How to Provide Ecopipam Therapy to Patients

Abstract

A method for reducing adverse events associated with administering ecopipam, the method comprising dosing according to a specific weight range and an associated dose escalation regimen, and a further downward dosing regimen for discontinuation of ecopipam.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS 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, the disclosure of which is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] Technical Field The present invention relates to methods for reducing adverse events associated with the administration of ecopipam ((6aS,13bR)-11-chloro-7-methyl-5,6,6a,8,9,13b-hexahydronaphtho[1,2-a][3]benzazepin-12-ol) and its pharmaceutically acceptable salts, such as ecopipam HCl.

[0003] Background technology Ecopipam is a small drug molecule with the chemical name ((6aS,13bR)-11-chloro-7-methyl5,6,6a,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 receptor family. Ecopipam (also known by the development codes EBS-101, PSYRX-101, and SCH-39166; C as the hydrochloride salt) 19 H 20 NOCl), as well as its structure and synthesis, are known. Ecopipam is being evaluated clinically in patients with Tourette's syndrome (also known as Tourette's disorder), childhood-onset fluency disorders (i.e., patients diagnosed with stuttering or a stuttering disorder), and 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 the administration of a single oral dose of ecopipam to each of three healthy subjects at doses of 25 mg, 100 mg, and 400 mg. After the 25 mg dose, all three subjects reported fatigue as the only side effect. After the 100 mg dose, all three subjects reported fatigue, and two subjects reported restlessness. After the 400 mg dose, restlessness and sedation were reported by all three subjects, while irritability 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 the administration of ecopipam to six adult psychiatric patients in a 4-week study. The dose was gradually 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 on days 18-28. Three patients (Nos. 1, 2, and 5) experienced improvement in extrapyramidal symptoms, while one patient (No. 4) experienced a significant induction of extrapyramidal symptoms (Table 4). Other reported side effects included 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 trial in patients with schizophrenia. Ecopipam was given orally according to a fixed dosing schedule of 25 mg bid on day 1, 50 mg bid on day 4, 100 mg bid on day 7, 200 mg bid on day 18, and 225 mg bid on day 21. Patients maintained the 225 mg bid dose until the end of the study on day 28. Seven patients completed the study at week 2, and five patients completed the study. The reasons for early discontinuation were lack of efficacy or refusal to take ecopipam. The most common side effect was dizziness, reported by four patients. Other side effects considered by the investigator to be possibly or probably related to treatment were hypokinesia, cogwheel rigidity, 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 patients with schizophrenia in a 4-week study. Dosing began with 10 mg bid in the morning on days 1–3, followed by 25 mg bid on days 4–6, 50 mg bid on days 7–9, 75 mg bid on days 10–17, and 100 mg bid on days 18–28. Dose reductions were permitted in the event of intolerable or intolerable adverse events. Seven patients completed the 4-week study; another four participated for 10 days or more; and four patients participated for 4 days or less. Reasons for early discontinuation included refusal to take the drug (eight patients) and exacerbation (two 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 at a dose of 100 mg for 8 consecutive days. Seven of the 10 participants experienced at least one adverse event, but their occurrence did not vary as a function of maintenance status. Headaches were reported six times during placebo maintenance and five times during ecopipam maintenance, while gastrointestinal upset (constipation, stomach pain) 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 of ecopipam daily, and a phase 3, placebo-controlled study of ecopipam in obese adult patients receiving 50 or 100 mg daily for 52 weeks. Patient weights ranged from 60 kg to 172 kg, with a mean weight of 100 kg. The studies included doses of 50 mg / day (1 study) or 100 mg / day (3 studies). For the 50 mg dose, the mean dose was 0.5 mg / kg, based on the subjects' mean weight, with a range of 0.29 to 0.83 mg / kg. At the 100 mg dose, the mean dose based on subject mean body weight was 1 mg / kg, with a range of 0.58 to 1.66 mg / kg. At the 100 mg dose, 85 to 92% of subjects experienced a treatment-emergent adverse event (TEAE), which was 6 to 9% higher than placebo. At the 100 mg dose, the most common adverse events were insomnia (8 to 11% higher than placebo), depression (8 to 13% higher than placebo), fatigue (7 to 13% higher than placebo), anxiety (8 to 11% higher than placebo), and somnolence (6 to 14% higher 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 clinical trial of ecopipam in 18 adults with TS. The dose was 50 mg / day orally administered before bedtime for 2 weeks, followed by 100 mg / day for 6 weeks. 100% of patients experienced adverse events. The incidence rates of the most common adverse events were generally higher than in Astrup et al. (2007). Two subjects discontinued participation early.

[0011] International Patent Application Publication No. WO 2014 / 012063 A1 proposes a pharmaceutical dosage form with a controlled-release component to reduce or eliminate the adverse side effects of ecopipam administration, and states that previous studies have shown that the peak adverse sedative effects of ecopipam occur within several hours of dose administration, and that these sedative effects may be related to high plasma levels at approximately 2-4 hours after dose administration, with peak effects occurring approximately 6-8 hours thereafter. The '063 publication also suggested a dosing regimen in which such frequent doses, three or four times daily, may be required.

[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 the use of ecopipam in subjects aged 6 to 22 years with Lesch-Nyhan syndrome. The trial was terminated early due to adverse effects. Most subjects weighed less than 30 kg, and subjects received doses ranging from 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, pp. 1272-1278, (August 2018) reported a 4-week, placebo-controlled, Phase 2b trial of ecopipam in subjects 7 to 17 years of age (PSY302). The total dose was 50 mg / day for subjects weighing 34 kg or less and 100 mg / day for subjects weighing more than 34 kg. The minimum subject weight was 20 kg. 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; for the 100 mg dose, the possible range was limited to approximately 2.86 mg / kg at the upper end (i.e., based on a 35 kg patient). The 50 mg dose began at 12.5 mg / day on days 1–3, then 25 mg / day on days 4–7, then 50 mg / day thereafter for the final 3 weeks. The 100 mg dose began at 25 mg / day on days 1–7, then 50 mg / day on days 8–14, then 100 mg / day thereafter for the final 2 weeks. The overall incidence of adverse events was not reported. Two subjects discontinued study participation related to adverse events while taking ecopipam during phase 2 of the crossover study: one from a rash on the upper arm, which was likely urticaria and was considered possibly unrelated because it was present before study initiation, and one from a worsening of tic severity. The incidence of TEAS is reported in Table 3. Summary of the Invention

[0014] Provided herein are methods for administering ecopipam. One embodiment is a method of orally administering ecopipam or a pharmaceutically acceptable salt thereof to a patient in need thereof, the method comprising: providing a first daily dose of ecopipam to the patient at a first daily dosage for a first period of at least 5 days, e.g., 7 days; providing a second daily dose of ecopipam to the patient at a second daily dosage greater than the first dosage for a second period of time following the first period, wherein the second period of time is at least 5 days, e.g., 7 days; and providing a third daily dose of ecopipam to the patient at a third daily dosage greater than the second dosage for a third period of time following the second period, wherein a) the third period of time is longer than 7 days and one or more of the following three conditions are met: (1) the daily dosage of ecopipam administered during the third period of time is 37.5 mg; (2) the first daily dosage is 1 / 3 of the third daily dosage and the second daily dosage is 2 / 3 of the third daily dosage; and (3) the patient weighs 18 kg or more and 23 kg or less; or (b) the third period of time is 7 days and the method further includes providing the patient with a fourth daily dosage of ecopipam for a fourth period of time after the third period, the fourth daily dosage being greater than the third daily dosage, and the fourth daily dosage being 2.41 mg / kg or less.

[0015] Another embodiment is a method of orally administering ecopipam or a pharmaceutically acceptable salt thereof to a patient in need thereof, the method comprising providing a first daily dose of ecopipam to the patient at a first daily dosage for a first period of about 7 days, and providing a second daily dose of ecopipam to the patient at a second daily dosage greater than the first daily dosage for a second period of time following the first period, the second period being about 7 days. providing a third daily dose of ecopipam to the patient at a third daily dosage greater than the second daily dosage for a third time period after the second time period, wherein the third time period is at least 7 days; and optionally providing a fourth daily dose of ecopipam to the patient at a fourth daily dosage greater than the third daily dosage for a fourth time period after the third time period, wherein (a) the patient weighs 18 kg or more The third period is greater than seven days if one or more of the following two conditions are met: (1) the daily ecopipam dose administered during the third period is 37.5 mg; (2) the first daily dosage is one-third the amount of the third daily dosage and the second daily dosage is two-thirds the amount of the third daily dosage; and (b) the third period is seven days and the method comprises administering a fourth daily dosage of ecopipam to a patient in a dose range of 23 kg or less. and providing to the patient a fourth daily dosage greater than or equal to 2.41 mg / kg, wherein the dosages are 2.41 mg / kg or less, and if the patient weighs greater than 23 kg but less than or equal to 34 kg, the first daily dosage is 12.5 mg, the second daily dosage is 25 mg, the third daily dosage is 37.5 mg, and the fourth daily dosage is 50 mg, and if the patient weighs greater than 34 kg but less than or equal to 44 kg, the first daily dosage is 12.If the patient weighs more than 44 kg but not more than 68 kg, the first daily dosage is 25 mg, the second daily dosage is 50 mg, the third daily dosage is 50 mg, and the fourth daily dosage is 75 mg; if the patient weighs more than 68 kg but not more than 83 kg, the first daily dosage is 25 mg, the second daily dosage is 50 mg, the third daily dosage is 100 mg, and the fourth daily dosage is 150 mg; if the patient weighs more than 83 kg, the first daily dosage is 25 mg, the second daily dosage is 50 mg, the third daily dosage is 100 mg, and the fourth daily dosage is 200 mg.

[0016] Another aspect is a method of discontinuing drug therapy from a patient receiving ecopipam or a pharmaceutically acceptable salt thereof according to the methods described herein, the discontinuing method comprising, after administering to the patient a previous dose of ecopipam or a pharmaceutically acceptable salt thereof, (a) providing the patient with a reduced daily dose of ecopipam or a pharmaceutically acceptable salt thereof in an amount in the range of about 20 mg to 30 mg less than the patient was administered in the previous dose; (b) repeating step (a) until the reduced daily dose 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, it is contemplated that optional features, including but not limited to components, compositional ranges thereof, substituents, conditions, and steps, may be selected from the various aspects, embodiments, and examples provided herein.

[0018] Further aspects and advantages will be apparent to those skilled in the art from a review of the following detailed description taken in conjunction with the drawings. While the method is susceptible to embodiment in various forms, the following description 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 explanation of the drawings]

[0019] [Figure 1] To further facilitate understanding of the present invention, figures are attached hereto together with detailed information regarding adverse events and other safety parameters related to Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0020] As an investigational drug, ecopipam is primarily provided in tablet and capsule form for oral administration. The tablet formulation has been used in 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 daily activities and quality of life and, if sufficiently severe, can lead to discontinuation of treatment. These effects of administering ecopipam appear to be dose-related.

[0021] The inventors made several determinations based on unpublished results from the PSY302 trial reported in Gilbert 2018. First, the overall safety analysis set incidence of adverse events in the ecopipam group was 80%, 15% higher than placebo subjects. Second, subjects receiving doses below 1.4 mg / kg / day (correlated with the 25th percentile in the trial) are unlikely to have substantial efficacy. Therefore, the present method optionally and preferably has a minimum full dose after titration of at least 1.4 mg / kg / day or greater than 1.4 mg / kg / day. Third, subjects receiving doses substantially higher than 2 mg / kg, e.g., greater than about 2.4 mg / kg, may not be well tolerated.

[0022] Additional results from the PSY302 trial are discussed next.

[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 occurred in the ecopipam group leading to early discontinuation. There were no fatal adverse events. Twenty subjects (50.0%) reported study drug-related adverse events while taking ecopipam, and 10 subjects (25.0%) reported study drug-related adverse events while taking placebo. Adverse events by treatment group are summarized in Figure Table 14-20-2. [Table 1]

[0024] Adverse events reported in 5% or more of subjects in either treatment group are shown in the table below.

[0025] The most frequently reported adverse events (≥5% of subjects) are shown in the table below [Table 2]

[0026] The severity of adverse events as assessed by the investigators is summarized in the table below. Most adverse events (144 / 149, 96.6%) were assessed by the investigators as mild or moderate in severity. Five subjects (12.5%) experienced adverse events assessed as severe, with two subjects (5.0%) taking ecopipam and three (7.5%) taking placebo. One of the severe adverse events during ecopipam treatment (insomnia) was considered almost certainly related to the study drug. The severe adverse event resolved without consequence and did not result in discontinuation. [Table 3]

[0027] Adverse events considered by the investigator to be probably, probably, or probably related to the study drug are summarized in the following table: In subjects taking ecopipam, the most frequently reported adverse events (≥7.5%) considered related to the study drug were nausea (10.0%), somnolence (10.0%), upper abdominal pain, decreased appetite, fatigue, headache, and sedation (all 7.5%). [Table 4]

[0028] No deaths occurred in the study. One subject experienced a psychiatric SAE 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 discontinued the study early due to a rash adverse event. One subject required a dose reduction due to a fatigue adverse event.

[0029] Additionally, there was an open-label extension study using the dosing method reported in Gilbert et al. (2018) (PSY302 OLE). Because subjects had discontinued ecopipam by the time they enrolled in the open-label extension study, they had to be titrated back to the full dose using the same method 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%) discontinued early, 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, seven subjects (26.9%) exceeded 12 months, and one subject (3.8%) received study drug for 24 months. The median number of days on treatment was 374.5 days, 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 1 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 not considered related to 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 two subjects (7.7%), one of which was an SAE (anxiety). Severe events were not considered related to the study drug. TEAES considered related to the study drug were reported by 13 subjects (50.0%), with nine subjects (34.6%) having moderate-severity events and four subjects (15.4%) having mild-severity events. Four subjects (15.4%) experienced one or more TEAEs that led to discontinuation of the study drug (suicidal ideation [n=3], depressed mood [n=2], and intrusive thoughts [n=1]). One of the depressed mood TEAEs that led to discontinuation was ongoing at the end of the study; the remainder had resolved. In all four cases (100%), the events were considered probably related to the study drug. Three subjects (11.5%) experienced adverse events of special interest (AESI), all three of which were moderate suicidal ideation events that led to study drug discontinuation. All AESIs (100%) were considered probably related to study drug.

[0031] An overall summary of TEAEs, Safety Analysis Set (Table 14.3.1.1), summary of TEAEs by System Organ Class (SOC) and Preferred Term (PT), Safety Analysis Set (Table 14.3.1.2), summary of TEAEs by SOC, PT, and severity, Safety Analysis Set (Table 14.3.1.3), summary of TEAEs by SOC, PT, and relationship to study drug, Safety Analysis Set (Table 14.3.1.4), summary of treatment-emergent AESIs by SOC and PT, Safety Analysis Set (Table 14.3.1.5), summary of serious TEAEs by SOC and PT, Safety Analysis Set (Table 14.3.1.6), and summary of TEAEs leading to study drug discontinuation by SOC and PT, Safety Analysis Set (Table 14.3.1.7) are provided in figures.

[0032] The TEAEs are summarized in the table below. [Table 5]

[0033] TEAEs reported by two or more subjects are summarized in the table below. The most frequently reported TEAEs (more than three subjects) were upper respiratory tract infection (five subjects, 19.2%), anxiety (three subjects, 11.5%), cerebral congestion (three subjects, 11.5%), and suicidal ideation (three subjects, 11.5%). [Table 6]

[0034] All AEs were assessed by the investigator as mild, moderate, or severe. Investigators assessed 71 / 78 TEAEs (91.0%) as mild or moderate in severity and 7 / 78 TEAEs (9.0%) as severe. Seven severe events occurred in two subjects (7.7%), as summarized in the table below. [Table 7]

[0035] Thirteen subjects (50.0%) experienced TEAEs that were deemed by the investigator to be related to the study drug. Nine subjects (34.6%) had related events of moderate severity, and four subjects (15.4%) had related events of mild severity. Related TEAEs experienced by two or more subjects are summarized in the table below. [Table 8]

[0036] There were no deaths in the study. One subject (3.8%) experienced an SAE of severe anxiety requiring hospitalization. The SAE was considered unrelated to study drug.

[0037] Four subjects (15.4%) in the safety analysis population experienced one or more TEAEs that led to discontinuation of study drug. All events (100%) were in psychiatric system disorder categories, and all events (100%) were considered probably related to study drug. One TEAE that led to discontinuation was ongoing at the end of the study (depressed mood), and the remainder resolved. Subjects with TEAEs that led to early discontinuation are summarized in the table below. The protocol required discontinuation of study drug if subjects experienced persistent symptoms of depression or suicidality. [Table 9]

[0038] Subjects with AESIs are summarized in the table below. Three subjects (11.5%) experienced the moderate TEAE of suicidal ideation. All three subjects (100%) discontinued study drug early due to these events, as required by the protocol. All three events (100%) were considered related to study drug and resolved. [Table 10]

[0039] One subject (3.8%) experienced a severe anxiety SAE assessed by the investigator as unrelated to study drug. The SAE resolved. Four subjects (15.4%) experienced one or more TEAEs (suicidal ideation [n=3], depressed mood [n=2], and intrusive thoughts [n=1]) that led to discontinuation of study drug. One of the depressed mood TEAEs that led to discontinuation was ongoing at the end of the study; the remainder resolved. Three subjects (11.3%) experienced an AESI, all three of which were moderate suicidal ideation events that led to study drug discontinuation. All AESIs (100%) were considered possibly related to study drug, and all events (100%) resolved.

[0040] Adverse events associated with ecopipam administration were found to be reduced by an initial titration method, as further described below. In contrast, studies were conducted in healthy adults with repeated oral doses of approximately 2 mg / kg ecopipam HCl, in which the dose was not titrated but given as a full dose from the start. Two cohorts of 12 and 18 subjects received multiple daily doses of ecopipam HCl, and 19 of 30 subjects (63.3%) experienced two or more treatment-emergent adverse events (TEAEs), withdrew consent, and underwent early termination procedures.

[0041] Provided herein are methods for providing ecopipam therapy or administering ecopipam to patients in need thereof using an initial, gradually increasing dosing regimen. The methods can mitigate one or more adverse events associated with the introduction of ecopipam and / or the introduction and continued use of ecopipam. The gradually increasing dosing regimen is believed to better accommodate the development of tolerance to ecopipam and increases in dosing. The methods are also effective in treating patients in need of ecopipam, for example, patients with TS, including children and adolescents with TS.

[0042] The dose administration methods are intended 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 otherwise specified.

[0043] In jurisdictions that prohibit the patenting of methods performed on the human body, the meaning of "administering" a composition to a human subject must be limited to prescribing a controlled substance that the human subject self-administers by any technique (e.g., orally, inhalation, topical application, injection, insertion, etc.). The related invention, in view of the disclosure herein, will be understood as a method of using ecopipam or a pharmaceutically acceptable salt thereof, or the use of ecopipam or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use as described herein. The broadest reasonable interpretation consistent with the statute or regulation defining patentable subject matter is intended. In jurisdictions that do not prohibit the patenting of methods performed on the human body, "administering" a composition includes both methods performed on the human body and also the aforementioned activities.

[0044] As used herein, the term "comprising" indicates the potential inclusion of other agents, elements, steps or features in addition to those specified.

[0045] The pharmacokinetics of oral ecopipam HCl was studied using a single oral dose of 200 mg ecopipam HCl administered to healthy volunteers. Non-compartmental PK analysis indicated that the half-life of ecopipam was 15.8 hours and the half-life of the active metabolite, N-desmethylcopipam, was 24.0 hours. The calculated mean time to steady-state plasma concentrations of ecopipam was approximately 80 hours, or about 3.3 days, and ranged from about 3 to 5 days, taking into account inter-subject variability. Thus, one embodiment of the methods herein provides a method of orally administering ecopipam or a pharmaceutically acceptable salt thereof using a dose-escalation titration schedule, where the period between dose escalations is at least 5 days, or more than 5 days, or 6 days, e.g., 7 days.

[0046] The amount of ecopipam administered to a patient in need thereof or provided herein to a patient may be determined by the patient's weight. Generally, the greater the patient's weight, the greater the complete dosage (absolute amount) for that patient may be. For example, the dose escalation regimen described herein may be designed to escalate to a final daily dosage ranging from about 37 mg / day to about 200 mg / day.

[0047] The number of doses increases from the first increment to the final, and the complete dose can also vary depending on the patient's weight. For patients weighing at least about 15 kg to about 30 kg or at least 18 kg to 23 kg, the number of doses increases until there are two or three complete doses, for example, two. Each dose increase can be after a period of at least 5, 6, or 7 days with the previous daily dose. For patients weighing at least about 20 kg or more than 23 kg, the number of doses increases until there are three or four complete doses, for example, three. Each dose increase can be after a period of at least 5, 6, or 7 days with the previous daily dose. In one type of method, each dose increase for any patient is after 7 days with the previous daily dose.

[0048] The amount of ecopipam administered to a patient in need thereof or provided herein can be more closely tied to the patient's body weight than previously 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 weighing 18 kg or more and 23 kg or less, the maximum dose can be 2.08 mg / kg / day or in the range of 1.67 to 2.08 mg / kg / day. In patients weighing more than 23 kg and less than or equal to 34 kg, the maximum dose can be 2.17 mg / kg / day, in the range of 1.47 to 2.17 mg / kg / day. In patients weighing more than 34 kg and less than or equal to 44 kg, the maximum dose can be 2.21 mg / kg / day, in the range of 1.70 to 2.21 mg / kg / day. In patients weighing more than 44 kg and less than or equal to 68 kg, the maximum dose can be 2.27 mg / kg / day, ranging from 1.47 to 2.27 mg / kg / day. In patients weighing more than 68 kg and less than or equal to 83 kg, the maximum dose can be 2.21 mg / kg / day, ranging from 1.81 to 2.21 mg / kg / day. In patients weighing more than 83 kg, the maximum dose can be 2.41 mg / kg / day.

[0049] The amount of the dose administered as the first dose, and the amount of each increment in the dose, can also be relative to the patient's body weight. For example, the absolute daily dose administered as the first dose can be in the range of about 10 mg to about 35 mg, or about 12.5 mg to about 25 mg. The first daily dose can be about 10 mg to about 15 mg, or about 12.5 mg, for patients weighing at least 18 kg and not more than 44 kg. The amount of the increment at each dose increase interval (e.g., every 5 days, every 6 days, or every 7 days) can be in the range of about 10 mg to about 15 mg, or about 12.5 mg, for patients weighing at least 18 kg and not more than 44 kg. The first daily dose can be in the range of about 20 mg to about 40 mg, or about 25 mg, for patients weighing more than 44 kg. In patients weighing more than 44 kg, the increase in daily dose at the first dose increase interval (e.g., 5, 6, or 7 days after the first daily dose) can be in the range of about 20 mg to about 40 mg, or about 25 mg. In patients weighing more than 44 kg, the increase in daily dose at the second dose increase interval can be in the range of about 20 mg to about 60 mg, or about 25 mg, or about 50 mg, e.g., about 25 mg in patients weighing more than 44 kg but less than or equal to 68 kg, and about 50 mg in patients weighing more than 68 kg. In patients weighing more than 44 kg, the increase in daily dose in the third dose increase interval can be in the range of about 20 mg to about 125 mg, or about 25 mg, or about 50 mg, or about 100 mg, e.g., 25 mg in patients weighing more than 44 kg but not more than 68 kg, about 50 mg in patients weighing more than 68 kg but not more than 83 kg, and 100 mg in patients weighing more than 83 kg.

[0050] In addition to, or independently of, the absolute dose amounts provided above, the initial dose and dose escalations can also be characterized as a percentage of a full dose. For example, the initial dose can be within the range of about 1 / 8 to about 1 / 3 of a full dose, e.g., 1 / 8, 1 / 6, 1 / 4, or 1 / 3 of a full dose. The initial daily dose can be about 1 / 3 of the total daily dose in patients weighing at least 18 kg and not more than 23 kg. The amount of increase in daily dose at each dose escalation interval (e.g., every 5 days, or every 6 days, or every 7 days) can be about 1 / 3 for patients weighing at least 18 kg and not more than 23 kg. The first daily dose can be about 1 / 4 or less of the total daily dose, e.g., 1 / 6 or 1 / 8 of the total daily dose, in patients weighing more than 23 kg. The first daily dose can be about ¼ to about ⅙ of the total daily dose, e.g., ¼ or ⅙ of the total daily dose, in patients weighing more than 23 kg and less than or equal to 83 kg. The first daily dose can be about ⅛ or less of the total daily dose, e.g., ⅛ of the total daily dose, in patients weighing more than 83 kg. In patients weighing more than 23 kg, the increase in daily dose at the first dose increase interval (e.g., 5 days, 6 days, or 7 days after the first daily dose) can range from about ⅛ to about ¼. In patients weighing more than 23 kg, the increase in daily dose at the second dose increase interval can range from about ⅙ to about ⅓, e.g., ⅙, ​​¼, or ⅓. In patients weighing more than 23 kg, the increase in daily dose in the third dose increase interval can be in the range of about ¼ to about ½, e.g., about ⅓, or about ¼, or about ½.

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

[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, the method comprising: providing a first daily dose of ecopipam to the patient at a first daily dosage amount for a first period of 7 days; providing a second daily dose of ecopipam to the patient at a second daily dosage amount that is greater than the first dosage amount for a second period of time following the first period, wherein the second period of time is 7 days; and providing a third daily dose of ecopipam to the patient at a third daily dosage amount that is greater than the second dosage amount for a third period of time following the second period; or (b) the third period is 7 days and the method further comprises providing a fourth daily dose of ecopipam to the patient during a fourth period after the third period, the fourth daily dose being greater than the third daily dose, and the fourth daily dose being less than or equal to 2.41 mg / kg.

[0053] In such methods, the third period can be more than 7 days, and the daily ecopipam dose administered during the third period can be 37.5 mg. Additionally or alternatively, the third period can be more than 7 days, and the first daily dosage can be 1 / 3 of the amount of the third daily dosage, and the second daily dosage can be 2 / 3 of the amount of the third daily dosage. Additionally or alternatively, the patient can have a weight of 18 kg or more and 23 kg or less.

[0054] In such methods, the third period is 7 days, and the method further comprises providing the patient with a fourth daily dose of ecopipam, the fourth daily dose being greater than the third daily dose, wherein the fourth daily dose is 2.41 mg / kg or less, and the first daily dose can be 1 / 4 of the fourth daily dose, the second daily dose can be 1 / 2 of the fourth daily dose, and the third daily dose can be 3 / 4 of the fourth daily dose. In such methods, the patient can optionally have a body weight of greater than 23 kg and less than or equal to 34 kg, and the fourth daily dose is 50 mg, and / or the patient can have a body weight of greater than 44 kg and less than or equal to 68 kg, and the fourth daily dose is 100 mg.

[0055] In such methods, the third period is 7 days, and the method further comprises providing the patient with a fourth daily dose of ecopipam, the fourth daily dose being greater than the third daily dose, wherein the fourth daily dose is 2.41 mg / kg or less, and the first daily dose can be 1 / 6 of the fourth daily dose, the second daily dose can be 1 / 3 of the fourth daily dose, and the third daily dose can be 2 / 3 of the fourth daily dose. In such methods, the patient can optionally have a body weight of greater than 34 kg and less than or equal to 44 kg, and the fourth daily dose is 75 mg, and / or the patient can have a body weight of greater than 68 kg and less than or equal to 83 kg, and the fourth daily dose is 150 mg.

[0056] In such methods, the third period is 7 days, and the method further comprises providing the patient with a fourth daily dose of ecopipam, the fourth daily dose being greater than the third daily dose, wherein the first daily dose can be 1 / 8 the amount of the fourth daily dose, the second daily dose can be 1 / 4 the amount of the fourth daily dose, and the third daily dose can be 1 / 2 the amount of the fourth daily dose, where the fourth daily dose is 2.41 mg / kg or less. In such methods, the patient can optionally have a body weight greater than 83 kg, and the fourth dose is 200 mg.

[0057] In such methods, the third period is 7 days, and the method further comprises providing the patient with a fourth daily dose of ecopipam, the fourth daily dose being greater than the third daily dose, and wherein if the fourth daily dose is 2.41 mg / kg or less, a specific 6 weight category method can be applied, where if the patient weighs more than 23 kg but less than or equal to 34 kg, the first daily dose is 12.5 mg, the second daily dose is 25 mg, the third daily dose is 37.5 mg, and the fourth daily dose is 50 mg; if the patient weighs more than 34 kg but less than or equal to 44 kg, the first daily dose is 12.5 mg, the second daily dose is 25 mg, the third daily dose is 37.5 mg, and the fourth daily dose is 50 mg; the first daily dosage is 25 mg, the second daily dosage is 50 mg, the third daily dosage is 50 mg, and the fourth daily dosage is 75 mg; and if the patient weighs more than 44 kg but less than or equal to 68 kg, the first daily dosage is 25 mg, the second daily dosage is 50 mg, the third daily dosage is 75 mg, and the fourth daily dosage is 100 mg; and if the patient weighs more than 68 kg but less than or equal to 83 kg, the first daily dosage is 25 mg, the second daily dosage is 50 mg, the third daily dosage is 100 mg, and the fourth daily dosage 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, the method comprising: providing a first daily dosage of ecopipam to the patient at the first daily dosage for a first period of about 7 days; providing a second daily dose of ecopipam to the patient for a second period of time after the first period of time, the second daily dose being greater than the first daily dose, wherein the second period of time is about 7 days; providing a third daily dose of ecopipam to the patient for a third time period after the second time period, the third daily dose being greater than the second daily dose, wherein the third time period is at least 7 days; optionally providing a fourth daily dose of ecopipam to the patient for a fourth time period after the third time period, the fourth daily dosage being greater than the third daily dosage; (a) the patient weighs 18 kg or more and 23 kg or less, and the third period is longer than 7 days if one or more of the following two conditions are met: (1) the daily ecopipam dose administered during the third period is 37.5 mg, and (2) the first daily dosage is 1 / 3 of the third daily dosage and the second daily dosage is 2 / 3 of the third daily dosage; (b) the third period of time is 7 days, and the method further comprises providing to the patient a fourth daily dose of ecopipam, the fourth daily dose being greater than the third daily dose, wherein the dosage is less than or equal to 2.41 mg / kg; if the patient weighs more than 23 kg but less than or equal to 34 kg, the first daily dosage is 12.5 mg, the second daily dosage is 25 mg, the third daily dosage is 37.5 mg, and the fourth daily dosage is 50 mg; if the patient weighs more than 34 kg but less than or equal to 44 kg, the first daily dosage is 12.5 mg, the second daily dosage is 25 mg, the third daily dosage is 50 mg, and the fourth daily dosage is 75 mg; if the patient weighs more than 44 kg but less than or equal to 68 kg, the first daily dosage is 25 mg, the second daily dosage is 50 mg, the third daily dosage is 75 mg, and the fourth daily dosage is 100 mg; if the patient weighs more than 68 kg but less than or equal to 83 kg, the first daily dosage is 25 mg, the second daily dosage is 50 mg, the third daily dosage is 100 mg, and the fourth daily dosage is 150 mg; If the patient weighs more than 83 kg, the first daily dosage is 25 mg, the second daily dosage is 50 mg, the third daily dosage is 100 mg, and the fourth daily dosage is 200 mg.

[0059] In any of the methods described herein, the fourth period of time can range from about 1 day to an unlimited number of days. For example, the fourth period of time and / or the subsequent period of time can be at least 1 day, or at least 2 days, or at least 1 week, or more 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 of time can be at least 2 days. The fourth period of time can be 1 week or more.

[0060] In any of the methods described herein, the patient can be aged from 6 years to under 18 years. In any of the methods described herein, the patient can be any age from 6 years to over. In any of the methods described herein, the patient can be aged 18 years or over.

[0061] In any of the methods described herein, ecopipam administration can be for the treatment of a patient in need thereof or a patient in need of a dopamine D1 antagonist. Ecopipam administration can be for the treatment of a patient in need of a selective dopamine D1 antagonist. Ecopipam administration can be for the treatment of a tic disorder or movement disorder. The tic disorder can be Tourette's syndrome, childhood autoimmune disorders associated with streptococcal infections (PANDAS), transient tic disorder, chronic tic disorder, or tic disorder not otherwise specified (NOS). The subject can exhibit motor tics (e.g., complex motor tics), vocal tics (e.g., complex vocal tics), or a combination thereof. Ecopipam administration can be for the treatment of childhood-onset dysphagia (stuttering). Ecopipam administration can be for the treatment of restless legs syndrome, restless legs syndrome with augmentation, or augmentation associated with restless legs syndrome. Ecopipam administration can be for the treatment of obesity, including in subjects with type 2 diabetes.

[0062] Specific contemplated dosage methods are set forth in the table below. In parentheses, the table includes optional combinations of dosage form amounts of 12.5 mg, 50 mg, 75 mg, and 100 mg per dosage form, e.g., tablet or capsule, to reach the target dosage amount. The methods for each weight category can be used individually or in combination with one or more of them as needed. [Table 11]

[0063] Further provided herein are methods for administering ecopipam to a patient on a descending dosing regimen to mitigate adverse events associated with withdrawal of ecopipam from the patient's body, the patient receiving the ecopipam therapy described herein, e.g., in an amount of about 2 mg / kg / day, or at a dose greater than 100 mg / day, or at a dose greater than 150 mg / day. In one embodiment of the present disclosure, a method for administering ecopipam to a patient receiving ecopipam includes, after administering a previous dose of ecopipam or a pharmaceutically acceptable salt thereof to the patient, (a) providing the patient with a reduced daily dose of ecopipam or a pharmaceutically acceptable salt thereof in an amount in the range of about 20 mg to 30 mg less than the patient received in the previous dose administration, (b) repeating step (a) until the reduced daily dose of ecopipam reaches 0 mg (a calculated non-negative dose equivalent to zero), and then (c) terminating administration of ecopipam. In embodiments, the patient's daily ecopipam dosage can be about 25 mg less per day than the patient received in the previous dosage. Optionally, the patient's daily ecopipam dosage can be about 1 / 16 or less, or 1 / 8 or less, or 1 / 4 less per day than the patient received in the previous dosage. In embodiments, the patient's daily ecopipam dosage can be about 1 / 4 less per day than the patient received in the previous dosage. In embodiments, step (b) can be performed daily, every other day, every three days, every four days, every five days, every six days, or every week. Daily or every other day frequencies are specifically contemplated. For example, a patient may be administered an increased daily dose of ecopipam (compared to the previous reduced dose) for up to 7 days, e.g., 1, 2, 3, 4, 5, 6, or 7 days, or 14, or 21, or 28 days. The withdrawal method can be applied to any type of patient, including children and adolescents at least 6 years of age and under 18 years of age, and adults, as well as patients with TS and other disease states described herein, or any combination thereof.

[0064] In any of the methods described herein, the dose of ecopipam can be taken in an empty stomach. In any of the methods described herein, the dose of ecopipam can be taken with water. In any of the methods described herein, the dose of ecopipam can be taken at bedtime. In any of the methods described herein, the patient can be instructed to take or provided with instructions to take the doses described herein.

[0065] In any of the ascending or dosing regimens and / or descending dosing regimens described herein, the daily dose administration can be divided into one or more doses, for example, a 25 mg / day dose can be divided into two 12.5 mg doses taken separately on the same day (i.e., bid).In any of the ascending or dosing regimens and / or descending dosing regimens described herein, it is specifically contemplated that the daily dose administration is a single dose administration event, i.e., once per day.Dose administration, such as a single dose administration event, can be in the evening.

[0066] The dose escalation described herein can provide a reduced incidence of adverse events compared to conventional known dose administration methods.

[0067] In embodiments, the dose escalation described herein can reduce the incidence of one or more treatment-related adverse events compared to alternative dosing regimens using the same complete final dose. For example, in the study of Example 1, the overall incidence of TEAEs using the method of the present invention was 61.8%, 12.4% higher than the placebo group, indicating a reduced incidence of adverse events compared to the method described in Gilbert et al. 2018, supra. The incidence of Cmax-related GI side effects, e.g., nausea, vomiting, diarrhea, and abdominal pain, was reduced. The incidence of Cmax-related CNS side effects, e.g., sedation and somnolence, was also reduced. The incidence of anorexia and rash was also reduced compared to the method described in Gilbert et al. 2018. Additionally or alternatively, the incidence of ecopipam discontinuation due to adverse events can be reduced compared to alternative dosing regimens using the same complete final dose by using a different method, e.g., one that uses a titration regimen that reaches an equivalent full dose more quickly and / or reaches a higher full dose in the same or shorter time period. Optionally, the comparison can be made within the same patient population, for example, 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] The dose-lowering regimen described herein can reduce adverse events associated with withdrawal from ecopipam. Such adverse events can be one or more of the above. For example, the adverse events can be one or more of the following: insomnia, depression, dyspepsia, somnolence, fatigue, anxiety, headache, vomiting, nausea, and abdominal pain. The reduced adverse events can be one or more of the following: nausea, sweating, tachycardia, dizziness, headache, tremors, and anxiety. In embodiments, adverse events, particularly those associated with the administration of ecopipam in children / adolescents, can be one or more of headache, upper abdominal pain, insomnia, somnolence, nausea, and vomiting. In embodiments, adverse events, particularly those associated with the administration of ecopipam in adults, can be one or more of sedation, insomnia, fatigue, somnolence, headache, muscle spasms, and anxiety. In one 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, the 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, for example, having the same disorder (e.g., Tourette's syndrome or stuttering disorder), the same weight range, or the same age group, or any combination thereof.

[0069] Example 1 This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase 2b study in pediatric subjects (ages 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, 153 subjects were randomized, and one enrolled subject was not randomized, did not receive study medication, and was not included in the analysis set. After a screening period of up to 28 days and completion of all pre-dose baseline visit assessments, 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 body weight. [Table 12]

[0070] Subjects who could not tolerate the dose were withdrawn from the study. Weight class assignments did not change during the study.

[0071] Subjects must have a minimum score of 20 on the YGTSS-TTS at the screening and baseline visits due to tic symptoms that, in the investigator's judgment, cause subjective discomfort (e.g., pain or injury), persistent social problems (e.g., social isolation or bullying), social and emotional problems, or functional interference (e.g., academic impairment). Subjects must not have taken any medications used to treat motor or vocal tics for at least 14 days prior to baseline.

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

[0073] Subjects whose weight changed during the study were not allowed to adjust their dose during the study. At the end of the 8-week treatment period, subjects discontinued therapy by receiving a reduced dose of ecopipam HCl or matching placebo until off study drug. Subjects who did not tolerate titration to the full assigned dose for their weight class were discontinued from the study. These subjects also had to have their current dose of study drug tapered according to their weight class.

[0074] The efficacy assessments used are described below.

[0075] The YGTSS is a clinician-administered rating scale used to quantify overall tic severity and specific subdomains of tic number, frequency, intensity, complexity, and interference. Each of these subdomains is scored separately for motor and vocal tics on a 5-point scale, then summed across both motor and vocal tics to obtain the YGTSS Total Tic Score (TTS), which ranges from 0 to 50. The YGTSS also provides an overall deficit rating (0 = "none" to 50 = "severe"). The YGTSS-Global Score (GS) is the sum of the motor, vocal, and deficit scores. The YGTSS has demonstrated acceptable internal consistency, good inter-rater reliability, and acceptable convergent and divergent validity. The YGTSS was assessed at screening, baseline, and weeks 4, 6, 8, and 12.

[0076] The Clinical Global Impression (CGI) scales consist of two 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 at all ill" to 7 = "extremely ill." The CGI Improvement scale ranges from 1 = "very improved" to 7 = "very worse." The CGI Severity and CGI Improvement scales were administered at specific clinic visits.

[0077] The Caregiver Global Impression of Change (CaGI-C) scale is a 7-item Likert scale that asks caregivers the following question: Overall, how (if at all) have the patient's symptoms changed since the start of the study (before treatment began)? The CaGI-C is rated as follows: 1 (very improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worsened), 6 (much worsened), and 7 (very worsened).

[0078] The Gilles de la Tourette Syndrome-Children and Adolescents Quality of Life Scale (C&A-GTS-QOL) is a patient-reported health-related quality of life scale developed for children and adolescents. The C&A-GTS-QOL is a 27-item questionnaire specific to TS that asks subjects to rate the extent to which their quality of life is affected by their symptoms. The C&A-GTS-QOL includes six subscales (cognitive, coprolalia, psychological, physical, 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 time using a visual analog scale (VAS) ranging from 0 to 100. 5 The following questions are assessed in each C&A-GTS-QOL subscale: Cognition (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, and 4) (range: 0–12) Coprolalia (Questions 5, 6, and 22) (Range: 0–12) ADL (Questions 2, 24, 26) (Range: 0-12)

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

[0080] An adverse event (AE) is defined as any untoward medical occurrence in a subject administered a study drug, not necessarily causally related to treatment. Thus, an AE can be any untoward and unintended sign (including abnormal clinical laboratory findings), symptom, or disease temporally associated with the use of the study drug, whether or not related to the study drug.

[0081] Abnormalities identified during medical examination (e.g., clinical laboratory parameters, vital signs, ECG data, physical examination) were to be defined as adverse events only if the abnormality met one of the following criteria: - Induced clinical signs or symptoms Active intervention was required - required interruption or discontinuation of study drug - Clinically important in the opinion of the investigator

[0082] A serious adverse event (SAE) was defined as an AE occurring with any dose of treatment, comparator, or placebo during any study phase (i.e., baseline, treatment, washout, or follow-up) that met one or more of the following: Caused death Immediately life-threatening -Required hospitalization or extension of an existing hospitalization ·Causing permanent or serious disability or incapacity -Causing birth defects or abnormalities There was a significant medical event that may have endangered the subject or required medical intervention to prevent one of the outcomes listed above.

[0083] Investigators were required to determine, in their medical judgment, whether there was a reasonable possibility that the AE could have been caused by the investigational product. If there was no valid reason to suggest a relationship, the AE was classified as "unrelated." If there was valid reason to suspect a possible causal relationship between the investigational product and the occurrence of the AE, even if undetermined, the AE was considered "related." If the relationship between the AE / SAE and the investigational product was determined to be "probable" or "probable," the event was considered to be related to the investigational product for purposes of expedited regulatory reporting.

[0084] The intensity of AE was evaluated according to the following scale: Mild (signs or symptoms are noticeable but easily tolerated) Moderate (enough discomfort to interfere with normal activities) Severe (incapacitated, unable to perform normal activities)

[0085] The Columbia-Suicide Severity Rating Scale (C-SSRS) was assessed at all visits except the 30-day follow-up visit. The C-SSRS is a low-burden instrument (approximately 5 minutes to complete) for assessing both suicidal behavior and ideation. The scale is suitable for subjects ranging from 6 years old to older age groups.

[0086] Additional safety outcomes assessed at baseline and weeks 4, 6, 8, and 12 included the following measures:

[0087] Abnormal Involuntary Movement Scale (AIMS): This scale records the occurrence of tardive dyskinesia in subjects receiving neuroleptic medications. The test is used to detect tardive dyskinesia and track its severity over time. It consists of three items that assess the presence and severity of movement disorders involving the face, mouth, limbs, and trunk, with a global rating ranging from 0 (absent) to 4 (severe).

[0088] Drug-Induced Akathisia Rating Scale (BARS): This scale assesses the severity of drug-induced akathisia. Objective and subjective items in the scale measure the subject's level of 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 0-3 rating scale: not at all = 0, very little = 1, quite a bit = 2, and very much = 3. SNAP-IV subscale scores are calculated by summing the scores of 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 measure for both determining the severity of OCD and monitoring improvement during treatment. The scale is a clinician-rated, 10-item scale that includes questions regarding the amount of time spent on obsessions / compulsions, the level of impairment or distress, and how much resistance and control the subject has over these thoughts. The severity of obsessions and compulsions is rated on a 5-point scale ranging from 0 to 4. The CY-BOCS total score is calculated as the sum of the 10 items, ranging from 0 to 40, with higher scores indicating more severe obsessions and compulsions.

[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 depression. Fourteen signs and symptoms are graded from 1 (normal) to 7 (most severe), and three signs and symptoms are graded from 1 (normal) to 5 (most severe). The raw summary score is the sum of all 17 items and ranges 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 two sections: a symptom checklist and a severity item. The symptom checklist is used to determine a child's symptom repertoire over the past week. Seven severity items are used to determine symptom severity and the PARS total score. Each severity item is coded from 0 (none) to 5 (most extreme). Not applicable is coded as 8, and don't know is coded as 9. The total score on the PARS is the sum of the seven severity items. The total score ranges from 0 to 35. The codes "8" and "9" are not included in the total.

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

[0094] A summary of the YGTSS-TTS scores and change from baseline observed at each time point in the modified intention-to-treat (mITT) set is presented in Table 9. The mITT set was all child and adolescent subjects with TS who were randomized, received at least one dose of study medication, and had at least one post-baseline scoring of the YGTSS. Mean YGTSS-TTS scores decreased in both treatment groups over the course of the study, with greater decreases observed in the ecopipam group compared to the placebo group. [Table 13]

[0095] The primary MMRM analysis of the change from baseline in YGTSS-TTS using multiple imputation for intercurrent events in the mITT set is provided in Table 10. At week 12, the least squares (LS) mean (SE) change from baseline in YGTSS-TTS was -9.87 (1.062) in the ecopipam group and -6.42 (1.006) in the placebo group; the difference in YGTSS-TTS LS mean (SE) between ecopipam and placebo was -3.44 (1.351), which was statistically significant (P=0.011). Comparing ecopipam with placebo across 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 YGTSS-TTS LS mean (SE) between ecopipam and placebo was -3.51 (1.346), which was statistically significant (P = 0.009). [Table 14]

[0096] The key secondary efficacy endpoint was the change in CGI-TS-S from baseline to week 12. Additional secondary efficacy endpoints were the change in CGI-TS-S from baseline to weeks 4, 6, and 8. The CGI severity scale ranges from 1 = "normal, not at all ill" to 7 = "extremely ill." A summary of the observed CGI-TS-S scores and change from baseline at each time point in the mITT set is provided in Table 16. Improvements (reductions) in mean CGI-TS-S scores were observed across both treatment arms, with greater improvements (reductions) observed in the ecopipam group compared to the placebo group. [Table 15]

[0097] MMRM analysis of the change from baseline in CGI-TS-S in the mITT set is provided in Table 17. A statistically significant reduction in 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, and the difference in CGI-TS-S LS mean (SE) between ecopipam and placebo was -0.37 (0.167), which was statistically significant (P = 0.027). The difference in 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 Weeks 6 (P = 0.001) and 8 (P = 0.001). [Table 16-1] [Table 16-2]

[0098] Similar results were observed in the MMRM analysis of the change from baseline in the CGI-TS-S when remote assessments were included in the model.

[0099] A secondary efficacy endpoint was the CGI-TS-I at week 12. Additional secondary efficacy endpoints were the CGI-TS-I at weeks 4, 6, and 8. The CGI-TS-I was completed at weeks 4, 6, 8, and 12 to measure clinical impression of improvement from baseline. The CGI improvement scale ranges from 1 = "much improved" to 7 = "much worse." A summary of CGI-TS-I scores at each time point in the mITT set is provided in Table 18. Clinical impression of improvement from baseline was observed throughout the study in both treatment groups, with a greater mean impression of improvement in the ecopipam group compared to the placebo group. [Table 17]

[0100] A secondary efficacy endpoint was the change in the YGTSS-GS from baseline to week 12. Additional secondary efficacy endpoints were the change in the YGTSS-GS from baseline to weeks 4, 6, and 8. The YGTSS-GS is the sum of motor, speech, and deficit scores and ranges from 0 to 100, with higher scores indicating more severe symptoms. A summary of the YGTSS-GS scores and change from baseline observed at each time point in the mITT set is provided in Table 20. Mean YGTSS-GS scores decreased in both treatment groups over the course of the study, with a greater decrease observed in the ecopipam group compared to the placebo group. [Table 18]

[0101] MMRM analysis of the change from baseline in YGTSS-GS in 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 YGTSS-GS LS mean (SE) between ecopipam and placebo was -7.86 (2.711), which was significant (P=0.004). Additional secondary efficacy endpoints were 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 compared to the placebo group at all time points, with all P values ​​less than 0.05. [Table 19-1] [Table 19-2]

[0102] Similar results were observed for the MMRM analysis of change from baseline on the YGTSS-GS when remote assessments were included in the model.

[0103] A secondary efficacy endpoint was the CaGI-C at week 12. Additional secondary efficacy endpoints were the CaGI-C at weeks 4, 6, and 8. The CaGI-C is a 7-item Likert scale that asks caregivers the following question: "Overall, how have your patient's symptoms changed (if any) since the start of the study (before treatment began)?" and rates it as follows: 1 (very improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worsened), 6 (much worsened), and 7 (much worsened). Thus, lower CaGI-C scores indicate a higher caregiver impression of improvement. A summary of CaGI-C scores at all time points in the mITT set is provided in Table 22. Lower mean CaGI-C scores were observed in the ecopipam group compared to the placebo group, indicating a greater caregiver impression of improvement. Within each treatment group, CaGI-C scores remained stable across the study from week 4 to week 12. [Table 20]

[0104] MMRM analysis of CaGI-C in the mITT set is provided in Table 23. At week 12, the LS mean (SE) CaGI-C scores were 2.94 (0.189) in the ecopipam group and 3.55 (0.172) in the placebo group; the difference in LS mean (SE) CaGI-C scores between ecopipam and placebo was -0.61 (0.223) and was significant (P=0.007). CaGI-C LS mean scores were significantly lower compared to the placebo group at all time points (indicating greater caregiver perception of improvement), with all P values ​​less than 0.05. [Table 21]

[0105] Similar results were observed for the MMRM analysis of CaGI-C when remote assessment was included in the model.

[0106] The secondary efficacy endpoint was the proportion of subjects with a 25% improvement on the YGTSS-TTS. Responders were defined as subjects with at least one 25% improvement on the YGTSS-TTS at any time between baseline and the 12-week visit.

[0107] A total of 53 subjects (73.6%) in the ecopipam group and 32 subjects (43.2%) in the placebo group demonstrated a 25% improvement in YGTSS-TTS at any time between baseline and the 12-week visit, with an odds ratio (95% CI) of 3.67 (1.82, 7.40), P<0.001.

[0108] The safety set included all subjects who received at least one dose of study drug. An overall summary of adverse events (AEs) in the safety set is provided below in Table 34. A total of 47 subjects (61.8%) in the ecopipam group and 38 subjects (49.4%) in the placebo group experienced adverse events during the study. Treatment-related AEs were reported by more subjects in the ecopipam group (26 subjects, 34.2%) compared to the placebo group (16 subjects, 20.8%). A total of three subjects experienced an SAE during the study. Four subjects (5.3%) in the ecopipam group and one subject (1.3%) in the placebo group experienced an AE that led to discontinuation of study drug.

[0109] A total of four subjects (two subjects in the ecopipam group, two subjects in the placebo group) reported COVID-19 AEs, three subjects had PTs for coronavirus infection, and one subject had a PT for a positive coronavirus test. The investigators considered three events to be mild in severity and one event to be moderate in severity. One subject in the ecopipam group had a COVID-19 AE that was considered severe enough to result in hospitalization. No subjects discontinued study drug or the study due to these events. [Table 22]

[0110] A summary of AEs occurring in two or more subjects in any treatment group by System Organ Class (SOC) and Preferred Term for the safety set is provided below in Table 35. A summary of all AEs by SOC and Preferred Term for the safety set is provided in Table 14.3.1.4.1 (see figure). 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 23-1] [Table 23-2]

[0111] 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 figure), and a summary of AEs by SOC, preferred term, and weight category for the safety set is provided in Table 14.3.1.4.1.3 (see figure). Most subjects (N=36 in the ecopipam group and N=35 in the placebo group) were in the intermediate weight category of >44 kg to ≤68 kg and received an initial maintenance dose of 100 mg. In this subject group, 23 of 36 subjects (63.9%) in the ecopipam group and 16 of 35 subjects (45.7%) in the placebo group had at least one adverse event.

[0112] 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 figure). 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 one 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 one AE.

[0113] A summary of adverse events by SOC and preferred term in subjects weighing >83 kg for the safety set is provided in Table 14.3.1.4.1.4 (see figure). In subjects weighing >83 kg, 6 of 8 subjects (75.0%) in the ecopipam group and 3 of 7 subjects (42.9%) in the placebo group had at least one AE. In the ecopipam group, headache, anxiety, and insomnia AEs were each reported in 2 subjects; all other AEs in both treatment groups were reported in 1 subject each. [Table 24-1] [Table 24-2]

[0114] 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 figure), and a summary of AEs by SOC, preferred term, and weight category for the safety set is provided in Table 14.3.1.4.1.3 (see figure). Most subjects (N=36 in the ecopipam group and N=35 in the placebo group) were in the intermediate weight category of >44 kg to ≤68 kg and received an initial maintenance dose of 100 mg. In this subject group, 23 of 36 subjects (63.9%) in the ecopipam group and 16 of 35 subjects (45.7%) in the placebo group had at least one adverse event.

[0115] 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 figure). 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 one 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 one AE.

[0116] A summary of adverse events by SOC and preferred term in subjects weighing >83 kg for the safety set is provided in Table 14.3.1.4.1.4 (see figure). In subjects weighing >83 kg, 6 of 8 subjects (75.0%) in the ecopipam group and 3 of 7 subjects (42.9%) in the placebo group had at least one AE. In the ecopipam group, headache, anxiety, and insomnia AEs were each reported in 2 subjects; all other AEs in both treatment groups were reported in 1 subject each.

[0117] Adverse events by dose phase (titration, maintenance, and down-titration / follow-up) A summary of AEs within the dose-finding phase and by visit for the safety set is provided below in Table 36. In both treatment groups, more subjects reported adverse events during week 1 of the dose-finding phase compared to weeks 2, 3, or 4 of the dose-finding phase (12 subjects [15.8%] in the ecopipam group and 12 subjects [15.6%] in the placebo group). A summary of AEs within the dose-finding phase for the safety set by SOC, PT, and visit is provided below in Table 14.3.1.4.1.5 (see figure). [Table 25]

[0118] A summary of AEs within the maintenance phase and AEs by visit for the safety set is provided below in Table 37. A summary of AEs within the maintenance phase, preferred terms, and AEs by visit for the safety set is provided below in Table 14.3.1.4.1.6 (see figure). [Table 26]

[0119] A summary of AEs by SOC and visit within the dose-down titration and follow-up phase for the safety set is provided below in Table 38. Most AEs reported during the dose-down titration phase occurred within the first 7 days of follow-up in both groups. A summary of AEs by SOC, PT, and visit within the dose-down titration and follow-up phase for the safety set is provided below in Table 14.3.1.4.1.7 (see figure). [Table 27]

[0120] Adverse events according to the Common Terminology Criteria for Adverse Event Grades 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).

[0121] 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 figure). Most adverse events reported in both treatment groups were mild or moderate in severity. No fatal or life-threatening AEs were reported during the study.

[0122] In the ecopipam group, 23 subjects (30.3%) experienced mild highest CTCAE grade AEs, 17 subjects (22.4%) experienced moderate highest CTCAE grade AEs, and 7 subjects (9.2%) experienced severe highest CTCAE grade AEs.

[0123] In the placebo group, 22 subjects (28.6%) experienced a mild highest CTCAE grade AE, 15 subjects (19.5%) experienced a moderate highest CTCAE grade AE, and 1 subject (1.3%) experienced a severe highest CTCAE grade AE.

[0124] A summary of CTCAE Grade 3 AEs by SOC and preferred term for the safety set is provided below in Table 39. A total of 7 subjects (9.2%) in the ecopipam group and 1 subject (1.3%) in the placebo group experienced AEs with the most severe CTCAE grade, with most severe AEs falling within the SOC for psychiatric disorders, and all severe AEs reported by 1 subject each. [Table 28]

[0125] Adverse events due to association A summary of treatment-related AEs by SOC and preferred term for the safety set is provided below in Table 40. A higher percentage of subjects in the ecopipam group (26 subjects, 34.2%) experienced treatment-related AEs compared with subjects in the placebo group (16 subjects, 20.8%). In the ecopipam group, the most commonly reported treatment-related AEs (reported in three or more subjects) included headache (7 subjects, 9.2%), somnolence (5 subjects, 6.6%), fatigue (5 subjects, 6.6%), insomnia including intermediate insomnia (4 subjects, 5.3%), restlessness (4 subjects, 5.3%), and nausea, anxiety, depressed mood, and irritability (each AE reported in three subjects, 3.9%). All other treatment-related AEs in the ecopipam group occurred in two or fewer subjects. In the placebo group, the most commonly reported treatment-related AEs (reported in three or more subjects) included anorexia (four subjects, 5.2%) and headache (three subjects, 3.9%). All other treatment-related AEs in the placebo group occurred in two or fewer subjects. [Table 29-1] [Table 29-2]

[0126] 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 figure). The CTCAE grade in most subjects with treatment-related AEs was mild in both treatment groups.

[0127] In the ecopipam group, 15 subjects (19.7%) experienced mild, highest CTCAE grade treatment-related AEs, 7 subjects (9.2%) experienced moderate, highest CTCAE grade treatment-related AEs, and 4 subjects (5.3%) experienced severe, highest CTCAE grade treatment-related AEs. Treatment-related AEs with the most severe CTCAE grade included nausea, facial pain, agitation, anxiety, irritability, restlessness, and thoughts of self-harm.

[0128] In the placebo group, 13 subjects (16.9%) experienced a mild, highest CTCAE-grade treatment-related AE, 2 subjects (2.6%) experienced a moderate, highest CTCAE-grade treatment-related AE, and 1 subject (1.3%) experienced a severe, highest CTCAE-grade treatment-related AE. The most severe treatment-related AE was suicidal ideation.

[0129] Adverse events by greatest severity and greatest relevance The severity of the AEs was assessed by the investigator as mild, moderate, or severe.

[0130] A summary of AEs and treatment-related AEs by maximum severity (i.e., mild, moderate, or severe) for the safety set is provided in Table 14.3.1.2.1 (see figure). In the ecopipam group, 12 subjects (15.8%) experienced a treatment-related AE with a maximum severity of mild, 10 subjects (13.2%) experienced a treatment-related AE with a maximum severity of moderate, and 4 subjects (5.3%) experienced a treatment-related AE with a maximum severity of severe. In the placebo group, 14 subjects (18.2%) experienced a treatment-related AE 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.

[0131] A summary of AEs and SAEs by maximum relevance (i.e., unrelated, probably, or probably) for the safety set is provided in Table 14.3.1.2.2 (see figure). In the ecopipam group, 21 subjects (27.6%) experienced adverse events considered unrelated to the study drug, 19 subjects (25.0%) experienced adverse events considered probably related to the study drug, and 7 subjects (9.2%) experienced adverse events considered probably related to the study drug. In the placebo group, 22 subjects (28.6%) experienced adverse events considered unrelated to the study drug, 16 subjects (20.8%) experienced adverse events considered probably related to the study drug, and 0 subjects experienced adverse events considered probably related to the study drug.

[0132] Two subjects in the ecopipam group experienced an SAE, both events considered unrelated to study drug, and one subject in the placebo group experienced an SAE considered possibly related to study drug.

[0133] A summary of AEs by greatest severity or greatest relevance at each study milestone (i.e., dose-finding phase, maintenance phase, tapering phase, or end-of-study drug) for the safety set is provided in Table 14.3.1.3 (see figure). Most AEs were reported during the dose-finding and maintenance phases of the study in both treatment groups, with fewer subjects reporting AEs during the tapering and end-of-study drug follow-up. In the ecopipam group, 24 subjects (31.6%) experienced an AE during the dose-finding phase, 30 subjects (39.5%) experienced an AE during the maintenance phase, 6 subjects (7.9%) experienced an AE during the tapering phase, and 15 subjects (19.7%) experienced an AE during the end-of-study drug follow-up phase. In the placebo group, 17 subjects (22.1%) experienced an AE during the dose-finding phase, 24 subjects (31.2%) experienced an AE during the maintenance phase, 2 subjects (2.6%) experienced an AE during the tapering phase, and 5 subjects (6.5%) experienced an AE during the end-of-study drug follow-up phase.

[0134] No deaths were reported during the study. A summary of SAEs by SOC and preferred term for the safety set is provided below in Table 41. A total of three subjects (all adolescents) experienced an SAE during the study. One subject in the placebo group experienced an SAE of suicidal ideation, which the investigator considered to be moderate in severity and possibly related to the study drug. Two subjects in the ecopipam group experienced SAEs, both of which the investigator considered to be moderate in severity and unrelated to the study drug. One of these subjects experienced an SAE of coronavirus infection that resolved after 8 days. Another subject had an SAE of vomiting, and based on the results of all tests, 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 figure). [Table 30]

[0135] A summary of treatment-terminating AEs by SOC and preferred term for the safety set is provided below in Table 42. A total of four subjects (5.3%) in the ecopipam group and one subject (1.3%) in the placebo group experienced a treatment-terminating AE. Two subjects (one in the ecopipam group and one in the placebo group) had an AE of suicidal ideation that led to treatment termination; all other treatment-terminating AEs occurred in only one subject. A summary of treatment-terminating AEs by SOC, preferred term, and highest CTCAE grade for the safety set is provided in Table 14.3.1.7.2 (see figure). [Table 31]

[0136] Adverse events of particular interest All subjects completed the AIMS and BARS throughout the course of the study to assess potential ecopipam-related extrapyramidal side effects (EPS) and movement disorders. In addition to the AIMS and BARS, a standardized MedDRA questionnaire for Parkinsonism was utilized to identify movement disorder AEs. No EPS-related movement disorders were identified in either the ecopipam or placebo groups. A summary of Parkinsonism-related AESIs by SOC and preferred term for the safety set is provided in Table 14.3.1.10.1 (see figure). A summary of AESIs related to ecopipam by SOC and preferred term for the safety set is provided below in Table 43. A total of 13 subjects (17.1%) in the ecopipam group and 10 subjects (13.0%) in the placebo group had at least one AESI related to ecopipam during the study. In the ecopipam group, the most common AESIs related to ecopipam were depressed mood (3 subjects, 3.9%) and intermediate insomnia (3 subjects, 3.9%). All other AESIs related to ecopipam in the ecopipam group occurred in one subject each. [Table 32]

[0137] A summary of Columbia-Suicide Severity Rating Scale (C-SSRS) results for the safety set is provided below in Table 45. At the 6-week and 14-day follow-up, no subjects had suicidal ideation or behavior, but these visits are not shown in the table. At baseline, lifetime suicidal ideation was similar between treatment groups, reported by 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 by up to 8 subjects (10.4%) in the placebo group and none 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 33]

[0138] The Abnormal Involuntary Movement Scale (AIMS) records the occurrence of tardive dyskinesia in subjects receiving neuroleptics and consists of items assessing the presence and severity of movement disorders involving the face, mouth, limbs, and trunk, as well as three global assessments. A summary of the AIMS total score for the safety set is provided below in Table 46. A reduction from baseline in the AIMS total score, indicating improvement, was observed in both treatment groups, with no significant differences between groups observed. [Table 34]

[0139] The Pharmaceutical 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. Total and global akathisia scores were low at baseline in both treatment groups and decreased slightly after baseline. No significant differences were observed between groups. A summary of the BARS set 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 figure). [Table 35-1] [Table 35-2]

[0140] 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 below in Table 48. A reduction from baseline in total score, indicating improvement in ADHD and ODD symptoms, was observed in both treatment groups. No significant differences were observed between groups. A summary of the SNAP-IV subset scores for the safety set is provided in Table 14.3.8.4 (see figure). [Table 36]

[0141] The Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) is designed to determine the severity of OCD and monitor improvement during treatment. The scale is a 10-item clinician-rated scale that includes questions regarding the amount of time spent on obsessions / compulsions, the level of impairment or distress, and how much resistance and control the subject has over these thoughts. The CY-BOCS total score is calculated as the sum of the 10 items, ranging from 0 to 40, with higher scores indicating more severe obsessions and compulsions. A summary of the CY-BOCS total score for the safety set is provided below in Table 49. A decrease from baseline in the CY-BOCS total score was observed in both treatment groups. No significant differences were observed between groups. [Table 37]

[0142] 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 categorized from 1 (normal) to 7 (most severe), and three signs and symptoms are categorized 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 scores for the safety set is provided in Table 50 below. A small decrease from baseline in CDRS-R scores was observed in both treatment groups. No notable differences were observed between treatment groups. [Table 38]

[0143] 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 reduction from baseline in the PARS total score, indicating symptom improvement, was observed in both treatment groups. No significant differences were observed between the treatment groups. [Table 39]

[0144] A total of 47 subjects (61.8%) in the ecopipam group and 38 subjects (49.4%) in the placebo group experienced adverse events during the study.

[0145] Most adverse events reported in both treatment groups were mild or moderate in severity. No fatal or life-threatening AEs were reported during the study.

[0146] Treatment-related AEs were reported in a higher proportion of subjects in the ecopipam group (26 subjects, 34.2%) compared with the placebo group (16 subjects, 20.8%).

[0147] 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 intermediate-duration 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%).

[0148] A total of three subjects (all adolescents) experienced an SAE during the study. One subject in the placebo group experienced an SAE of suicidal ideation, which the investigator considered to be moderate in severity and possibly related to the study drug. Two subjects in the ecopipam group experienced an SAE (one subject had an SAE of vomiting and one subject had an SAE of coronavirus infection), and both SAEs were considered by the investigator to be moderate in severity and unrelated to the study drug.

[0149] A total of four subjects (5.3%) in the ecopipam group and one subject (1.3%) in the placebo group experienced AEs that led to treatment termination. Two subjects (one in the ecopipam group and one in the placebo group) had an AE of suicidal ideation that led to treatment termination, and all other AEs that led to treatment termination occurred in only one subject.

[0150] EPS movement disorders were not noted in any subject in either the ecopipam or placebo groups.

[0151] A total of 13 subjects (17.1%) in the ecopipam group and 10 subjects (13.0%) in the placebo group had at least one ecopipam-related AESI during the study. In the ecopipam group, the most common ecopipam-related AESIs were depressed mood (3 subjects, 3.9%) and intermediate insomnia (3 subjects, 3.9%).

[0152] No significant differences were observed between the ecopipam and placebo groups in clinical laboratory results, vital signs, weight gain, ECG findings, C-SSRS, and safety outcome measures.

[0153] A total of four subjects (two in the ecopipam group, two in the placebo group) reported COVID-19 AEs. The investigators considered three events to be mild and one event to be moderate in severity. One subject in the ecopipam group had a COVID-19 AE that was considered severe enough to result in hospitalization. No subjects discontinued study drug or the study due to these events.

[0154] Example 2 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., patients with TS who were at least 6 years old and less than 18 years old, and patients were titrated up to the full dose according to the same schedule.

[0155] Preliminary analysis of the data shows the following trends and comparisons with the PSY302 open-label extension study described above. [Table 40] [Table 41]

[0156] The present disclosure illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein. The terms and expressions employed are used as terms of description and not of limitation, and the use of such terms and expressions is not intended to indicate the exclusion of equivalents of the features shown and described or portions thereof. It is recognized that various modifications are possible within the scope of the present invention. Thus, while the present invention has been specifically disclosed by preferred embodiments and optional features, it should be understood that modifications and variations of the concepts disclosed herein may be utilized by those skilled in the art, and such modifications and variations are deemed to be within the scope of the present invention.

[0157] Throughout this specification and the claims that 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.

[0158] Throughout this specification, when a composition is described as comprising components or materials, it is contemplated that the composition can also consist essentially of, or consist of, any combination of the listed components or materials, unless otherwise stated. Similarly, when a method is described as comprising particular steps, it is contemplated that the method can also consist essentially of, or consist of, any combination of the listed steps, unless otherwise stated. The inventions illustratively disclosed herein can be practiced in the absence of any element or step not specifically disclosed herein.

[0159] The methods disclosed herein, and their individual steps, can be performed manually and / or with the assistance of, or automation provided by, electronic devices. While the processes are described with reference to specific embodiments, those skilled in the art will readily understand that other ways of performing the operations associated with the methods may be used. For example, unless otherwise stated, the order of various steps may be changed without departing from the scope or spirit of the methods. In addition, some of the individual steps may be combined, omitted, or further subdivided into additional steps.

[0160] All patents, publications, and references cited herein are hereby incorporated by reference in their entirety. In the event of a conflict between the present disclosure and the incorporated patents, publications, and references, the present disclosure shall control.

Claims

1. 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 said patient at the first daily dosage for a first period of 7 days; providing a second daily dosage of ecopipam to the patient at a second daily dosage greater than the first dosage for a second period of time after the first period of time, wherein the second period of time is 7 days; providing a third daily dosage of ecopipam to the patient for a third time period after the second time period, the third daily dosage being greater than the second dosage; (a) the third period is longer than 7 days, and one or more of the following three conditions are met: (1) the daily dosage of ecopipam administered during the third period is 37.5 mg; (2) the first daily dosage is one-third of the third daily dosage and the second daily dosage is two-thirds of the third daily dosage; and (3) the patient weighs between 18 kg and 23 kg; or (b) the third period of time is 7 days, the method further comprising providing the patient with a fourth daily dose of ecopipam, at a fourth daily dosage greater than the third daily dosage, for a fourth period of time after the third period of time, wherein the fourth daily dosage is 2.41 mg / kg or less.

2. 10. The method of claim 1, wherein the third period of time is greater than 7 days and the daily ecopipam dose administered during the third period of time is 37.5 mg.

3. 3. The method of claim 1 or 2, wherein the third period of time is greater than 7 days, the first daily dosage is 1 / 3 of the amount of the third daily dosage, and the second daily dosage is 2 / 3 of the amount of the third daily dosage.

4. The method of any one of claims 1 to 3, wherein the patient has a weight of 18 kg or more and 23 kg or less.

5. 10. The method of claim 1, wherein the third period of time is 7 days, and the method further comprises providing the patient with a fourth daily dose of ecopipam, the fourth daily dose being greater than the third daily dose, and the fourth daily dose is less than or equal to 2.41 mg / kg.

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

7. 7. The method of claim 6, wherein the patient has a body weight of greater than 23 kg and less than or equal to 34 kg, and the fourth daily dosage is 50 mg.

8. 7. The method of claim 6, wherein the patient has a body weight of greater than 44 kg and less than or equal to 68 kg, and the fourth daily dosage is 100 mg.

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

10. 10. The method of claim 9, wherein the patient has a body weight of greater than 34 kg and less than or equal to 44 kg, and the fourth daily dosage is 75 mg.

11. 10. The method of claim 9, wherein the patient has a body weight of greater than 68 kg and less than or equal to 83 kg, and the fourth daily dosage is 150 mg.

12. 6. The method of claim 5, wherein the first daily dosage is 1 / 8 the amount of the fourth daily dosage, the second daily dosage is 1 / 4 the amount of the fourth daily dosage, and the third daily dosage is 1 / 2 the amount of the fourth daily dosage.

13. 13. The method of claim 12, wherein the patient has a body weight greater than 83 kg and the fourth daily dosage is 200 mg.

14. 7. The method of claim 6, wherein the fourth daily dosage is 50 mg if the patient has a body weight of greater than 23 kg but not greater than 34 kg, and wherein the fourth daily dosage is 100 mg if the patient has a body weight of greater than 44 kg but not greater than 68 kg.

15. 10. The method of claim 9, wherein the fourth daily dosage is 75 mg if the patient has a body weight of greater than 34 kg but not greater than 44 kg, and wherein the fourth daily dosage is 150 mg if the patient has a body weight of greater than 68 kg but not greater than 83 kg.

16. if the patient has a body weight of greater than 23 kg but not greater than 34 kg, the first daily dosage is 12.5 mg, the second daily dosage is 25 mg, the third daily dosage is 37.5 mg, and the fourth daily dosage is 50 mg; if the patient has a body weight of greater than 34 kg but not greater than 44 kg, the first daily dosage is 12.5 mg, the second daily dosage is 25 mg, the third daily dosage is 50 mg, and the fourth daily dosage is 75 mg; 6. The method of claim 5, wherein the first daily dosage is 25 mg, the second daily dosage is 50 mg, the third daily dosage is 75 mg, and the fourth daily dosage is 100 mg when the patient has a body weight of greater than 44 kg but less than or equal to 68 kg, and the first daily dosage is 25 mg, the second daily dosage is 50 mg, the third daily dosage is 100 mg, and the fourth daily dosage is 150 mg when the patient has a body weight of greater than 68 kg but less than or equal to 83 kg.

17. 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 said patient at the first daily dosage for a first period of about 7 days; providing a second daily dosage of ecopipam to the patient at a second daily dosage greater than the first daily dosage for a second period of time after the first period of time, wherein the second period of time is about 7 days; providing a third daily dosage of ecopipam to the patient, the third daily dosage being greater than the second daily dosage, for a third period of time after the second period of time, wherein the third period of time is at least 7 days; optionally providing a fourth daily dosage of ecopipam to the patient for a fourth time period after the third time period, the fourth daily dosage being greater than the third daily dosage; (a) the patient has a body weight of 18 kg or more and 23 kg or less, and the third period is longer than 7 days if one or more of the following two conditions are met: (1) the daily ecopipam dose administered during the third period is 37.5 mg, and (2) the first daily dosage is one-third of the amount of the third daily dosage and the second daily dosage is two-thirds of the amount of the third daily dosage; (b) the third period of time is 7 days, and the method further comprises providing the patient with a fourth daily dose of ecopipam, the fourth daily dose being greater than the third daily dose, wherein the fourth daily dose is less than or equal to 2.41 mg / kg; if the patient weighs more than 23 kg but less than or equal to 34 kg, the first daily dosage is 12.5 mg, the second daily dosage is 25 mg, the third daily dosage is 37.5 mg, and the fourth daily dosage is 50 mg; if the patient weighs more than 34 kg but less than or equal to 44 kg, the first daily dosage is 12.5 mg, the second daily dosage is 25 mg, the third daily dosage is 50 mg, and the fourth daily dosage is 75 mg; if the patient weighs more than 44 kg but less than or equal to 68 kg, the first daily dosage is 25 mg, the second daily dosage is 50 mg, the third daily dosage is 75 mg, and the fourth daily dosage is 100 mg; if the patient has a body weight of greater than 68 kg but less than or equal to 83 kg, the first daily dosage is 25 mg, the second daily dosage is 50 mg, the third daily dosage is 100 mg, and the fourth daily dosage is 150 mg; wherein the first daily dosage is 25 mg, the second daily dosage is 50 mg, the third daily dosage is 100 mg, and the fourth daily dosage is 200 mg if the patient has a body weight greater than 83 kg.

18. The method of any one of claims 5 to 17, wherein the fourth period of time is at least 2 days.

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

20. 10. The method of any one of the preceding claims, wherein the patient has an age between 6 and 18 years old.

21. 10. The method of any one of the preceding claims, wherein the patient is aged 18 years or older.

22. 10. 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. 10. 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, if applicable, is administered once per day.

24. 10. The method of any one of the preceding claims, wherein the administration of ecopipam is for the treatment of Tourette's syndrome.

25. 10. The method of any one of the preceding claims, wherein the method reduces one or more adverse events, e.g., compared to conventional methods.

26. 10. The method of any one of the preceding claims, wherein the method increases the effectiveness of ecopipam therapy, e.g., compared to conventional methods.

27. 1. A method of discontinuing drug therapy from a patient receiving ecopipam or a pharmaceutically acceptable salt thereof, comprising: after administration of a previous dose of ecopipam or a pharmaceutically acceptable salt thereof to said patient; (a) providing said patient with a reduced daily dosage of ecopipam or a pharmaceutically acceptable salt thereof in an amount ranging from about 20 mg to 30 mg less than said patient was administered with said previous dosage; (b) repeating step (a) until the reduced daily dosage of ecopipam or a pharmaceutically acceptable salt thereof is 0 mg; and then (c) terminating the administration of ecopipam or a pharmaceutically acceptable salt thereof.

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

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

30. 30. The method of any one of claims 27-29, wherein the reduced daily dosage is about ¼ less per day than the patient was administered with the first dosage.

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

32. 32. The method of any one of claims 27 to 31, wherein the patient has received ecopipam or a pharmaceutically acceptable salt thereof for the treatment of Tourette's syndrome.

Images