Methods of providing ecopipam therapy to patient

Abstract

The present invention relates to a method for reducing adverse events associated with the administration of ecopipam (ecopipam). The methods include administration in specific weight ranges and associated incremental dosage regimens, and further decreasing dosage regimens for ecopipam stop.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] The benefit of U.S. Provisional Patent Application No. 63 / 424,084, filed on November 9, 2022, is claimed under 35 U.S.C. §119(e), the disclosure of which is incorporated herein by reference in its entirety for all purposes. Technical Field

[0003] The present invention relates to methods of 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 pharmaceutically acceptable salts thereof, such as ecopipam HCl. Background Art

[0004] Ecopipam is a small drug molecule with the chemical name (6aS,13bR)-11-chloro-7-methyl-5,6,6a,8,9,13b-hexahydronaphtho[1,2-a][3]benzazepin-12-ol. Ecopipam is a benzazepine derivative that is a selective antagonist of the dopamine D1 receptor family. Ecopipam (known under the development codes EBS-101, PSYRX-101, and SCH-39166; C 19 H 20 NOCl as the hydrochloride salt) as well as its structure and synthesis are known. Ecolpipan is being clinically evaluated in patients with Tourette Syndrome (also known as Tourette's syndrome), childhood-onset dysphasia (i.e., patients who stutter or are diagnosed with a stuttering disorder), and Restless Legs Syndrome.

[0005] Karlsson et al., "Evaluation of SCH 39166at PET ligand for central dopamine receptor binding and occupancy in man" Psychopharmacology 121:300-308 (1995) reported that a single oral dose of 25 mg, 100 mg, and 400 mg of ecolopam was administered orally to each of three healthy subjects. 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, all three subjects reported restlessness and sedation, while two subjects reported irritation.

[0006] De Beaurepaire et al., "An Open Trial of the Di Antagonist SCH 39166 in Six Cases of Acute Psychotic States," Psychopharmacology, 121: 323-327 (1995), reported the administration of ecolpiram to six adult, psychotic patients in a four-week study. The dose was gradually increased every three days, initially from 50 mg / day to 200 mg / day, followed by an increase to a dose of 400 mg / day on days 10 to 17 of administration and to 600 mg / day on days 18 to 28 of administration. There was improvement in extrapyramidal symptoms in three patients (Nos. 1, 2, and 5), but there was a significant induction of extrapyramidal symptoms in one patient (No. 4) (Table 4). Other reported side effects were nausea and vomiting (three patients), hypotension, dizziness, and headache (one patient each).

[0007] 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 the use of ecolpiram in patients with schizophrenia in a 3-week study. Ecolpiram was administered orally according to the following fixed dose schedule: Day 1: 25 mg twice a day, Day 4: 50 mg twice a day, Day 7: 100 mg twice a day, Day 18: 200 mg twice a day, Day 21: 225 mg twice a day. Patients remained on the 225 mg twice a day dose until the end of the study on Day 28. Seven patients completed the 2 weeks, and five patients completed the study. The reasons for premature discontinuation were lack of efficacy or refusal to take ecolpiram. The most common side effect was dizziness, reported by four patients. Other side effects considered possibly or probably related to treatment, according to the researchers, were: decreased motor function, cogwheeling, nausea, anxiety, insomnia, and somnolence.

[0008] 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 that 17 schizophrenia patients were orally administered ecolpiram in a 4-week study. Doses were given in the morning, starting with 10 mg twice a day on days 1 to 3, 25 mg twice a day on days 4 to 6, 50 mg twice a day on days 7 to 9, 75 mg twice a day on days 10 to 17, and 100 mg twice a day on days 18 to 28. Dose reductions were allowed in the event of patient intolerance or unacceptable adverse events. Seven patients completed the 4-week study, four others participated for 10 days or longer, and four patients participated for 4 days or shorter. The reasons for early discontinuation were refusal to take medication (8 patients) and exacerbation (2 patients). The most common adverse events were agitation, anxiety, and restlessness.

[0009] Haney et al. "Effects of ecopipam, a selective dopamine D1 antagonist, on smoked cocaine self-administration by humans," Psychopharmacology 155:330-337 (2001) reported the use of ecopipam in 10 non-treatment-seeking cocaine users. Ecopipam was administered at a dose of 100 mg at night for 8 consecutive days. Seven of the ten participants experienced at least one adverse event, but its occurrence did not vary depending on maintenance condition. Headaches were reported six times during the placebo maintenance period and five times during the ecopipa maintenance period, while gastrointestinal disturbances (constipation, stomach pain) occurred twice during the placebo maintenance period and twice during the ecopipa maintenance period.

[0010] Astrup et al., "Randomized Controlled Trials of the D1 / D5 Antagonist Ecopipam for Weight Loss in Obese Subjects" OBESITY, 15(7): 1717-1731 (2007) report 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 obese adult patients receiving 50 or 100 mg of ecopipam daily for 52 weeks. The weight range of the patients was 60 kg to 172 kg, with a mean weight of 100 kg. The studies included doses of 50 mg / day (one study) or 100 mg / day (three studies). For the 50 mg dose, the mean dose based on mean subject weight was 0.5 mg / kg and ranged from 0.29 to 0.83 mg / kg. For the 100 mg dose, the mean dose based on mean subject weight was 1 mg / kg and ranged from 0.58 to 1.66 mg / kg. For the 100 mg dose, 85-92% of subjects experienced treatment-emergent adverse events (TEAEs), 6-9% more than placebo. At the 100 mg dose, the most common adverse events were insomnia (8-11% more than placebo), depression (8-13% more than placebo), fatigue (7-13% more than placebo), anxiety (8-11% more than placebo), and somnolence (6-14% more than placebo).

[0011] Gilbert et al., "A D1 Receptor Antagonist, Ecopipam, for Treatment of Ticsin Tourette Syndrome," Clinical Neuropharmacology, 37(1):26-30 (2014) reported a trial of ecopipam in 18 adults with TS. Dosage was 50 mg / day for 2 weeks, followed by 100 mg / day for 6 weeks, administered orally before bedtime. 100% of patients experienced adverse events. The incidence of the most common adverse events was generally higher than in Astrup et al., 2007. Two subjects discontinued participation early.

[0012] International Patent Application Publication WO 2014 / 012063 A1 proposes a pharmaceutical dosage form with a controlled-release component to reduce or eliminate adverse side effects of ecolopam administration. It notes that previous studies have shown that peak adverse sedative effects of ecolopam occur within several hours of administration, and that these sedative effects can be associated with higher plasma levels at these times, as the effects peak approximately 2 to 4 hours after administration and dissipate 6 to 8 hours thereafter. The '063 publication also suggests that frequent dosing, such as three or four times daily, may be necessary.

[0013] Khasnavis et al., “A double-blind, placebo-controlled, crossover trial of the selective dopamine D1 receptor antagonist ecopipamin in patients with Lesch-Nyhan disease,” Mol. Genet. Metab., 118:160-6 (2016), reported the use of ecopipamin in subjects aged 6-22 years with Lesch-Nyhan disease. The study was terminated early due to side effects. Most subjects weighed less than 30 kg; subjects received doses ranging from 1.81 mg / kg / day to 4.65 mg / kg / day.

[0014] 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, No. 8, pp. 1272-80, (August 2018) reported a 4-week, placebo-controlled, Phase 2b trial (PSY302) of ecopipam in subjects aged 7 to 17 years. If the subject weighed ≤ 34 kg, the full dose was 50 mg / day, and for subjects > 34 kg, the full dose was 100 mg / day. 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, and for the 100 mg dose, the upper limit of the possible range was approximately 2.86 mg / kg (i.e., based on a 35 kg patient). Dosing with 50 mg was initiated at 12.5 mg / day for days 1 to 3, followed by 25 mg / day for days 4 to 7, and then 50 mg / day for the final three weeks. Dosing with 100 mg was initiated at 25 mg / day for days 1 to 7, 50 mg / day for days 8 to 14, and then 100 mg / day for the final two weeks. No overall incidence of adverse events was reported. Two subjects discontinued study participation related to adverse events while taking ecolpipan during the second period of the crossover study: one subject developed an upper arm rash believed to be urticaria and possibly unrelated to the study as it was present before the start of the study; and one subject experienced worsening of tic severity. The incidence of TEAS is reported in Table 3. Summary of the Invention

[0015] Methods of administering ecolpipant are provided herein. One aspect is a method of orally administering ecolpipant or a pharmaceutically acceptable salt thereof to a patient in need thereof, comprising: providing the patient with a first daily dose of ecolpipant at a first daily dosage for a first period of at least 5 days, such as seven days; providing the patient with a second daily dose of ecolpipant 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 at least 5 days, such as seven days; and providing the patient with a third daily dose of ecolpipant at a third daily dosage greater than the second dosage for a third period of time after the second period of time, wherein (a) the third period of time is greater than seven days and satisfies One or more of the following three conditions: (1) the daily dose of ecolpiram administered in the third time period is 37.5 mg; (2) the first daily dose is 1 / 3 of the amount of the third daily dose, and the second daily dose is 2 / 3 of the amount of the third daily dose; and (3) the patient's weight is ≥18 kg to ≤23 kg; or (b) the third time period is seven days and the method further comprises providing the patient with a fourth daily dose of ecolpiram at a fourth daily dose greater than the third daily dose for a fourth time period after the third time period, wherein the fourth daily dose is 2.41 mg / kg or less.

[0016] Another aspect is a method of orally administering ecolpipan or a pharmaceutically acceptable salt thereof to a patient in need thereof, comprising: providing the patient with a first daily dose of ecolpipan at a first daily dose for a first period of about seven days; providing the patient with a second daily dose of ecolpipan at a second daily dose greater than the first daily dose for a second period of time after the first period of time, wherein the second period of time is about seven days; and providing the patient with a third daily dose of ecolpipan at a third daily dose greater than the second daily dose for a third period of time after the second period of time, wherein the third period of time is at least seven days; and optionally administering the patient with a third daily dose greater than the third daily dose for a third period of time after the second period of time. A fourth daily dose of ecolopam is provided to the patient for a fourth time period after the third time period; wherein (a) the third time period is greater than seven days when the patient weighs ≥18 kg to ≤23 kg and satisfies one or more of the following two conditions: (1) the daily ecolopam dose administered during the third time period is 37.5 mg; and (2) the first daily dose is 1 / 3 of the amount of the third daily dose, and the second daily dose is 2 / 3 of the amount of the third daily dose; and (b) the third time period is seven days and the method further comprises providing the patient with a fourth daily dose of ecolopam that is greater than the third daily dose. providing a fourth daily dose of ecolopam, wherein the dosage is 2.41 mg / kg or less; and wherein when the patient's weight is >23 kg to ≤34 kg, then 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 when the patient's weight is >34 kg to ≤44 kg, then 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; and when the patient's weight is >44 kg to ≤68 kg When the patient's weight is >68 kg to ≤83 kg, then the first daily dose is 25 mg, the second daily dose is 50 mg, the third daily dose is 75 mg, and the fourth daily dose is 100 mg; and when the patient's weight is >68 kg to ≤83 kg, then the first daily dose is 25 mg, the second daily dose is 50 mg, the third daily dose is 100 mg, and the fourth daily dose is 150 mg; and when the patient's weight is >83 kg, then the first daily dose is 25 mg, the second daily dose is 50 mg, the third daily dose is 100 mg, and the fourth daily dose is 200 mg.

[0017] Another aspect is a method of discontinuing medical therapy from a patient receiving ecolpiram or a pharmaceutically acceptable salt thereof according to the methods described herein, the method of discontinuing comprising: after administering a previous dose of ecolpiram or a pharmaceutically acceptable salt thereof to the patient, (a) providing the patient with a reduced daily dose of ecolpiram or a pharmaceutically acceptable salt thereof in an amount within the range of about 20 mg to 30 mg less than the amount administered to the patient at the previous dose; and (b) repeating step (a) until the reduced daily dose of ecolpiram or a pharmaceutically acceptable salt thereof is 0 mg; and then (c) terminating administration of ecolpiram or a pharmaceutically acceptable salt thereof.

[0018] For the compositions and methods described herein, optional features including, but not limited to, components, compositional ranges thereof, substitutions, conditions, and steps are contemplated as being selected from the various aspects, embodiments, and examples provided herein.

[0019] Other aspects and advantages will become apparent to those skilled in the art from the review of the following detailed description taken in conjunction with the drawings. Although the method is susceptible to different forms of embodiment, the following description includes specific embodiments with the understanding that the present disclosure is illustrative and is not intended to limit the invention to the specific embodiments described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] To further facilitate understanding of the present invention, figures and detailed information regarding adverse events and other safety parameters associated with Example 1 are attached. DETAILED DESCRIPTION

[0021] As an investigational drug, ecolpipan is available in tablet and capsule form, primarily for oral administration. The tablet formulation has been used in clinical trials. Common adverse reactions or events associated with ecolpipan therapy have previously been reported as insomnia, depression, drowsiness, fatigue, and anxiety. Adverse events may interfere with daily activities and quality of life and, if severe, may lead to discontinuation of therapy. These effects of ecolpipan administration appear to be dose-related.

[0022] The inventors made several determinations from unpublished results from the PSY302 study described in Gilbert 2018. First, the safety analysis set incidence of adverse events in the icopipan group was 80% overall, which was 15% more than the placebo subjects. Second, subjects taking doses below 1.4 mg / kg / day (associated with the 25th percentile in the study) would be unlikely to have significant efficacy. Therefore, the methods of the present invention optionally and preferably have a minimum full dose of at least 1.4 mg / kg / day or greater than 1.4 mg / kg / day after titration. Third, subjects taking doses substantially greater than 2 mg / kg, e.g., greater than about 2.4 mg / kg, may not have been well tolerated.

[0023] Additional results from the PSY302 study will now be described.

[0024] Adverse events were 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, of which 80 occurred while subjects were taking ecolpiram and 69 occurred while subjects were taking placebo. One SAE occurred in the placebo group and one adverse event led to premature discontinuation in the ecolpiram group. There were no fatal adverse events. Twenty subjects (50.0%) reported study drug-related adverse events while taking ecolpiram and 10 subjects (25.0%) reported study drug-related adverse events while taking placebo. Adverse events by treatment group are summarized in Table 14-20-2 of the Figures.

[0025] Adverse Events Overview Table

[0026]

[0027] Adverse events reported in ≥5% of subjects in either treatment group are presented in the table below.

[0028] The most commonly reported adverse events (≥5% of subjects) are shown in the table below.

[0029] Table of adverse events reported in ≥5% of subjects in either treatment group (safety analysis set, all subjects received at least 1 dose of study drug)

[0030]

[0031]

[0032] The severity of adverse events, as assessed by the investigator, is summarized in the table below. The majority of adverse events (144 / 149, 96.6%) were assessed by the investigator to be mild or moderate in severity. Five subjects (12.5%) experienced adverse events assessed as serious, 2 subjects (5.0%) taking concomitant ecolpiram and 3 (7.5%) taking placebo. One of the serious adverse events during ecolpiram treatment (insomnia) was almost certainly considered related to the study drug. No serious adverse events led to discontinuation and no consequences were reported.

[0033] Adverse Event Severity Table

[0034]

[0035] Adverse events considered by the investigator to be possibly, probably, or almost certainly related to study drug are summarized in the table below. The most commonly reported adverse events (≥7.5%) considered to be related to study drug in subjects taking ecolopam were nausea (10.0%), somnolence (10.0%), upper abdominal pain, decreased appetite, fatigue, headache, and sedation (all 7.5%).

[0036] Adverse events that are possibly, probably, or almost certainly related to the study drug

[0037]

[0038]

[0039] No deaths occurred during the study. Ten days after the final study visit but within the 30-day post-treatment observation period (approximately 55 days after the last dose of ecolpiram), one subject experienced a SAE of psychiatric distress. One subject prematurely discontinued the study due to an adverse event of rash. One subject required a dose reduction due to an adverse event of fatigue.

[0040] In addition, an open-label extension study was conducted using the dosing method described in Gilbert et al. 2018 (PSY302 OLE). Because the subjects stopped taking ecolopam at the time they were enrolled in the open-label extension study, they had to be titrated back to full dose using the same method described above in Gilbert et al. 2018. Twenty-six subjects participated 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 prematurely, including four subjects (15.4%) due to adverse events. Overall, 14 subjects (53.8%) were exposed to study drug for at least 12 months, 7 subjects (26.9%) had >12 months, and 1 subject (3.8%) took study drug for 24 months. The median number of treatment days was 374.5, ranging from 1 to 752 days.

[0041] 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 reported adverse events were non-treatment-induced and 78 were TEAEs. One subject (3.8%) had 15 TEAEs, while the number of adverse events reported by other subjects ranged from one to seven. The most commonly reported TEAEs (>3 subjects) were upper respiratory tract infection (5 subjects, 19.2%), anxiety (3 subjects, 11.5%), cerebral congestion (the verbatim term "head congestion"; 3 subjects, 11.5%), and suicidal ideation (3 subjects, 11.5%). One subject (3.8%) experienced an SAE that was not considered related to the study drug; there were no fatal adverse events. Twenty-three subjects (88.5%) experienced TEAEs classified as mild or moderate in severity. Two subjects (7.7%) reported seven severe TEAEs, one of which was an SAE (anxiety). None of the serious events were considered related to the study drug. 13 subjects (50.0%) reported TEAEs considered related to the study drug, 9 subjects (34.6%) had events of moderate severity, and 4 subjects (15.4%) had events of mild severity. 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 TEAEs of depressed mood that led to discontinuation persisted at the end of the study; the remaining ones resolved. In all 4 (100%), the events were considered possibly related to the study drug. Three subjects (11.5%) experienced adverse events of particular concern (AESI); all 3 were events of moderate suicidal ideation that led to discontinuation of the study drug. All AESI (100%) were considered possibly related to the study drug and resolved.

[0042] Tables providing an overall summary of TEAEs (Safety Population) (Table 14.3.1.1), a summary of TEAEs by system organ class (SOC) and preferred term (PT) (Safety Population) (Table 14.3.1.2), a summary of TEAEs by SOC, PT, and severity (Safety Population) (Table 14.3.1.3), a summary of TEAEs by SOC, PT, and relationship to study drug (Safety Population) (Table 14.3.1.4), a summary of treatment-emergent AEs by SOC and PT (Safety Population) (Table 14.3.1.5), a summary of serious TEAEs by SOC and PT (Safety Population) (Table 14.3.1.6), and a summary of TEAEs leading to study drug discontinuation by SOC and PT (Safety Population) (Table 14.3.1.7) are provided in the Figures.

[0043] TEAEs are summarized in the table below

[0044] Table 16: Summary of Treatment-Emergent Adverse Events (Safety Population)

[0045]

[0046] TEAEs reported by 2 or more subjects are summarized in the table below. The most frequently reported TEAEs (>3 subjects) were upper respiratory tract infection (5 subjects, 19.2%), anxiety (3 subjects, 11.5%), cerebral congestion (3 subjects, 11.5%), and suicidal ideation (3 subjects, 11.5%).

[0047] Table 17: Treatment-emergent adverse events occurring in >2 subjects (Safety Population)

[0048]

[0049] All AEs were assessed by the investigator as mild, moderate, or severe. The investigator assessed the severity of 71 / 78 TEAEs (91.0%) as mild or moderate, and 7 / 78 TEAEs (9.0%) were rated as severe. Seven serious events occurred in two subjects (7.7%), as summarized in the table below.

[0050] Table 18: Subjects Experiencing Severe Treatment-Emergent Adverse Events (Safety Population)

[0051]

[0052]

[0053] Thirteen subjects (50.0%) experienced TEAEs that were considered by the investigator to be related to 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.

[0054] Table 19: Treatment-emergent adverse events considered to be related to study drug reported by >2 subjects (Safety Population)

[0055] Source: Table 14.3.1.4

[0056] Abbreviation: TEAE, treatment-emergent adverse event Note: Subjects were counted once per system organ class and once per preferred term. The relationships shown are the strongest relationships reported for a particular subject (related > not related). Adverse events with a missing relationship or a possibly or probably related relationship were considered related. Adverse events with an unlikely or not related relationship were considered not related.

[0057] There were no deaths on the study. One subject (3.8%) experienced a severe anxiety SAE requiring hospitalization. The SAE was not considered related to study drug.

[0058] Four subjects (15.4%) in the safety population experienced one or more TEAEs that led to study drug discontinuation. All events (100%) were in the psychiatric disorder system organ class, and all events (100%) were considered possibly related to the study drug. One TEAE that led to discontinuation persisted at the end of the study (depressed mood); the remaining ones resolved. Subjects with TEAEs that led to premature discontinuation are summarized in the table below. If a subject experienced persistent symptoms of depression or suicidal tendencies, the protocol required study drug discontinuation.

[0059] Table 20: Subjects with Treatment-Emergent Adverse Events Who Discontinued Study Drug (Safety Population)

[0060]

[0061]

[0062] The subjects with AESI are summarized in the table below. Three subjects (11.5%) experienced a moderate TEAE of suicidal ideation. All 3 subjects (100%) prematurely discontinued study drug due to these events as required by the protocol. All 3 events (100%) were considered related to study drug and resolved.

[0063] Table 21: Subjects with Adverse Events of Particular Interest (Safety Population)

[0064]

[0065] One subject (3.8%) experienced an SAE of severe anxiety, which was assessed by the investigator as not related to study drug. The SAE resolved. Four subjects (15.4%) experienced one or more TEAEs that led to study drug discontinuation (suicidal ideation [n=3], depressed mood [n=2], and intrusive thoughts [n=1]). One of the TEAEs of depressed mood that led to discontinuation persisted at the end of the study; the remainder resolved. Three subjects (11.3%) experienced AESIs; all 3 were events of moderate suicidal ideation that led to study drug discontinuation. All AESIs (100%) were considered possibly related to study drug and all events (100%) resolved.

[0066] It has been found that adverse events associated with the administration of ecolpiram can be reduced by an initial dose titration approach, as further described below. As a point of comparison, a study was conducted in healthy adults with repeated oral doses of approximately 2 mg / kg of ecolpiram HCl, in which the dose was not titrated upward but rather given at the full dose from the beginning. Multiple daily doses of ecolpiram HCl were administered to two groups of 12 and 18 subjects; 19 of the 30 subjects (63.3%) experienced more than one treatment-emergent adverse event (TEAE), withdrew consent, and underwent early termination procedures.

[0067] Provided herein are methods for providing or administering ecolpipan therapy to a patient in need of ecolpipan using an ascending initial dosing regimen. These methods can mitigate one or more adverse events associated with the introduction of ecolpipan and / or the introduction and continued use of ecolpipan. It is believed that the ascending dosing regimen better matches the development of tolerance to ecolpipan with dose increases. These methods are also effective for treating patients in need of ecolpipan, such as patients with TS, including children and adolescents with TS.

[0068] Unless otherwise stated, it is contemplated that methods of administration encompass embodiments comprising any combination of one or more of the other optional elements, features, and steps further described below, including those illustrated in the Figures and Examples.

[0069] In jurisdictions that prohibit the granting of patents on methods practiced on humans, the meaning of "administering" a composition to a human subject shall be limited to prescribing a controlled substance to be self-administered by a human subject by any technique (e.g., oral, inhalation, surface coating, injection, insertion, etc.). The relevant invention will be understood in light of the disclosure herein as a method of using ecolopam or a pharmaceutically acceptable salt thereof, or using ecolopam or a pharmaceutically acceptable salt thereof to prepare a medicament for use as described herein. It is contemplated that the broadest reasonable interpretation consistent with the law or regulation defining patentable subject matter be adopted. In jurisdictions that do not prohibit the granting of patents on methods practiced on humans, "administering" a composition includes both methods practiced on humans as well as the aforementioned activities.

[0070] As used herein, the term "comprising" means that other reagents, elements, steps or features may be included in addition to those stated.

[0071] Pharmacokinetic studies of orally administered ecolpiam HCl were conducted using a single oral dose of 200 mg of ecolpiam HCl administered to healthy volunteers. Non-compartmental PK analysis showed that the half-life of ecolpiam was 15.8 hours, and the half-life of the active metabolite, N-desmethylecolpiam, was 24.0 hours. The calculated mean time to steady-state plasma concentration of ecolpiam was about 80 hours or about 3.3 days, and considering the variability between subjects, the range was about 3 to 5 days. Thus, one aspect of the methods herein provides a method of orally administering ecolpiam, or a pharmaceutically acceptable salt thereof, using an increasing dose titration schedule, wherein the time between dose increases is at least 5 days, or more than 5 days, or 6 days, for example, 7 days.

[0072] The amount of ecolopam administered to a patient in need of ecolopam or provided to a patient herein can be determined by the patient's weight. Generally speaking, the greater the patient's weight, the greater the total dose (absolute amount) administered to the patient. For example, the dose escalation regimen described herein can be designed to increase to a final daily dose within the range of about 37 mg / day to about 200 mg / day.

[0073] The number of doses increases from the first to the end, and the full dose also can be different depending on the patient's weight. For a patient whose body weight is at least about 15kg and about 30kg or lower or at least 18kg and 23kg or lower, the number of doses increases until the full dose can be 2 or 3, for example, 2. Each dose increase can be after at least 5 days, or 6 days, or 7 days of the previous daily dose. For a patient whose body weight is at least about 20kg or greater than 23kg, the number of doses increases until the full dose can be 3 or 4, for example, 3. Each dose increase can be after at least 5 days, or 6 days, or 7 days of the previous daily dose. In a type of method, each dose increase of any patient will be after 7 days of the previous daily dose.

[0074] The amount of ecolopam administered to a patient in need of ecolopam or provided to a patient herein can be more strictly correlated to the patient's weight than previously known methods. For example, the maximum amount of ecolopam 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 within the range of 1.67 to 2.08 mg / kg / day. In patients weighing greater than 23 kg and 34 kg or less, the maximum dose can be 2.17 mg / kg / day, within the range of 1.47 to 2.17 mg / kg / day. In patients weighing greater than 34 kg and 44 kg or less, the maximum dose can be 2.21 mg / kg / day, within the range of 1.70 to 2.21 mg / kg / day. In patients weighing greater than 44 kg and 68 kg or less, the maximum dose may be 2.27 mg / kg / day, within a range of 1.47 to 2.27 mg / kg / day. In patients weighing greater than 68 kg and 83 kg or less, the maximum dose may be 2.21 mg / kg / day, within a range of 1.81 to 2.21 mg / kg / day. In patients weighing greater than 83 kg, the maximum dose may be 2.41 mg / kg / day.

[0075] The amount of the dose administered as the first dose and the amount of each dose increase can also be relative to the patient's 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. For patients weighing at least 18 kg and 44 kg or less, the first daily dose 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 44 kg or less, the increase in the daily dose at each dose increase interval (e.g., every 5 days, or 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 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. In patients weighing more than 44 kg, the increase in the daily dose at the first dose increase interval (e.g., after 5 days, or 6 days, or 7 days of the first daily dose) can be in the range of about 20 mg to about 40 mg, or about 25 mg. In patients weighing greater than 44 kg, the amount of increase in the daily dose at the second dose increase interval may be in the range of about 20 mg to about 60 mg, or about 25 mg, or about 50 mg, for example, about 25 mg in patients weighing greater than 44 kg to 68 kg or less, and about 50 mg in patients weighing greater than 68 kg. In patients weighing greater than 44 kg, the amount of increase in the daily dose at the third dose increase interval may be in the range of about 20 mg to about 125 mg, or about 25 mg, or about 50 mg, or about 100 mg, for example, about 25 mg in patients weighing greater than 44 kg to 68 kg or less, about 50 mg in patients weighing greater than 68 kg and 83 kg or less, and 100 mg in patients weighing greater than 83 kg.

[0076] In addition to the absolute dose provided above or irrelevant, initial dose and dosage increase can also be characterized by the fraction of full dose.For example, initial dose can be in the range of about 1 / 8 to about 1 / 3 of full dose, such as 1 / 8, 1 / 6, 1 / 4 or 1 / 3 of full dose.In patients with body weight of at least 18kg and 23kg or lower, initial daily dose can be about 1 / 3 of full daily dose.For patients with body weight of at least 18kg and 23kg or lower, daily dose can be about 1 / 3 of each dosage increase interval (such as every 5 days, or every 6 days, or every 7 days).When weight is greater than 23kg, such as in patients with 1 / 6 or 1 / 8 of full daily dose, the first daily dose can be about 1 / 4 or lower full daily dose.When weight is greater than 23kg and 83kg or lower, such as in patients with 1 / 4 or 1 / 6 of full daily dose, the first daily dose can be about 1 / 4 to about 1 / 6 of full daily dose. In patients weighing more than 83kg, the first daily dose can be about 1 / 8 or less of the full daily dose, for example, 1 / 8 of the full daily dose. In patients weighing more than 23kg, the increase in daily dose at the first dose increase interval (for example, after 5 days, or 6 days, or 7 days of the first daily dose) can be in the range of about 1 / 8 to about 1 / 4. In patients weighing more than 23kg, the increase in daily dose at the second dose increase interval can be in the range of about 1 / 6 to about 1 / 3, for example, 1 / 6 or 1 / 4 or 1 / 3. In patients weighing more than 23kg, the increase in daily dose at the third dose increase interval can be in the range of about 1 / 4 to about 1 / 2, for example, about 1 / 3, or about 1 / 4, or about 1 / 2.

[0077] In various embodiments, ecolpimam or ecolpimam therapy can be used interchangeably with a pharmaceutically acceptable salt of ecolpimam, e.g., ecolpimam HCl. References herein to ecolpimam or ecolpimam therapy should be understood to apply to both ecolpimam and a pharmaceutically acceptable salt and in each case constitute an express disclosure of a pharmaceutically acceptable salt of ecolpimam, e.g., ecolpimam HCl.

[0078] In one aspect, a method of orally administering ecolpipan or a pharmaceutically acceptable salt thereof to a patient in need thereof is provided, comprising: providing the patient with a first daily dose of ecolpipan at a first daily dosage for a first period of seven days; providing the patient with a second daily dose of ecolpipan 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 seven days; providing the patient with a third daily dose of ecolpipan at a third daily dosage greater than the second dosage for a third period of time after the second period of time, wherein (a) the third period of time is greater than seven days and satisfies the following three conditions: One or more of: (1) the daily dose of ecolpiram administered in the third time period is 37.5 mg; (2) the first daily dose is 1 / 3 of the amount of the third daily dose, and the second daily dose is 2 / 3 of the amount of the third daily dose; and (3) the patient's weight is ≥18 kg to ≤23 kg; or (b) the third time period is seven days and the method further includes providing the patient with a fourth daily dose of ecolpiram at a fourth daily dose that is greater than the third daily dose for a fourth time period after the third time period, wherein the fourth daily dose is 2.41 mg / kg or less.

[0079] In such methods, the third time period may be greater than seven days, and the daily dose of ecolpiram administered during the third time period may be 37.5 mg. Additionally or alternatively, the third time period may be greater than seven days, and the first daily dose may be 1 / 3 of the amount of the third daily dose, and the second daily dose may be 2 / 3 of the amount of the third daily dose. Additionally or alternatively, the patient may weigh ≥18 kg to ≤23 kg.

[0080] In such methods, when the third time period is seven days and the method further comprises providing the patient with a fourth daily dose of ecolopam at a fourth daily dose that is greater than the third daily dose, and the fourth daily dose is 2.41 mg / kg or less, the first daily dose may be 1 / 4 of the amount of the fourth daily dose, the second daily dose may be 1 / 2 of the amount of the fourth daily dose, and the third daily dose may be 3 / 4 of the amount of the fourth daily dose. In such methods, the patient's weight optionally may be >23 kg to ≤34 kg and the fourth daily dose is 50 mg, and / or the patient's weight may be >44 kg to ≤68 kg and the fourth daily dose is 100 mg.

[0081] In such methods, when the third time period is seven days and the method further comprises providing the patient with a fourth daily dose of ecolopam at a fourth daily dose that is greater than the third daily dose, and the fourth daily dose is 2.41 mg / kg or less, the first daily dose may be 1 / 6 of the amount of the fourth daily dose, the second daily dose may be 1 / 3 of the amount of the fourth daily dose, and the third daily dose may be 2 / 3 of the amount of the fourth daily dose. In such methods, the patient's weight optionally may be >34 kg to ≤44 kg and the fourth dose is 75 mg, and / or the patient's weight may be >68 kg to ≤83 kg and the fourth dose is 150 mg.

[0082] In such methods, when the third time period is seven days and the method further comprises providing the patient with a fourth daily dose of ecolopam at a fourth daily dose that is greater than the third daily dose, and the fourth daily dose is 2.41 mg / kg or less, the first daily dose may be 1 / 8 of the amount of the fourth daily dose, the second daily dose may be 1 / 4 of the amount of the fourth daily dose, and the third daily dose may be 1 / 2 of the amount of the fourth daily dose. In such methods, the patient's weight may optionally be >83 kg and the fourth dose is 200 mg.

[0083] In such methods, when the third time period is seven days and the method further comprises providing the patient with a fourth daily dose of ecolopam at a fourth daily dose that is greater than the third daily dose, and the fourth daily dose is 2.41 mg / kg or less, a specific 6-weight band method can be applied, wherein when the patient weighs >23 kg to ≤34 kg, then 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; and when the patient weighs >34 kg to ≤44 kg, then the first daily dose is is 12.5 mg, the second daily dose is 25 mg, the third daily dose is 50 mg, and the fourth daily dose is 75 mg; and when the patient's weight is >44 kg to ≤68 kg, then the first daily dose is 25 mg, the second daily dose is 50 mg, the third daily dose is 75 mg, and the fourth daily dose is 100 mg; and when the patient's weight is >68 kg to ≤83 kg, then the first daily dose is 25 mg, the second daily dose is 50 mg, the third daily dose is 100 mg, and the fourth daily dose is 150 mg.

[0084] A more specific method contemplated is a method of orally administering ecolpipant or a pharmaceutically acceptable salt thereof to a patient in need thereof, comprising: providing to the patient a first daily dose of ecolpipant at a first daily dose for a first period of about seven days; providing to the patient a second daily dose of ecolpipant at a second daily dose greater than the first daily dose for a second period of time following the first period of time, wherein the second period of time is about seven days; providing to the patient a third daily dose of ecolpipant at a third daily dose greater than the second daily dose for a third period of time following the second period of time, wherein the third period of time is at least seven days; optionally providing to the patient a fourth daily dose of ecolpipant at a fourth daily dose greater than the third daily dose for a fourth period of time following the third period of time;

[0085] wherein (a) the third time period is greater than seven days when the patient's weight is ≥18 kg to ≤23 kg and one or more of the following two conditions are met: (1) the daily dose of ecolpiram administered during the third time period is 37.5 mg; (2) the first daily dose is 1 / 3 of the amount of the third daily dose, and the second daily dose is 2 / 3 of the amount of the third daily dose; (b) the third time period is seven days and the method further comprises providing the patient with a fourth daily dose of ecolpiram at a fourth daily dose that is greater than the third daily dose, wherein the dose is 2.41 mg / kg or less; and wherein when the patient's weight is >23 kg to ≤34 kg, then 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; and when the patient's weight is >34 kg g to ≤44 kg, then the first daily dose is 12.5 mg, the second daily dose is 25 mg, the third daily dose is 50 mg, and the fourth daily dose is 75 mg; and when the patient's weight is >44 kg to ≤68 kg, then the first daily dose is 25 mg, the second daily dose is 50 mg, the third daily dose is 75 mg, and the fourth daily dose is 100 mg; and when the patient's weight is >68 kg to ≤83 kg, then the first daily dose is 25 mg, the second daily dose is 50 mg, the third daily dose is 100 mg, and the fourth daily dose is 150 mg; and when the patient's weight is >83 kg, then the first daily dose is 25 mg, the second daily dose is 50 mg, the third daily dose is 100 mg, and the fourth daily dose is 200 mg.

[0086] In any of the methods described herein, the fourth time period can range from about 1 day to an unlimited number of days. For example, the fourth and / or final time period 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 time period can be at least 2 days. The fourth time period can be more than 1 week.

[0087] In any of the methods described herein, the patient can be ≥6 years old to <18 years old. In any of the methods described herein, the patient can be ≥6 years old to any age. In any of the methods described herein, the patient can be ≥18 years old.

[0088] In any of the methods described herein, the administration of ecolpipan can be used to treat patients in need thereof or patients in need of a dopamine D1 antagonist. The administration of ecolpipan can be used to treat patients in need of a selective dopamine D1 antagonist. The administration of ecolpipan can be used to treat tics or movement disorders. The tics can be Tourette syndrome, pediatric autoimmune disorders associated with streptococcal infection (PANDAS), transient tics, chronic tics, or tics not otherwise listed (NOS). The subject can exhibit motor tics (e.g., complex motor tics), vocal tics (e.g., complex vocal tics), or a combination thereof. The administration of ecolpipan can be used to treat childhood-onset speech disorders (stuttering). The administration of ecolpipan can be used to treat restless legs syndrome, restless legs syndrome with increased symptoms, or restless legs syndrome associated with increased symptoms. The administration of ecolpipan can be used to treat obesity, including subjects with type 2 diabetes.

[0089] Specific contemplated administration methods are described in the table below. In parentheses, the table includes optional combinations of dosage form amounts (e.g., tablets or capsules) of 12.5 mg, 50 mg, 75 mg, and 100 mg per dosage form to achieve the target dose. Each weight band method can be used individually or in combination of one or more thereof, as desired.

[0090]

[0091] Further provided herein is a method of administering ecolpipan to a patient in a decreasing dosing regimen to alleviate adverse events associated with discontinuing ecolpipan from the patient's body, wherein the patient has been receiving ecolpipan therapy as described herein, for example, in an amount of about 2 mg / kg / day, or in a dose greater than 100 mg / day, or in a dose greater than 150 mg / day. In one embodiment of the present disclosure is a method of administering ecolpipan to a patient receiving ecolpipan, comprising, after administering a previous dose of ecolpipan or a pharmaceutically acceptable salt thereof to the patient, (a) providing the patient with a reduced daily dose of ecolpipan or a pharmaceutically acceptable salt thereof in an amount within the range of about 20 mg to 30 mg less than the amount administered to the patient at the previous dose, and (b) repeating step (a) until the reduced daily dose of ecolpipan or a pharmaceutically acceptable salt thereof is 0 mg (the calculated non-negative dose is equivalent to zero); and then (c) terminating the administration of ecolpipan. In an embodiment, the reduced daily dose of ecolopam administered to a patient may be an amount of about 25 mg less per day compared to the amount administered to the patient at the previous dose. Optionally, the reduced daily dose of ecolopam administered to a patient may be an amount of about 1 / 16 or less, or 1 / 8 or less, or 1 / 4 less per day compared to the amount administered to the patient at the previous dose. In an embodiment, the reduced daily dose of ecolopam administered to a patient may be an amount of about 1 / 4 less per day compared to the amount administered to the patient at the previous dose. In an embodiment, step (b) may be performed at a frequency of every day, or every other day, or every three days, or every four days, or every five days, or every six days, or every week. Specifically encompassing a frequency of every day or every other day. For example, a patient can be administered a reduced daily dose of ecolopam (compared to the previous dose before the start of the reduced dosing) for up to 7 days, e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, or 14 days, or 21 days, or 28 days. The discontinuation approach can be applied to any type of patient, including children and adolescents who are at least six years old and less than 18 years old, and patients with TS, and patients with other disease conditions described herein, or any combination thereof.

[0092] In any of the methods described herein, the dose of ecolopam can be taken in a fasting state. In any of the methods described herein, the dose of ecolopam can be taken with water. In any of the methods described herein, the dose of ecolopam can be taken at bedtime. In any of the methods described herein, the patient can be instructed to take a dose as described herein or instructions can be provided to the patient.

[0093] In any of the increasing or dosing regimens and / or decreasing dosing regimens described herein, daily 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., twice a day). Specifically, it is expected that in any of the increasing or dosing regimens and / or decreasing dosing regimens described herein, daily administration is a single dosing event, i.e., once a day. Administration, for example, a single dosing event can be at night.

[0094] The dose escalation described herein may provide a reduced incidence of adverse events compared to previously known dosing methods.

[0095] In some embodiments, the dose escalation described herein can reduce the incidence of one or more treatment-related adverse events compared to an alternative dosing regimen using the same full final dose. For example, in the study of Example 1, the overall incidence of TEAEs determined using the methods of the present invention was 61.8%, 12.4% higher than in the placebo group, demonstrating a reduced incidence of adverse events compared to the method described in Gilbert et al., 2018, described above. The incidence of Cmax-related GI side effects, such as nausea, vomiting, diarrhea, and abdominal pain, was reduced. The incidence of Cmax-related CNS side effects, such as sedation and somnolence, was also reduced compared to the method described in Gilbert et al., 2018. Additionally or alternatively, the incidence of discontinuation of ecolpipan due to adverse events can be reduced compared to an alternative dosing regimen using the same full final dose using a different method, such as a titration regimen that reaches an equivalent full dose more quickly and / or a regimen that reaches a higher full dose in the same or shorter time period. Optionally, the comparison can be made within the same patient population, eg, those with the same disorder (eg, Tourette's syndrome or a stuttering disorder), the same weight range, or the same age group, or any combination thereof.

[0096] The decreasing dosage regimen as described herein can alleviate the adverse events associated with stopping ecolpiram. Such adverse events can be one or more of the adverse events described above. For example, the adverse event can be one or more of the group of insomnia, depression, dyspepsia, drowsiness, fatigue, anxiety, headache, vomiting, nausea, abdominal pain. The adverse events reduced can be one or more of the group of nausea, sweating, tachycardia, dizziness, headache, tremor and anxiety. In an embodiment, the adverse events particularly associated with the use of ecolpiram in children / adolescents can be one or more of headache, upper abdominal pain, insomnia, drowsiness, nausea and vomiting. In an embodiment, the adverse events particularly associated with the use of ecolpiram in adults can be one or more of sedation, insomnia, fatigue, drowsiness, headache, muscle twitching and anxiety. In one embodiment, the type of adverse event reduced is a central nervous system-related event (e.g., sedation, insomnia, drowsiness 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 that is reduced is somnolence. In another type of embodiment, the type of adverse event that is reduced is headache. Optionally, the comparison can be made within the same patient population, e.g., those with the same condition (e.g., Tourette syndrome or a stuttering disorder), the same weight range, or the same age group, or any combination thereof.

[0097] Example 1

[0098] This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase 2b study in pediatric subjects (aged ≥6 to <18 years) with Tourette syndrome. A total of 150 subjects are planned to participate in the study. A total of 154 subjects will be recruited and 153 subjects will be randomized; 1 participating subject was not randomized, did not receive study drug, and was not included in the analysis set. After a screening period of up to 28 days and after all pre-dose baseline visit assessments have been completed, eligible subjects will be randomized 1:1 to receive a target steady-state dose of 2 mg / kg / day of ecolpipan HCl or matching placebo for a continuous titration period as described in the table below, followed by an 8-week treatment period. Randomization is by weight classification.

[0099] Weight (kg) Dosage (mg) Week 1 Dosage (mg) Week 2 Dosage (mg) Week 3 Dosage (mg) Continue at Week 4 ≥18 to ≤23 12.5 25(2×12.5) 37.5(3×12.5) 37.5(3×12.5) >23 to ≤34 12.5 25(2×12.5) 37.5(3×12.5) 50 >34 to ≤44 12.5 25(2×12.5) 50 75 >44 to ≤68 25(2×12.5) 50 75 100 >68 to ≤83 25(2×12.5) 50 100 150(2×75) >83 25(2×12.5) 50 100 200(2×100)

[0100] Subjects who could not tolerate the dose were discontinued from the study.Weight band assignments were not changed during the study.

[0101] Subjects must have a minimum score of 20 on the YGTSS-TTS with tic symptoms at screening and baseline visits, causing 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., decreased academic performance), in the investigator's judgment. Subjects must not have taken any medication for motor or vocal tics for at least 14 days prior to baseline.

[0102] Subjects were randomized 1:1 to receive the target full (steady-state) dose of 2 mg / kg / day of ecolic HCl tablets or matching placebo tablets. All doses were taken orally once daily in the evening.

[0103] Subjects who did not experience weight change during the study had their dose not adjusted for the duration of the study. At the end of the 8-week treatment period, subjects were titrated off therapy by receiving either ecolpiram HCl or matching placebo, decreasing by 25 mg / day until study drug was discontinued. Subjects who could not tolerate dose titration to the full assigned dose for their weight stratum were discontinued from the study. These subjects also had their current study drug dose gradually reduced based on their weight stratum.

[0104] The efficacy assessments used are described below.

[0105] YGTSS is a rating scale for clinical completion of the specific subdomain for quantifying overall tic severity and tic number, frequency, intensity, complexity and interference. Each of these subdomains is scored by a 5-point system for motor and vocal tics respectively, and motor and vocal tics are summed up subsequently to obtain a YGTSS tic total score (TTS), ranging from 0 to 50. YGTSS (0 = " none " to 50 = " severe ") for total impairment rating is also provided. YGTSS overall score (GS) is the summation of motor, voice and impairment ratings. YGTSS has shown acceptable internal consistency, good inter-frame reliability and acceptable convergence and divergence validity. YGTSS was assessed at screening, baseline and at the 4th week, 6th week, 8th week and 12th week.

[0106] The Clinical Global Assessment (CGI) scale consists of two reliable and valid 7-item Likert-type scales used to assess the severity and change of clinical symptoms. The CGI Severity scale ranges from 1 = "normal, not at all sick" to 7 = "very sick." The CGI Improvement scale ranges from 1 = "very improved" to 7 = "very much worse." The CGI Severity and CGI Improvement scales are administered at specific visits.

[0107] The Caregiver's Global Impression of Change (CaGI-C) scale is a 7-item Likert scale that asks caregivers the following question: Overall, how have the patient's symptoms changed, if at all, since the start of the study (before treatment began)? The CaGI-C is rated as follows: 1 (very much improved), 2 (a lot improved), 3 (minimal improved), 4 (no change), 5 (minimal worse), 6 (a lot worse), and 7 (very much worse).

[0108] The Tourette Syndrome-Quality of Life Scale for Children and Adolescents (C&A-GTS-QOL) is a patient-reported health-related quality of life measure developed for children and adolescents. The C&A-GTS-QOL is a 27-item questionnaire for TS that asks subjects to assess the extent to which their symptoms affect their quality of life. The C&A-GTS-QOL contains 6 subscales (cognitive, coprophenomena, psychological, physical, obsessive-compulsive disorder, and ADL) and uses a 5-point Likert scale ranging from 0 = "never" to 4 = "always". Subjects were also asked about their overall satisfaction with their life at that time using a visual analog scale (VAS) scale between 0 and 100. 5 The following questions are assessed in each C&A-GTS-QOL subscale:

[0109] Cognition (questions 11, 12, 13, 14, 18, 20, 21, 23) (range: 0-32)

[0110] Psychological (questions 15, 16, 17, 19, 25, 27) (range: 0-24)

[0111] Obsessive-compulsive disorder (questions 7, 8, 9, and 10) (range: 0 to 16)

[0112] Physical (questions 1, 3, and 4) (range: 0-12)

[0113] Coprolalia (questions 5, 6, and 22) (range: 0-12)

[0114] ADL (questions 2, 24, and 26) (range: 0-12)

[0115] Scores for the six subscales were generated by summing the items and, for ease of interpretation, converted to a scale of 0 to 100. The total score generated by the sum of the subscale scores was also normalized to a scale of 0 to 100.

[0116] An adverse event (AE) is defined as any untoward medical occurrence in a subject administered an investigational drug that does not necessarily have a causal relationship to the treatment. An AE can therefore be any unfavorable and unexpected sign (including abnormal laboratory findings), symptom, or disease that is temporally associated with the use of an investigational drug, whether or not related to the investigational drug.

[0117] Abnormalities identified during medical testing (e.g., laboratory parameters, vital signs, ECG data, physical examination) were defined as AEs only if the abnormality met one of the following criteria:

[0118] Induce clinical signs or symptoms

[0119] Active intervention is required

[0120] Need for study drug discontinuation or interruption

[0121] Clinically significant in the opinion of the investigator

[0122] A serious adverse event (SAE) was defined as an AE occurring during any study period (i.e., baseline, treatment, washout, or follow-up) at any dose of the investigational product, comparator, or placebo that met one or more of the following:

[0123] Causes death

[0124] ● Immediately life-threatening

[0125] ●Need for hospitalization or extension of existing hospitalization

[0126] Causes persistent or significant disability or incapacity

[0127] ●Causing congenital abnormalities or birth defects

[0128] A significant medical event that could have endangered the subject or might have required medical intervention to prevent one of the outcomes listed above

[0129] The investigator, based on their medical judgment, determines whether there is a reasonable possibility that the AE may be caused by the investigational product. If there is no justifiable reason to suggest a relationship, the AE is classified as "unrelated." If there is any justifiable reason (even if unconfirmed) to suspect a causal relationship between the investigational product and the occurrence of the AE, the AE is considered "related." If the relationship between the AE / SAE and the investigational product is determined to be "possible" or "probable," the event is considered related to the investigational product for the purposes of expedited regulatory reporting.

[0130] The intensity of AEs was assessed according to the following scale:

[0131] Mild (aware of signs or symptoms but well tolerated)

[0132] Moderate (sufficient discomfort to interfere with normal activities)

[0133] Severe (disabling, unable to perform normal activities)

[0134] The Columbia-Suicide Severity Rating Scale (C-SSRS) was assessed at all visits except the 30-day follow-up. The C-SSRS is a low-burden (approximately 5 minutes to complete) instrument that assesses suicidal behavior and ideation. The scale is suitable for subjects aged 6 years to older.

[0135] Additional safety outcomes assessed at baseline and weeks 4, 6, 8, and 12 included the following scales:

[0136] Abnormal Involuntary Movement Scale (AIMS): This scale records the presence of tardive dyskinesia in subjects receiving neuroleptics. This test is used to detect tardive dyskinesia and track its severity over time. It consists of a three-item global assessment that assesses the presence and severity of movement disorders involving the face, mouth, limbs, and trunk, along with a scale of 0 (absent) to 4 (severe).

[0137] Barnes 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, which ranges from 0 (normal) to 3 (extremely severe). BARS also includes an overall assessment of akathisia, which ranges from 0 (absent) to 5 (severe).

[0138] Attention Deficit Hyperactivity Disorder (SNAP-IV) Questionnaire: This measure is designed to assess symptoms of ADHD and oppositional defiant disorder (ODD) in children and adolescents. The SNAP-IV is based on a 0 to 3 rating scale: not at all = 0, only a little = 1, quite a bit = 2, and very much = 3. Subscale scores on the SNAP-IV are calculated by summing the scores for the items in the subset and dividing by the number of items in the subset. Scores for any subset are expressed as the mean score for each item.

[0139] Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS): This assessment is a reliable and valid scale used to determine the severity of OCD and monitor improvement during treatment. The scale is a clinician-rated, 10-item scale that includes questions about the time spent on obsessions / compulsions, the degree of impairment or distress, and how much resistance and control the subject has over these thoughts. The severity of compulsions and obsessions is rated on a 5-point scale of 0 to 4. The CY-BOCS total score is calculated as the sum of the 10 items and ranges from 0 to 40, with higher scores indicating more severe obsessions and compulsions.

[0140] Children's Depression Rating Scale-Revised (CDRS-R): This is a clinically validated rating scale designed to assess psychiatric signs and symptoms of depression. Fourteen signs and symptoms are rated from 1 (normal) to 7 (worst), and three signs and symptoms are rated from 1 (normal) to 5 (worst). The total score is the sum of all 17 items and ranges from 17 to 113.

[0141] Children's Anxiety Rating Scale (PARS): This scale is a clinician-rated instrument used to assess the severity of anxiety symptoms associated with common anxiety and general anxiety in children and adolescents. PARS has two parts: a symptom checklist and a severity item. The symptom checklist is used to determine a list of symptoms the child has had during 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 not knowing is coded as 9. The total score of the PARS is the sum of the seven severity items. The total score ranges from 0 to 35. Codes "8" and "9" are not included in the sum.

[0142] The primary efficacy endpoint was the change from baseline to end of treatment in the YGTSS-TTS compared with placebo at Week 12. The YGTSS-TSS ranges from 0 to 50, with higher scores indicating more severe symptoms.

[0143] A summary of the observed YGTSS-TTS scores and the change from baseline at each time point for the modified intention-to-treat (mITT) set is presented in Table 9. The mITT set was all children and adolescent subjects with TS who were randomized, received at least one dose of study drug, and had a post-baseline YGTSS score of at least 1. Within the study, mean YGTSS-TTS scores decreased in both treatment groups, with greater decreases observed in the ecolopam group compared to the placebo group.

[0144] Table 1. Yale Tic Severity Scale-Total Tic Score (YGTSS-TTS): Overview (mITT Set)

[0145]

[0146] Abbreviations: Max, maximum; Min, minimum; mITT, modified intention-to-treat; YGTSS-TTS=Yale Tic Total Severity Scale-Total Tic Score.

[0147] aThe baseline for each post-baseline visit was defined as the baseline for subjects with data at that visit.

[0148] Note: Baseline is defined as the last measurement obtained before the first dose of double-blind treatment on Day 1.

[0149] The primary MMRM analysis of the change from baseline in the YGTSS-TTS using multiple imputation of intermittent events from the mITT set is provided in Table 10. At Week 12, the least squares (LS) mean (SE) change from baseline in the YGTSS-TTS was -9.87 (1.062) in the ecolpipan group and -6.42 (1.006) in the placebo group; the difference in the YGTSS-TTS LS mean (SE) between ecolpipan and placebo was -3.44 (1.351) and statistically significant (P=0.011). For the comparison of ecolpipan versus placebo during all visits, the YGTSS-TTS LS mean (SE) change from baseline was -8.52 (1.786) in the ecolpipan group and -5.02 (1.418) in the placebo group; the difference in the YGTSS-TTS LS mean (SE) between ecolpipan and placebo was -3.51 (1.346) and statistically significant (P = 0.009).

[0150] Table 2. Yale Tic Total Severity Scale-Total Tic Score (YGTSS-TTS): MMRM Analysis of Change from Baseline - Multiple Imputation for Intercurrent Events (mITT Set)

[0151] Placebo N=75 Ecolpipan N=74 Comparison (ecolpipan vs. placebo) LS mean (SE) -5.02(1.418) -8.52(1.786) LS mean (SE) difference -3.51(1.346) 95% confidence interval of the difference (-6.14，-0.87) P value for the model 0.009 Comparison by visit Week 4 LS mean (SE) -3.74(0.856) -6.32(0.900) LS mean (SE) difference (ecolpipan-placebo) -2.58(1.110) 95% confidence interval of the difference (-4.76，-0.41) p-value 0.020 Week 6 LS mean (SE) -4.22(0.826) -7.94(0.864) LS mean (SE) difference (ecolpipan-placebo) -3.72(1.056) 95% confidence interval of the difference (-5.79，-1.65) p-value <0.001 Week 8 LS mean (SE) -5.68(0.948) -9.96(0.987) LS mean (SE) difference (ecolpipan-placebo) -4.28(1.250) 95% confidence interval of the difference (-6.73，-1.83) p-value <0.001 Week 12 LS mean (SE) -6.42(1.006) -9.87(1.062) LS mean (SE) difference (ecolpipan-placebo) -3.44(1.351) 95% confidence interval of the difference (-6.09，-0.79) p-value 0.011

[0152] Abbreviations: ANCOVA, analysis of covariance; LS, least squares; mITT, adjusted intention-to-treat; MMRM, mixed model for repeated measures; YGTSS-TTS, Yale Tic Severity Scale-Total Tic Score.

[0153] Note: For subjects who discontinued treatment due to treatment-related adverse events or lack of efficacy, missing data were imputed multiple times from the placebo group using similar subjects (relevant demographic / baseline characteristics).

[0154] Note: Baseline is defined as the last measurement obtained before the first dose of double-blind treatment on Day 1.

[0155] Note: Change from baseline in YGTSS score as a continuous variable was based on an MMRMANCOVA model with an unstructured covariate matrix including the following items: baseline value, region, age group (children 6 to 11 years and adolescents 12 to 17 years), visit, treatment group, and visit-treatment interaction.

[0156] 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 sick" to 7 = "very sick." A summary of the observed CGI-TS-S scores and the change from baseline at each time point for the mITT set is presented in Table 16. Within the study, the mean CGI-TS-S scores improved (decreased) in both treatment groups, with greater improvements (decreases) observed in the ecolpipan group compared to the placebo group.

[0157] Table 3. Clinical Global Impression of Severity of Tourette Syndrome (CGI-TS-S): Overview (mITT Set)

[0158]

[0159] Abbreviations: CGI-TS-S; Clinical Global Impression of Severity of Tourette's Syndrome; Max, maximum; Min, minimum; mITT, adjusted intention-to-treat.

[0160] aThe baseline for each post-baseline visit was defined as the baseline for subjects with data at that visit.

[0161] Note: Baseline is defined as the last measurement obtained before the first dose of double-blind treatment on Day 1.

[0162] The MMRM analysis of the change from baseline in the CGI-TS-S of the mITT set is provided in Table 17. Compared to the placebo group, a statistically significant greater reduction in the Clinical Impression of TS Severity was observed in the icopipan group at week 12. At week 12, the change from baseline in the CGI-TS-S LS mean (SE) was -0.91 (0.141) in the icopipan group and -0.53 (0.130) in the placebo group; the difference in CGI-TS-S LS between icopipan and placebo was -0.37 (0.167) and statistically significant (P = 0.027). The difference in CGI-TS-S LS mean (SE) between icopipan and placebo did not reach statistical significance at week 4 (P = 0.064), but was significant at week 6 (P = 0.001) and week 8 (P = 0.001).

[0163] Table 4. Clinical Global Impression of Severity of Tourette Syndrome (CGI-TS-S): MMRM Analysis of Change from Baseline (mITT Set)

[0164]

[0165]

[0166] Abbreviations: ANCOVA, analysis of covariance; CGI-TS-S, Clinical Global Impression of Tourette's Syndrome Severity; LS, least squares; mITT, adjusted intention-to-treat; MMRM, mixed model for repeated measures.

[0167] Note: Baseline is defined as the last measurement obtained before the first dose of double-blind treatment on Day 1.

[0168] Note: Change from baseline in CGI-TS-S as a continuous variable was based on an MMRMANCOVA model with an unstructured covariate matrix including the following items: baseline value, region, age group (children 6 to 11 years and adolescents 12 to 17 years), visit, treatment group, and visit-treatment interaction.

[0169] Similar results were observed for the MMRM analysis of changes from baseline in CGI-TS-S when remote assessments were included in the model.

[0170] The 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 and measured the Clinical Impression of Improvement relative to baseline. The CGI Improvement Scale ranged from 1 = "very improved" to 7 = "very worse." A summary of the CGI-TS-I scores for each time point in the mITT set is provided in Table 18. In the study, Clinical Impression of Improvement relative to baseline was observed in both treatment groups, with the ecolpipant group having a greater mean impression of improvement compared to the placebo group.

[0171] Table 5. Clinical Global Impression of Improvement in Tourette Syndrome (CGI-TS-I): Overview (mITT Set)

[0172]

[0173]

[0174] Abbreviations: CGI-TS-I, Clinical Global Impression of Improvement in Tourette Syndrome; CGI-TS-S, Clinical Global Impression of Severity in Tourette Syndrome; mITT, modified intention-to-treat.

[0175] a Baseline CGI-TS-S score for subjects with a CGI-TS-I score only

[0176] Secondary efficacy endpoints were the change in YGTSS-GS from baseline to week 12. Additional secondary efficacy endpoints were the change in YGTSS-GS from baseline to weeks 4, 6, and 8. YGTSS-GS is the sum of movement, voice, and impairment scores and is within the range of 0 to 100, with the higher scores indicating the more severe symptoms. The YGTSS-GS scores observed and the summary of the change relative to baseline at each time point for the mITT set are presented in Table 20. Within the study, the average YGTSS-GS scores in the two treatment groups decreased, with a greater decrease observed in the ecolpipan group compared to the placebo group.

[0177] Table 6. Yale Tic Severity Scale-Total Score (YGTSS-GS): Overview (mITT Set)

[0178]

[0179]

[0180] Abbreviations: Max, maximum; Min, minimum; mITT, modified intention-to-treat; YGTSS-GS = Yale Total Tic Severity Scale-total score.

[0181] aBaseline is defined as the baseline for subjects with data at the visit.

[0182] Note: Baseline is defined as the last measurement obtained before the first dose of double-blind treatment on Day 1.

[0183] The MMRM analysis of the YGTSS-GS of the mITT set relative to the change of baseline is provided in Table 21. At week 12, the change of YGTSS-GS LS mean (SE) relative to baseline was -21.41 (2.291) in the ecolpipan group and -13.56 (2.113) in the placebo group; the difference of YGTSS-GS LS mean (SE) between ecolpipan and placebo was -7.86 (2.711) and was significant (P=0.004). Additional secondary efficacy endpoints were the changes of YGTSS-GS from baseline to the 4th, 6 and 8 weeks. At all time points, the YGTSS-GS LS mean values had significantly greater improvement relative to baseline in the ecolpipan group compared with the placebo group, with all P values <0.05.

[0184] Table 7. Yale Tic Total Severity Scale-Total Score (YGTSS-GS): MMRM Analysis of Change from Baseline (mITT Set)

[0185] Abbreviations: ANCOVA, analysis of covariance; LS, least squares; mITT, adjusted intention-to-treat; MMRM, mixed model for repeated measures; YGTSS-GS, Yale Tic Severity Scale-total score.

[0186] Note: Baseline is defined as the last measurement obtained before the first dose of double-blind treatment on Day 1.

[0187] Note: Change from baseline in YGTSS-GS as a continuous variable was based on an MMRMANCOVA model with an unstructured covariate matrix including the following items: baseline value, region, age group (children 6 to 11 years and adolescents 12 to 17 years), visit, treatment group, and visit-treatment interaction.

[0188] Similar results were observed for the MMRM analysis of changes from baseline in YGTSS-GS when remote assessments were included in the model.

[0189] The secondary efficacy endpoint was CaGI-C at week 12. Additional secondary efficacy endpoints were 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 the patient's symptoms changed (if any) since the start of the study (before treatment began)?" and is rated as follows: 1 (very much improved), 2 (a lot improved), 3 (minimal improved), 4 (no change), 5 (minimal worse), 6 (a lot worse), and 7 (very much worse). Therefore, the lower the CaGI-C score, the better the caregiver's impression of improvement. An overview of the CaGI-C scores at all time points in the mITT set is provided in Table 22. In the study, lower mean CaGI-C scores were observed in the ecolpipan group compared to the placebo group, indicating a better caregiver impression of improvement. Within each treatment group, the CaGI-C score remained stable in the study from week 4 to week 12.

[0190] Table 8. Caregiver Global Impression of Change (CaGI-C): Overview (mITT Set)

[0191] Abbreviations: CaGI-C, Caregiver Global Impression of Change; Max, maximum; Min, minimum; mITT, adjusted intention-to-treat.

[0192] The MMRM analysis of CaGI-C for the mITT set is provided in Table 23. At week 12, the LS mean (SE) CaGI-C score was 2.94 (0.189) in the ecolpipan group and 3.55 (0.172) in the placebo group; the difference in LS mean (SE) CaGI-C score between ecolpipan and placebo was -0.61 (0.223) and was significant (P = 0.007). At all time points, the CaGI-C LS mean score was significantly lower in the ecolpipan group compared to the placebo group (indicating a better caregiver impression of improvement), with all P values < 0.05.

[0193] Table 9. Caregiver Global Impression of Change (CaGI-C): MMRM Analysis (mITT Set)

[0194]

[0195]

[0196] Abbreviations: ANCOVA, analysis of covariance; CaGI-C, caregiver global impression of change; LS, least squares; mITT, adjusted intention-to-treat; MMRM, mixed model for repeated measures.

[0197] Note: CaGI-C is a continuous variable. The MMRMANCOVA model with an unstructured covariance matrix included the following terms: region, age group (children aged 6 to 11 years and adolescents aged 12 to 17 years), visit, treatment group, and visit-treatment interaction.

[0198] Similar results were observed for MMRM analysis of CaGI-C when remote assessment was included in the model.

[0199] The secondary efficacy endpoint was the percentage of subjects with a 25% improvement in the YGTSS-TTS. A responder was defined as a subject with at least one 25% improvement in the YGTSS-TTS at any time between the baseline and Week 12 visits.

[0200] A total of 53 subjects (73.6%) in the ecolpipan group and 32 subjects (43.2%) in the placebo group had a 25% improvement in the YGTSS-TTS at any time between baseline and the Week 12 visit; odds ratio (95% CI) was 3.67 (1.82, 7.40), P < 0.001.

[0201] The safety set included all subjects who received at least one dose of study drug. A general summary of adverse events (AEs) for the safety set is provided in Table 34 below. A total of 47 subjects (61.8%) in the ecolpipan group and 38 subjects (49.4%) in the placebo group experienced AEs during the study. A higher number of subjects in the ecolpipan group (26 subjects, 34.2%) reported treatment-related AEs compared to the placebo group (16 subjects, 20.8%). A total of 3 subjects experienced SAEs during the study. Four subjects (5.3%) in the ecolpipan group and 1 subject (1.3%) in the placebo group experienced AEs that led to study drug discontinuation.

[0202] A total of 4 subjects (2 in the ecolpiram group and 2 in the placebo group) reported COVID-19 AEs: 3 subjects had PTs of coronavirus infection and 1 subject had PTs of a positive coronavirus test. The investigator considered 3 events to be mild in severity and 1 event to be moderate in severity. One subject in the ecolpiram group had a COVID-19 AE that was considered severe due to hospitalization. No subjects discontinued study drug or study status due to these events.

[0203] Table 10. Overall overview of adverse events (safety set)

[0204] Placebo (N=77) n (%) Ecolpipan (N=76) n (%) Any AE 38(49.4) 47(61.8) SAE 1(1.3) 2(2.6) Level 3 AE 1(1.3) 7(9.2) Dealing with related AEs 16(20.8) 26(34.2) Treatment-related serious AEs 1(1.3) 0 AEs leading to discontinuation of study treatment 1(1.3) 4(5.3) AEs causing death 0 0

[0205] Abbreviations: AE, adverse event; SAE, serious adverse event.

[0206] NOTE: Treatment-related AEs are AEs for which the relationship to the treatment is “probably related” or “possibly related” or absent.

[0207] NOTE: AEs were new or worsened after the first dose of study drug.

[0208] NOTE: The percentages are based on the number of objects in the security set.

[0209] Source: Table 14.3.1.1 (see figure).

[0210] AEs occurring in ≥2 subjects in the treatment group by system organ class (SOC) and preferred term for the safety set are provided in Table 35 below. A summary of all AEs by SOC and preferred term for the safety set is provided in Table 14.3.1.4.1 (see Figure). The SOCs with the highest incidence (>20% of subjects in the ecolpipan group) included psychiatric disorders (ecolpipan: 22 subjects, 28.9%; placebo: 12 subjects, 15.6%) and neurologic disorders (ecolpipan: 20 subjects, 26.3%; placebo: 10 subjects, 13.0%). In the ecolpipan 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%).

[0211] Table 11. Summary of Adverse Events Emerging in ≥2 Subjects in Treatment Group by System Organ Class (SOC) and Preferred Term (Safety Set)

[0212]

[0213]

[0214] Abbreviation: AE = adverse event.

[0215] NOTE: The percentages are based on the number of objects in the security set.

[0216] Note: Adverse events are coded using MedDRA version 23.1. Objects with multiple events within the same preferred term / system organ class are counted only once.

[0217] Source: Table 14.3.1.4.1 (see figure)

[0218] A summary of AEs by SOC, preferred term, and initial maintenance daily dose content 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 band for the safety set is provided in Table 14.3.1.4.1.3 (see Figure). The majority of subjects (N=36 in the ecolpipan group and N=35 in the placebo group) were in the mid-range weight band of >44 kg to ≤68 kg and had an initial maintenance dose of 100 mg. In this group of subjects, 23 of 36 subjects (63.9%) in the ecolpipan group and 16 of 35 subjects (45.7%) in the placebo group had at least one AE.

[0219] An overview 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 ecolpiram 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 ecolpiram group and 11 of 17 subjects (64.7%) in the placebo group had at least one AE.

[0220] A summary of all AEs by SOC and preferred term for subjects weighing >83 kg in the safety set is provided in Table 14.3.1.4.1.4 (see Figure). Among subjects weighing >83 kg, 6 of 8 subjects (75.0%) in the ecolpipan group and 3 of 7 subjects (42.9%) in the placebo group had at least one AE. In the ecolpipan group, headache, anxiety, and insomnia were reported by 2 subjects each; all other AEs were reported by 1 subject each in both treatment groups.

[0221] Table 35. Summary of Adverse Events Emerging in ≥2 Subjects in Treatment Group by System Organ Class (SOC) and Preferred Term (Safety Set)

[0222]

[0223]

[0224] Abbreviation: AE = adverse event.

[0225] NOTE: The percentages are based on the number of objects in the security set.

[0226] Note: Adverse events are coded using MedDRA version 23.1. Objects with multiple events within the same preferred term / system organ class are counted only once.

[0227] Source: Table 14.3.1.4.1 (see figure).

[0228] A summary of AEs by SOC, preferred term, and initial maintenance daily dose content 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 band for the safety set is provided in Table 14.3.1.4.1.3 (see Figure). The majority of subjects (N=36 in the ecolpipan group and N=35 in the placebo group) were in the mid-range weight band of >44 kg to ≤68 kg and had an initial maintenance dose of 100 mg. In this group of subjects, 23 of 36 subjects (63.9%) in the ecolpipan group and 16 of 35 subjects (45.7%) in the placebo group had at least one AE.

[0229] An overview 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 ecolpiram 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 ecolpiram group and 11 of 17 subjects (64.7%) in the placebo group had at least one AE.

[0230] A summary of all AEs by SOC and preferred term for subjects weighing >83 kg in the safety set is provided in Table 14.3.1.4.1.4 (see Figure). Among subjects weighing >83 kg, 6 of 8 subjects (75.0%) in the ecolpipan group and 3 of 7 subjects (42.9%) in the placebo group had at least one AE. In the ecolpipan group, headache, anxiety, and insomnia were reported by 2 subjects each; all other AEs were reported by 1 subject each in both treatment groups.

[0231] Adverse events by dosing period (titration, maintenance, and down-titration / follow-up)

[0232] A summary of AEs by SOC and visit during the titration period for the safety set is provided below in Table 36. In both treatment groups, more subjects (12 subjects [15.8%] in the ecolpiram group and 12 subjects [15.6%] in the placebo group) reported AEs during Week 1 of the titration period compared to Weeks 2, 3, or 4 of the titration period. A summary of AEs by SOC, PT, and visit during the titration period for the safety set is provided in Table 14.3.1.4.1.5 (see Figure).

[0233] Table 36. Summary of adverse events by system organ class and visit during the titration period (safety set).

[0234]

[0235] Abbreviation: AE = adverse event.

[0236] NOTE: The percentages are based on the number of objects in the security set.

[0237] Note: Adverse events are coded using MedDRA version 23.1. Objects with multiple events within the same preferred term / system organ class are counted only once.

[0238] Source: Table 14.3.1.4.1.5 (see figure).

[0239] A summary of AEs by SOC and visit during the maintenance period for the safety set is provided below in Table 37. A summary of AEs by SOC, preferred term, and visit during the maintenance period for the safety set is provided in Table 14.3.1.4.1.6 (see figure).

[0240] Table 12. Summary of adverse events by system organ class and visit during the maintenance period (safety set).

[0241]

[0242] Abbreviation: AE = adverse event.

[0243] NOTE: The percentages are based on the number of objects in the security set.

[0244] Note: Adverse events are coded using MedDRA version 23.1. Objects with multiple events within the same preferred term / system organ class are counted only once.

[0245] Source: Table 14.3.1.4.1.6 (see figure).

[0246] A summary of the AEs by SOC and visit during the down-titration and follow-up period for the safety set is provided in Table 38 below. The majority of AEs reported during the down-titration period occurred within the first 7 days of follow-up in both groups. A summary of the AEs by SOC, PT, and visit during the down-titration and follow-up period for the safety set is provided in Table 14.3.1.4.1.7 (see Figure).

[0247] Table 38. Summary of adverse events by system organ class and visit during the down-titration and follow-up period (safety set).

[0248] Abbreviation: AE = adverse event.

[0249] NOTE: The percentages are based on the number of objects in the security set.

[0250] Note: Adverse events are coded using MedDRA version 23.1. Objects with multiple events within the same preferred term / system organ class are counted only once.

[0251] Source: Table 14.3.1.4.1.7 (see figure).

[0252] Adverse events according to the Common Terminology Criteria for Adverse Events

[0253] 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).

[0254] An overview of the AEs by SOC, preferred term, and highest CTCAE level for the safety set is provided in Table 14.3.1.4.2 (see Figure). The severity of most AEs reported in both treatment groups was mild or moderate. No fatal or life-threatening AEs were reported during the study.

[0255] In the ecolopam group, 23 subjects (30.3%) experienced AEs with a maximum CTCAE grade of mild, 17 subjects (22.4%) experienced AEs with a maximum CTCAE grade of moderate, and 7 subjects (9.2%) experienced AEs with a maximum CTCAE grade of severe.

[0256] In the placebo group, 22 subjects (28.6%) experienced AEs with a maximum CTCAE grade of mild, 15 subjects (19.5%) experienced AEs with a maximum CTCAE grade of moderate, and 1 subject (1.3%) experienced an AE with a maximum CTCAE grade of severe.

[0257] An overview of CTCAE Grade 3 AEs by SOC and preferred term for the safety set is provided in Table 39 (see Figure). A total of 7 subjects (9.2%) in the ecolpiram group (1.3%) and 1 subject in the placebo group experienced a severe AE of the highest CTCAE grade; the majority of severe AEs were in the Psychiatric Disorders SOC, and all severe AEs were reported in 1 subject each.

[0258] Table 39. Overview of CTCAE Grade 3 Adverse Events by System Organ Class and Preferred Term (Safety Set).

[0259]

[0260]

[0261] Abbreviations: AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events.

[0262] NOTE: The percentages are based on the number of objects in the security set.

[0263] Note: AEs were coded using MedDRA version 23.1. The highest level of the event occurring in the subject within the system organ class and the highest level of each unique preferred term within the system organ class were counted once.

[0264] Source: Table 14.3.1.8 (see figure).

[0265] Adverse events by relationship

[0266] An overview of treatment-related AEs by SOC and preferred term for the safety set is provided in Table 40 (see Figure). A higher percentage of subjects experienced treatment-related AEs in the ecolpipan group (26 subjects, 34.2%) compared to subjects in the placebo group (16 subjects, 20.8%). In the ecolpipan group, the most frequently reported treatment-related AEs (reported in ≥3 subjects) included headache (7 subjects, 9.2%), somnolence (5 subjects, 6.6%), fatigue (5 subjects, 6.6%), insomnia, including middle-of-the-night insomnia (4 subjects, 5.3%), restlessness (4 subjects, 5.3%), and nausea, anxiety, depressed mood, and irritability (each AE reported in 3 subjects, 3.9%). All other treatment-related AEs occurred in ≤2 subjects in the ecolpipan group. In the placebo group, the most frequently reported treatment-related AEs (reported in ≥3 subjects) included decreased appetite (4 subjects, 5.2%) and headache (3 subjects, 3.9%). All other treatment-related AEs occurred in ≤2 subjects in the placebo group.

[0267] Table 40. Summary of treatment-related adverse events by system organ class and preferred term (safety set).

[0268]

[0269]

[0270]

[0271] Abbreviations: AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities.

[0272] NOTE: Treatment-related AEs are AEs for which the relationship to the treatment is “probably related” or “possibly related” or absent.

[0273] NOTE: The percentages are based on the number of objects in the security set.

[0274] Note: Adverse events are coded using MedDRA version 23.1. Objects with multiple events within the same preferred term / system organ class are counted only once.

[0275] Source: Table 14.3.1.6.1 (see figure).

[0276] 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 highest CTCAE grade for the majority of subjects with treatment-related AEs in both treatment groups was mild.

[0277] In the ecolpiran group, 15 subjects (19.7%) experienced mild treatment-related AEs, up to a CTCAE grade of mild, 7 subjects (9.2%) experienced moderate treatment-related AEs, up to a CTCAE grade of severe, and 4 subjects (5.3%) experienced severe treatment-related AEs, up to a CTCAE grade of severe. Treatment-related AEs up to a CTCAE grade of severe included nausea, facial pain, agitation, anxiety, irritability, restlessness, and thoughts of self-harm.

[0278] In the placebo group, 13 subjects (16.9%) experienced a treatment-related AE with a maximum CTCAE grade of mild, 2 subjects (2.6%) experienced a treatment-related AE with a maximum CTCAE grade of moderate, and 1 subject (1.3%) experienced a treatment-related AE with a maximum CTCAE grade of severe. The maximum CTCAE grade of severe treatment-related AE was suicidal ideation.

[0279] Adverse events by greatest severity and greatest relevance

[0280] The severity of AEs was rated by the investigator as mild, moderate, or severe.

[0281] An overview 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 ecolpipan group, 12 subjects (15.8%) experienced a treatment-related AE of mild severity, 10 subjects (13.2%) experienced a treatment-related AE of moderate severity, and 4 subjects (5.3%) experienced a treatment-related AE of severe severity. In the placebo group, 14 subjects (18.2%) experienced a treatment-related AE of mild severity, 1 subject (1.3%) experienced a treatment-related AE of moderate severity, and 1 subject (1.3%) experienced a treatment-related AE of severe severity.

[0282] A summary of AEs and SAEs by greatest relevance (i.e., not related, possibly, or probably) for the safety set is provided in Table 14.3.1.2.2 (see Figure). In the ecolopam group, 21 subjects (27.6%) experienced AEs considered not related to study drug, 19 subjects (25.0%) experienced AEs considered possibly related to study drug, and 7 subjects (9.2%) experienced AEs considered probably related to study drug. In the placebo group, 22 subjects (28.6%) experienced AEs considered not related to study drug, 16 subjects (20.8%) experienced AEs considered possibly related to study drug, and 0 subjects experienced AEs considered probably related to study drug.

[0283] Two subjects in the ecolopam group experienced SAEs; both events were considered unrelated to study drug; one subject in the placebo group experienced an SAE that was considered possibly related to study drug.

[0284] An overview of the most severe or most relevant AEs by study milestone (i.e., titration, maintenance, taper, or discontinuation of study drug) for the safety set is provided in Table 14.3.1.3 (see Figure). Most AEs were reported during the titration and maintenance phases of the study in both treatment groups, with fewer subjects reporting AEs during the taper and discontinuation follow-up periods. In the ecolpipan group, 24 subjects (31.6%) experienced AEs during the titration phase, 30 subjects (39.5%) experienced AEs during the maintenance phase, 6 subjects (7.9%) experienced AEs during the taper phase, and 15 subjects (19.7%) experienced AEs during the discontinuation follow-up period. In the placebo group, 17 subjects (22.1%) experienced AEs during the titration period, 24 subjects (31.2%) experienced AEs during the maintenance period, 2 subjects (2.6%) experienced AEs during the taper period, and 5 subjects (6.5%) experienced AEs during the discontinuation of study drug follow-up period.

[0285] No deaths were reported during the study period.

[0286] An overview of SAEs by SOC and preferred term for the safety set is provided in Table 41. During the study, a total of 3 subjects (all adolescents) experienced SAEs. 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 ecolpiramide group experienced SAEs; both were considered by the investigator to be moderate in severity and not related to the study drug. One of these subjects experienced an SAE of coronavirus infection, which resolved after 8 days. The other subject had an SAE of vomiting, and based on the results of all examinations, the gastroenterologist believed that the subject had ulcerative colitis or Crohn's disease. An overview of SAEs by SOC and preferred term for the safety set according to age group is provided in Table 14.3.1.9.2 (see figure).

[0287] Table 41. Summary of serious adverse events by system organ class and preferred term (safety set).

[0288]

[0289]

[0290] Abbreviations: AE, serious adverse event; MedDRA, Medical Dictionary for Regulatory Activities.

[0291] NOTE: The percentages are based on the number of objects in the security set.

[0292] Note: AEs were coded using MedDRA version 23.1. Objects with multiple events within the same preferred term / system organ class were counted only once.

[0293] Source: Table 14.3.1.9.1 (see figure).

[0294] A summary of AEs that led to treatment discontinuation by SOC and preferred term for the safety set is provided in Table 42 below. A total of 4 subjects (5.3%) in the ecolpiram group and 1 subject (1.3%) in the placebo group experienced AEs that led to treatment discontinuation. Two subjects (1 in the ecolpiram group and 1 in the placebo group) had an AE of suicidal ideation that led to treatment discontinuation; all other AEs that led to treatment discontinuation each occurred in only 1 subject. A summary of AEs that led to treatment discontinuation by SOC, preferred term, and highest CTCAE for the safety set is provided in Table 14.3.1.7.2 (see Figure).

[0295] Table 42. Summary of Adverse Events Leading to Treatment Discontinuation by System Organ Class and Preferred Term (Safety Set).

[0296]

[0297] Abbreviations: AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities.

[0298] NOTE: The percentages are based on the number of objects in the security set.

[0299] Note: AEs were coded using MedDRA version 23.1. Objects with multiple events within the same preferred term / system organ class were counted only once.

[0300] Source: Table 14.3.1.7.1 (see figure).

[0301] Adverse events of particular concern

[0302] In order to assess potential extrapyramidal side effects (EPS) and dyskinesia associated with ecolpipan, AIMS and BARS were administered to all subjects during the study. In addition to AIMS and BARS, the normalized MedDRA query for Parkinson's disease was used to identify dyskinesia AEs. EPS-related dyskinesia was not identified in the ecolpipan or placebo groups. An overview of the AESIs by SOC and preferred terms for the safety set is provided in Table 14.3.1.10.1 (see Figure).

[0303] A summary of the AESIs for ecolpiram by SOC and preferred term for the safety set is provided in Table 43 below. During the study, a total of 13 subjects (17.1%) in the ecolpiram group and 10 subjects (13.0%) in the placebo group had at least one AESI for ecolpiram. In the ecolpiram group, the most common AESIs for ecolpiram included depressed mood (3 subjects, 3.9%) and mid-night insomnia (3 subjects, 3.9%). All other AESIs for ecolpiram in the ecolpiram group occurred in 1 subject each.

[0304] Table 43. Summary of Adverse Events of Particular Interest for Ecolpipan by System Organ Class and Preferred Term (Safety Set)

[0305]

[0306] Abbreviations: AE, adverse event; AESI, adverse event of particular interest; MedDRA, Medical Dictionary for Regulatory Activities.

[0307] NOTE: AESI for ecolpipan based on SOC / PT reporting.

[0308] NOTE: The percentages are based on the number of objects in the security set.

[0309] Note: AEs were coded using MedDRA version 23.1. Objects with multiple events within the same preferred term / system organ class were counted only once.

[0310] Source: Table 14.3.1.10.2 (see figure).

[0311] An overview of the Columbia-Suicide Severity Rating Scale (C-SSRS) results for the safety set is provided in Table 45 below. At the 6th week and 14th day follow-up, the subject did not have suicidal ideation or behavior, and therefore these visits are not presented in the table. At baseline, life suicidal ideation was similar between treatment groups and reported in 16 subjects (21.1%) in the ecolpipan group and 12 subjects (15.6%) in the placebo group. During the dosing period in the study, up to 8 subjects (10.4%) in the placebo group and no subject in the ecolpipan group reported suicidal ideation. One subject (1.3%) in the ecolpipan group reported suicidal ideation during the 7-day follow-up. No subject reported suicidal behavior during the study (after baseline).

[0312] Table 45. Overview of the Columbia-Suicide Severity Rating Scale (C-SSRS) (Safety Set)

[0313]

[0314] aBaseline was defined as the last measurement obtained before the first dose of double-blind treatment on Day 1.

[0315] Note: Suicidal ideation is the sum of questions 1 through 5, and suicidal behavior is the sum of questions 6 through 10.

[0316] Note: n(%) refers to the number and percentage of subjects who experienced at least one event during the treatment period.

[0317] Source: Table 14.3.8.1 (see figure).

[0318] The Abnormal Involuntary Movement Scale (AIMS) records the presence of tardive dyskinesia in subjects receiving neuroleptics and consists of the presence and severity of movement disorders involving the face, mouth, limbs, and trunk, as well as 3 global judgment ratings. An overview of the AIMS total scores for the safety set is provided in Table 46 below. A decrease in the AIMS total score relative to baseline was observed in both treatment groups, indicating improvement; no significant differences were observed between the groups.

[0319] Table 46. Summary of Abnormal Involuntary Movement Scale (AIMS) Total Score (Safety Set)

[0320] Abbreviations: AIMS, abnormal involuntary movement scale; Max, maximum value; Min, minimum value.

[0321] aBaseline was defined as the last measurement obtained before the first dose of double-blind treatment on Day 1.

[0322] NOTE: The AIMS total score is calculated by summing the severity of the 10 items, which are rated on a scale of 0 to 4, ranging from 0 to 40.

[0323] Source: Table 14.3.8.2 (see figure).

[0324] The Barnes Akathisia Rating Scale (BARS) assesses the severity of drug-induced akathisia. An overview of the total BARS and overall scores for the safety set is provided in Table 47 below. Total and overall akathisia scores were lower at baseline and slightly decreased after baseline in both treatment groups. No significant differences were observed between the groups. An overview of the BARS subset scores for the safety set (objective, subjective awareness of restlessness, and subjective distress associated with restlessness) is provided in Table 14.3.8.3 (see Figure).

[0325] Table 47. Summary of Barnes Akathisia Rating Scale (BARS) Total and Global Scores (Safety Set)

[0326] Abbreviations: BARS, Barnes Akathisia Rating Scale; Max, maximum value; Min, minimum value.

[0327] aBaseline was defined as the last measurement obtained before the first dose of double-blind treatment on Day 1.

[0328] NOTE: Objective akathisia, subjective awareness of restlessness, and subjective distress related to restlessness are rated on a 4-point scale from 0-3 and summed to give a total score ranging from 0 to 9.

[0329] NOTE: The overall clinical rating of akathisia is rated on a 6-point scale from 0 to 5.

[0330] Source: Table 14.3.8.3 (see figure).

[0331] The Attention Deficit Hyperactivity Disorder (SNAP-IV) questionnaire is designed to assess ADHD and ODD symptoms in children and adolescents. A summary of the SNAP-IV questionnaire total scores for the safety set is provided in Table 48 below. A decrease in the total score relative to baseline was observed in both treatment groups, indicating improvement in ADHD and ODD symptoms. No significant differences were observed between the groups. A summary of the SNAP-IV subset scores for the safety set is provided in Table 14.3.8.4 (see Figure).

[0332] Table 48. Summary of Total Scores for the Attention Deficit Hyperactivity Disorder (SNAP-IV) Questionnaire (Safety Set)

[0333]

[0334] Abbreviations: Max, maximum value; Min, minimum value; SNAP-IV, attention deficit hyperactivity disorder.

[0335] aBaseline was defined as the last measurement obtained before the first dose of double-blind treatment on Day 1.

[0336] Note: Inattention and Hyperactivity / Impulsive Behavior is the average of 9 questions, Oppositional Defiant Disorder is the average of 8 questions, Inattention / Hyperactivity and Aggression / Defiance is the average of 5 questions, Conners Index is the average of 10 questions, Theory is the average of 6 questions, and Behavior is the average of 4 questions. All questions are rated on a 4-point scale ranging from 0 to 3.

[0337] Source: Table 14.3.8.4 (see figure).

[0338] The Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) for children is designed to determine the severity of OCD and monitor improvement during treatment. The scale is a clinician-rated, 10-item scale that includes questions about the time spent on obsessions / compulsions, the degree 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. An overview of the CY-BOCS total scores for the safety set is provided in Table 49 below. A decrease in the CY-BOCS total score relative to baseline was observed in both treatment groups. No significant differences were observed between the groups.

[0339] Table 49. Summary of the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) Total Score (Safety Set).

[0340] Abbreviations: CY-BOC, Yale-Brown Obsessive-Compulsive Scale for Children; Max, maximum value; Min, minimum value.

[0341] aBaseline was defined as the last measurement obtained before the first dose of double-blind treatment on Day 1.

[0342] Note: The CY-BOCS total score is calculated as the sum of the first 10 items and ranges from 0 to 40, where higher scores indicate more severe obsessions and compulsions.

[0343] Source: Table 14.3.8.5 (see figure).

[0344] The Depression Rating Scale-Revised (CDRS-R) for children is a clinically validated rating scale designed to assess the signs and symptoms of depression. Fourteen signs and symptoms are rated from 1 (normal) to 7 (most severe), and three signs and symptoms are rated from 1 (normal) to 5 (most severe). The original total score is the sum of all 17 items, ranging from 17 to 113. An overview of the CDRS-R original summary score for the safety set is provided in Table 50 below. A slight decrease in CDRS-R scores relative to baseline was observed in the two treatment groups. No significant differences were observed between the treatment groups.

[0345] Table 50. Summary of Children's Depression Rating Scale-Revised (CDRS-R) Raw Summary Scores (Safety Set)

[0346] Abbreviations: CDRS-R, Children's Depression Rating Scale-revised; Max, maximum value; Min, minimum value.

[0347] aBaseline was defined as the last measurement obtained before the first dose of double-blind treatment on Day 1.

[0348] Note: The original total score of the CDRS-R is the sum of all 17 items. If there are no missing records, the range is 17 to 113. Source: Table 14.3.8.6 (see figure).

[0349] The Children's Anxiety Rating Scale (PARS) is a clinician-rated instrument for assessing the severity of anxiety symptoms associated with common anxiety and general anxiety in children and adolescents. A summary of the PARS total scores for the safety set is provided in Table 51 below. A decrease in the PARS total score relative to baseline was observed in both treatment groups, indicating improvement in symptoms. No significant differences were observed between the treatment groups.

[0350] Table 51. Summary of the Children's Anxiety Rating Scale (PARS) total score (safety set).

[0351] Abbreviations: Max, maximum value; Min, minimum value; PARS, Children's Anxiety Rating Scale.

[0352] aBaseline was defined as the last measurement obtained before the first dose of double-blind treatment on Day 1.

[0353] Note: The PARS total score is a sum of 7 severity items. The total score ranges from 0 to 35.

[0354] Source: Table 14.3.8.7 (see figure).

[0355] A total of 47 subjects (61.8%) in the ecolpipan group and 38 subjects (49.4%) in the placebo group experienced AEs during the study.

[0356] Most AEs reported in both treatment groups were mild or moderate in severity. No fatal or life-threatening AEs were reported during the study.

[0357] Treatment-related AEs were reported in a greater proportion of subjects in the ecolpipan group (26 subjects, 34.2%) compared to the placebo group (16 subjects, 20.8%).

[0358] In the ecolpipan group, the most commonly reported treatment-related AEs (>5% of subjects) included headache (7 subjects, 9.2%), somnolence (5 subjects, 6.6%), fatigue (5 subjects, 6.6%), insomnia, including middle-of-the-night 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%).

[0359] During the study, a total of 3 subjects (all adolescents) experienced SAEs. 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 ecolopam group experienced SAEs (1 subject had an SAE of vomiting and 1 subject had an SAE of coronavirus infection); both SAEs were considered by the investigator to be moderate in severity and not related to the study drug.

[0360] A total of 4 subjects (5.3%) in the ecolpipan group and 1 subject (1.3%) in the placebo group experienced AEs that led to treatment discontinuation. Two subjects (1 in the ecolpipan group and 1 in the placebo group) had an AE of suicidal ideation that led to treatment discontinuation; all other AEs that led to treatment discontinuation occurred in only 1 subject each.

[0361] No EPS dyskinesias were observed in subjects in the ecolpipan or placebo groups.

[0362] During the study, a total of 13 subjects (17.1%) in the ecolpipan group and 10 subjects (13.0%) in the placebo group had at least one AESI specific to ecolpipan. In the ecolpipan group, the most common AESIs for ecolpipan included depressed mood (3 subjects, 3.9%) and mid-night insomnia (3 subjects, 3.9%).

[0363] No insignificant differences were observed between the ecolpipan group and the placebo group for laboratory results, vital signs, weight gain, ECG findings, C-SSRS, and safety outcome scales.

[0364] A total of 4 subjects (2 in the ecolpiram group and 2 in the placebo group) reported COVID-19 AEs. The investigators considered 3 events to be mild in severity and 1 event to be moderate in severity. One subject in the ecolpiram group had a COVID-19 AE that was considered severe due to hospitalization. No subjects discontinued study drug or study status due to these events.

[0365] Example 2

[0366] The dosing regimen described in Example 1 above was used in a 52-week open-label extension study in the same category of patients, ie, those with TS and aged at least six years and less than 18 years, in which patients were titrated to the full dose according to the same schedule.

[0367] Preliminary analysis of the data showed the following trends and comparisons to the PSY302 open-label extension study described above.

[0368] Overview of Treatment-Emergent Adverse Events (Safety Population)

[0369]

[0370] Abbreviations: SAE, serious adverse event; TEAE, treatment-emergent adverse event. Note: TEAEs with a possible, probable, or absent relationship were considered related for PSY-302 OLE or probably for Example 1-OLE.

[0371] Table: Treatment-emergent adverse events occurring in ≥2 subjects (safety population)

[0372]

[0373]

[0374] Abbreviation: TEAE, treatment-emergent adverse event defined as possible and probable (missing data are included in PSY302 OLE and excluded in Example 1-OLE. For PSY302 OLE, subjects were counted once per system organ class and once per preferred term. Multiple events for the same subject were included in Example 1-OLE.

[0375] The disclosure of the illustrative description herein can be suitably practiced in the absence of any elements, restrictions not specifically disclosed herein. The terms and expressions used are used as terms of description and are not restrictive, and in the use of such terms and expressions, it is not intended to exclude the equivalents or parts thereof of the features shown and described. It should be recognized that within the scope of the present invention, various modifications are possible. Therefore, it should be understood that, although the present invention has been specifically disclosed by preferred embodiments and optional features, modifications and variations of the concepts disclosed herein can be adopted by those skilled in the art, and it is believed that the modifications and variations are within the scope of the present invention.

[0376] Throughout this specification and the claims that follow, unless the context otherwise requires, the word "comprise" and variations (e.g., "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 any other group of integers or steps.

[0377] Throughout this specification, unless otherwise described, when a composition is described as comprising components or materials, it is contemplated that the composition may also consist essentially of or consist of any combination of the described components or materials. Similarly, unless otherwise described, when a method is described as comprising specific steps, it is contemplated that the described method may also consist essentially of or consist of any combination of the described steps. The invention illustratively disclosed herein may suitably be practiced in the absence of any element or step not specifically disclosed herein.

[0378] The practice of the methods disclosed herein and their corresponding steps can be performed manually and / or by means of an electronic device or automation provided by the electronic device. Although the processes have been described with reference to specific embodiments, it will be readily understood by those skilled in the art that other ways of performing the actions associated with these methods can be used. For example, unless otherwise described, the order of the various steps can be changed without departing from the scope or spirit of the described methods. In addition, some of the individual steps can be combined, omitted, or further subdivided into other steps.

[0379] 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. A method for orally administering ecopipam or a pharmaceutically acceptable salt thereof to a patient in need thereof, comprising: providing said patient with a first daily dose of ecolpipan at a first daily dosage for a first period of seven days; providing the patient with a second daily dose of ecolpipan at a second daily dose greater than the first dose for a second time period following the first time period, wherein the second time period is seven days; and providing the patient with a third daily dose of ecolpipan in a third daily dose greater than the second dose for a third time period after the second time period, in (a) the third time period is greater than seven days and satisfies one or more of the following three conditions: (1) the daily dosage of ecolpiram administered during the third time period is 37.5 mg; (2) 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; and (3) the patient's weight is ≥18 kg to ≤23 kg; or (b) the third time period is seven days and the method further comprises providing the patient with a fourth daily dose of ecolpipant at a fourth daily dose that is greater than the third daily dose for a fourth time period after the third time period, wherein the fourth daily dose is 2.41 mg / kg or less.

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

3. The method of claim 1 or 2, wherein the third time period is greater than seven days and 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 according to any one of claims 1 to 3, wherein the patient has a body weight of ≥18 kg to ≤23 kg.

5. The method of claim 1, wherein the third period of time is seven days and the method further comprises providing the patient with a fourth daily dose of ecolopam at a fourth daily dose that is greater than the third daily dose, wherein the fourth daily dose is 2.41 mg / kg or less.

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

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

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

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

10. The method of claim 9, wherein the patient weighs >34 kg to ≤44 kg and the fourth administered amount is 75 mg.

11. The method of claim 9, wherein the patient's body weight is >68 kg to ≤83 kg and the fourth administered amount is 150 mg.

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

13. The method of claim 12, wherein the patient's body weight is >83 kg and the fourth administered amount is 200 mg.

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

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

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

17. A method of orally administering ecolopam or a pharmaceutically acceptable salt thereof to a patient in need thereof, comprising: providing said patient with a first daily dose of ecolpipan in a first daily dosing amount for a first period of about seven days; providing the patient with a second daily dose of ecolpipan at a second daily dose greater than the first daily dose for a second time period following the first time period, wherein the second time period is about seven days; providing the patient with a third daily dose of ecolpipan at a third daily dose greater than the second daily dose for a third time period after the second time period, wherein the third time period is at least seven days; and optionally providing said patient with a fourth daily dose of ecolpipan in a fourth daily amount greater than said third daily amount for a fourth time period following said third time period; in (a) the third period of time is greater than seven days when the patient's weight is ≥18 kg to ≤23 kg and one or more of the following two conditions are met: (1) the daily dose of ecolpiram administered during the third period of time is 37.5 mg; and (2) the first daily dose is 1 / 3 of the amount of the third daily dose, and the second daily dose is 2 / 3 of the amount of the third daily dose; and (b) the third period of time is seven days and the method further comprises providing the patient with a fourth daily dose of ecolopam at a fourth daily dose that is greater than the third daily dose, wherein the dose is 2.41 mg / kg or less; and wherein When the patient's weight is >23 kg 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 When the patient's weight is >34 kg 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; and When the patient's weight is >44 kg 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 When the patient's weight is >68 kg 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; and When the patient's weight is >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.

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

20. The method according to any one of the preceding claims, wherein the patient is aged ≥6 to <18 years.

21. The method according to any one of the preceding claims, wherein the patient is ≥18 years old.

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

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

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

25. The method of any preceding claim, wherein the method reduces one or more adverse events, eg, compared to a previous method.

26. The method of any preceding claim, wherein the method increases the efficacy of ecolopam therapy, eg, compared to a previous method.

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

28. The method of claim 27, wherein the patient's age ranges from at least 6 years to less than 18 years.

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

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

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

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

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