 1.

[0095] The primary MMRM analysis of change from Baseline in YGTSS-TTS using multiple imputation for intercurrent events for the mITT set is provided in Table 10. At Week 12, the YGTSS-TTS least squares (LS) mean (SE) change from Baseline was -9.87 (1.062) in the ecopipam group and -6.42 (1.006) in the placebo group; the difference in the YGTSS-TTS LS mean (SE) between ecopipam and placebo was -3.44 (1.351) and was statistically significant (P=0.011). For the comparison of ecopipam versus placebo over all visits, the YGTSS-TTS LS mean (SE) change from Baseline was -8.52 (1.786) in the ecopipam group and -5.02 (1.418) in the placebo group; the difference in the YGTSS-TTS LS mean (SE) between ecopipam and placebo was -3.51 (1.346) and was statistically significant (P=0.009). Table 2. Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS): MMRM Analysis of Change From Baseline – Multiple Imputation for Intercurrent Events (mITT Set) Placebo Ecopipam N=75 N=74PATENT Attorney Docket No. 33087 / 54179 Placebo Ecopipam N=75 N=74 LS M SE 642 1006 987 1062ts or lack of efficacy, missing data are multiple imputed using similar subjects (relevant demographic / baseline characteristics) from the placebo arm. Note: Baseline is defined as the last measurement taken before the first dose of double-blind treatment on Day 1. Note: Change from baseline in YGTSS score as a continuous variable is based on MMRM ANCOVA model with an unstructured covariance matrix including the following terms: Baseline value, region, age group (children 6 to 11 years and adolescents 12 to 17 years), visit, treatment group and visit-by-treatment interaction.

[0096] The key secondary efficacy endpoint was the change in CGI-TS-S from Baseline to Week 12. An additional secondary efficacy endpoint was the change in CGI-TS-S from Baseline to Weeks 4, 6, and 8. The CGI severity scale ranges from 1 = “normal, not ill at all” to 7 = “extremely ill.” A summary of observed CGI-TS-S scores and changes from Baseline at each time point for the mITT set is provided in Table 16. Improvements (decreases) in mean CGI-TS- S scores were observed over the study in both treatment groups, with greater improvements (decreases) observed in the ecopipam group compared to the placebo group. Table 3. Clinical Global Impression of Tourette Syndrome Severity (CGI-TS-S): Summary (mITT Set) Placebo (N=75) Ecopipam (N=74) Visit Chan e from Chan e from ) )PATENT Attorney Docket No.33087 / 54179 Placebo (N=75) Ecopipam (N=74) Visit Change from Change from Sttiti Ob d B liaB li Ob d B liaB li ) )ase e a eac pos- ase e vs s e e as su jecs ase e o ose w aa a a vs . Note: Baseline is defined as the last measurement taken before the first dose of double-blind treatment on Day 1.

[0097] The MMRM analysis of change from Baseline in CGI-TS-S for the mITT set is provided in Table 17. A statistically significantly greater reduction in the clinical impression of TS severity at Week 12 was observed in the ecopipam group compared to the placebo group. At Week 12, the CGI-TS-S LS mean (SE) change from Baseline was -0.91 (0.141) in the ecopipam group and -0.53 (0.130) in the placebo group; the difference in the CGI-TS-S LS mean (SE) between ecopipam and placebo was -0.37 (0.167) and was statistically significant (P=0.027). The difference in the CGI-TS-S LS mean (SE) between ecopipam and placebo did not reach statistical significance at Week 4 (P=0.064), but was significant at Week 6 (P=0.001) and Week 8 (P=0.001). Table 4. Clinical Global Impression of Tourette Syndrome Severity (CGI-TS-S): MMRM Analysis of Change From Baseline (mITT Set) Placebo Ecopipam N=75 N=74PATENT Attorney Docket No. 33087 / 54179 Placebo Ecopipam N=75 N=74 Diff E i Pl b i LS M SE 024 0127Note: Baseline is defined as the last measurement taken before the first dose of double-blind treatment on Day 1. Note: Change from baseline in CGI-TS-S as a continuous variable is based on MMRM ANCOVA model with an unstructured covariance matrix including the following terms: baseline value, region, age group (children 6 to 11 years and adolescents 12 to 17 years), visit, treatment group and visit-by-treatment interaction. Similar results were observed for the MMRM analysis of change from Baseline in CGI-TS-S when remote assessments were included in the model.

[0098] A secondary efficacy endpoint was the CGI-TS-I at Week 12. An additional secondary efficacy endpoint was the CGI-TS-I at Weeks 4, 6, and 8. The CGI-TS-I was completed at Weeks 4, 6, 8, and 12, and measures the clinical impression of improvement from Baseline. The CGI improvement scale ranges from 1 = “very much improved” to 7 = “very much worse.” A summary of CGI-TS-I scores at each time point for the mITT set is provided in Table 18. A clinical impression of improvement from Baseline was observed over the study in both treatment groups with a greater mean impression of improvement in the ecopipam group compared to the placebo group.PATENT Attorney Docket No. 33087 / 54179 Table 5. Clinical Global Impression of Tourette Syndrome Improvement (CGI-TS-I): Summary (mITT Set) Visit Placebo Ecopipam Statistics N=75 N=74a CGI-TS-S Baseline scores only for subjects with CGI-TS-I scores

[0099] A secondary efficacy endpoint was the change in YGTSS-GS from Baseline to Week 12. An additional secondary efficacy endpoint was the change in YGTSS-GS from Baseline to Weeks 4, 6, and 8. The YGTSS-GS is the sum of the motor, vocal, and impairment scores and ranges from 0 to 100, with higher scores indicating more severe symptoms. A summary of observed YGTSS-GS scores and changes from Baseline at each time point for the mITT set is provided in Table 20. Mean YGTSS-GS scores decreased in both treatment groups over the study, with larger decreases observed in the ecopipam group compared to the placebo group.PATENT Attorney Docket No. 33087 / 54179 Table 6. Yale Global Tic Severity Scale - Global Score (YGTSS-GS): Summary (mITT Set) Placebo Ecopipam (N=75) (N=74) m ) ) ) )a Baseline is defined as subjects’ baseline for those with data at visit. Note: Baseline is defined as the last measurement taken before the first dose of double-blind treatment on Day 1.

[0100] The MMRM analysis of change from Baseline in YGTSS-GS for the mITT set is provided in Table 21. At Week 12, the YGTSS-GS LS mean (SE) change from Baseline was -21.41 (2.291) in the ecopipam group and -13.56 (2.113) in the placebo group; the difference in the YGTSS-GS LS mean (SE) between ecopipam and placebo was -7.86 (2.711) and was significant (P=0.004). An additional secondary efficacy endpoint was the change in YGTSS-GS from Baseline to Weeks 4, 6, and 8. Significantly greater improvements from Baseline in YGTSS-GS LS mean were observed in the ecopipam group compared to the placebo group at all time points with all P values being <0.05.PATENT Attorney Docket No. 33087 / 54179 Table 7. Yale Global Tic Severity Scale – Global Score (YGTSS-GS): MMRM Analysis of Change from Baseline (mITT Set) Placebo Ecopipam N=75 N=74p u ; - , v y . Note: Baseline is defined as the last measurement taken before the first dose of double-blind treatment on Day 1. Note: Change from baseline in YGTSS-GS as a continuous variable is based on MMRM ANCOVA model with an unstructured covariance matrix including the following terms: baseline value, region, age group (children 6 to 11 years and adolescents 12 to 17 years), visit, treatment group and visit-by-treatment interaction.

[0101] Similar results were observed for the MMRM analysis of change from Baseline in YGTSS-GS when remote assessments were included in the model.PATENT Attorney Docket No. 33087 / 54179

[0102] A secondary efficacy endpoint was the CaGI-C at Week 12. An additional secondary efficacy endpoint was the CaGI-C at Weeks 4, 6, and 8. The CaGI-C is a 7-item Likert scale that asks the caregiver the following question: “Overall, how have the patient’s symptoms changed (if at all) since the beginning of the study (before starting treatment)?” and is rated as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). Therefore, lower CaGI-C scores indicate a greater caregiver impression of improvement. A summary of CaGI-C scores at all time points for the mITT set is provided in Table 22. Lower mean CaGI-C scores, indicating a greater caregiver impression of improvement, were observed in the ecopipam group compared to the placebo group over the study. Within each treatment group, the CaGI-C scores remained steady over the study from Week 4 to Week 12. Table 8. Caregiver Global Impression of Change (CaGI-C): Summary (mITT Set) Visit Placebo Ecopipam d.

[0103] The MMRM analysis of CaGI-C for the mITT set is provided in Table 23. At Week 12, the LS mean (SE) CaGI-C score was 2.94 (0.189) in the ecopipam group and 3.55 (0.172) in the placebo group; the difference in the LS mean (SE) CaGI-C score between ecopipam and placebo was -0.61 (0.223) and was significant (P=0.007). CaGI-C LS mean scores werePATENT Attorney Docket No.33087 / 54179 significantly lower (indicating a greater caregiver impression of improvement) in the ecopipam group compared to the placebo group at all time points with all P values being <0.05. Table 9. Caregiver Global Impression of Change (CaGI-C): MMRM Analysis (mITT Set) Placebo Ecopipam N=75 N=74squaes; , o e e -o- ea; , xe oe o epeae easues. Note: CaGI-C is a continuous variable. MMRM ANCOVA model with an unstructured covariance matrix including the following terms: region, age group (children 6 to 11 years and adolescents 12 to 17 years), visit, treatment group and visit-by-treatment interaction.PATENT Attorney Docket No. 33087 / 54179

[0104] Similar results were observed for the MMRM analysis of CaGI-C when remote assessments were included in the model.

[0105] A secondary efficacy endpoint was the percentage of subjects with a 25%, improvement on the YGTSS-TTS. A responder was defined as a subject who at least once had a 25% improvement of YGTSS-TTS at any time between Baseline and the Week 12 visit.

[0106] A total of 53 subjects (73.6%) in the ecopipam group and 32 subjects (43.2%) in the placebo group had a 25% improvement in YGTSS-TTS at any time between Baseline and the Week 12 visit; the odds ratio (95% CI) was 3.67 (1.82, 7.40), P<0.001.

[0107] The safety set included all subjects who received at least 1 dose of study drug. An overall summary of Adverse Events (AEs) for the safety set is provided in Table 34 below. A total of 47 subjects (61.8%) in the ecopipam group and 38 subjects (49.4%) in the placebo group experienced an AE during the study. Treatment-related AEs were reported in a higher number of subjects in the ecopipam group (26 subjects, 34.2%) compared to the placebo group (16 subjects, 20.8%). A total of 3 subjects experienced an SAE during the study. Four subjects (5.3%) in the ecopipam group and 1 subject (1.3%) in the placebo group experienced an AE leading to discontinuation of study drug.

[0108] A total of 4 subjects (2 subjects in the ecopipam group and 2 subjects in the placebo group) reported COVID-19 AEs: 3 subjects with a PT of coronavirus infection and 1 subject with a PT of coronavirus test positive. The investigator considered 3 events as mild in severity and 1 event as moderate in severity. One of the subjects in the ecopipam group had a COVID-19 AE considered serious due to hospitalization. No subject discontinued study drug or the study due to these eventsPATENT Attorney Docket No. 33087 / 54179 Table 10. Overall Summary of Adverse Events (Safety Set) Placebo Ecopipam (N=77) (N=76)o e: ea e - e a e s we e s w e a o s p o ea e as oss y e a e o o a y e a ed” or missing. Note: AEs are newly occurring or worsening after first dose of study drug. Note: Percentages are based on number of subjects in the safety set. Source: Table 14.3.1.1 (See Figures).

[0109] A summary of AEs occurring in ≥2 subjects in either treatment group by system organ class (SOC) and preferred term for the safety set is provided in Table 35 below. A summary of all AEs by SOC and preferred term for the safety set is provided in Table 14.3.1.4.1 (see the Figures). The SOCs with the highest incidence (>20% of subjects in the ecopipam group) included psychiatric disorders (ecopipam: 22 subjects, 28.9%; placebo: 12 subjects, 15.6%) and nervous system disorders (ecopipam: 20 subjects, 26.3%; placebo: 10 subjects, 13.0%). In the ecopipam group, the most commonly reported AEs (reported in ≥5 subjects) included headache (12 subjects, 15.8%), insomnia (7 subjects, 9.2%), fatigue (6 subjects, 7.9%), somnolence (6 subjects, 7.9%), and nasopharyngitis (5 subjects, 6.6%). In the placebo group, the most commonly reported AEs (reported in ≥4 subjects) included headache (7 subjects, 9.1%), nasopharyngitis (4 subjects, 5.2%), and decreased appetite (4 subjects, 5.2%). Table 11. Summary of Adverse Events Occurring in ≥2 Subjects in Either Treatment Group by System Organ Class and Preferred Term (Safety Set) Placebo EcopipamPATENT Attorney Docket No. 33087 / 54179 Placebo Ecopipam System Organ Class (N=77) (N=76) Pr f rr d T rm n (%) n (%)Note: Percentages are based on number of subjects in the safety set. Note: Adverse events are coded using MedDRA version 23.1. A subject is counted only once for multiple events within the same preferred term / system organ class. Source: Table 14.3.1.4.1 (See Figures)

[0110] A summary of AEs by SOC, preferred term, and initial maintenance daily dose level for the safety set is provided in Table 14.3.1.4.1.1 (See Figures), and a summary of AEs by SOC, preferred term, and weight band for the safety set is provided in Table 14.3.1.4.1.3 (See Figures). The majority of subjects (N=36 in the ecopipam group and N=35 in the placebo group) were in the mid-range weight band of >44 kg to ≤68 kg and had an initial maintenance dose of 100 mg. In this group of subjects, 23 of 36 subjects (63.9%) in the ecopipam group and 16 of 35 subjects (45.7%) in the placebo group had at least 1 AE.PATENT Attorney Docket No. 33087 / 54179

[0111] A summary of AEs by SOC, preferred term, and region for the safety set is provided in Table 14.3.1.4.1.2 (See Figures). In North America, 37 of 64 subjects (57.8%) in the ecopipam group and 27 of 60 subjects (45.0%) in the placebo group had at least 1 AE. In Europe, 10 of 12 subjects (83.3%) in the ecopipam group and 11 of 17 subjects (64.7%) in the placebo group had at least 1 AE.

[0112] A summary of AEs by SOC and preferred term in subjects >83 kg in body weight for the safety set is provided in Table 14.3.1.4.1.4 (See Figures). In subjects >83 kg in body weight, 6 of 8 subjects (75.0%) in the ecopipam group and 3 of 7 subjects (42.9%) in the placebo group had at least 1 AE. In the ecopipam group, AEs of headache, anxiety, and insomnia were reported in 2 subjects each; all other AEs in both treatment groups were reported in 1 subject each. Table 35. Summary of Adverse Events Occurring in ≥2 Subjects in Either Treatment Group by System Organ Class and Preferred Term (Safety Set) Placebo Ecopipam System Organ Class (N=77) (N=76)PATENT Attorney Docket No. 33087 / 54179 Headache 7 (9.1) 12 (15.8) Somnolence 2 (2.6) 6 (7.9)Note: ercentages are based on number o subjects n t e sa ety set. Note: Adverse events are coded using MedDRA version 23.1. A subject is counted only once for multiple events within the same preferred term / system organ class.Source: Table 14.3.1.4.1 (See Figures).

[0113] A summary of AEs by SOC, preferred term, and initial maintenance daily dose level for the safety set is provided in Table 14.3.1.4.1.1 (See Figures), and a summary of AEs by SOC, preferred term, and weight band for the safety set is provided in Table 14.3.1.4.1.3 (See Figures). The majority of subjects (N=36 in the ecopipam group and N=35 in the placebo group) were in the mid-range weight band of >44 kg to ≤68 kg and had an initial maintenance dose of 100 mg. In this group of subjects, 23 of 36 subjects (63.9%) in the ecopipam group and 16 of 35 subjects (45.7%) in the placebo group had at least 1 AE.

[0114] A summary of AEs by SOC, preferred term, and region for the safety set is provided in Table 14.3.1.4.1.2 (See Figures). In North America, 37 of 64 subjects (57.8%) in the ecopipam group and 27 of 60 subjects (45.0%) in the placebo group had at least 1 AE. In Europe, 10 of 12 subjects (83.3%) in the ecopipam group and 11 of 17 subjects (64.7%) in the placebo group had at least 1 AE.

[0115] A summary of AEs by SOC and preferred term in subjects >83 kg in body weight for the safety set is provided in Table 14.3.1.4.1.4 (See Figures). In subjects >83 kg in body weight, 6 of 8 subjects (75.0%) in the ecopipam group and 3 of 7 subjects (42.9%) in the placebo group had at least 1 AE. In the ecopipam group, AEs of headache, anxiety, and insomnia were reported in 2 subjects each; all other AEs in both treatment groups were reported in 1 subject each.PATENT Attorney Docket No. 33087 / 54179

[0116] Adverse Events by Dosing Phase (Titration, Maintenance, and Down Titration / Follow-Up)

[0117] A summary of AEs by SOC and visits within the titration phase for the safety set is provided in Table 36 below. In both treatment groups, more subjects reported AEs during the first week of the titration phase (12 subjects [15.8%] in the ecopipam group and 12 subjects [15.6%] in the placebo group) compared to Week 2, 3, or 4 of the titration phase. A summary of AEs by SOC, PT, and visits within the titration phase for the safety set is provided in Table 14.3.1.4.1.5 (See Figures). Table 36. Summary of Adverse Events by System Organ Class and Visits Within the Titration Phase (Safety Set). Placebo Ecopipam (N=77) (N=76) k 4 ) .5) 6) 3) 3) 9) 3). Note: Percentages are based on number of subjects in the safety set. Note: Adverse events are coded using MedDRA version 23.1. A subject is counted only once for multiple events within the same preferred term / system organ class. Source: Table 14.3.1.4.1.5 (See Figures).

[0118] A summary of AEs by SOC and visits within the maintenance phase for the safety set is provided in Table 37 below. A summary of AEs by SOC, preferred term, and visits within the maintenance phase for the safety set is provided in Table 14.3.1.4.1.6 (See Figures).PATENT Attorney Docket No. 33087 / 54179

[0119] Table 12. Summary of Adverse Events by System Organ Class and Visits Within the Maintenance Phase (Safety Set). Placebo Ecopipam (N=77) (N=76) 12 ) .2) ) ) ) ) ) ) ) )Note: Adverse events are coded using MedDRA version 23.1. A subject is counted only once for multiple events within the same preferred term / system organ class. Source: Table 14.3.1.4.1.6 (See Figures).

[0120] A summary of AEs by SOC and visits within the down titration and follow-up phase for the safety set is provided in Table 38 below. The majority of AEs reported during the down titration phase occurred within the first 7 days of follow-up in both groups. A summary of AEs by SOC, PT and visits within the down titration and follow-up phase for the safety set is provided in Table 14.3.1.4.1.7 (See Figures).PATENT Attorney Docket No. 33087 / 54179 Table 38. Summary of Adverse Events by System Organ Class and Visits Within the Down Titration and Follow-up Phase (Safety Set) Placebo Ecopipam (N=77) (N=76) y upNote: Adverse events are coded using MedDRA version 23.1. A subject is counted only once for multiple events within the same preferred term / system organ class. Source: Table 14.3.1.4.1.7 (See Figures).

[0121] Adverse Events by Common Terminology Criteria for Adverse Events Grade

[0122] AEs were graded by the investigator using the National Cancer Institute - Common Terminology Criteria for Adverse Events (CTCAE) as follows: Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3), Life threatening or disabling (Grade 4), and Fatal (Grade 5).

[0123] A summary of AEs by SOC, preferred term, and highest CTCAE grade for the safety set is provided in Table 14.3.1.4.2 (See Figures). The majority of AEs reported in both treatment groups were mild or moderate in severity. No fatal or life-threatening AEs were reported during the study.

[0124] In the ecopipam group, 23 subjects (30.3%) experienced AEs with a highest CTCAE grade of mild, 17 subjects (22.4%) experienced AEs with a highest CTCAE grade of moderate, and 7 subjects (9.2%) experienced AEs with a highest CTCAE grade of severe.PATENT Attorney Docket No. 33087 / 54179

[0125] In the placebo group, 22 subjects (28.6%) experienced AEs with a highest CTCAE grade of mild, 15 subjects (19.5%) experienced AEs with a highest CTCAE grade of moderate, and 1 subject (1.3%) experienced an AE with a highest CTCAE grade of severe.

[0126] A summary of CTCAE Grade 3 AEs by SOC and preferred term for the safety set is provided in Table 39 below. A total of 7 subjects (9.2%) in the ecopipam group and 1 subject (1.3%) in the placebo group experienced an AE with a highest CTCAE grade of severe; most of the severe AEs were in the SOC of psychiatric disorders, and all severe AEs were reported in 1 subject each. Table 39. Summary of CTCAE Grade 3 Adverse Events by System Organ Class and Preferred Term (Safety Set). Placebo Ecopipam System Organ Class (N=77) (N=76)Note: AEs are coded using MedDRA version 23.1. A subject was counted once at the highest grade for which the event occurred in the system organ class and the highest grade for each unique preferred term within that system organ class. Source: Table 14.3.1.8 (See Figures).

[0127] Adverse Events by Relationship

[0128] A summary of treatment-related AEs by SOC and preferred term for the safety set is provided in Table 40 below. A higher percentage of subjects in the ecopipam group (26 subjects, 34.2%) experienced treatment-related AEs compared to subjects in the placebo group (16 subjects, 20.8%). In the ecopipam group, the most commonly reported treatment-related AEsPATENT Attorney Docket No. 33087 / 54179 (reported in ≥3 subjects) included headache (7 subjects, 9.2%), somnolence (5 subjects, 6.6%), fatigue (5 subjects, 6.6%), insomnia including middle insomnia (4 subjects, 5.3%), restlessness (4 subjects, 5.3%), and nausea, anxiety, depressed mood, and irritability (each AE reported in 3 subjects, 3.9%). All other treatment-related AEs in the ecopipam group occurred in ≤2 subjects. In the placebo group, the most commonly reported treatment-related AEs (reported in ≥3 subjects) included decreased appetite (4 subjects, 5.2%) and headache (3 subjects, 3.9%). All other treatment-related AEs in the placebo group occurred in ≤2 subjects. Table 40. Summary of Treatment-related Adverse Events by System Organ Class and Preferred Term (Safety Set) Placebo Ecopipam System Organ Class (N=77) (N=76)PATENT Attorney Docket No. 33087 / 54179 Placebo Ecopipam System Organ Class (N=77) (N=76) Pr f rr d T rm n (%) n (%) orm ss ng. Note: Percentages are based on number of subjects in the safety set. Note: Adverse events are coded using MedDRA version 23.1. A subject is counted only once for multiple events within the same preferred term / system organ class. Source: Table 14.3.1.6.1 (See Figures).

[0129] A summary of treatment-related AEs by SOC, preferred term, and highest CTCAE for the safety set is provided in Table 14.3.1.6.2 (See Figures). The highest CTCAE grade for most subjects with treatment-related AEs was mild in both treatment groups.

[0130] In the ecopipam group, 15 subjects (19.7%) experienced treatment-related AEs with a highest CTCAE grade of mild, 7 subjects (9.2%) experienced treatment-related AEs with a highest CTCAE grade of moderate, and 4 subjects (5.3%) experienced treatment-related AEs with a highest CTCAE grade of severe. Treatment-related AEs with a highest CTCAE grade of severe included nausea, facial pain, agitation, anxiety, irritability, restlessness, and self-injurious ideation.

[0131] In the placebo group, 13 subjects (16.9%) experienced treatment-related AEs with a highest CTCAE grade of mild, 2 subjects (2.6%) experienced treatment-related AEs with a highest CTCAE grade of moderate, and 1 subject (1.3%) experienced a treatment-related AE with a highest CTCAE grade of severe. The treatment-related AE with a highest CTCAE grade of severe was suicidal ideation.

[0132] Adverse Events by Maximum Severity and Maximum Relatedness

[0133] The severity of AEs was assessed by the investigator as mild, moderate, or severe.PATENT Attorney Docket No. 33087 / 54179

[0134] A summary of AEs and treatment-related AEs by maximum severity (ie, mild, moderate, or severe) for the safety set is provided in Table 14.3.1.2.1 (See Figures). In the ecopipam group, 12 subjects (15.8%) experienced treatment-related AEs with a maximum severity of mild, 10 subjects (13.2%) experienced treatment-related AEs with a maximum severity of moderate, and 4 subjects (5.3%) experienced treatment-related AEs with a maximum severity of severe. In the placebo group, 14 subjects (18.2%) experienced treatment-related AEs with a maximum severity of mild, 1 subject (1.3%) experienced a treatment-related AE with a maximum severity of moderate, and 1 subject (1.3%) experienced a treatment-related AE with a maximum severity of severe.

[0135] A summary of AEs and SAEs by maximum relatedness (i.e., unrelated, possible, or probable) for the safety set is provided in Table 14.3.1.2.2 (See Figures). In the ecopipam group, 21 subjects (27.6%) experienced AEs that were considered unrelated to study drug, 19 subjects (25.0%) experienced AEs that were considered possibly related to study drug, and 7 subjects (9.2%) experienced AEs that were considered probably related to study drug. In the placebo group, 22 subjects (28.6%) experienced AEs that were considered unrelated to study drug, 16 subjects (20.8%) experienced AEs that were considered possibly related to study drug, and 0 subjects experienced AEs that were considered probably related to study drug.

[0136] Two subjects in the ecopipam group experienced an SAE; both events were considered unrelated to study drug; 1 subject in the placebo group experienced an SAE, which was considered possibly related to study drug.

[0137] A summary of AEs by maximum severity or maximum relatedness for each study milestone (i.e., titration phase, maintenance phase, taper down phase, or off study drug) for the safety set is provided in Table 14.3.1.3 (See Figures). Most AEs were reported during the titration and maintenance phases of the study in both treatment groups, with fewer subjects reporting AEs during the taper down phase and the off study drug follow-up phase. In the ecopipam group, 24 subjects (31.6%) experienced AEs during the titration phase, 30 subjects (39.5%) experienced AEs during the maintenance phase, 6 subjects (7.9%) experienced AEs during the taper down phase, and 15 subjects (19.7%) experienced AEs during the off study drug follow-up phase. In the placebo group, 17 subjects (22.1%) experienced AEs during the titration phase, 24 subjects (31.2%) experienced AEs during the maintenance phase, 2 subjects (2.6%)PATENT Attorney Docket No. 33087 / 54179 experienced AEs during the taper down phase, and 5 subjects (6.5%) experienced AEs during the off study drug follow-up phase.

[0138] No deaths were reported during the study. A summary of SAEs by SOC and preferred term for the safety set is provided in Table 41 below. A total of 3 subjects (all adolescents) experienced SAEs during the study. One subject in the placebo group experienced an SAE of suicidal ideation, which the investigator considered as moderate in severity and possibly related to study drug. Two subjects in the ecopipam group experienced SAEs; both were considered by the investigator to be moderate in severity and unrelated to study drug. One of these subjects experienced an SAE of coronavirus infection, which resolved after 8 days. The other subject had an SAE of vomiting, and based on the results of all examinations, the gastroenterologist considered the subject to have ulcerative colitis or Crohn’s disease. A summary of SAEs by SOC and preferred term by age group for the safety set is provided in Table 14.3.1.9.2 (See Figures). Table 41. Summary of Serious Adverse Events by System Organ Class and Preferred Term (Safety Set) Placebo Ecopipam Overall System Organ Class (N=77) (N=76) (N=153)Note: AEs are coded using MedDRA version 23.1. A subject is counted only once for multiple events within the same preferred term / system organ class. Source: Table 14.3.1.9.1 (See Figures).

[0139] A summary of AEs leading to treatment termination by SOC and preferred term for the safety set is provided in Table 42 below. A total of 4 subjects (5.3%) in the ecopipam group and 1 subject (1.3%) in the placebo group experienced an AE leading to treatment termination. Two subjects (1 in the ecopipam group and 1 in the placebo group) had an AE of suicidal ideation that led to treatment termination; all other AEs leading to treatment termination occurred in only 1 subject each. A summary of AEs leading to treatment termination by SOC, preferred term, and highest CTCAE grade for the safety set is provided in Table 14.3.1.7.2 (See Figures).PATENT Attorney Docket No. 33087 / 54179 Table 42. Summary of Adverse Events Leading to Treatment Termination by System Organ Class and Preferred Term (Safety Set) Placebo Ecopipam System Organ Class (N=77) (N=76)Note: AEs are coded using MedDRA version 23.1. A subject is counted only once for multiple events within the same preferred term / system organ class. Source: Table 14.3.1.7.1 (See Figures).

[0140] Adverse Events of Special Interest

[0141] In order to assess potential ecopipam-related extrapyramidal side effects (EPS) and movement disorders, all subjects were administered the AIMS and the BARS over the course of the study. In addition to the AIMS and the BARS, standardized MedDRA queries for Parkinsonism were utilized to identify movement disorder AEs. No EPS-related movement disorders were identified in either the ecopipam or placebo groups. A summary of AESIs for Parkinsonism by SOC and preferred term for the safety set is provided in Table 14.3.1.10.1 (See Figures). A summary of AESIs for ecopipam by SOC and preferred term for the safety set is provided in Table 43 below. A total of 13 subjects (17.1%) in the ecopipam group and 10 subjects (13.0%) in the placebo group had at least 1 AESI for ecopipam during the study. In the ecopipam group, the most common AESIs for ecopipam included depressed mood (3 subjects, 3.9%) and middle insomnia (3 subjects, 3.9%). All other AESIs for ecopipam in the ecopipam group occurred in 1 subject each. Table 43. Summary of Adverse Events of Special Interest for Ecopipam by System Organ Class and Preferred Term (Safety Set) Placebo EcopipamPATENT Attorney Docket No. 33087 / 54179 Placebo Ecopipam System Organ Class (N=77) (N=76) Pr f rr d T rm n (%) n (%)Note: AESI for Ecopipam based on SOC / PT reporting. Note: Percentages are based on number of subjects in the safety set. Note: AEs are coded using MedDRA version 23.1. A subject is counted only once for multiple events within the same preferred term / system organ class. Source: Table 14.3.1.10.2 (See Figures).

[0142] A summary of the Columbia Suicide Severity Rating Scale (C-SSRS) results for the safety set is provided in Table 45 below. At Week 6 and the 14-day follow-up, no subject had suicidal ideation or behavior and hence these visits are not presented in the table. At Baseline, lifetime suicidal ideation was similar between treatment groups and was reported in 16 subjects (21.1%) in the ecopipam group and 12 subjects (15.6%) in the placebo group. During the dosing period in the study, suicidal ideation was reported in up to 8 subjects (10.4%) in the placebo group and no subjects in the ecopipam group. One subject (1.3%) in the ecopipam group reported suicidal ideation at the 7-day follow-up. No subjects reported suicidal behavior during the study (post-Baseline). Table 45. Summary of Columbia Suicide Severity Rating Scale (C-SSRS) (Safety Set) Placebo EcopipamPATENT Attorney Docket No. 33087 / 54179 Suicidal Behavior (6-10) 0 0 Week 4 Since Last Visit Suicidal Ideation (1-5) 8 (10.4) 0 Suicidal Behavior (6-10) 0 0u p u w p v u g . Source: Table 14.3.8.1 (See Figures).

[0143] The Abnormal Involuntary Movement Scale (AIMS) records the occurrences of tardive dyskinesia in subjects receiving neuroleptic medications and consists of rating the presence and severity of movement disorders involving the face, mouth, extremities, and trunk, as well as 3 items of global judgment. A summary of the AIMS total scores for the safety set is provided in Table 46 below. A decrease from Baseline in the AIMS total scores, indicating an improvement, was observed in both treatment groups; no notable differences between groups were observed. Table 46. Summary of Abnormal Involuntary Movement Scale (AIMS) Total Score (Safety Set) Visit Placebo Ecopipam Statistics (N=77) (N=76)PATENT Attorney Docket No. 33087 / 54179 n 74 71 Mean (SD) 4.5 (8.45) 4.3 (6.77) Median 00 004, ranging from 0 to 40. Source: Table 14.3.8.2 (See Figures).

[0144] The Barnes Akathisia Rating Scale (BARS) assesses the severity of drug-induced akathisia. A summary of the BARS total and global scores for the safety set is provided in Table 47 below. The total and global akathisia scores were low at Baseline and decreased slightly post- Baseline in both treatment groups. No notable differences between groups were observed. A summary of the BARS subset scores (objective, subjective – awareness of restlessness, and subjective – distress related to restlessness) for the safety set is provided in Table 14.3.8.3 (See Figures). Table 47. Summary of Barnes Akathisia Rating Scale (BARS) Total and Global Scores (Safety Set) Placebo Ecopipam Subset Visit Statistics (N=77) (N=76)PATENT Attorney Docket No. 33087 / 54179 Placebo Ecopipam Subset Visit Statistics (N=77) (N=76) W k 4 74 71Note: Objective Akathisia, Subjective Awareness of Restlessness and Subjective Distress Related to Restlessness are rated on a 4-point scale from 0 – 3 and are summed yielding a Total Score ranging from 0 to 9. Note: Global clinical assessment of akathisia is rated on 6-point scale from 0-5. Source: Table 14.3.8.3 (See Figures).

[0145] The Swanson, Nolan, and Pelham Questionnaire (SNAP-IV) is designed to assess ADHD and ODD symptoms in children and adolescents. A summary of the SNAP-IV questionnaire total scores for the safety set is provided in Table 48 below. A decrease from Baseline in the total scores, indicating an improvement in ADHD and ODD symptoms, was observed in both treatment groups. No notable differences between groups were observed. A summary of the SNAP-IV subset scores for the safety set is provided in Table 14.3.8.4 (See Figures). Table 48. Summary of Swanson, Nolan, and Pelham (SNAP-IV) Questionnaire Total Score (Safety Set) Placebo EcopipamPATENT Attorney Docket No. 33087 / 54179 Placebo Ecopipam Visit Statistics (N=77) (N=76) W k 6 72 71Note: nattent on and yperactv ty / mpu s v ty be av or s an average o 9 quest ons, Oppos t ona e ant sorder is an average of 8 questions, Inattention / Overactivity and Aggression / Defiance is an average of 5 questions, Conners Index is an average of 10 questions, Academic is an average of 6 questions and Deportment is an average of 4 questions. All questions are rated on 4-point scale ranging from 0-3. Source: Table 14.3.8.4 (See Figures).

[0146] The Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) is designed to determine severity of OCD and to monitor improvement during treatment. The scale is a clinician-rated, 10-item scale that includes questions about the amount of time spent on obsessions / compulsions, level of impairment or distress, and how much resistance and control subjects have over these thoughts. The CY-BOCS total score is computed as the sum of the 10 items, ranging from 0 to 40, with higher scores indicating more severe compulsions and obsessions. A summary of the CY-BOCS total score for the safety set is provided in Table 49 below. A decrease from Baseline in CY-BOCS total score was observed in both treatment groups. No notable differences between groups were observed. Table 49. Summary of Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) Total Score (Safety Set). Visit Placebo EcopipamPATENT Attorney Docket No. 33087 / 54179 Visit Placebo Ecopipam Statistics (N=77) (N=76) W k 6Note: CY-BOCS total score is computed as the sum of the first 10 items, ranging from 0 to 40, with higher scores indicating more severe compulsions and obsessions. Source: Table 14.3.8.5 (See Figures).

[0147] The Children’s Depression Rating Scale-Revised (CDRS-R) is a clinically validated rating scale designed to assess psychiatric signs and symptoms of depression. Fourteen signs and symptoms are rated from 1 (normal) to 7 (most severe), and 3 signs and symptoms are rated from 1 (normal) to 5 (most severe). The raw summary score is the sum of all 17 items, ranging from 17 to 113. A summary of the CDRS-R raw summary score for the safety set is provided in Table 50 below. A slight decrease from Baseline in CDRS-R score was observed in both treatment groups. No notable differences between treatment groups were observed. Table 50. Summary of Children’s Depression Rating Scale-Revised (CDRS-R) Raw Summary Score (Safety Set) Visit Placebo Ecopipam i i 77 7PATENT Attorney Docket No. 33087 / 54179 Visit Placebo Ecopipam Statistics (N=77) (N=76)Note: The raw summary score for the CDRS-R is the sum of all 17 items, ranging from 17 to 113 if no missing records. Source: Table 14.3.8.6 (See Figures).

[0148] The Pediatric Anxiety Rating Scale (PARS) is a clinician-rated instrument for assessing the severity of anxiety symptoms associated with common anxiety disorders and generalized anxiety in children and adolescents. A summary of the PARS total score for the safety set is provided in Table 51 below. A decrease from Baseline in PARS total score, indicating an improvement in symptoms, was observed in both treatment groups. No notable differences between treatment groups were observed. Table 51. Summary of Pediatric Anxiety Rating Scale (PARS) Total Score (Safety Set). Visit Placebo Ecopipam Statistics (N=77) (N=76)PATENT Attorney Docket No. 33087 / 54179 Visit Placebo Ecopipam Statistics (N=77) (N=76) 71 66o e: e o a sco e o e s o a o e seve y e s. e o a sco e a ges o o . Source: Table 14.3.8.7 (See Figures).

[0149] A total of 47 subjects (61.8%) in the ecopipam group and 38 subjects (49.4%) in the placebo group experienced an AE during the study.

[0150] The majority of AEs reported in both treatment groups were mild or moderate in severity. No fatal or life-threatening AEs were reported during the study.

[0151] Treatment-related AEs were reported in a higher proportion of subjects in the ecopipam group (26 subjects, 34.2%) compared to the placebo group (16 subjects, 20.8%).

[0152] In the ecopipam group, the most commonly reported treatment-related AEs (>5% of subjects) included headache (7 subjects, 9.2%), somnolence (5 subjects, 6.6%), fatigue (5 subjects, 6.6%), insomnia including middle insomnia (4 subjects, 5.3%), and restlessness (4 subjects, 5.3%). In the placebo group, the most commonly reported treatment-related AE was decreased appetite (4 subjects, 5.2%).

[0153] A total of 3 subjects (all adolescents) experienced SAEs during the study. One subject in the placebo group experienced an SAE of suicidal ideation, which the investigator considered as moderate in severity and possibly related to study drug. Two subjects in the ecopipam group experienced SAEs (1 subject had an SAE of vomiting and 1 subject had an SAE of coronavirus infection); both SAEs were considered by the investigator to be moderate in severity and unrelated to study drug.

[0154] A total of 4 subjects (5.3%) in the ecopipam group and 1 subject (1.3%) in the placebo group experienced an AE leading to treatment termination. Two subjects (1 in the ecopipam group and 1 in the placebo group) had an AE of suicidal ideation that led to treatment termination; all other AEs leading to treatment termination occurred in only 1 subject each.PATENT Attorney Docket No. 33087 / 54179

[0155] No EPS movement disorders were seen in subjects in either the ecopipam or placebo group.

[0156] A total of 13 subjects (17.1%) in the ecopipam group and 10 subjects (13.0%) in the placebo group had at least 1 AESI for ecopipam during the study. In the ecopipam group, the most common AESIs for ecopipam included depressed mood (3 subjects, 3.9%) and middle insomnia (3 subjects, 3.9%).

[0157] No meaningful differences between the ecopipam group and placebo group were observed for laboratory results, vital signs, gain in body weight, ECG findings, C-SSRS, and the safety outcome scales.

[0158] A total of 4 subjects (2 subjects in the ecopipam group and 2 subjects in the placebo group) reported COVID-19 AEs. The investigator considered 3 events as mild and 1 event as moderate in severity. One of the subjects in the ecopipam group had a COVID-19 AE considered serious due to hospitalization. No subject discontinued study drug or the study due to these events

[0159] Example 2

[0160] The dosing method described in Example 1 above was used in a 52 week open label extension study in the same class of patients, i.e. having TS and aged at least six years and less than 18 years, wherein patients were titrated up to full doses according to the same schedule.

[0161] A preliminary analysis of data shows the following trends and comparisons with the PSY302 open label extension study described above.

[0162] Overview of Treatment-Emergent Adverse Events (Safety Population) Category n (%) PSY 302 OLE Example 1-OLEPATENT Attorney Docket No. 33087 / 54179 Fatal SAE 0 0 Abbreviations: SAE, serious adverse event; TEAE, treatment-emergent adverse eventNote: TEAEs with a relationship of probable, possible, or missing were considered related for PSY-302 OLE, probably or possibly for Example 1-OLE. Table: Treatment-Emergent Adverse Events Occurring in ≥ 2 Subjects (Safety Population) System organ class Preferred PSY302 OLE Example 1-OLE term Ecopipam N=26 Ecopipam N = 124 of which 80 had(missing data included for PSY302 OLE, missing data excluded for Example 1-OLE. For PSY302 OLE, subjects were counted once for each system organ class and once for each preferred term. Multiple episodes in same subject included in Example 1-OLE.

[0163] The present disclosure illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions indicates the exclusion of equivalents of the features shown and described or portions thereof. ItPATENT Attorney Docket No. 33087 / 54179 is recognized that various modifications are possible within the scope of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be falling within the scope of the invention.

[0164] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise” and variations such as “comprises” and “comprising” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0165] Throughout the specification, where compositions are described as including components or materials, it is contemplated that the compositions can also consist essentially of, or consist of, any combination of the recited components or materials, unless described otherwise. Likewise, where methods are described as including particular steps, it is contemplated that the methods can also consist essentially of, or consist of, any combination of the recited steps, unless described otherwise. The invention illustratively disclosed herein suitably may be practiced in the absence of any element or step which is not specifically disclosed herein.

[0166] The practice of a method disclosed herein, and individual steps thereof, can be performed manually and / or with the aid of or automation provided by electronic equipment. Although processes have been described with reference to particular embodiments, a person of ordinary skill in the art will readily appreciate that other ways of performing the acts associated with the methods may be used. For example, the order of various of the steps may be changed without departing from the scope or spirit of the method, unless described otherwise. In addition, some of the individual steps can be combined, omitted, or further subdivided into additional steps.

[0167] All patents, publications and references cited herein are hereby fully incorporated by reference. In case of conflict between the present disclosure and incorporated patents, publications and references, the present disclosure should control.

Claims

PATENT Attorney Docket No. 33087 / 54179 What is Claimed:

1. A method of orally administering ecopipam or a pharmaceutically acceptable salt thereof to a patient in need thereof comprising: providing a first daily dosage of ecopipam to the patient in a first daily dosage amount for a first period of time of seven days; providing a second daily dosage of ecopipam to the patient in a second daily dosage amount, greater than the first dosage amount, for a second period of time following the first period, wherein the second period of time is seven days; and providing a third daily dosage of ecopipam to the patient in a third daily dosage amount, greater than the second dosage amount, for a third period of time following the second period, wherein (a) the third period of time is greater than seven days and one or more of the following three conditions is met (1) the ecopipam daily dosage amount administered in the third period of time is 37.5 mg; (2) the first daily dosage amount is 1 / 3 the amount of the third daily dosage amount and the second daily dosage amount is 2 / 3 the amount of the third daily dosage amount; and (3) the patient has a weight of ≥18 kg to ≤23 kg; or (b) the third period of time is seven days and the method further comprises providing a fourth daily dosage of ecopipam to the patient in a fourth daily dosage amount greater than the third daily dosage amount, for a fourth period of time following the third period, wherein the fourth daily dosage amount is 2.41 mg / kg or less.

2. The method of claim 1, wherein the third period of time is greater than seven days and the daily ecopipam dose administered in the third period of time is 37.5 mg.

3. The method of claim 1 or 2, wherein the third period of time is greater than seven days and the first daily dosage amount is 1 / 3 the amount of the thirdPATENT Attorney Docket No. 33087 / 54179 daily dosage amount and the second daily dosage amount is 2 / 3 the amount of the third daily dosage amount.

4. The method of any one of claims 1 to 3, wherein the patient has a weight of ≥18 kg to ≤23 kg.

5. The method of claim 1, wherein the third period of time is seven days and the method further comprises providing a fourth daily dosage of ecopipam to the patient in a fourth daily dosage amount greater than the third daily dosage amount, wherein the fourth daily dosage amount is 2.41 mg / kg or less.

6. The method of claim 5, wherein the first daily dosage amount is 1 / 4 the amount of the fourth daily dosage amount, the second daily dosage amount is 1 / 2 the amount of the fourth daily dosage amount, and the third daily dosage amount is 3 / 4 the amount of the fourth daily dosage amount.

7. The method of claim 6, wherein the patient has a weight of >23 kg to ≤34 kg and the fourth daily dosage amount is 50 mg.

8. The method of claim 6, wherein the patient has a weight of >44 kg to ≤68 kg and the fourth daily dosage amount is 100 mg.

9. The method of claim 5, wherein the first daily dosage amount is 1 / 6 the amount of the fourth daily dosage amount, the second daily dosage amount is 1 / 3 the amount of the fourth daily dosage amount, and the third daily dosage amount is 2 / 3 the amount of the fourth daily dosage amount.

10. The method of claim 9, wherein the patient has a weight of >34 kg to ≤44 kg and the fourth dosage amount is 75 mg.

11. The method of claim 9, wherein the patient has a weight of >68 kg to ≤83 kg and the fourth dosage amount is 150 mg.

12. The method of claim 5, wherein the first daily dosage amount is 1 / 8 the amount of the fourth daily dosage amount, the second daily dosage amount isPATENT Attorney Docket No. 33087 / 54179 1 / 4 the amount of the fourth daily dosage amount, and the third daily dosage amount is 1 / 2 the amount of the fourth daily dosage amount.

13. The method of claim 12, wherein the patient has a weight of >83 kg and the fourth dosage amount is 200 mg.

14. The method of claim 6, wherein when the patient has a weight of >23 kg to ≤34 kg then the fourth daily dosage amount is 50 mg and when the patient has a weight of >44 kg to ≤68 kg then the fourth daily dosage amount is 100 mg.

15. The method of claim 9, wherein when the patient has a weight of >34 kg to ≤44 kg then the fourth daily dosage amount is 75 mg and when the patient has a weight of >68 kg to ≤83 kg then the fourth daily dosage amount is 150 mg.

16. The method of claim 5, wherein when the patient has a weight of >23 kg to ≤34 kg then the first daily dosage amount is 12.5 mg, the second daily dosage amount is 25 mg, the third daily dosage amount is 37.5 mg, and the fourth daily dosage amount is 50 mg; and when the patient has a weight of >34 kg to ≤44 kg then the first daily dosage amount is 12.5 mg, the second daily dosage amount is 25 mg, the third daily dosage amount is 50 mg, and the fourth daily dosage amount is 75 mg; and when the patient has a weight of >44 kg to ≤68 kg then the first daily dosage amount is 25 mg, the second daily dosage amount is 50 mg, the third daily dosage amount is 75 mg, and the fourth daily dosage amount is 100 mg; and when the patient has a weight of >68 kg to ≤83 kg then the first daily dosage amount is 25 mg, the second daily dosage amount is 50 mg, the third daily dosage amount is 100 mg, and the fourth daily dosage amount is 150 mg.

17. A method of orally administering ecopipam or a pharmaceutically acceptable salt thereof to a patient in need thereof comprising: providing a first daily dosage of ecopipam to the patient in a first daily dosage amount for a first period of time of about seven days;PATENT Attorney Docket No. 33087 / 54179 providing a second daily dosage of ecopipam to the patient in a second daily dosage amount, greater than the first daily dosage amount, for a second period of time following the first period, wherein the second period of time is about seven days; providing a third daily dosage of ecopipam to the patient in a third daily dosage amount, greater than the second daily dosage amount, for a third period of time following the second period, wherein the third period of time is at least seven days; and optionally providing a fourth daily dosage of ecopipam to the patient in a fourth daily dosage amount, greater than the third daily dosage amount, for a fourth period of time following the third period; wherein (a) the third period of time is greater than seven days when the patient has a weight of ≥18 kg to ≤23 kg and one or more of the following two conditions is met (1) the daily ecopipam dose administered in the third period of time is 37.5 mg; and (2) the first daily dosage amount is 1 / 3 the amount of the third daily dosage amount and the second daily dosage amount is 2 / 3 the amount of the third daily dosage amount; and (b) the third period of time is seven days and the method further comprises providing a fourth daily dosage of ecopipam to the patient in a fourth daily dosage amount greater than the third daily dosage amount, wherein the dosage amount is 2.41 mg / kg or less; and wherein when the patient has a weight of >23 kg to ≤34 kg then the first daily dosage amount is 12.5 mg, the second daily dosage amount is 25 mg, the third daily dosage amount is 37.5 mg, and the fourth daily dosage amount is 50 mg; and when the patient has a weight of >34 kg to ≤44 kg then the first daily dosage amount is 12.5 mg, the second daily dosage amount is 25 mg, the third daily dosage amount is 50 mg, and the fourth daily dosage amount is 75 mg; and when the patient has a weight of >44 kg to ≤68 kg then the first daily dosage amount is 25 mg, the second daily dosage amount is 50 mg, the third daily dosage amount is 75 mg, and the fourth daily dosage amount is 100 mg; and when the patient has a weight of >68 kg to ≤83 kg then the first daily dosagePATENT Attorney Docket No. 33087 / 54179 amount is 25 mg, the second daily dosage amount is 50 mg, the third daily dosage amount is 100 mg, and the fourth daily dosage amount is 150 mg; and when the patient has a weight of >83 kg then the first daily dosage amount is 25 mg, the second daily dosage amount is 50 mg, the third daily dosage amount is 100 mg, and the fourth daily dosage amount is 200 mg.

18. The method of any one of claims 5 to 17, wherein the fourth period of time is at least two days.

19. The method of claim 18, wherein the fourth period of time is more than one week.

20. The method of any one of the preceding claims, wherein the patient has an age of ≥6 years to <18 years.

21. The method of any one of the preceding claims, wherein the patient has an age of ≥18 years.

22. The method of any one of the preceding claims, wherein one or more of the first daily dosage, the second daily dosage, the third daily dosage, and the fourth daily dosage, are administered once per day.

23. The method of any one of the preceding claims, wherein each of the first daily dosage, the second daily dosage, the third daily dosage, and the fourth daily dosage, when applicable, is administered once per day.

24. The method of any one of the preceding claims, wherein the ecopipam administration is for the treatment of Tourette Syndrome.

25. The method of anyone of the preceding claims, wherein the method decreases one or more adverse events, e.g. compared to prior methods.

26. The method of anyone of the preceding claims, wherein the method increases efficacy of ecopipam therapy, e.g. compared to prior methods.PATENT Attorney Docket No. 33087 / 54179 27. A method of withdrawing pharmaceutical therapy from a patient receiving ecopipam or a pharmaceutically acceptable salt thereof comprising: following administration of a previous dosage of ecopipam or a pharmaceutically acceptable salt thereof to the patient, (a) providing a decreased daily dosage of ecopipam or a pharmaceutically acceptable salt thereof to the patient in an amount in a range of about 20 mg to 30 mg less than the patient was administered in the previous dosage; and (b) repeating step (a) until the decreased daily dosage of ecopipam or a pharmaceutically acceptable salt thereof is 0 mg; and then (c) terminating administration of ecopipam or a pharmaceutically acceptable salt thereof.

28. The method of the claim 27, wherein the patient is in an age range of at least 6 years old to less than 18 years old.

29. The method of claim 27 or 28, wherein the decreased daily dosage amount is about 25 mg less per day than the patient was administered in the previous dosage.

30. The method of any one of claims 27 to 29, wherein the decreased daily dosage amount is about 1 / 4 less per day than the patient was administered in the first dosage.

31. The method of any one of claims 27 to 30, wherein step (b) is carried out daily.

32. The method of any one of claims 27 to 31, wherein the patient was receiving ecopipam or a pharmaceutically acceptable salt thereof for treatment of Tourette Syndrome.

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