A method for treating a neurological disease in a recreational drug user

Abstract

The present disclosure relates to the method of treating neurological disease in a recreational drug user by administering an effective amount of soticlestat or a pharmaceutically acceptable salt thereof, wherein the treatment does not produce the potential of drug abuse.

Description

A METHOD FOR TREATING A NEUROLOGICAL DISEASEIN A RECREATIONAL DRUG USERTECHNICAL FIELD

[0001] The present disclosure relates to a method of treating neurological disease in a recreational drug user by administering an effective amount of soticlestat or a pharmaceutically acceptable salt thereof, wherein the treatment does not produce the potential of drug abuse.BACKGROUND

[0002] The enzyme cholesterol 24-hydroxylase (CH24H), also known as cytochrome P450 46A1 (CYP461) is mostly expressed in neurons where it catalyzes the hydroxylation of cholesterol to the oxysterol 24-hydroxychole sterol (24HC) in the endoplasmic reticulum. 24HC has rapid efflux from neurons into the extracellular space and moves through the blood brain barrier into systemic circulation for hepatic elimination. However, high levels of CH24H activity can increase 24HC levels in the extracellular space where it can act as a positive allosteric modulator of N-methyl-D-aspartate (NMD A) receptor activity in neurons. High levels of 24HC can increased tonic neuronal hyperactivity resulting increased activity of NMDA receptor, depolarization, and excitotoxicity. 24HC-mediated neuronal hyperactivity could contributed to developmental and epileptic encephalopathies (DEE). DEE is characterized by seizures, developmental delay or regression, and affects approximately 100,000-200,000 people in the USA. DEE includes a number of orphan syndromes, including Lennox-Gastaut syndrome (LGS), with an estimated prevalence of 1-5 individual per 10,000 worldwide, and Dravet syndrome (DS), with an estimated prevalence of 1 individual per 15,700 people in the USA. Many DEE patients experience daily seizures resulting in a lower quality of life and significant morbidity. The seizures of most patients are refractory to current anti-seizure treatments and therefore there is a significant need for an effective therapy.

[0003] Soticlestat is a potent inhibitor of cholesterol-24 hydroxylase (CH24H) in the brain. Although the exact therapeutic mechanisms of soticlestat still remain to be fully understood, pharmacological modulation of CH24H can potentially alter the function of N- methyl-D-aspartate (NMDA) receptors because 24S-hydroxycholesterol (24HC), the metabolic product of CH24H reaction, is known as an endogenous modulator of the NMDA (Paul et al. 2013) receptors. Therefore, soticlestat can be considered an indirect NMDAmodulator, which is mediated by 24HC reduction.

[0004] Since high levels of 24HC may enhance NMDA receptor activation, reducing 24HC -mediated NMDA activity with soticlestat may produce tolerance that leads to dependency and abuse potential. For example, the triazolobenzodiazepine alprazolam (Xanax) increases the affinity of GABA at the GABAA receptor, increasing the amplitude of chloride channel opening, which produces negative modulation of the NMDA receptor. Alprazolam use produces tolerance and dependency increasing the risk for abuse and severe withdrawal effects upon discontinuation. In view of soticlestat modulating NMDA activity, it is therefore important to determine whether reduction of 24HC levels by administering soticlestat treatment for epilepsy would lead to dependency and the potential for abuse similar to alprazolam in recreational drug users.SUMMARY

[0005] The present disclosure provides a method for treating neurological disease in a recreational drug user by administering an effect amount of soticlestat or pharmaceutically acceptable salt thereof.

[0006] One aspect of the disclosure provides a method for treating a neurological disease in a recreational drug user comprising administering to the user in need thereof a pharmaceutically effective amount of soticlestat or a pharmaceutically acceptable salt thereof.

[0007] Another aspect of the disclosure provides a method for treating a neurological disease in a recreational drug user and a means for avoiding potential abuse effects comprising administering to the user in need thereof an effective amount of soticlestat or a pharmaceutically acceptable salt thereof.

[0008] In one embodiment, the recreational drug user is a non-dependent recreational drug user that has used a recreational drug multiple times in their lifetime.

[0009] In one embodiment, the recreational drug user has used a CNS depressant or is currently using a CNS depressant.

[0010] In one embodiment, the recreational drug user has used, or is currently using a hallucinogen or dissociative drug.

[0011] In one embodiment, the recreational drug user has used, or is currently using cocaine, morphine, marijuana, opioid, stimulant, or cannabinoid,

[0001] An additional aspect of the disclosure provides a method for treating a neurological disease in a recreational drug user without drug abuse potential comprising administering to the user in need thereof a pharmaceutically effective amount of soticlestat or apharmaceutically acceptable salt thereof, wherein the method produces a similar incidence of treatment emergent adverse events (TEAEs) as administering a placebo.

[0002] A further aspect of the disclosure provides administering a pharmaceutically effective amount of soticlestat or a pharmaceutically acceptable salt thereof to a recreational drug user produces less incidence of TEAEs compared to a CNS depressant drug, wherein the TEAEs may include e.g., somnolence, euphoric mood, feeling of relaxation compared to a CNS depressant drug.

[0003] Another aspect of the disclosure provides a method of treating the neurological disease in a recreational drug user comprising administering to the user in need thereof a pharmaceutically effective amount of soticlestat or pharmaceutical acceptable salt thereof, wherein the method results in no drug abuse potential.

[0004] In one embodiment, the neurological disease treated is epilepsy. In a further embodiment, the neurological disease treated is Dravet syndrome or Lennox-Gastaut syndrome.

[0005] In some embodiment, the neurological disease treated is seizures.BRIEF DESCRIPTION OF THE DRAWINGS

[0006] FIG. 1 shows reinforcing effect off soticlestat in cocaine-trained rats. In the figure C: Cocaine (0.32 mg / kg / infiision); Cl: cocaine acquisition; C2: cocaine reinstatement;S: Saline (0.2 mL / infiision); SI: saline extinction; S2: saline washout; TAK-935: soticlestat. Mean number of infusions taken in 2-h test sessions averaged over 3 consecutive days ± SEM.§ = p<0.05 significantly different from SI. f = p<0.05 significantly different from Cl.

[0007] FIG. 2 shows a flow diagram of trial I phases by number of subjects.

[0008] FIG. 3 shows an example of the visual analogue scale unipolar and bipolar assessment.

[0009] FIG. 4 shows the Mean “Drug Liking Effect” in participants taking alprazolam compared to placebo over time evaluated with a visual analogue scale (VAS) during the qualification phase.

[0010] FIG. 5 shows the Mean “Overall Liking Effect” in participants taking alprazolam compared to placebo evaluated with a visual analogue scale (VAS) at time points 8 and 23 hours during the qualification phase.

[0011] FIG. 6 shows the Mean “Take Again” in participants treated with 2 mg alprazolam compared to placebo evaluated with a visual analogue scale (VAS) at 8 and 23 hours duringthe qualification phase.

[0012] FIG. 7 shows the Mean “Bad Effects” in participants treated with 2 mg alprazolam compared to placebo over time evaluated with a visual analogue scale (VAS) during the qualification phase.

[0013] FIG. 8 shows the Mean “Good Effects” in participants treated with 2 mg alprazolam compared to placebo over time evaluated with a visual analogue scale (VAS) during the qualification phase.

[0014] FIG. 9 shows the Mean “High” in participants treated with 2 mg alprazolam compared to placebo over time evaluated with a visual analogue scale (VAS) during the qualification phase.

[0015] FIG. 10 shows the Mean “Alertness / Drowsiness” in participants treated with 2 mg alprazolam compared to placebo over time evaluated with a visual analogue scale (VAS) during the qualification phase.

[0016] FIG. 11 shows the Mean “Any Effects” in participants treated with 2 mg alprazolam compared to placebo over time evaluated with a visual analogue scale (VAS) during the qualification phase.

[0017] FIG. 12 shows the Mean “Drug Liking Effects” over time in participants treated with soticlestat, alprazolam, or placebo evaluated with a visual analogue scale (VAS) during the treatment phase.

[0018] FIG. 13 shows the Mean “Overall Drug Liking Effect” in participants treated with soticlestat, alprazolam, or placebo evaluated with a visual analogue scale (VAS) at 12 and 24 hours after tablet administration during the treatment phase.

[0019] FIG. 14 shows the Mean “Take Drug Again Effect” in participants treated with soticlestat, alprazolam, or placebo evaluated with a visual analogue scale (VAS) at 12 and 24 hours after tablet administration during the treatment phase.

[0020] FIG. 15 shows the hourly Mean “Bad Effects” in participants treated with soticlestat, alprazolam, or placebo evaluated with a visual analogue scale (VAS) during the treatment phase.

[0021] FIG. 16 shows hourly Mean “Good Effects” in participants taking soticlestat, alprazolam, or placebo evaluated with a visual analogue scale (VAS) during the treatment phase.

[0022] FIG. 17 shows hourly Mean “High” in participants treated with soticlestat, alprazolam, or placebo evaluated with a visual analogue scale (VAS) during the treatment phase.

[0023] FIG. 18 shows the Mean “Alertness / Drowsiness” in participants treated with soticlestat, alprazolam, or placebo overtime evaluated with a visual analogue scale (VAS) during the treatment phase.

[0024] FIG. 19 shows the Mean “Any Effects” over time evaluated with a visual analogue scale (VAS) during the treatment phase.

[0025] FIG. 20 shows the mean plasma concentration of soticlestat over time.

[0026] FIG. 21 shows the mean plasma concentration of soticlestat N-oxide metabolite M-I over time.

[0027] FIG. 22 shows the mean plasma concentration of alprazolam over time.DETAILED DESCRIPTION

[0028] The term “recreational drug user” is a subject that has used a prescribed or nonprescribed CNS depressant, opioid, stimulant, cannabinoid, hallucinogen, and dissociative drug multiple times, (such as at least 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times) in their lifetime. In one embodiment, the “recreational drug user” has used a non-prescribed CNS depressant, opioid, stimulant, cannabinoid, hallucinogen, and dissociative drug at least once in the previous 12 weeks before the treatment.

[0029] The term “non-dependent recreational drug user” is a subject without dependence to a prescribed or non-prescribed CNS depressant, opioid, stimulant, cannabinoid, hallucinogen, and dissociative drug.

[0030] In one embodiment, the “non-dependent recreational drug user” is a subject without dependence to a non-prescribed CNS depressant, opioid, stimulant, cannabinoid, hallucinogen, and dissociative drug.

[0031] The term “dependent recreational drug user” is a subject that is currently using a prescribed or non-prescribed CNS depressant, opioid, stimulant, cannabinoid, hallucinogen, and dissociative drug and would incur withdraw effects upon discontinuation.

[0032] In one embodiment, “dependent recreational drug user” is a subject that is currently using a non-prescribed CNS depressant, opioid, stimulant, cannabinoid, hallucinogen, and dissociative drug and would incur withdraw effects upon discontinuation.

[0033] The term “subject” is a human. In one embodiment, the subject is a “participant” who was deemed eligible to participate in the trial and has entered the qualification phase or treatment phase.

[0034] The term “CNS depressant drug” includes benzodiazepines and sedative-hypnotics. Examples of benzodiazepines include clonazepam, diazepam, alprazolam, triazolam,estazolam, chlordiazepoxide, clorazepate, lorazepam, halazepam, oxazepam, midazolam, prazepam, temazepam, quazepam, flunitrazepam, and flurazepam. Examples of sedativehypnotics include citalopram, escitalopram, paroxetine, zolpidem, eszopiclone, zopiclone, suvorexant, lemborexant, estazolam, tasimelteon, daridorexant, ramelteon, doxepin, gammahydroxybutyrate, barbiturates, propofol / fospropofol, and zaleplon.

[0035] A hallucinogen or dissociated drug may comprise ketamine, nitrous oxide, phencyclidine, or dextromethorphan-based cough syrups. An opioid may comprise cocaine, morphine, fentanyl, heroin, oxycodone, or codeine.

[0036] The acronym “VAS” stands for visual analogue scale. All VAS were scored on a 100-point scale, as shown in FIG. 3. The VAS may be administered as bipolar or unipolar scales, as appropriate, and the choice is determined by the nature of the subjective effect being measured. When VAS are administered as bipolar scales, the neutral point equals 50 (Drug Liking, Overall Drug Liking, Take Drug Again, Alertness / Drowsiness VAS). The neutral point was also labeled with an anchor, such as “neither like nor dislike.” When VAS are administered as unipolar scales, the neutral point equals 0, and anchors were presented using text such as “Not at all” (score = 0) to “Extremely” (score = 100; e.g., Good, Bad, High, and Any Effects VASs). Scales that refer specifically to drug (e.g., Drug Liking, Good Effects VAS, Bad Effects VAS, and Any Effects VAS) are not administered pre-dose.

[0037] The term “Emax” as used herein refers to maximum effect as assessed by a unipolar or bipolar visual analogue scale.

[0038] Pharmacokinetic (PK) parameters describe how the body interacts with the drug and includes measures such Tmax and soticlestat concentration at 24 hours post-dose. Pharmacodynamic (PD) parameters describe how the drug affects the body. The PK and PD parameters were assessed after a single dose of soticlestat. PD of soticlestat and the CNS depressant, alprazolam was assessed in the trial by the VAS Emax of select drug abuse potential and safety measures.

[0039] The term “Emin” as used herein refers to minimum effect as assessed by a unipolar or bipolar visual analogue scale. The terms “TEmax” and “TEmin” as used herein refer to the time to maximum effect and time to minimum effect, respectively. The terms “AOEC” and “AUEC” as used herein refers to the area over or under the curve from 0 to 8 hours for the PD assessments.

[0040] “Drug abuse potential” was assessed by response on a visual analogue scale (VAS) maximum effect (Emax), between soticlestat and a CNS depressant drug or placebo in a recreational drug user. Drug abuse potential can indicate the likelihood of a recreational druguser to develop drug tolerance, continue use beyond therapeutic need, increase dosage, experience withdrawal symptoms, or other addictive behavior.

[0041] The term “pc” is the Drug Liking VAS Emax for alprazolam. The term pp is the Drug Liking VAS Emax for placebo. The term “pr” is the “Drug Liking” VAS Emax for soticlestat. Each value represents a mean response used to test the null hypothesis (Ho) versus the abuse potential Hain the primary and secondary PD analyses.

[0042] The term “M-I” refers to the N-oxide metabolite of soticlestat.

[0043] The term “24HC” is an abbreviation for 24S-hydroxycholesterol. The term “CH24H” is an abbreviation for cholesterol-24 hydroxylase. The term “CNS” is an abbreviation for central nervous system.

[0044] The term “CRU” is the acronym for clinical research unit. The term “CSA” as used herein is the acronym for Controlled Substances Act. The term “CSR” as used herein in the acronym for clinical study report. The term “C-SSRS” as used herein is the acronym for Columbia Suicide Severity Rating Scale.

[0045] The term “DEE” is the acronym for developmental epileptic encephalopathy. The term “DS” as used herein is the acronym for Dravet syndrome.

[0046] The acronyms TEAE, SAE, and AE stands for treatment-emergent adverse event, severe adverse event, and adverse event. A severe adverse event is defined as any untoward medical occurrence at any dose, which requires hospitalization, results in persistent or significant disability / capacity, is life threatening, wherein the participant is at risk of death, results in death, or requires intervention to prevent death.

[0047] The term “THC” is an abbreviation for tetrahydrocannabinol. The term “CYP” is an abbreviation for cytochrome P-450. The term “NMDA” is an abbreviation for N-methyl-D- aspartate.

[0048] The term “UDS” used herein is the acronym for urine drug screen.

[0049] The acronym “WOCBP” stands for women of childbearing potential.

[0050] The term “Tmax” is defined as time after dosing wherein the drug plasma concentration reaches the point of maximum concentration. The term “Cmax” is defined as the highest plasma concentration of the drug. The term “AUC” is defined as the area under the concentration-time curve, wherein from time 0 to the last quantifiable concentration is “AUClasf ’ and from time 0 to infinity is “AUC<»”.

[0051] The term “CV%” is the coefficient of variation is a measure of the data points around the mean and is calculated from the formula: ((standard deviation / mean)x 100).

[0052] The term “healthy” is herein defined as no clinically relevant abnormalitiesidentified by a detailed medical history, complete physical examination, vital signs, 12-lead ECG, and clinical laboratory tests.Soticlestat has the following chemical structure:Its chemical name is (4-benzyl-4-hydroxypiperidin-l-yl)-(2-pyridin-4-ylpyridin-3- yl)methanone, or (4-benzyl-4-hydroxypiperidin-l-yl) (2, 4' -bipyridin-3- yl)methanone. Soticlestat can be prepared according to the methods and procedures described in International publication number WO 2013 / 054822.

[0053] Soticlestat is bioavailable through oral administration and potently inhibits cholesterol 24-hydroxylase (CH24H) enzyme activity, which converts cholesterol to 24S- hydroxy cholesterol (24HC).

[0054] Studies have demonstrated that soticlestat modulates glutamatergic signaling and significantly reduces spontaneous seizure in murine models. The phase 2 clinical study TAK- 935-2002 (ELEKTRA) showed efficacy of soticlestat in participants with DS or LGS who had seizures that were intractable to current anti-seizure medications.

[0055] Soticlestat is a novel compound that is not pharmacologically similar to any existing drugs of abuse. For a compound with novel mechanism of action, such as soticlestat, the USFDA recommends a safety comparison with an appropriate positive control of a depressant listed under schedule IV of the CSA. According to FDA guidance (US Department of Health and Human Services, FDA, Center for Drug Evaluation and Research (CDER): Assessment of Abuse Potential of Drugs, January 2017), ideally, “the positive control should be an FDA-approved drug that is pharmacologically similar to the test drug and scheduled under the Controlled Substances Act (CSA).” Therefore, to meet the requirement for regulatory filing and registration, a clinical trial was conducted to test the relative abuse potential of soticlestat in healthy adult nondependent recreational drug users with CNS depressant experience in comparison with a schedule IV CNS depressant (e.g., a benzodiazepine). The clinical trial disclosed herein provides a comprehensive assessment of the relative abuse potential of soticlestat, which includes nonclinical and clinical assessments. The study results may also be informative for abuse potential in dependent recreational drug users.

[0056] Overall, the data with soticlestat does not suggest any particular class of drugs of abuse as an ideal positive control; therefore, a benzodiazepine was selected as a positive control, as these have some similarities in therapeutic effects to soticlestat (ie, anticonvulsant effects) and a similar potential general indication (i.e., treatment of seizure disorders).

[0057] Benzodiazepines, and more specifically alprazolam, has been used, as positive control, in a number of prior human abuse potential studies of anti-epileptic drugs with novel pharmacology (Levy-Cooperman et al. 2016; Schoedel et al. 2017; Schoedel et al. 2018a; Schoedel et al. 2018b).

[0058] Combining studies of a phase 1 and the placebo-controlled parts of phase 2 studies, the incidence of abuse related, treatment-emergent adverse events (TEAEs) was 17.9% for soticlestat versus 9.6% for placebo consisted mostly of dizziness and somnolence. Focusing on abuse-related TEAEs that emerged on Day 1 of treatment, the time most relevant to human abuse, the incidence of abuse-related TEAEs was 4.7% for participants on soticlestat versus 1.8% for participants on placebo. There were only three reports of euphoric mood by participants receiving soticlestat. Although two cases of euphoric mood were reported within 1 to 2 hours of soticlestat dosing, evaluation of PD parameters for these participants did not show a marked effect on 24HC concentrations at this time, indicating that the effects were unlikely related to soticlestat.

[0059] To date, there have been 10 clinical studies of soticlestat, including phase 1 single rising dose (SRD) and multiple rising dose (MRD) studies in healthy participants and phase 2 studies in DEE and patients with complex regional pain syndrome (CRPS) (e.g., NCT02201056, NCT02906813, NCT02539134, NCT02497235, NCT03166215, NCT03650452 (ELEKTRA). Overall, soticlestat was safe and well tolerated, and there were no observed dose responses for TEAEs in 2 SRD studies where the healthy participants were dosed with up to 1350 mg and 1200 mg.

[0060] In the phase lb / 2a and phase 2 studies completed to date, the safety and tolerability data indicate that soticlestat was generally safe and well tolerated in participants with developmental epileptic encephalopathies (DEEs) at doses up to 300 mg BID (weight-based dosing for <60 kg) with initial dose up-titration.

[0061] All subsequent repeated-dose studies implemented dose up-titration / optimization to the target dose levels of up to 300 mg BID. In previous a clinical study, soticlestat was administered as BID doses and no clinically meaningful accumulations were observed following multiple BID doses (accumulation ratio 1.05). No individual or population doseresponse for safety events were observed during the dose up-titration / optimization andmaintenance periods, indicating that soticlestat is well tolerated up to 300 mg BID.

[0062] In a previous clinical soticlestat study, TEAEs were all mild except for 1 case of acute psychosis (severe), insomnia (severe), and distractibility (moderate) reported by the same participant. The conditions of the TEAEs were reversible, and all participants recovered. There were no serious adverse events (SAEs). No clear dose-response relationship was observed for any specific TEAE across all dose cohorts. Altogether, the previous clinical studies provided guidance for selecting tolerable and safe soticlestat dosages in the abuse potential trial.

[0063] Preclinical studies can also indicate the abuse potential of soticlestat. One aspect of the present disclosure tests the abuse potential of soticlestat in a rat model by comparing discrimination between soticlestat and ketamine, and measuring differences in selfadministration between cocaine and soticlestat (Example 1). Table 1 shows soticlestat exposure level in rats after administration of different dosage amounts. Figure 1 shows rat self-administration of soticlestat in comparison with saline after acquisition and extinction of cocaine self-administration.

[0064] Another aspect of the present disclosure provides a method for treating a neurological disease in a recreational drug user comprising administering to the user in need thereof a pharmaceutically effective amount of soticlestat or a pharmaceutically acceptable salt thereof.

[0065] Another aspect of the present disclosure provides a method for treating a neurological disease in a recreational drug user and a means for avoiding potential abuse effects comprising administering to the user in need thereof an effective amount of soticlestat or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, the recreational drug user is a non-dependent recreational drug user.

[0067] In some embodiments, the recreational drug user has used a CNS depressant or is currently using a CNS depressant.

[0068] In some embodiments, the CNS depressant comprises a benzodiazepine or sedativehypnotic.

[0069] In some embodiments, the benzodiazepine comprises clonazepam, diazepam, alprazolam, triazolam, estazolam, chlordiazepoxide, clorazepate, lorazepam, halazepam, oxazepam, midazolam, prazepam, temazepam, quazepam, flunitrazepam, and flurazepam.

[0070] In some embodiments, the sedative-hypnotic comprises citalopram, escitalopram, paroxetine, zolpidem, eszopiclone, zopiclone, suvorexant, lemborexant, estazolam,tasimelteon, daridorexant, ramelteon, doxepin, gamma-hydroxybutyrate, barbiturates, propofol / fospropofol, and zaleplon.

[0071] In some embodiments, the recreational drug user has used or is currently using a benzodiazepine or sedative-hypnotic.

[0072] In some embodiments, the benzodiazepine or sedative-hypnotic comprises alprazolam, clonazepam, diazepam, triazolam, estazolam, chlordiazepoxide, , flunitrazepam, , clorazepate, halazepam, lorzepam, flurazepam, oxazepam, midazolam, prazepam, temazepam, quazepam, , citalopram, escitalopram, paroxetine, barbiturate, zolpidem, suvorexant, lemborexant, Estazolam, tasimelteon, doxepin, ramelteon, zaleplon, eszopiclone, suvorexant, zopiclone, propofol / fospropofol, or gamma-hydroxybutyrate.

[0073] In some embodiments, the recreational drug user has used or is currently using a hallucinogen or dissociative drug.

[0074] In some embodiments, the hallucinogen or dissociative drug comprises ketamine, nitrous oxide, phencyclidine, or dextromethorphan-based cough syrups (often labeled DXM).

[0075] In some embodiments, the recreational drug user has used or is currently using cocaine, morphine, marijuana, opioid, stimulant, or cannabinoid.

[0076] In some embodiments, the recreational drug user has used a recreational drug multiple times in their lifetime.

[0077] In some embodiments, the treatment method produces a similar incidence of treatment emergent adverse events (TEAEs) as the placebo.

[0078] In some embodiments, the treatment method produces less incidence of TEAEs such as somnolence, euphoric mood, feeling of relaxation compared to a CNS depressant drug.

[0079] In some embodiments, the treatment method results in a reduced incidence of drug abuse potential.

[0080] In some embodiments, the drug abuse potential is determined by the difference in “Drug liking” response on a visual analogue scale (VAS) maximum effect (Emax), between soticlestat and a CNS depressant drug of at least 10 points, at least 20 points, or at least 30 points.

[0081] In some embodiments, the drug abuse potential is determined by the difference in “Overall Drug Liking” on a visual analogue scale (VAS) maximum effect (Emax) between soticlestat and a CNS depressant drug “at this moment” of at least 10 points, at least 20 points, or at least 30 points.

[0082] In some embodiments, the drug abuse potential is determined by the difference in “Take Drug Again” on a visual analogue scale (VAS) maximum effect (Emax) betweensoticlestat and a CNS depressant drug of at least 10 points, at least 20 points, or at least 30 points.

[0083] In some embodiments, the drug abuse potential is determined by a difference in “Drug Liking” response on a visual analogue scale (VAS) maximum effect (Emax) between soticlestat and placebo.

[0084] In some embodiments, the drug abuse potential is determined by a difference in “Overall Drug Liking” response on a visual analogue scale (VAS) maximum effect (Emax) between soticlestat and placebo of at least 10 points, at least 20 points, at least 30 points.

[0085] In some embodiments, the drug abuse potential is determined by a difference in “Take Drug Again” response on a visual analogue scale (VAS) maximum effect (Emax) between soticlestat and placebo of at least 10 points, at least 20 points, or at least 30 points.

[0086] In some embodiments, the pharmaceutically effective amount of soticlestat is from about 100 mg to about 1000 mg.

[0087] In some embodiments, the pharmaceutically effective amount of soticlestat is about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about lOOOmg.

[0088] In some embodiments, the pharmaceutically effective amount of soticlestat is administered in one, two, or three divided doses.

[0089] In some embodiments, the neurological disease is epilepsy.

[0090] In some embodiments, the epilepsy is rare epilepsy, developmental epileptic encephalopathy, or epileptic type disease.

[0091] In some embodiments, the neurological disease is Dravet syndrome or Lennox- Gastaut syndrome.

[0092] In some embodiments, the neurological disease is seizures.

[0093] In some embodiments, the seizure is associated with Dravet syndrome or Lennox- Gastaut syndrome in patients 2 years of age and older.

[0094] In some embodiments, the seizure is associated with Dravet syndrome or Lennox- Gastaut syndrome in patients 12-14 years of age.

[0095] In some embodiments, the seizure is associated with Dravet syndrome or Lennox- Gastaut syndrome in patients 14-16 years of age.

[0096] In some embodiments, the seizure is associated with Dravet syndrome or Lennox- Gastaut syndrome in patients 16-18 years of age.

[0097] In some embodiments, the seizure is associated with Dravet syndrome or Lennox- Gastaut syndrome in patients 18 years of age and older.

[0098] In some embodiments, the seizure is focal onset seizures, major motor seizures, major motor drop seizures, focal seizures with secondary generalization, infantile spasms, primary generalized tonic-clonic seizures, partial onset seizures with or without secondary generalization, simple partial seizures, complex partial seizures, simple absence seizures, and complex absence seizures.

[0099] In some embodiments, the neurological disease is migraine or complex regional pain syndrome.

[0100] The clinical trial disclosed herein was a phase 1, randomized, double-blind, doubledummy, active- and placebo-controlled study, consisting of screening, qualification, treatment, and follow-up phase, with the treatment phase consisting of a 5 -way crossover study to determine the relative abuse potential of oral doses of soticlestat compared to a single oral dose of 2 mg of alprazolam and placebo in healthy adult, nondependent recreational drug users with CNS depressant experience. This was an inpatient study, wherein the participants were closely monitored for the emergence of any adverse events (AEs). The study evaluated the relative abuse potential of different soticlestat dose levels compared with the placebo and positive control alprazolam and added further data to the overall risk-benefit profile for treatment of DS and LGS.Phase I trial - Qualification phase

[0101] Eligibility required subject tests for pregnancy, infectious disease, and urine drug screening are as described in Tables 2 and 3. Study assessments and procedures were performed on the days and time points outlined in the Table 3. Approximately 110 participants were enrolled into the qualification phase of the study. Each participant participated in a screening visit (Visit 1) to determine eligibility within 28 days of the first dose in the qualification phase. Eligible participants participated in an inpatient, qualification phase (from Day -1 through Day 3) to determine if participants could discriminate the drug effects of the positive control, 2 mg of alprazolam, when compared with placebo, and to demonstrate tolerance to the alprazolam 2 mg dose.

[0102] The qualification phase of the study was a 2 x 2 crossover design with oral doses of alprazolam 2 mg and matching placebo. An overview of the study design described above is provided Table 4A of Example 2. Each participant was randomized to receive alprazolam or placebo in a double-blind, crossover manner. On each dosing day during the qualification phase, participants fasted for at least 8 hours pre-dose and for 4 hours post-dose. Drug administration on the qualification phase days were separated by a washout period of approximately 24-hours. Pharmacodynamic (PD) response to alprazolam or placebo wasassessed by participants using a unipolar or bipolar visual analogue scale, e.g., see FIG. 3 and Table 10 to determine the drug abuse potential on the CNS depressant positive control.

[0103] The mean VAS Emax for each PD response in the qualification phase overtime was plotted for the primary and secondary PD endpoints, see FIGS. 4-11.Phase I trial - Treatment Phase

[0104] Participants who meet eligibility criteria entered the inpatient treatment phase . The last study drug administration in the qualification phase and the first study drug administration in the treatment phase was separated by a washout interval of at least 4 days. Participants released after the qualification phase, entered the clinical research unit (CRU) the day before dosing (baseline [Bs] / treatment day-1) of the treatment period. If participants were confined to the clinic from qualification phase to treatment phase, they did not perform the Bs / treatment day-1 assessments. Continued participant eligibility was ensured before participant randomization and monitored for SAEs.

[0105] Participation in the treatment phase and safe discharge required obtaining the clinical laboratory tests listed in Tables 2 and 6. During the treatment phase of the study, participants received a dose (double-dummy) on each dosing day and some remained confined to the clinical testing facility throughout the treatment phase. Participants confined to the clinic throughout the treatment phase, did not repeat the Bs / treatment Day-1 procedures before each treatment period. Treatment periods were separated by a minimum of 7 days between dosing.

[0106] Study drug administration during each treatment phase period occurred on the first day of each treatment period followed by PD, PK, and safety assessments for up to 24 hours post-dose at the study site. At each treatment phase period, participants fasted for at least 8 hours pre-dose and for 4 hours post-dose. Although soticlestat has a relatively short plasma 11 / 2 (2.6 to 8.7 hours for oral tablets), study drug administered during the treatment phase periods was separated by a washout interval of 7 days because the PD biomarker for soticlestat treatment (i.e., 24HC reduction in plasma) returns to baseline slowly, e.g., within 7 days after treatment is stopped (i.e., PD washout).

[0107] Each participant was randomized to receive oral treatments (1 in each treatment phase period) in a double-blind crossover fashion. The treatment phase is based on a 5- treatment, 10-sequence, 5-period Williams square crossover design with treatments A, B, C, D, and E as defined previously (treatment phase paradigm shown in Table 4B of Example 2).

[0108] The study assessed the relative abuse potential of a single dose of soticlestat at thehighest proposed therapeutic level of 300 mg administered BID and single supratherapeutic dose levels of 600 and 900 mg in recreational drug users. Further, single doses higher than 900 mg (e.g., a single dose up to 1350 mg) was previously found to be safe and well tolerated when administered as a single dose in the phase 1 studies, as described above.

[0109] Three dose levels were chosen to determine PD dose response, if any, and were guided by exposure and safety data from previous clinical studies. Table 5 lists the drug tablet count required to reach each drug dosage level.

[0110] An estimated sample size of 39 participants in the modified-completer analysis set provided at least 90% power to test each of the hypotheses for the primary PD endpoint. Participant disposition, demographics, and baseline characteristics are shown Tables 7-9.

[0111] Power calculations used a paired t-test and assumed a true SD of 23 points for within-participant differences for each planned treatment comparison on the Drug Liking VAS Emax, a true mean difference of 26 points between alprazolam 2 mg and placebo, and a true mean difference of 0 points between placebo and each dose of soticlestat. Approximately 50 qualified participants were randomized equally to the 10 sequences in the treatment phase, with the intent to ensure at least 39 participants in the modified-completer analysis set (Table 4B).

[0112] Participants randomized in completer analysis set completed all treatment periods of the treatment phase and had at least 1 response on the VAS for Drug Liking “at this moment” within 2 hours post-dose (hence within approximately 2 hours of historical time of first occurrence of Cmax [tmax] of soticlestat and alprazolam) for each treatment. The modified- completer analysis set includes all participants in the completer analysis set, excluding those participants with Drug Liking “at this moment” VAS Emax scores that met the following elimination criteria: Similar Emax scores (within a 5-point difference) for a participant across all treatments (including placebo), or Emax (positive control) <55, or Emax (placebo) - Emax (positive control) >5. The modified completer analysis participant set was used for the PD analysis. PD endpoints were assessed in both the qualification and the treatment phase. Each endpoint reflects the participant nonmissing values, mean, standard error, minimum, first quartile (QI), median, third quartile (Q3) and maximum for each treatment and each paired difference among treatments. Table 10 provides detailed VAS descriptions and anchor endpoints for each PD measure.

[0113] The following hypotheses were tested for the primary PD endpoint of Drug Liking “at this moment” VAS Emax. (1) Validation test of the sensitivity and integrity of the study: Does the positive control (C) produce mean responses that show greater abuse potentialcompared with placebo (P)?Ho: ic - pp <15 vs Ha: pc - pp > 15 where piC and piP are the mean Drug Liking VAS Emax for alprazolam and placebo, respectively.(2) Does the test drug (T) produce mean responses that show less abuse potential compared to positive control?Ho: pc - T <0 vs Ha: pc - pr > 0 where pT is mean Drug Liking VAS Emax for soticlestat. The hypothesis was tested separately for each soticlestat dose. Rejection of each null hypothesis would suggest lower relative abuse potential of soticlestat compared to alprazolam. (3) Does the test drug produce mean responses that show similar abuse potential compared with placebo?Ho: pr - pp >11 vs EL: pr - pp < 11This hypothesis was tested separately for each soticlestat dose. Rejection of each null hypothesis would suggest that soticlestat does not produce an abuse-related signal.

[0114] All hypotheses for the primary endpoint were tested at 1 -sided 0.05 level of significance. The hypotheses were tested sequentially in the order listed. Within the second and third hypotheses, testing was ordered from low to high soticlestat dose (300 mg, 600 mg, and 900 mg). No adjustments to p-values were made. All hypotheses were evaluated using nominal p-values. Analysis of the PD primary endpoints were performed on the modified-completer analysis set. A linear mixed effects model containing treatment, period, sequence, and first- order carryover (if applicable) as fixed effects, and participant as random effect, evaluated the hypotheses for the primary endpoint. If the variances across treatment groups showed potential heterogeneity, the model was fitted to allow unequal variances across treatment groups. If non-normality of residuals is detected in the model, a paired t-test or sign test was used as appropriate for hypothesis testing. If a potential carryover effect was detected then a carryover effect term was included in the mixed effects model.

[0115] The following hypotheses were evaluated for key and other secondary endpoints. Comparisons among treatments were evaluated at 1 -sided significance level 0.05 for hypothesis 1 and 2, and 2-sided significance level 0.10 for hypothesis 3:(1) Positive control (alprazolam) (C) versus placebo (P):Ho: pc - pp <0 vs Ha: pc - pp > 0(2) Positive control (alprazolam) (C) versus each dose of soticlestat (T):Ho: pc - pr <0 vs Ha: pc - pr > 0(3) Each dose of soticlestat (T) versus placebo (P):Ho: pT - pp = 0 vs Ha: pr - pp 0

[0116] No adjustments to p-values were made and all hypotheses were evaluated using nominal p-values. Key and other secondary PD endpoints were analyzed with the same linear mixed effects model or nonparametric approaches (as appropriate) as the primary endpoint analysis, using the modified-completer analysis set and following the same strategy for determining the analysis method.

[0117] In addition to the hypotheses testing, an exploratory PD endpoints included time to maximum (Emax ) and minimum (Emin) effect (TEmax) and (TEmin), and area over or under the effect curve from 0 to 8 hours (AOEC or AUEC), as applicable for the following assessments: drug liking “at this moment” VAS (Emin, TEmax, TEmin, and AUEC), overall drug liking VAS (Emin), take drug again VAS (Emin), bad drug effects “at this moment” VAS (TEmax and AUEC), good drug effects “at this moment” VAS (TEmax and AUEC), high “at this moment” VAS (TEmax and AUEC), alertness / drowsiness “at this moment” by bipolar VAS (Emin, TEmin, and AOEC), any drug effect “at this moment” VAS (Emax, TEmax, and AUEC), drug similarity VAS (12-hour score) and concentration-response relationship(s) with drug liking “at this moment” VAS (Emax).

[0118] Another aspect provides a method of treating the neurological disease in a recreational drug user comprising administering to the user in need thereof a pharmaceutically effective amount of soticlestat or pharmaceutical acceptable salt thereof, wherein the method results in no drug abuse potential. In one aspect, the drug abuse potential is determined by the difference in “Drug liking” response on a visual analogue scale (VAS) maximum effect (Emax) between soticlestat and a CNS depressant drug “at this moment” of at least 10 points of at least 20 points, at least 30 points (Table 11). In another aspect, the drug abuse potential is determined by the difference in “Overall Drug Liking” Emax between soticlestat and a CNS depressant drug of at least 10 points, at least 20 points, at least 30 points (Table 12). In another aspect, the drug abuse potential is determined by the difference in “Take Drug Again” on a visual analogue scale (VAS) maximum effect (Emax) between soticlestat and a CNS depressant drug of at least 10 points of least 20 points, at least 30 points (Table 13).

[0119] In another aspect, the drug abuse potential is determined by a difference in Drug Liking response “at this moment” on a visual analogue scale (VAS) maximum effect (Emax) between soticlestat and placebo (Table 11). In another aspect, the drug abuse potential isdetermined by a difference in “Overall Drug Liking” response on a visual analogue scale (VAS) maximum effect (Emax) between soticlestat and placebo is less than the margin of 11 (Table 12). In another aspect, the drug abuse potential is determined by a difference in “Take Drug Again” response on a visual analogue scale (VAS) maximum effect (Emax) between soticlestat and placebo is less than the margin of 11 (Table 13). The mean response for each treatment over time in the treatment phase is plotted for the primary and secondary PD endpoints, FIGS. 12-19.

[0120] In addition, to recording PD endpoints during the treatment phase, participants were asked to compare the similarity of their present PD VAS assessment with recreational drugs they had used in the past (Table 14).

[0121] These and other aspects may be characterized by one or more optional embodiments. In one embodiment, the pharmaceutically effective amount of soticlestat or a pharmaceutically acceptable salt thereof is from about 100 mg to about 1000 mg per day, administered in one, two, or three divided doses. In another embodiment, the pharmaceutically effective amount of soticlestat or a pharmaceutically acceptable salt thereof is about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg or about 900mg.

[0122] The exploratory pharmacokinetic endpoint assessed by plasma concentration of soticlestat, soticlestat metabolite M-I, and alprazolam (FIGS. 20-22) Safety Analysis

[0123] All participants, including those who discontinue early (except those who withdraw consent and refuse further contact), completed a safety follow-up visit 1 week (±3 days) after the last administered blinded study drug in the treatment phase.

[0124] All adverse effects (AEs) were coded using the Medical Dictionary for Regulatory Activities (MedDRA) and characterized as pretreatment and treatment-emergent according to the intake of the study drugs. TEAEs were summarized by treatment showing the number and percentage of participants who experienced at least 1 TEAE and the number of TEAEs reported (Tables 15 and 16). A by-participant adverse event (AE) data listing including reported term, coded term, treatment, severity, and relationship to treatment was provided. TEAEs leading to discontinuation and severe adverse effects (SAEs) are listed separately. Vital signs data were summarized by study phase and treatment and listed by participant. Observed values and changes from baseline are presented. Physical examination abnormalities, ECG results, clinical laboratory values, and C-SSRS responses were reported by sponsors.

[0125] Another aspect provides a method for treating a neurological disease in a recreational drug user comprising administering to the user in need thereof a pharmaceutically effective amount of soticlestat or a pharmaceutically acceptable salt thereof, wherein the method produces a similar incidence of treatment emergent adverse events (TEAEs) as administering a placebo. In another aspect, administering a pharmaceutically effective amount of soticlestat or a pharmaceutically acceptable salt thereof to a recreational drug user produces less incidence of TEAEs compared to a CNS depressant drug, wherein the TEAEs may include e.g., somnolence, euphoric mood, feeling of relaxation compared to a CNS depressant drug.

[0126] One embodiment of the disclosure is a method of treating a neurological disease in a non-dependent recreational drug user, comprising administering an effective amount of soticlestat or pharmaceutically acceptable salt. In another embodiment, the method of treating a neurological disease in a dependent recreational drug user, comprising administering an effective amount of soticlestat or pharmaceutically acceptable. In one embodiment, the method of treating the neurological disease comprising administering a therapeutically effective amount of soticlestat or pharmaceutically effective salt reduces seizure frequency. In a further embodiment, the neurological disease treated is a rare epilepsy, a developmental epileptic encephalopathy, or epileptic type disease. In one embodiment, the method treats Dravet syndrome or Lennox-Gastaut syndrome in recreational drug users 12-14 years of age. In some embodiments, the method treats Dravet syndrome or Lennox-Gastaut syndrome in recreational drug users 14-16 years of age. In some embodiments, the method treats Dravet syndrome or Lennox-Gastaut syndrome in recreational drug users from 16-18 years of age. In another embodiment, the method treats Dravet syndrome or Lennox-Gastaut syndrome in patients 18 years of age and older. In yet another embodiment, the trial results inform on soticlestat abuse potential effect when treating severe epilepsy, such as Dravet syndrome or Lennox-Gastaut syndrome, in patients 2 years of age and older.

[0127] In some embodiments, the method disclosure herein treats focal onset seizures, major motor seizures, major motor drop seizures, focal seizures with secondary generalization, infantile spasms, primary generalized tonic-clonic seizures, partial onset seizures with our without secondary generalization, simple partial seizures, complex partial seizures, simple absence seizures, and complex absence seizures. In yet another embodiment, the method treats the neurological disease, migraine or complex regional pain syndrome.EXAMPLEExample 1: Rat Study to Evaluate Abuse Potential of Soticlestat in RatsObjective

[0128] In preclinical studies, soticlestat produced no abuse-like behavioral effects in rats or dogs, e.g., excitation, hyperactivity, stereotypy, somnolence, sedation, or “wetdog” shakes, at doses <500 mg / kg (juvenile rats), <300 mg / kg (adult rats) or <30 mg / kg (dogs). Although soticlestat may exert its pharmacological action through indirect effects on NMDA receptors, in a rat discrimination study, soticlestat did not mimic (generalize) with ketamine effects, indicating that it does not share subjective similarities to ketamine, a prototypic NMDA receptor antagonist. The experiments described below compared discrimination of ketamine compared to soticlestat and self-administration of cocaine compared to soticlestat.Study Design

[0129] In the first part of the study, mildly food-restricted male Lister hooded rats were trained to discriminate ketamine (5.0 mg / kg intraperitoneally [IP]) from vehicle (IP) in 2- lever operant chambers on an FRIO food reinforcement schedule. Ketamine and soticlestat (n=8 / group) were tested orally. “Generalization” and “No generalization” were defined as >80% and <20% responding on the drug paired lever.

[0130] In the second part of the study, mildly food restricted male Lister hooded rats (n=52) were implanted with a femoral vein catheter terminating in the vena cava. Rats were trained to self-administer cocaine (0.32 mg / kg / 0.2 mL infusion in daily 2-hr sessions on an FR5 drug reinforcement schedule (maximum of 50 infusions / session). Acquisition included three consecutive sessions of > 25 cocaine infusions / session. Extinction included three consecutive sessions mean < 5 saline infusion / session. After extinction on saline (intravenously), soticlestat was substituted in the model by administering unit-doses of 0.03, 0.1, 0.3, and 1.0 mg / kg / infusion (n = 8 / dose group) to determine whether solticlestat could be substituted for cocaine. Testing sessions were 2 hrs on a FR5 schedule for a minimum of 5 and a maximum of 10 sessions. Positive reinforcement criteria required a significantly greater number of selfadministered infusions than vehicle control, with a mean > 5 infusions / session. Blood samples were taken for soticlestat determinations. Self-administration results were analyzed by 2-way ANOVA with treatment and animal as factors, and t-test for each group separately. All phases of the studies were GLP -compliant.Results

[0131] Oral ketamine dose -dependently generalized to the IP ketamine cue: 29.3%, 14.0%, 53.3%, 97.6% and 92.5% drug-associated responding at 3, 10, 20, 30 and 50 mg / kg orally,respectively. No generalization to ketamine was evoked by soticlestat: 36.9%, 25.9%, 3.9% and 8.6% drug-paired responding at 3, 10, 30, and 100 mg / kg orally, respectively. These soticlestat doses yielded plasma exposures in rats 0.061 to 7.44-times Cmax at the highest clinical dose.

[0132] Cocaine supported robust self-administration (46.8±0.81 inf / 2h session [n=52]) that extinguished on saline substitution (3.2±0.14 inf / 2h session [n=52]). Soticlestat at 0.03, 0.1, 0.3 and 1.0 mg / kg / inf) supported 7.0±1.23, 7.7±1.94, 6.3±0.62, and 5.8±0.97 inf / 2h session, respectively (all n=8) that were not significantly greater than vehicle control (5.1±1.12 inf / 2h session [n=8]). Table 1 shows the mean ± SD soticlestat exposure CO (ng / mL), clinical Cmax (ng / mL), and relative exposure per soticlestat dose..Table 1. Solticlestat exposure relative to the clinical Cmax at maximum therapeutic dose.

[0133] Figure 1 shows that soticlestat did not serve as a positive reinforcer compared to cocaine.Example 2: Clinical Trial to Determine Relative Abuse Potential of SoticlestatObjective

[0134] In humans, acute and chronic administration of soticlestat in patients and healthy participants did not produce effects (i.e., sedative, stimulant, mood-elevating, or hallucinogenic effects) consistent with those of abused drugs, even when administered at supratherapeutic doses.The primary objective of the phase I study was to determine the relative abuse potential of a single oral dose of soticlestat compared to a single oral dose of 2 mg of alprazolam and placebo in healthy adults with nondependent recreational central nervous system depressant drug use.

[0135] Because of the flat dose-response observed with benzodiazepines on subjective measures such as Drug Liking (Levy-Cooperman et al. 2016), only 1 dose was included inthe current study. The 2 mg dose of alprazolam was selected because it has been used in previous human abuse potential studies and was not expected to produce the sedation often observed with the higher 3 mg dose, which may interfere with the collection of subjective PD measures.

[0136] In a rat model, chronic soticlestat dosing and then withdrawal did not produce physical dependence at plasma values that were up to approximately 20-fold the maximum observed concentration (Cmax) at the maximum recommended human dose (MRHD) of 300 mg BID. In addition, soticlestat did not have reinforcing properties in an intravenous (IV) self-administration rat model at plasma levels of up to 1.4-fold the MRHD and did not generalize to the interoceptive cue produced by ketamine in rats at plasma concentrations of up to approximately 7.4-fold the Cmax at the MRHD.Study Design

[0137] The study design was randomized, double-blind, double-dummy, active- and placebo-controlled, with a 5-way crossover study. Within 28 days of the first alprazolam dose participants were screened for eligibility based on inclusion and exclusion criteria with 110 being the targeted number of selected subjects. Another secondary objective of the phase I study determined the trough mean plasma concentration at 24 hours, Tmax, and the safety of soticlestat compared to placebo and alprazolam as measured by treatment emergent adverse events (TEAEs).Screening and Qualification phase

[0138] Subjects were screened for inclusion and exclusion criteria and those eligible entered the qualification phase. The qualification phase tested the participant response and tolerance to the CNS depressant drug alprazolam. Participants passing the qualification phase were eligible to enter the treatment phase. The duration of the clinical study lasted 11 weeks, of which 5 weeks were the qualification and treatment phase. Figure 2 shows the participant number flow during different phases of the trial.

[0139] The qualification phase included 110 participants randomized to either alprazolam or matching placebo treatment in a 2-sequence crossover on day 1 and 2. Participants were required to satisfactorily complete the qualification phase and continue to meet all of the defined inclusion criteria and none of the exclusion criteria to enter the treatment phase. Satisfactory qualification stage completion required the participant’s Emax on “at the moment” Drug Liking VAS in response to alprazolam to be numerically >15 points higher than that of placebo and the participant’s Emax to be >65 points with alprazolam. The participant was also required to have an acceptable placebo response based on the DrugLiking VAS, defined as a Emax between 40 and 60 points, i.e., a score considered neutral on the scale, meaning neither like nor dislike. The participant had acceptable overall responses to alprazolam and placebo on the subjective measures, as judged by the investigator or designee. The safety data available following study drug administration indicated that the participant would be able to tolerate the alprazolam 2 mg dose planned for the treatment phase, as judged by the investigator, including no missing PD assessments within 4 hours of drug administration. The participant's general behavior suggests that the participant could successfully complete the study, as judged by the investigator.

[0140] The treatment phase PD endpoints and response anchors are described in Table 10. The primary PD endpoint includes a maximum effect (Emax) for Drug Liking “at this moment” assess by a bipolar visual analogue scale (VAS) (0-100 points). The secondary key endpoints were “Overall Drug Liking” assessed by a bipolar VAS (0-100 points), and “Take Drug again” assessed by a bipolar VAS (0-100 points). Participants recorded other secondary endpoints, such as Bad Effects, Good Effects, High, and Any Effects, using a unipolar VAS. Figure 3 shows an example of the unipolar and bipolar VAS scale. The “Drug Liking” and “Overall Drug Liking” response anchors were strong disliking=0, neither like nor dislike=50, and strong liking=100. The “Take Drug Again” VAS bipolar response anchors were “definitely not” =0, “neutral’ -50, and “definitely so”=100. The Unipolar scale response anchors were “not at all”=0 and “extremely’ - 100. The alertness / drowsiness assessment used a bipolar scale with response anchors of “very drowsy”=0, “neither drowsy nor alert”=50, and “very alert’ - 100. Safety was measured by the incidence of treatment-emergent adverse events (TEAEs). The overall TEAEs and the events data are shown in Tables 15 and 16 below.Inclusion criteria

[0141] Criteria required for participant eligibility included being healthy as determined by the investigator, between 18 to 55 years of age, a body mass index of 18.5 to 35.0 kg / m2, and a minimum body weight of 50.0 kg at screening, with prior CNS recreational depressant use, e.g., benzodiazepines, barbiturates, zolpidem, eszopiclone, zopiclone, propofol / fospropofol, gamma-hydroxybutyrate) at least 10 times in their lifetime and at least once in the 12 weeks before screening. Participants must also have recreational experience with at least 1 other drug class associated with abuse e.g., opioids, stimulants, cannabinoids, hallucinogens, or dissociative, at least 10 times in their lifetime. Female participants of childbearing potential must have a negative pregnancy test at screening, admission to the qualification phase (before receiving any study drug), admission to the treatment phase, and the participant’s last clinicvisit was processed using the local laboratory. Additional pregnancy tests (serum or urine) may be performed throughout the study at the investigator’s discretion. Female participants of must agree to use an effective or highly effective method of birth control as defined, during the study and for 32 days following the last dose of study drug.Exclusion criteria

[0142] Subjects were excluded if they participated in a previous soticlestat clinical study. Subjects were ineligible subjects if they self-reported a history of drug or alcohol dependence (within the past 1 year, except caffeine or nicotine, before the screening visit) and assessed by the investigator at screening visit or participated in a treatment program or rehabilitation (lifetime) for alcohol or substance dependence (other than nicotine or caffeine). Participants were asked to abstain from alcohol for 24 hours before each study visit. If a participant presented with a positive breath alcohol test at any visit after the screening visit, the participant may be rescheduled to repeat the breathalyzer test at the respective admission visit and can only be admitted upon a negative result being obtained. Participants were also asked to abstain from recreational drug use, including THC, throughout the study, from screening until after the follow-up visit or early termination.

[0143] Abstinence was confirmed via UDS at screening, at admission [Day -1] to the qualification phase, and at check-in for the treatment phase. If a participant presented with a positive UDS at screening, investigator may determine if the screening visit may continue that day or if it should be continued another day. In these cases, an investigator may have conducted a screening visit over multiple days. If a participant presented with a positive UDS (excluding (tetrahydrocannabinol [THC]) at admission to the qualification phase, the participant was not admitted but may, at the discretion of the investigator, repeat the UDS at a later date and be admitted to the qualification phase upon a negative UDS being obtained.

[0144] Participants with a positive alcohol breathalyzer test or positive urine drug screen (UDS) for substances of abuse at admission, except tetrahydrocannabinol (THC) were excluded. If a participant presented with a positive UDS, excluding THC, the subject may be rescheduled to repeat the UDS and can only be admitted upon a negative UDS being obtained, excluding THC. Positive THC UDS were permitted at admission of the treatment phase as long as the subject is not impaired at admission, in the clinical judgment of the investigator.

[0145] Heavy smokers or users of other types of nicotine products (>20 cigarettes equivalent per day) or subjects unable to abstain from smoking for at least 2 hours before and at least 8 hours after dosing were deemed ineligible to participate. Subjects consumingexcessive amounts of caffeine, defined as greater than 4 servings (1 serving equivalent to approximately 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per day were deemed ineligible to participate. Use of any concomitant medications (including prescription and nonprescription medications, herbal remedies, or vitamin supplements) within 7 days (or 5 times the 11 / 2, if known) before the first study drug administration in the qualification phase and throughout the study restricted participation.

[0146] The use of over-the-counter medications (except acetaminophen or ibuprofen) were restricted for at least 14 days (or 5-times the 11 / 2 of the drug, if known) before first study drug administration in the qualification phase and throughout the study. Subjects taking all non-study medications, including prescription, over-the-counter, herbal therapies, or vitamin supplements 30 days before screening were documented. The investigator determined if the prior / concomitant medication(s) could affect the participant’s eligibility to participate or continue to participate in the study.

[0147] The exceptions of concomitant drug include use of a stable thyroid hormone replacement medication for at least 3 months before first dosing in the qualification phase, oral contraceptive and hormone replacement therapy if use is consistent (i.e., no change in oral contraceptive) throughout the study.

[0148] Subjects were disqualified for using any drug known to be a significant inducer of cytochrome P-450 (CYP) 3 A, CYP2C19, uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A9 or UGT2B4 enzymes, and / or P-glycoprotein (P-gp), including St. John’s wort, within 28 days before the first dose in the qualification phase. Appropriate resources were consulted to determine probability of study drug interaction e.g., Flockhart Table.

[0149] Subjects were disqualified for using any investigational drug within 5 x the known elimination 11 / 2, or, if the 11 / 2 is unknown, within 30 days of first anticipated study drug administration in the qualification phase, or an investigational biologic product within 90 days before the first anticipated study drug administration in the qualification phase.

[0150] Subjects were also disqualified for having any clinically significant medical conditions, which in the opinion of the investigator would jeopardize the safety of the participant or the validity of the study results, e.g., any major cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, ophthalmologic, immunologic, dermatologic, neurologic, oncologic, musculoskeletal, psychiatric disease, including an established diagnosis of an underlying psychotic illness, or abnormal clinical assessment upon physical examination, medical history, 12-lead ECG, vital signs, or clinical laboratory values. In addition, subjects were disqualified for having a history or presence of any of thefollowing: established QT prolongation; atrial fibrillation; long QT syndrome; torsades de pointes; bradyarrhythmia; uncompensated heart failure; any 12-lead ECG with repeated demonstration of Fridericia-corrected QT interval (QTcF) >470 msec in female participants, >450 msec in male participants, and / or a QRS interval >120 msec at screening; family history (anamnesis or first degree relative with history) of unexplained sudden death or long QT syndrome; evidence of clinically significant hepatic or renal impairment including (but not limited to) alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2x the upper limit of normal (ULN), or clinically significant renal impairment as shown by estimated creatinine clearance < 80 mL / min (using the Cockcroft-Gault equation); history of severe allergic reaction (including anaphylaxis) to any food, medications, or bee sting, or a history of previous status asthmaticus; history of allergy or hypersensitivity to alprazolam or related drugs; testing positive for hepatitis B, hepatitis C, or HIV at the screening visit; any significant illness, of any nature, including coronavirus disease 2019 (COVID- 19) -related fever and symptoms, requiring hospitalization, emergency treatment, or isolation (community mandated quarantine) within 4 weeks before screening or during the study and as determined by the investigator; donated or lost more than 500 m of whole blood within 30 days preceding entry into the treatment phase; breastfeeding; and unsuitable or unlikely to comply with the study protocol for any reason by the investigator. If any participant was found to be pregnant during the study, she would have been immediately withdrawn from the study. In addition, any pregnancies in the partner of a male participant during the study, or for 90 days after the last dose, should also be recorded following authorization from the participant’s partner. Male participants were not required to use barrier contraception. Donation of sperm is not allowed during the study and within 90 days following the last administration of the study drug.

[0151] Subjects were excluded from the study for any positive response on the Columbia Suicide Severity Rating Scale (C-SSRS) or has a risk of suicide according to the investigator’s judgment based on the assessment of the C-SSRS at screening or baseline or has made a suicide attempt in the previous 12 months before dosing in the qualification phase.

[0152] Subjects were screened by clinical laboratory tests for eligibility to participate at screening and at the beginning the of the qualification stage. Clinical laboratory test assessed treatment safety at discharge from the treatment phase (day 30). The list of laboratory tests are provided in Table 2 below. The schedule of tests for the screening and qualification, and treatment phase are provided in Tables 3 and 6, respectively.Table 2. Clinical Laboratory TestsALT: alanine aminotransferase: AST: aspartate aminotransferase; FSH: follicle-stimulating hormone; THC: tetrahydrocannabinol; WOCBP: women of child-bearing potential. a Site to calculate the creatinine clearance only at screening visit for inclusion criteria. b Collected at baseline; however, results are not required to assess participant eligibility. c If urinalysis was positive for protein, blood, nitrite and / or leukocyte esterase, a microscopic examination (for red blood cells, white blood cells, bacteria, casts, and epithelial cells) was performed.

[0153] The screening and qualification phase schedule of procedures is shown in Table 3 below.Table 3. Schedule for Screening and Qualification PhasesContinued - Schedule for Screening and Qualification PhasesAE: adverse event; C-SSRS: Columbia Suicide-Severity Rating Scale; DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders-IV text revision; ECG: electrocardiogram; ET : early termination; FSH: follicle-stimulating hormone; HAV IgG: hepatitis A vims immunoglobulin G; HAV IgM: hepatitis A vims immunoglobulin M; HBsAg: hepatitis B vims surface antigen; HCVab: hepatitis C antibody; IP: investigational product; PD: pharmacodynamic; QP: qualification phase; SAE: serious adverse event; THC: tetrahydrocannabinol; UDS: urine dmg screen; VAS: visual analogue scale; WOCBP: women of childbearing potential.aThe 28-day screening window may be extended upon sponsor approval. Some screening visit assessments were distributed over multiple days upon clinical investigator discretion.bIf a participant discontinued early during the qualification phase, ET procedures were performed before discharge (if possible). Timing of discharge to be determined by the clinical investigator. Timing of ET procedures may also be determined by the clinical investigator. Participants who discontinue after the qualification phase (after Day 3) and before receiving their first dose of IP in the treatment phase need not attend an ET visit.cFor this study, the critical component were the VAS assessments, and these should be performed as close to the scheduled times defined in this protocol as possible. All other study assessments were performed in a consistent order per site’s standard practice.dAdmission occurred in the morning to ensure adequate time for pre-dose review of UDS results.eParticipants were confined between qualification phase and treatment phase upon discretion of the clinical investigator.Assign a single participant identifier number.gWeight only.11Full physical examination only conducted at screening. A brief symptom-directed physical examination will be conducted on Day -1 and before discharge on qualification phase Day 3.1Review of results from screening visit are required before dosing on Day 1.JConducted at clinical investigator discretion.kConducted by a clinical investigator using clinical judgment, when participant is positive for THC / cannabinoids1Includes pulse rate, respiratoiy rate, temperature, systolic and diastolic blood pressures. Vital signs are measured after a resting period of at least 5 minutes in a sitting position.mInvestigators completed vital sign assessments within 30 minutes before 2 -hour post-dose time point. If this could not occur before completing the VAS assessments, vital sign assessments were performed after the VAS assessments.nConducted after a resting period of approximately 5 minutes in a supine position.0Retraining was allowed, as needed.pRandomization was performed anytime between Day -1 check-in and pre-dose.qIncludes VASs for Drug Liking, High, Good Effects, Alertness / Drowsiness, Bad Effects, and Any Effects measured at the nominal timepoints (±5 minutes).rAt pre-dose, only the VASs for High, and Alertness / Drowsiness, are administered. On Day 2, the pre-dose VAS may be omitted if participants completed the 23 hour VASsFor Day 2, should be conducted before the Day 2 dosing. For Day 3, site may collect VAS anytime between 23 and 24 hours after dosing. Site should try and complete as close to Day 2 timing as possible.

[0154] The qualification stage lasted 4 days and tested the participant’s tolerance for the 2 mg alprazolam dose. Table 4A below shows the Qualification stage treatment paradigm. able 4A, Qualification phase

[0155] For treatment phase eligibility, subjects were required to show drug abuse effect, tolerance, and safety after administration of 2 mg alprazolam. For example, on the assessment of drug liking (“at the moment” Drug Liking VAS), eligible participants had Emax on “at the moment” Drug Liking VAS in response to alprazolam numerically >15 points higher than that of placebo, and an Emax of >65 points with alprazolam. Eligible participants had an acceptable placebo response based on the Drug Liking VAS, defined as a Emax between 40 and 60 points (i.e., a score considered neutral on the scale, meaning neither like nor dislike), inclusive.

[0156] Tolerance of the 2 mg alprazolam dose (planned for the treatment phase) included not missing PD assessments within 4 hours of drug administration, and a general behavior suggestive that the participant could successfully complete the study, as judged by the investigator.

[0157] The results showed the participants administered 2 mg alprazolam scored higher on Mean Drug Liking, Overall Mean Drug Liking, and Mean Take Drug Again VAS scores than subjects administered placebo (FIGS. 4-6). The Mean Bad Effects VAS scores from subjects administered 2 mg alprazolam compared to placebo were slightly higher (FIG. 7); whereas subjects administered 2 mg alprazolam compared to placebo had significantly higher Mean Good Effects and Mean High VAS scores over 8 hours (FIGS. 8 and 9, respectively). The mean Alertness / Drowsiness VAS scores was lower in subjects administered 2 mg alprazolam compared to placebo (FIG. 10), and theMean Any Effects VAS scores were higher in subjects administered 2 mg alprazolam compared to placebo (FIG. 11). The qualification phase data indicated that alprazolam, as a CNS depressant drug, has a high potential of abuse effect, validating the use of alprazolam as a CNS depressant for comparison with soticlestat in the treatment phase.

[0158] Table 4B shows the treatment phase paradigm. The treatment phrase included 50 qualified participants randomized to Sequence 1-10, with a wash out period of 7 days between the 5 periods (doses). The single dose treatments were administered on the first day of each period.Table 4B. Treatment Phase of TrialTreatment A: Soticlestat 300 mg; Treatment B: Soticlestat 600 mg; Treatment C: Soticlestat 900 mg;Treatment D: Alprazolam 2 mg; Treatment E: Placebo.bSequences are based on a Williams design (Williams 1949) (i.e., uniform within sequences, uniform within periods, and balanced with respect to first- order carryover effects). The specific sequences used here were calculated using the crossdes package (Package ‘crossdes’; Construction of crossover designs, April, 2022) inR (R Core Team

[2021] , R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria).

[0159] All treatments were by oral administration and in single dose, once on day 1 of each treatment period. Table 5 shows the 100 mg tablet / capsule number administered to reach the desired dosage in the treatment phase. Table 5 shows the schedule of procedures for the treatment phase.Table 5. Treatment Description by Tablet / Capsule CountaPlacebo that matches 100 mg soticlestat tablets.bOverencapsulated alprazolam.cPlacebo that matches overencapsulated alprazolam 2 mg.

[0160] Study drug was administered in a double-blind, double-dummy manner with the oral doses of soticlestat or matching placebo and overencapsulated alprazolam 2 mg or matching placebo administered at each treatment period in the treatment phase. The sponsor supplied study site(s) with soticlestat (TAK-935) 100 mg tablets, and placebo for match 100 mg tablets in high- density polyethylene bottles with induction seal and child-resistant caps. Each bottle contained a label that includes pertinent study information and caution statements. For more information on the study drug, please see the study pharmacy manual. Soticlestat clinical study material were labeled according to the country’s regulatory requirements. Soticlestat and placebo were provided in openlabel configuration, and unblinded study site staff prepared blinded dosing before administration to participants. Alprazolam 2 mg and matching placebo were compounded and supplied for use in this protocol. Instructions for preparation of overencapsulated alprazolam 2 mg and matching placebo can be found in the pharmacy manual.Table 6. Schedule of Procedures for the Treatment PhaseTable 6. Continued - Schedule of Procedures for the Treatment PhaseTable 6. Continued - Schedule of Procedures for the Treatment PhaseAE: adverse event; Bs: baseline; CRU: clinical research unit; C-SSRS: Columbia Suicide-Severity Rating Scale; DC: discontinuation; ECG: electrocardiogram; ET: early termination; FU: follow-up; PD: pharmacodynamics; SAE: serious adverse event; THC: tetrahydrocannabinol; Tx: treatment; UDS: urine drug screen; VAS: visual analogue scale; WOCBP: women of childbearing potential.There was a minimum of 4-day washout between qualification phase and treatment phase. Participants entered into the CRU the day before dosing (Day -1) of the qualification phase and can be released between qualification phase and treatment phase. If released after the qualification phase, participants entered into the CRU the day before dosing (Bs / treatment Day -1) of the treatment period. In some cases, the site may need to postpone dosing in the treatment phase and in such cases, site may release participant and repeat the Bs / treatment Day -1 procedures upon return to clinic, and recheck the participant into the site. Treatment periods were separated by a minimum of 7 days between dosing. Participants should remain confined throughout the treatment phase.aIf participants are confined to the clinic from qualification phase to treatment phase, they need not perform the check-in (Bs / treatment Day -1) assessments (excluding safety laboratory test and the alpha 1-acid glycoprotien). Site should unblind and ensure participant meets qualification eligibility criteria before randomizing these participants and continue to monitor for S AEs and document concomitant medications. If participants are confined to the clinic throughout the treatment phase, they need not to repeat the check-in (Bs / Treatment Day -1) procedures again after checking in the participant to the CRU.bParticipants can be discharged at washout upon clinical investigator discretion. If participants are discharged, site clinical investigator to determine if any safety assessments should be administered at discharge. All assessment described in the continued eligibility checks (h) need to be performed at re-check in. Of the other Day -1 safety assessments, only the C-SSRS is required to be administered. All other safety assessments need only be repeated if deemed appropriate by the clinical investigator.cThe time window for this visit (7 days ±3 days) is measured from Day 1 of treatment period 5, which is the last dose given in the study. This clinic visit may be substituted with a phone call.dIf a participant should discontinue early during the treatment phase, ET procedures should be performed. If participant is confined at time of discontinuation, timing of discharge to be determined by the clinical investigator. Timing of ET procedures may also be determined by the clinical investigator.

[0161] Dose assignments were captured in the audit by trial electronic data capture (EDC). Of the 58 participants entering the treatment phase, 14 participants discontinued early. Table 7 below shows the disposition of the participants.Table 7. Disposition of Participants (Treatment Phase)aThe overall column is based on all participants who were randomized in the treatment phase.

[0162] Table 8 shows the demographics of the participants in the treatment phase.Table 8. Participant Demographics during Treatment PhaseaThe overall column is based on the safety analysis set, which consists of all participants who received at least 1 dose in the treatment phase

[0163] Table 9 shows the baseline characteristics of participants during the treatment phase.Table 9. Baseline Characteristics of ParticipantsaThe overall column is based on the safety analysis set, which consists of all participants who received a least 1 dose in the treatment phase

[0164] Steps implemented to overcome perception of potential bias included removing the 14 discontinued participants from the primary analyses prior to database block, and restarting randomization assignments for subsequent cohorts at the end of the list, e.g., working backwards from the 100thrandomization number.

[0165] The primary and key secondary analyses are based on the modified-completer analysis set, which consists of all participants in the completer analysis set, excluding those whose Drug Liking “at this moment” VAS Emax scores meet one of the following elimination criteria: similar Emax scores (within a 5 -points difference) for a participant across all study treatments (including placebo), an Emax (positive control) < 55, and Emax (placebo) - Emax (positive control) > 5.

[0166] Testing conditions for pharmacodynamics (PD) assessments remained as consistent as possible across the study. Participants were monitored carefully to ensure that they completed the PD assessments appropriately, e.g., reasonable attempts were made to rouse participants who fall asleep during testing cycles. The PD VAS assessments completed by participants are shown in Table 10.Table 10. VAS Descriptions

[0167] PD measures were recorded electronically. Before completing the computerized PD measures, all participants underwent a scripted training and practice regimen. Eligible participants who appear to have difficulty differentiating between bipolar and unipolar VAS (e.g., making errors such as selecting 50 as neutral for a unipolar scale) or difficulty distinguishing between “at this moment” and “next-day” measures during the qualification phase underwent additional practice training on the difference between the scale types.Results

[0168] Table 11 shows the results of the primary endpoint is the maximum effect (Emax) of “Drug Liking” at this moment as assessed by a bipolar visual analogue scale (VAS) (0-100 points). The difference in Emax of “Drug Liking” between 2 mg alprazolam and placebo is significantly greater than 15, which further supports study validity. The difference in Emax of “Drug Liking” between 2 mg alprazolam and each dose of soticlestat is significantly greater than zero, indicating that soticlestat has less abuse potential than alprazolam. The difference in Emax of “Drug Liking” between each dose of soticlestat and placebo is significantly less than 11, indicating that soticlestat has a similar abuse potential to placebo. The data in Table 11 is depicted in FIG. 12.Table 11. Primary Analysis Results of Drug Liking “At This Moment”

[0169] The primary analysis above was performed with data from the treatment phase on the modified completer analysis set, consisting of participants who completed the treatment phase and did not meet any elimination criteria for the modified completer analysis set. Hypotheses were tested sequentially in the order shown, each at 1 -sided significance level 0.05. A margin of 15 was used to compare alprazolam to placebo in an upper-tailed test; a margin of 0 was used to compare alprazolam to each dose of soticlestat in an upper tailed test; a margin of 11 was used to compare each dose of soticlestat to placebo in a lower tailed test. If a hypothesis test resulted in p>0.05, subsequent hypotheses were not tested. A linear mixed model was used unless residuals in the model were not normal; if residuals were not normal, then a paired t-test or sign test was used according to pre-specified rules in the statistical analysis plan.aP -value is 1-sided from the sign test and median difference is reported;bP -value is 1 -sided from paired t-test and mean difference is reported; Confidence intervals are 1 -sided.

[0170] Table 12 shows the key secondary endpoint of maximum effect (Emax) of “Overall Drug Liking” as assessed by a bipolar VAS (0-100). The difference in Emax of overall drug liking between alprazolam 2mg and placebo is greater than zero, supporting validity of the study. The difference in Emax of overall drug liking between alprazolam 2 mg and each dose of soticlestat is greater than zero, which indicates that soticlestat has less abuse potential than alprazolam. The difference in Emax of overall drug liking between each dose of soticlestat and placebo is consistent with zero, which supports the claim that soticlestat has similar abuse potential to placebo. The data in Table 12 is depicted in FIG. 13.Table 12. Maximum Effect of Overall Drug Liking

[0171] The analysis above was performed with data from the treatment phase on the modified completer analysis set, consisting of participants who completed the treatment phase and did not meet any elimination criteria for the modified completer analysis set. Hypotheses for secondary endpoints were evaluated with nominal p-values with no multiplicity adjustment. Comparisons between alprazolam and placebo, and alprazolam and each dose of soticlestat were evaluated at 1-sided alpha level 0.05 with a margin of 0. Comparisons between each dose of soticlestat and placebo were evaluated at 2-sided alpha level of 0.10 with a margin of 0; a p-value >0.10 means results are consistent with the null hypothesis of no difference between soticlestat and placebo. The analysis was performed using a linear mixed model is the residuals were normal. However, if residuals were not normal, a paired t-test or sign test was used according to pre-specified rules in the statistical analysis plan.aP -value is 1 -sided from the sign test and median difference is reported;bP- value is 2-sided from paired t-test and mean difference is reported; Confidence intervals are 1 -sided.

[0172] Table 13 shows the key secondary endpoint of maximum effect (Emax) of “Take Drug Again” assessed “overall” by a bipolar VAS (0-100 points). The difference in Emax of Take Drug Again between alprazolam 2 mg and placebo is greater than zero, which supports the validity of using alprazolam in the study. The claim that soticlestat has less abuse potential than alprazolam is supported by the zero difference in Emax of Take Drug Again between alprazolam 2 mg and each dose of soticlestat. The zero difference in Emax of Take Drug Again between each dose of soticlestat and placebo supports the claim that soticlestat has similar abuse potential to placebo. The data in Table 13 is depicted in FIG. 14.Table 13. Maximum Effect of Take Drug Again

[0173] The analysis was performed with data from the treatment phase on the modified completer analysis set consisting of participants who completed the treatment phase and did not meet any elimination criteria for the modified completer analysis set. Hypotheses for secondary endpoints were evaluated with nominal p-values with no multiplicity adjustment. Comparisons between alprazolam and placebo, and alprazolam and each dose of soticlestat were evaluated at 1 -sided alpha level 0.05 with a margin of 0. Comparisons between each dose of soticlestat and placebo were evaluated at 2-sided alpha level of 0.10 with a margin of 0; a p-value >0. 10 means results are consistent with the null hypothesis of no difference between soticlestat and placebo. A linear mixed model used unless residuals were not normal. If residuals were not normal in the model, then a paired t-test or sign test was used according to pre-specified rules in the statistical analysis plan.aP-value is 1 -sided from the sign test and median difference is reported; bP-value is 2-sided from paired t-test and mean difference is reported; Confidence intervals are 1 -sided.

[0174] The Drug Similarity VAS assessed how similar the soticlestat effects were as compared to other recreational drugs previously consumed by the study participant. Table 14 shows the question participants were asked regarding previous drug use. The exact list of drugs was customized for each participant based on the drugs he or she reported using in the recreational drug use history collected at the screening assessment. In addition, all participants were asked to compare the drug they most recently received with placebo.Table 14. Similarity VASVIDMA: 3,4-methylenedioxy-methamphetamine; THC: tetrahydrocannabinol; VAS:visual analogue scale.

[0175] Other secondary endpoints are Bad drug effects, Good drug effects and High (Emax) assessed “at this moment” by a unipolar VAS (0-100 points). Another secondary endpoint were safety measures, such as incidence of treatment-emergent adverse events (TEAEs).

[0176] Participants reported treatment emergent adverse events (TEAEs) during the treatment phase. Table 15 shows the total TEAEs by treatment and TEAEs that were treatment related, serious, and lead to study discontinuation. The data in table 15 is based on the safety analysis set, which consists of all participants who received at least one dose of the study drug in the treatment phase.Table 15. Overall Treatment Emergent Adverse Events

[0177] Table 16 shows the incidence of treatment emergent event types (preferred term)reported by at least two participants during the treatment phase by study drug and placebo. Reporting participants received at least one dose of the study drug in the treatment phase. Table 16. Incidence of TEAE in Relation to Drug Treatment

[0178] Other safety endpoints included clinical laboratory values, vital signs, electrocardiograms (ECGs), and presence of suicidal ideation or behavior based on the C- SSRS responses.Pharmacokinetic data

[0179] Plasma concentrations of soticlestat and soticlestat metabolite (M-I) were measured by high-performance liquid chromatography with tandem mass spectrometry. Plasma concentrations of alprazolam were measured using a validated liquid chromatography tandem mass spectrometry assay.

[0180] The mean plasma concentration of soticlestat in subjects administered 300 mg, 600 mg, or 900 mg soticlestat reached Tmax (ng / ml) between 0.5 and 1 hour after dosing (FIG. 20). The mean plasma concentration of the soticlestat N-oxide metabolite M-I in subjects administered 300 mg, 600 mg, or 900 mg soticlestat reached Tmax (ng / ml) between 0.5 and 1 hour after dosing (FIG. 21). The mean plasma concentration of the alprazolam in subjects administered 2 mg alprazolam reached Tmax (ng / ml) between 0.5 and 1 hour after dosing (FIG. 22).

[0181] The soticlestat mean plasma concentration in subjects administered 300 mg, 600 mg, or 900 mg soticlestat is 0 ng / ml 24 hours after dosing (FIG. 20). The soticlestat N-oxide metabolite M-I mean plasma concentration in subjects administered 300 mg, 600 mg, or 900 mg soticlestat is 0 ng / ml 24 hours after dosing (FIG. 21). The alprazolam mean plasma concentration in subjects administered 2 mg alprazolam is approximately 10 ng / ml (FIG. 22).EQUIVALENTS AND SCOPE

[0182] In the claims articles such as "a," "an," and "the" may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all group members are present in, employed in, or otherwise relevant to a given product or process.

[0183] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is / are referred to as comprising particular elements and / or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms "comprising" and "containing" are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0184] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particularembodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0185] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

CLAIMS1. A method for treating a neurological disease in a recreational drug user comprising administering to the user in need thereof a pharmaceutically effective amount of soticlestat or a pharmaceutically acceptable salt thereof.2 A method for treating a neurological disease in a recreational drug user and a means for avoiding potential abuse effects comprising administering to the user in need thereof an effective amount of soticlestat or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 or 2, wherein the recreational drug user is a non-dependent recreational drug user.4 The method of claim 1, 2 or 3, wherein the recreational drug user has used a CNS depressant or is currently using a CNS depressant.

5. The method of claim 4, wherein the CNS depressant is a benzodiazepine or sedativehypnotic.

6. The method of claim 5, wherein the benzodiazepine is clonazepam, diazepam, alprazolam, triazolam, estazolam, chlordiazepoxide, clorazepate, lorazepam, halazepam, oxazepam, midazolam, prazepam, temazepam, quazepam, flunitrazepam, or flurazepam.

7. The method of claim 5, wherein the sedative-hypnotic is citalopram, escitalopram, paroxetine, zolpidem, eszopiclone, zopiclone, suvorexant, lemborexant, estazolam, tasimelteon, daridorexant, ramelteon, doxepin, gamma-hydroxybutyrate, barbiturates, propofol / fospropofol, or zaleplon.

8. The method of claim 1, 2, or 3, wherein the recreational drug user has used or is currently using a benzodiazepine or sedative-hypnotic.

9. The method of claim 8, wherein the benzodiazepine or sedative-hypnotic is alprazolam, clonazepam, diazepam, triazolam, estazolam, chlordiazepoxide, , flunitrazepam, clorazepate, halazepam, lorzepam, flurazepam, oxazepam, midazolam, prazepam,temazepam, quazepam, citalopram, escitalopram, paroxetine, barbiturate, zolpidem, suvorexant, lemborexant, Estazolam, tasimelteon, doxepin, ramelteon, zaleplon, eszopiclone, suvorexant, zopiclone, propofol / fospropofol, or gamma-hydroxybutyrate.

10. The method of claim 1, 2, or 3, wherein the recreational drug user has used or is currently using a hallucinogen or dissociative drug.

11. The method of claim 10, wherein the hallucinogen or dissociative drug is ketamine, nitrous oxide, phencyclidine, or dextromethorphan-based cough syrups (often labeled DXM).

12. The method of claim 1, 2, or 3, wherein the recreational drug user has used or is currently using cocaine, morphine, marijuana, opioid, stimulant, or cannabinoid.

13. The method of any one of preceding claims, wherein the recreational drug user has used a recreational drug multiple times in their lifetime.

14. The method of any one of preceding claims, wherein the method produces a similar incidence of treatment emergent adverse events (TEAEs) as a placebo.

15. The method of any one of preceding claims, wherein the method produces less incidence of TEAEs such as somnolence, euphoric mood, feeling of relaxation compared to a CNS depressant drug.

16. The method of any one of preceding claims, wherein the method results in a reduced incidence of drug abuse potential.

17. The method of claim 16, wherein the drug abuse potential is determined by the difference in “Drug liking” response on a visual analogue scale (VAS) maximum effect (Emax), between soticlestat and a CNS depressant drug of at least 10 points, at least 20 points, or at least 30 points.

18. The method of claim 16, wherein the drug abuse potential is determined by the difference in “Overall Drug Liking” on a visual analogue scale (VAS) maximum effect (Emax) between soticlestat and a CNS depressant drug “at this moment” of at least 10 points,at least 20 points, or at least 30 points.

19. The method of claim 16, wherein the drug abuse potential is determined by the difference in “Take Drug Again” on a visual analogue scale (VAS) maximum effect (Emax) between soticlestat and a CNS depressant drug of at least 10 points, at least 20 points, or at least 30 points.

20. The method of claim 16, wherein the drug abuse potential is determined by a difference in “Drug Liking” response on a visual analogue scale (VAS) maximum effect (Emax) between soticlestat and placebo.

21. The method of claim 16, wherein the drug abuse potential is determined by a difference in “Overall Drug Liking” response on a visual analogue scale (VAS) maximum effect (Emax) between soticlestat and placebo of at least 10 points, at least 20 points, or at least 30 points.

22. The method of claim 16, wherein the drug abuse potential is determined by a difference in “Take Drug Again” response on a visual analogue scale (VAS) maximum effect (Emax) between soticlestat and placebo of at least 10 points, at least 20 points, or at least 30 points.

23. The method of any one of preceding claims, wherein the pharmaceutically effective amount of soticlestat is from about 100 mg to about 1000 mg per day, administered in one, two, or three divided doses.

24. The method of claim 23, wherein the pharmaceutically effective amount of soticlestat is about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, or about 900 mg per day.

25. The method of any one of preceding claims, wherein the neurological disease is epilepsy.

26. The method of claim 25, wherein the epilepsy is rare epilepsy, developmental epileptic encephalopathy, or epileptic type disease.

27. The method of any one of preceding claims, wherein the neurological disease is Dravet syndrome or Lennox-Gastaut syndrome.

28. The method of any one of claims 1-24, wherein the neurological disease is seizures.

29. The method of claim 28, wherein the seizure is associated with Dravet syndrome or Lennox-Gastaut syndrome in patients 2 years of age and older.

30. The method of claim 28, wherein the seizure is associated with Dravet syndrome or Lennox-Gastaut syndrome in patients 12-14 years of age.

31. The method of claim 28, wherein the seizure is associated with Dravet syndrome or Lennox-Gastaut syndrome in patients 14-16 years of age.

32. The method of claim 28, wherein the seizure is associated with Dravet syndrome or Lennox-Gastaut syndrome in patients 16-18 years of age.

33. The method of claim 28, wherein the seizure is associated with Dravet syndrome or Lennox-Gastaut syndrome in patients 18 years of age and older.

34. The method of claim 28, wherein the seizure is focal onset seizures, major motor seizures, major motor drop seizures, focal seizures with secondary generalization, infantile spasms, primary generalized tonic-clonic seizures, partial onset seizures with or without secondary generalization, simple partial seizures, complex partial seizures, simple absence seizures, and complex absence seizures.

35. The method of any one of claims 1-24, wherein the neurological disease is migraine or complex regional pain syndrome.

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