Gastro-resistant controlled release oral dosage forms

Abstract

This disclosure relates to gastro-resistant, controlled release dosage forms comprising Compound (I): F O N N O (I), or a pharmaceutically acceptable salt and / or solvate thereof, the pharmacokinetic properties of these dosage forms, and the preparation of the same. The novel dosage forms disclosed herein are useful in reducing the risk of QT prolongation in a subject and in treating a disorder in a subject in need thereof, e.g., a subject diagnosed with schizophrenia, for example, in treating the negative symptoms in a subject diagnosed with schizophrenia having the CYP2D6 EM genotype. 20 24 21 97 17 13 S ep 2 02 4 A B S T R A C T S e p 2 0 2 4 2 1 9 7 1 7 1 3 2 0 2 4 F O N N O

Description

Equipment Type Autosampler G1367B autosampler and G1330B thermostat (Agilent) LC pump G1311A quaternary pump and G1322A degasser (Agilent) Column oven G1316A thermostatted column compartment (Agilent) Detector EP10+ HSID^ (Ionics) System care Needle rinsing solvent             80 / 20 (v / v) Acetonitrile / water solution Needle rinsing programming Step Description 1 Wash needle in flush port for 15 seconds 2 Drow def amount from sample, 200 pL / min, 1 mm offset 3 Wash needle in flush port for 15 seconds 4 Inject 5 Remote start pulse, duration 10 x 12.5 msec Analysis conditions Injection volume                 5 pL Runtime                      6.0 min Retention times (ri) Analyte Rt (min) MIN-101 (C YR-101) ca. 2.9 BFB-520 ca. 2.3 BFB-999 ca. 2.4 CYR-101-d6 ca. 2.9 BFB-784 ca. 2.4 2024219717   13 Sep 2024 • LC equipment no. 3 [5] Description Equipment Type Autosampler Acquity UPLC Sample Manager FTN (Waters) LC pump Acquity UPLC I-Class (Waters) Columnoven Acquity UPLC Column Heater (Waters) Detector XevoTQ-S (Waters) System care Needle rinsing solvent Exterior (Wash) Interior (Purge) Needle rinsing programming 80 / 20 (v / v) Acetonitrile / water solution 65 / 35 (v / v) Acetonitrile / water solution Pre-mjection wash: 0 second Post-injection wash: 6 seconds Analysis conditions Injection volume                 0.5 pL Run time                       6.0 min Retention times (Rt) Analyte Rt (min) MIN-101 (CYR-101) ca. 3.0 BFB-520 ca. 2.4 BFB-999 ca. 2.4 CYR-101 -d6 ca. 2.9 BFB-784 ca. 2.5 2024219717   13 Sep 2024 • LC equipment no. 2 [3] Description Equipment Type Autosampler Acquity UPLC (Waters) LC pump Column oven Acquity UPLC high temperature column heater (Waters) Detector API 4000 (AB Sciex) System care Needle rinsing solvent Strong solvent Weak solvent 80 / 20 (v / v) Acetonitrile / water solution 2000 pL 65 / 35 (v / v) Acetonitrile / water solution 4000 uL Analysis conditions Injection volume 1 pl Injection mode Partial loop Run time 6.0 min Retention times (re) Anaiyte Rt (min) MIN-101 (CYR-101) ca. 2.9 BFB-520 ca. 2.3 BFB-999 ca. 2.4 CYR-101-d6 ca. 2.9 BFB-784 ca. 2.4 Data processing and acceptance criteria • Data processing [2] MIN-101 (CYR-101) BFB-520 BFB-999 Calibration range LLOQ (ng / mL) 0.2500 0.2500 0.2500 ULOQ (ng / mL) 200.0 50.00 50.00 Response MIN-101 peak area / CYR-lOl-d.6 peak area BFB-520 peak area / BFB-784 peak area BFB-999 peak area / BFB-784 peak area Regression model 1 / X2 weighted simple linear regression 1 / X2 weighted simple linear regression 1 / X2 weighted simple linear regression 2024219717   13 Sep 2024 Example 7: Synopsis of Protocol MIN-101C06 Name of Sponsor / Company: Minerva Neurosciences, Inc.____________________________________________________________ Name of Investigational Product: MIN-101___________________________________________________________________ Study Title: A Phase 1, Open-Label, Randomized, 3-Treatment Sequence, 3-Period, SingleDose, Crossover Study in CYP2D6 Extensive Metaboliser Healthy Subjects to Compare the Pharmacokinetic Properties of 2 Gastro-Resistant and 1 Comparator Modified Release Formulations of MIN-101 and its Metabolites Followed by Food Effect Testing of the Selected Gastro-Resistant Controlled Release Formulation Objectives: Primary: Part 1: PK Evaluation • To evaluate the pharmacokinetic (PK) profiles of MIN-101 and its main metabolites (BFB-520 and BFB-999) following administration of 2 Gastro-Resistant and 1 Comparator Modified Release (MR) formulations of MIN-101 in healthy cytochrome P450 (CYP) 2D6 Extensive Metaboliser (EM) male and female subjects • To Select 1 gastro-resistant MR formulation for use in fed state. Part 2: Food effect • To evaluate the effect of food (given as a high fat, high calorie meal) on the bioavailability of MIN-101 and its main metabolites when the selected gastro-resistant MR formulation is administered as a single dose of 32 mg to healthy CYP2D6 EM male and female subjects. Secondary: Part 1: PK Evaluation • To provide additional information on the safety and tolerability of single doses of MIN-101 in healthy CYP2D6 EM male and female subjects. • To evaluate the relationship between plasma levels of MIN-101 and its main metabolites on electrocardiogram (ECG) parameters including QT / QTcF Part 2: Food effect • To evaluate the safety and tolerability of the selected MR formulation in healthy CYP2D6 EM male and female subjects in fed as compared to fasted state. 2024219717   13 Sep 2024 Methodology: This is a single-center, 2-part, phase 1 study. Part 1: PK Evaluation Part 1 is an open-label, randomised, 3-treatment sequence, 3-period study to evaluate the PK profile of MIN-101 and its metabolites (BFB-520 and BFB-999) after single oral administration of 3 formulations of MIN-101 (2 prototypes of CR gastro-resistant (GR) formulations and Icomparator MR formulation). Each subject will receive a single dose of each of the formulations over the 3 periods. There will be a washout of 14 ± 2 days between the three periods. In total, 16 healthy CYP2D6 EM male or female subjects (with an ideal equal gender split, but a minimum of 6 of each sex) will be dosed to ensure data in 12 evaluable subjects. To be evaluable, subjects must have received all 3 formulations and have sufficient data for the primary objective of Part 1 of the study. Subjects must provide written informed consent to participate in the study before evaluations are performed or any laboratory samples are collected. Subjects will be evaluated for study eligibility during the screening period. After written informed consent is obtained, a complete medical history will be documented. A complete physical examination will be conducted, including measurement of vital signs, ECG (triplicate), body weight, and height. Hematology, clinical chemistry and urinalysis will be performed for all subjects. All subjects must be willing to use an acceptable double-barrier method of birth control with their partners from Screening through 90 days after the last dose. Part 2: Food effect Subjects who completed part 1 of the study will return and receive a further single oral dose of one of the selected GR prototype under fed conditions to allow the assessment of food effect by comparison of the PK properties to those obtained in Part 1. Part 2 will commence after a review of the PK and safety data to decide which GR formulation will be used. There will be a wash-out period of 14 ± 2 days after part 1 has been completed. The end-of-study or early withdrawal assessments will be performed 5-9 days after the last received dose.___________________________________________________________________________________________________ Number of Subjects (planned): In total, 16 healthy CYP2D6 EM male or female subjects (with an ideal equal gender split, but a minimum of 6 of each sex) will be dosed to ensure data in 12 evaluable subjects. Subjects who are withdrawn for non-IMP related adverse events (AEs) will be replaced as required to ensure 12 evaluable subjects for Part 1 and for Part 2, at the end of the clinical study. Subjects withdrawn due to an IMP-related AE will not be replaced. 2024219717   13 Sep 2024 Diagnosis and Main Criteria for Inclusion / Exclusion: Inclusion Criteria Subjects must satisfy all of the following inclusion criteria during screening to be enrolled in the study: 1. Confirmed CYP 2D6 extensive metaboliser genotype defined as a subject that has at least one functional allele (*1, or *2) but has no non-functional allele, meaning any combination of *1 and *2, and a decreased function allele (*10, *17 or *41) is allowed via documented testing 2. Subject has given voluntary written informed consent before performance of any study related procedure 3. Must be 18 to 45 years of age, inclusive 4. Subject must be a healthy male or female as indicated by thefollowing: • Clinical chemistries, haematology, and urinalysis tests must be within normal, allowable limits (if out of range, and with the exception of potassium, magnesium, and calcium, must be considered clinically significant to be exclusionary) and performed within 21 days of receiving first dose of study drug • Body mass index of between 18 and 30 kg / m2, inclusive • Normal vital signs after 5 minutes resting in supine position: o 95 mm Hg < systolic blood pressure <140 mm Hg o 50 mm Hg < diastolic blood pressure < 90 mm Hg o 50bpm < heart rate < 90 bpm o Normal 12-lead ECG defined as: P <120 ms, 120 ms < PR < 210 ms, QRS < 120 ms, QTc (Fridericia) < 430 msec for males and < 440 msec for females (incomplete right bundle branch block can be accepted) 5. Agree to abstain from all medication (except for allowed birth control defined in inclusion criteria 6), including non-prescription and prescription medication (including vitamins and natural or herbal remedies, e.g. St. John’s Wort) for 21 days before the first dose with IMP on period 1 until discharged from the study (end of post study medical following period 4) 6. Subject agrees to use the following methods of birth control: Female subjects of child bearing potential must be willing to use two methods of contraception throughout and up to 30 days after completion of the study. One of which must be a highly effective method defined as one which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. The following highly effective contraception methods acceptable for this study are: • Surgical sterilization (i.e., bilateral tubal ligation / salpingectomy, hysterectomy for female subjects or partners; vasectomy for male subjects orpartners) • Placement of an intrauterine device or intrauterine system • Hormonal contraception (implantable, patch, injectable) PLEASE NOTE: Oral hormonal contraceptives are not permitted in this study. • True sexual abstinence when this is in hne with the preferred and usual lifestyle of the subject, periodic abstinence (e.g. calendar ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of the trial and withdrawal are NOT acceptable methods of contraception) 2024219717   13 Sep 2024 The following acceptable methods can be used as a second form of contraception during the study: • Barrier methods for female subjects include either their partner's use of a condom or the subject's use of an occlusive cap [diaphragm or cervical / vault caps] with spermicidal foam, gel, film, cream, or suppository Female subjects who are post-menopausal (defined as spontaneous amenorrhea for at least 1 year or spontaneous amenorrhea for at least 6 months confirmed by Follicle stimulating hormone [FSH] result of >40 lU / mL) are eligible for this study. Male subjects Male subjects who have been sterilised or have partners of non-childbearing potential (including homosexual men) are required to use one barrier method of contraception. This is to prevent unintended exposure of the partner to the study drug via seminal fluid (for male subjects, this must be a condom or their partner's use of an occlusive cap [diaphragm or cervical / vault caps]. Male subjects who have partners of childbearing potential must be willing to use one barrier method of contraception with their partners throughout the study (a condom or their partner's use of an occlusive cap [diaphragm or cervical / vault caps]). Their partners must also be using a highly effective method of birth control defined as one in which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as sterilisation, implants, injectables, combined oral contraceptives, and intrauterine devices for up to 90 days after completion of the study. Subjects must agree to inform the Investigator if their partner becomes pregnant during this time. 7. Must be willing and able to communicate and participate in the whole study. 8. Willing to eat all the food supplied throughout the study 2024219717   13 Sep 2024 Exclusion Criteria Subjects meeting any of the following exclusion criteria are not to be enrolled in the study: 1. A history of clinically significant gastrointestinal disease (especially peptic ulcerations, gastrointestinal bleeding, ulcerative colitis, Crohn’s disease or Irritable Bowel Syndrome); renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic or psychiatric disease (especially those with a past history of clinically significant depression, suicidal ideation or suicide attempts), or cardiovascular disease, or any other condition which, in the opinion of the principle investigator, would jeopardize the safety of the subject or impact the validity of the study results 2. Acute diarrhea or constipation in the 7 days before the predicted first study day. If screening occurs >7 days before first study day, this criterion will be determined on first study day. Diarrhea is defined as the passage of liquid feces and / or a stool frequency of > 3 times per day. Constipation will be defined as a failure to move the bowels more frequently than every other day 3. Subject has donated blood within 90 days or plasma within 30 days of study dosing 4. Regular alcohol consumption in males >21 units per week and females > 14 units per week (1 Unit = % pint beer, 25 mL of 40% spirit or a 125 mL glass of wine) 5. Subject has a borderline or long QTc Fridericia interval as defined by screening readings of >430 msec for males and >440 for females or a personal or familial history of long QT syndrome 6. Subject has participated in a clinical trial within 90 days prior to study initiation 7. F emales who are pregnant or breast feeding 8. Subject has used any prescription medication or over-the-counter (OTC) medication, including vitamin supplements, within 21 days prior to day -1 9. Subject has been treated with any known P450 2D6 or 3A4 enzymes altering drugs (e.g., beta blockers, antidepressants, antipsychotics, certain antibiotics such as erythromycin, ketoconazole, rifampicin, trimethoprim or clarithromycin, benzodiazepine such as alprazolam or midazolam, antihistamines such as chlorpheniramine, calcium channel blockers such as amlodipine or diltiazem, or PDE5 inhibitors) within 30 days prior to the study 10. Subject has smoked or used nicotine products within 2 months prior to or during the study 11. Subject has sought advice from or been referred to a GP or counsellor for abuse or misuse of alcohol, non-medical drugs, medicinal drugs or other substance abuse, e.g. solvents 12. Subject has a positive blood screen for HIV, Hepatitis B surface antigen (HBsAg), and Hepatitis C Antibody 13. Any current or previous use of drugs such as opiates, cocaine, ecstasy, or intravenous amphetamines and / or a positive mine screen for alcohol or drugs of abuse. Subjects who admit to occasional past use of cannabis will not be excluded as long as they have a negative drugs-of-abuse test and have been abstinent from cannabis use for at least 3 months 14. Subject has a current uncontrolled inter-current illness (i.e., active infection) or has had a clinically significant illness within the last 30 days prior to Day -1 15. Subject has had major surgery within 28 days of study entry, or 12 months prior to study for gastrointestinal surgery. 16. Failure to satisfy the investigator of fitness to participate for any otherreason. 2024219717   13 Sep 2024 Test Product, Dosage, and Route of Administration: Part 1: After fasting for 10 hours overnight, on the morning of dosing days, study drug will be administered with 240 mL of noncarbonated water. Subjects will have their first meal at lunch time. Subjects will receive a single oral administration of each of the following regimens in a randomized manner, separated by a 14±2 days washout period: Regimen A: 32 mg MIN-101 of the current modified-release formulation (comparator) identified as MR-32 formulation administered in the fasted state Regimen B: 32 mg MIN-101 of Gastro-resistant CRFormulation identified as GR-01: administered in the fasted state Regimen C:32 mg MIN-101 of Gastro-resistant CRFormulation identified as GR-02: administered in the fasted state Part 2: In Part 2, subjects will receive 1 oral dose of the selected gastro-resistant CR formulation (GR-01 or GR-02) in the fed state. After fasting for 10 horns overnight, on the morning of Day 1, subjects will be given a high-fat, high-calorie breakfast before study drug administration. Subjects will consume the meal over a 25-minute period or less. After completing the meal, and 30 minutes after the start of the meal, study drug will be administered. All study drugs will be administered orally with 240 mL of noncarbonated water. Water will be allowed as desired except for 1 hour before and 1 horn after drug administration. Reference Therapy, Dosage and Mode of Administration: Not Applicable. 32mg MIN-101 of the current modified release formulation to be used as a comparator._______________________________________________________________________________________ Duration of Subject Participation / Duration of Study / Duration of Treatment: Selection: Up to 21 days prior to first dose period 1 Institutionalization: From morning of Day -1 up to Day 4 for 4 separate periods Washout Period: 14±2 days from previous period dosing End-of-study visit: 7 (± 2 days) days after the last dose Total study length (including a screening period of 21 days): Up to 78 Days. 2024219717   13 Sep 2024 EVALUATION CRITERIA Pharmacokinetics: Plasma will be stored at -80°C until analysis. Plasma samples will be analyzed for MIN-101 and its metabolites BFB-520 and BFB-999 using a validated LC-MS / MS method. Blood samples for MIN-101 will be collected at time 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 14, 16, 20, 24, 28, 32, 36, 48, 60, and 72 hours post-dose on Day 1 of all periods. The following key plasma PK parameters will be calculated using non-compartmental methods: Cmax, Tmax, Tiag, partial AUC (e.g., AUCn, AUC24), AUCiast, AUG,. and tv2. Additional PK parameters may be included if deemed appropriate. ECG to be detailed as there will be PK / PD assessment The effects on cardiovascular variables will be evaluated by means of descriptive statistics and frequency tabulations. These tables will include observed values and changes from Baseline values (the pre-dose ECG will be used as Baseline) to allow detection of clinically relevant changes in individuals. The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, QT interval, and QTc interval corrected for heart rate using QTcF. QTcF values will be tabulated for their absolute values and also tabulated relative to Baseline measurements in order to detect individual QTcF changes. Descriptive statistics of QTcF intervals and changes from Baseline will be summarised at each scheduled time point. The percent of subjects with QTc interval > 450 milhseconds, > 480 milliseconds, or > 500 milliseconds will be summarised as will the percent of subjects with QTcF interval increases from Baseline of 30 to 59 milliseconds or > 60 milliseconds. Important abnormalities in ECG waveform that are changes from the Baseline readings will be reported (e.g., changes in T-wave morphology or the occurrence ofU-waves). Safety and Tolerability: The incidence of adverse events and clinically significant abnormal laboratory, vital signs and ECGs values will be recorded based upon Investigator observation and subject reporting. STATISTICAL CONSIDERATIONS Sample size: The sample size for this study is based upon both quantitative and qualitative consideration. In previous single dose experience with EM subjects, the inter-subject coefficient of variance (CV) for plasma AUC and Cmax for MIN-101 reference formulation is estimated to be about 30% and 50%, respectively. Therefore, the selected sample size of 12 to 16 completers should be sufficient to address the objectives of this study and to detect the occurrence of rare adverse events should such event are likely due to treatment with MIN-101. Every effort will be made to have an equal number of males and females enrolled. Pharmacokinetics: Pharmacokinetic parameters will be summarized by mean, standard deviation, standard error of the mean, coefficient of variation, minimum, median, and maximum, as appropriate, for each formulation and between the selected MR formulation for each food condition. The 90% confidence intervals for the ratio of mean log-transformed plasma partial AUC, AUCiast, and AUC , and Cmax will be constructed using the estimated least squares means and intra-subject variance from a mixed effects model. Additional analysis will be performed if deemed necessary including the relationship between plasma levels of MIN-101 and its main metabolites and changes in QTcF intervals. Safety: Safety and tolerability of MIN-117 will be based upon the review of individual values and summary statistics. Incidence of treatment-emergent adverse events will be tabulated by counts and percentages. Abnormalities in clinical laboratory, vital signs, and ECG will be based on pre-defined normal ranges and will be tabulated by dose group showing subject counts and percentages. 2024219717   13 Sep 2024

[00324] Examples 8-11 detail an open-label, randomized, 3-treatment sequence, 3-period study to evaluate the PK profile of MIN-101 and its metabolite BFB-520 after single oral administration of 3 formulations of MIN-101 (2 prototypes of CR gastro-resistant (GR) formulations (GR-01 and GR-02) and 1 comparator MR formulation (MEG2)). Each subject received a single dose of each of the formulations over the 3 periods. There was a washout of 14 ± 2 days between the three periods.

[00325] In the Examples, various tables are shown which include the plasma concentrations time profile of various compounds, including, for example, IH-Isoindol-l-one, 2-[[l-[2-(4-Fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, i.e., Compound (I). In these Tables, the use of the “MIN-101” or “MIN101” is intended to refer to the free base, i.e., Compound (I). Example 8: In Vivo Pharmacokinetic Analysis of MIN-101 in CR GR-01 Tablets, CR GR-02 Tablets, and MR 32 mg Capsules (MR32) (tau = 72 h)

[00326] MR32 - 12 subjects (cross-over)

[00327] Geo Mean Cmax: 28.34 ng / mL

[00328] Median Tmax: 2.00 H AUC(o-tau): 291.55 ng-H / mL 2024219717   13 Sep 2024 Table 8. MR32 Mean MIN-101 Plasma Concentrations and Parameters MR32 MR32 MfN-101 PLASMA CONCENTRATIONS andAUCcrt Hours MEAN Sd Sm CV% 5 «,00 6,00 8.08 0,08 0.25 8,08 8,08 0.03 0,5 S.5S 7,42 6,48 113,08 1 19.. SS 7,24 5.44 38,77 -1,5 23,96 7,68 6,33 32.84 2 24,16 7,89 5,97 32,64 2,5 24,68 +5,.47 5,49 26,24 3 22,96 5,41 4,71 24.54 3,5 20,34 5 38 4,21 26,46 4 13,45 5,61 4,92 28,S3 5 21,54 18,38 7.17 48,80 15,19 6,89 4,91 45,33 7 11,86 5,89 3,82 49,52 S 10,36 4 69 3,39 45,27 to 12,46 5,94 4,95 47.65 42 12,68 5,64 4,41 44,58 14 10,33 4,86 3,98 47,85 46 7.74 3,44 2.54 40,56 20 4.12 2..25 4,85 54,63 24 3,11 1,82 1,48 52 21 28 2,38 2,24 1,38 93,57 32 1,45 4,42 0,36 97,56 36 0,98 4,15 0,65 119,73 46 ¢.20 0,35 0,27 176.,68 SO 0,83 0,12 0,06 346,41 72 C04 0,13 8,07 346,41 CMax ngM 29.52 ACO 6.70 30,48 Tmax H 2,42 1,33 0,39 54,98 AUCS-t 291.55 68,12 53.61 22,88

[00329] See Figure 4.

[00330] GR-01 - 12 subjects (cross-over)

[00331] Geo Mean     18.82 ng / mL

[00332] Median Tmax: 4.50 H 2024219717   13 Sep 2024 AUC(o-tau): 284.52 ng H / mL Relative Bioavailability versus MR32: F% Ci!iax: 69.9%, F% AUQo-tau): 101.3% Table 9. GR-01 Individual MIN-101 Plasma Concentrations and Parameters GR91 GR91 MEAN 8BN-W PLASMA CONCENTRATIONS and AUCo- Hours 1-MiN-101 2-MIN-101 3-M5N-101 S^!N-101 S-MiN-101 7^HN-1C1 8-M1N-W1 9-MiN-lOI <0-MW-<B1 11-MW-1G1 12-MttMd tS-MPMOI 0 0.00 0,08 0.00 0,00 0.00 0.00 0.00 0.00 0.00 0,06 0.00 0,90 0,25 0.00 0,08 0.90 0,00 0.00 0,00 0.00 0.00 0.06 0.06 0,00 0,00 0;S 0,00 0,00 0,00 0,00 0.00 0,00 0.00 0.90 0.06 0 06 O.OO 9,80 1 0,00 0,00 0,69 0,00 0.90 0,00 0,00 0.G0 4.22 0 06 O.OO 9,80 i.S 0,00 0,00 6.26 0,00 0.00 0.00 0.38 0,00 0.42 0.06 0,00 7,98 2 3.03 5,42 10.88 2,50 0.00 0,00 <3.23 0,00 8.71 <8.93 0,48 B,14 2.5 15.05 13.82 11.87 12.14 0.00 3,45 <2.42 3,00 12.78 24.17 23.30 7,62 3 17,85 17,81 11,10 13,88 0.39 13.78 11.08 24.92 12.98 26.98 28.00 10,13 S 5 15,58 21.53 10.97 12,31 6.52 10.86 <0.94 28.13 13.86 25,78 24.91 12.18 4 20,68 19.93 8,23 11.96 15,23 9,53 8,04 22.91 17,64 24.78 22.55 11.36 5 17,05 17.24 8,66 14.68 15.63 8,44 <4.90 17.95 12,92 24.46 12.86 12,99 6 15.26 14.41 8.89 13.16 13.39 6.06 <2.35 11,72 7.62 19,24 5.64 10.42 7 $.61 11.29 6.28 12.62 10.69 4.71 11,51 13,35 5..70 17,83 9.72 $.08 3 7.46 7.20 5.58 11.86 10.51 3,51 8.19 16,53 13.39 14.16 5,82 5.52 40 4,39 5,10 12.68 11.88 6,19 2.71 <8.08 17.00 18.05 8,98 13,19 10,59 12 9,45 5,59 10.24 20,15 7.24 3,06 <2.22 13.92 16.31 <1.15 13.3$ 12,47 14 13,11 10.14 12,91 17,73 7.12 3,52 <2.83 12.02 14.42 <1.87 20.32 6,38 10 10,98 8,35 1253 16.38 6,40 3,18 7,19 11.25 13.48 <3.26 13.44 9,02 20 5,54 3,88 4,69 8,36 4,95 2,95 2,44 7,99 8.52 9.78 5.S2 3.23 24 5,57 1,94 3,21 6.73 6.31 2,38 290 12.21 3.96 <0.97 3,63 7,08 28 4,31 1,64 3,18 255 3 91 2,35 147 7,57 3.79 <0.31 0,54 5,89 3*2 3,50 1,58 2,73 1.18 3,55 5*0 0.68 3,59 2.79 7,59 0,67 3,49 38 2,37 1,66 1,34 0.54 2,14 12.25 0.90 106 6.56 3.73 9,37 3.69 48 1.32 9,73 9,28 9, CO 2,04 2,55 9.90 0.09 0.90 0.58 9.09 1.79 60 0.00 0,43 9,09 9,60 :,33 1,33 0.00 0,09 0.90 9.00 9,09 9.45 72 0,00 9,69 9,60 0.00 0,41 0.44 090 900 6.00 0 00 000 927 CMax 20.6 21.5 12.7 20.2 <5.6 <2.S 18.1 28.2 18,1 26.7 28.0 12.7 Trnax H 4,9 3.5 18.0 12.0 5,9 3.0 10.0 3.5 10,6 3.0 3.0 5,0 AUCO-t H.ng / mi 281.8 219.3 236.1 309,7 282,8 237,0 213,8 357 2 289,7 430,4 279,0 283.8 FA'JC 94.0 93.5 98.8 172,8 92.0 112,6 80.0 92.5 78,9 <43,6 76.0 93.5 F Cm ax 85.3 72.9 48,6 110.5 54.2 69.1 74.4 68.4 37 7 <18.9 76.9 45.7 2024219717   13 Sep 2024 Table 10. GR-01 Mean MIN-101 Plasma Concentrations and Parameters GRC1 GR01      PLASMA CONCENTRATIONS sins AU Co-5 Hours MEAN $d Sm cv% S 0,80 0.80 8,00 6.00 0,25 8,00 0.06 0,60 0,00 o(5 0,80 0,08 8,00 0.00 8,35 1 22 0,65 346,41 1,5 1,25 2,77 1.95 220,78 2 5,75 5,57 4,67 96,91 2.5 11,71 7.48 5.46 63,63 3 15,54 7.84 6,88 50,45 3,5 15,04 7,SI 5,89 4.3,68 4 15 99 6,08 5.27 38,00 5 14,62 4.66 3,26 31,47 § 11,35 4.17 3,33 36,70 7 10,33 3,53 2.64 34,63 8 9,39 3,S3 3,25 41,81 10 15,69 5.39 4,42 50,45 12 11,20 4.85 3,48 41,34 14 11,76 4.5? 3,33 39,73 15 10.50 4.87 3,96 46,01 20 5,49 2,33 1,85 42,43 24 5,57 3 30 2,58 59,31 28 3,56 2,80 2.04 70,67 32 3,10 2,85 1,50 66,88 38 2,42 3,33 2,05 137,58 48 0,77 0,92 0,77 119,51 SO 0,30 0,51 0,40 171,48 72 8,15 0.24 0,20 159,83 CMax ng / mi 19.59 5,74 4,61 29,30 Tmax H 5,00 3,43 3,00 57,19 AUCO-t H.ngfml 284,52 SO,S3 41,49 21,38 F AUG 101 30 29,16 20,50 23,79 F Cmax 69,98 23,92 17.64 34,22

[00333] See Figure 5.

[00334] GR-02 - 12 subjects (cross-over)

[00335] Geo Mean     15.43 ng / mL 2024219717   13 Sep 2024 AUC(o-tau): 253.01 ng H / mL Relative Bioavailability versus MR32: F% Ci!iax: 54.33%, F% AUQo-tau): 86.9% Table 11. GR-02 Individual MIN-101 Plasma Concentrations and Parameters GR02 SRC2 VEAN MW-WIPLASKA CONCENTRATIONS          and AUCo-t W.ro; Hours l-MtN-161 2-W.M01 S-WiK-ld 4-M!N-tG1 5-MN-161 7-RWM01 s-susmo: 16-MN-101 It-MtN-tOI 12-Mlfi-<01 I3-M1N-10: 14-MIN-161 <5 '2,03 0.06 0.39 0.60 990 3.00 0.30 0.60 3.66 0.00 005 C.CO 0,00 3,25 0.00 ¢,06 0.59 0.60 990 3,00 0,00 0.00 9,03 0.00 0.09 0,60 0.99 C.5 3,02 6.GO 9,00 0.06 0.09 O.GC 0,30 0,00 3,60 0.00 006 5.00 0,60 9,03 0.06 0.39 6.00 9.90 3,00 6,39 6.69 3,80 6.60 9.66 8.80 6,69 1.5 3.3-2 0.GO 0,90 6.00 0.09 9,00 9.90 e,«< 9.63 ¢,90 6,89 0.60 2.93 2 2,93 0,06 0.4< 9,00 9,70 3.00 6.39 0,60 8.60 0.00 0-03 8.86 6.85 2.5 2.13 9,00 1.27 6.69 i.:7 1,06 0.90 1.24 2,48 1.02 0.59 279 11.87 3 4,71 6.41 2,68 ¢.06 2,98 1 52 0.8S 2,55 2.87 5.08 4.14 3.81 11,48 6,5 3,35 1.16 3.38 0.35 2,<o 2.14 1.26 3.14 5,27 11.72 7.24 3,¢3 14.33 4 3.72 2.20 3,96 1.17 2.19 2,25 1,21 3,45 6.24 12,80 8.53 3.45 12,39 5 893 6.06 3.49 2,00 13.46 2.87 2.49 4.67 7.52 14,53 7,78 8.84 1<A7 6 7.60 9,39 2£1 3,92 10.83 3 37 1,94 4,24 6.94 11.33 5.59 fi.CS 8.75 7 5,38 5.00 3.5S 5,86 7,32 3.15 2,36 4.52 4.86 19,78 5.23 8.19 8,67 8 5.11 4.28 2.89 5.14 640 3.30 2,58 5,76 S,02 6.39 11,43 6,95 10.05 13 4.32 3,92 5.82 12,63 4,28 3,26 9,25 5.39 13.25 12.88 <1,15 15,14 12 15.08 2.81 6.3< 924 23.26 3.27 6,31 6.67 21,59 17.68 13,85 :6,18 25.98 14 11,82 7.64 7.57 10.68 18,73 3,42 3 77 10.16 11.<5 18.50 15.3? 9.68 28,85 IS 997 5.70 11.48 7.68 15.89 8.22 2.81 1994 8,53 9 32 18.54 7.85 19.75 20 10,06 6,27 6.82 3,77 6,34 3,19 0,94 7.56 4,28 8.94 0.83 4.94 8.44 24 3.29 4.59 5,97 5,95 6,89 1236 0.84 1097 8.98 7.48 13.76 <3.32 3.67 25 5.23 3,21 4.04 4.43 1,64 13^9 6,48 <0.58 16,72 6,28 10,95 ?,C5 3.54 32 8,21 4,06 2,91 3,35 0.44 6,48 9,90 7,92 555 3.93 4.75 4.80 us 35 4,24 2.75 1.59 2.12 9,90 2.87 6,39 4.57 4,94 1,66 2.03 3,42 6.49 48 1.72 0.63 0,58 0.56 0.09 9,43 9.90 ¢,91 0.60 ¢.55 0.39 0.54 ¢.90 60 O.flO 1.34 0.41 fl, 06 0,09 0.60 6.39 6.65 8.60 6.00 9,03 C.31 0,69 72 9,03 0.28 0.39 0.60 9,90 3.00 6.39 6.69 8.66 0,60 9.03 C.OO 6.69 15.1 7,9 <1.5 19.7 20.3 13.2 8.3 11.6 21.3 17.7 19,5 18.2 29.9 Tmax H <2.0 14,0 16,9 14.0 <2,0 7S.fi 12,0 24.0 12.0 12,0 <o.O 12.0 14,0 AUCO-t Kna-'m! 318.6 190.0 183,2 132,0 247.4 233,2 53,0 368.3 270,7 300,5 357 4 298,3 338.9 FAUC 95.4 61,5 78,S 1019 38,8 <922 IS.S 75.9 73.2 100.5 97.3 57,5 116.3 F Cmdx 47.3 50.9 44.0 58.6 70.3 7< 4 26.0 25.6 45 0 77 5 53.7 5S2 191.1 2024219717   13 Sep 2024 Table 12. GR-02 Mean MIN-101 Plasma Concentrations and Parameters GROS GROS MN- 101 PLASMA CONCENTRATIONS and AUCs-t Hours MEAN Sd Sm CV% 3 0,30 0,00 0,80 0,00 8,25 3.00 8,08 8,08 0,08 0,5 0,80 0,00 0,80 0,00 1 8,08 8,08 6,08 0,08 1.5 8,18 0.59 0,31 375,28 2 0,88 1,95 1,04 288,78 2,5 1,98 3,29 1,89 166,30 3 3.22 3,03 1,90 94,21 3,5 4,69 4,39 3,38 93,89 4 5,20 4,14 3,38 79,73 8 7,05 3,94 3,24 55,85 s 8,10 3,20 2,66 51,99 7 5,68 2,83 2,08 44,82 s 5,95 2,84 2,19 47,70 10 7.85 4,27 3,79 54,29 12 12,81 7,69 6,62 60,64 14 12,05 7,28 5,38 68,38 16 ■0.53 5,24 3,98 49,25 £0 6,23 2,37 1,78 37,95 24 7,72 4,01 3,23 52.81 28 6,48 4,15 3,47 63,88 32. 4,36 2,90 2,24 68,52 38 2,35 1,62 1,28 69,09 48 0,50 0,34 6,28 68,46 60 0.21 0,41 0,30 197,67 72 0,82 9,06 0,84 375,28 CMax ng / ml 15,43 8,70 5,37 43,38 Tma>: H 15,23 5,20 3,67 34.:2 AU£a-t 253,01 85.28 65,81 33.71 FAUC 88.94 24.39 16,36 26,05 F Cmax 54,33 23.89 17,99 42,50

[00337] See Figure 6. 2024219717   13 Sep 2024 Table 13. Comparison of MR32, GR-01, and GR-02 MIN-101 Plasma Concentrations. MR32 GROt and GR62 Mean M&MS1 Plasma Concentrations tnctfmO hours GROI-Mean GRG2-Mean 8 2,00 0,00 8,00 G,25 0,00 ¢.00 8,00 0,5 8.56 0.00 0,00 1 18,68 0,35 8,00 1,5 23,86 1 25 0,16 2 24,16 5.75 0,68 2,5 24,68 11,71 1.98 3 22.06 15,54 3,22 22,34 16,64 4,SS 4 19,45 15,99 5,20 5 21,54 14,82 7,85 $ 15,19 «,35 6,16 7 11,89 10,33 5.38 8 10,38 9.39 5,95 10 12,48 10,89 7,86 12 12,66 «,26 12,81 14 10,33 1:1.78 12 38 15 7.74 19,56 18,63 2:0 4,12 5.49 6.23 24 3,11 5,57 7.72 28 2,30 3,96 6,49 32 1.45 3,10 4,36 38 0.26 2,42 2,35 48 0,26 0.77 0,50 60 0,03 0,30 8.21 0,04 0.15 0,82 Max ngim! 28,.5 19,6 154 Tmax H 2 4 6,0 15,2 AUCO-t H.ng / mi 291,6 284,5 253,01 FAUC REF 181.3 86,54 F Cmax REF 69,9 54,33

[00338] See Figure 7. 2024219717   13 Sep 2024 Table 14. Comparison of MR32, GR-01, and GR-02 MIN-101 Plasma Concentrations - Rates of Increase and Decrease. MR32 and GRG1 yean WN101 Plasma Cone. Rates of increase and Decrease Hours MR32-RATE GR01-RATE GR02-RATE 0 0,00 0,80 8,00 ITS O 6,00 0,00 0.00 8,5 26,25 0,80 8,00 1 26,24 0.70 0,80 1,5 8,56 1,00 0,31 2 0,39 9,80 1,05 2,5 1,03 11,92 2,60 3 0,00 7.68 2,48 3,5 0,00 1,08 2,94 4 0,00 6,80 1,02 5 2,09 6.80 1,85 6 0,00 0,00 0,00 7 0,00 6,60 8,08 8 0,00 0.00 0,09 16 1,05 0,65 0,96 12 0,10 0,29 2.48 14 0,00 6,25 0,00 16 0,00 0,00 0.00 20 0,00 0,88 8,00 24 6,00 0,02 0,37 28 0,00 0,08 8.00 32 6,00 0,00 0,00 36 0,00 6.80 0,00 VMax {ng / mp / H 26,2 11,9 2,9 Time of VMax 6,50 2,58 3,50 TEST7MR32 REF 6.45 0.11

[00339] During each time interval (dt) the plasma concentration (Cp) of MIN-101 increases or decreases. From t=0 to Tmax, the rate of increase Vmax = d(Cp) / dt. After the Vmax, the rates are decreasing. SeeFigure8. 2024219717   13 Sep 2024 Example 9: In Vivo Pharmacokinetic Analysis of BFB-520 in CR GR-01 Tablets, CR GR-02 Tablets, and MR 32 mg Capsules (MR32) (tau = 72 h)

[00340] MR32 - 12 subjects (cross-over)

[00341] Geo Mean Cmax: 1.77 pg ml.

[00342] Median Tmax: 6.00 H AUC(o-tau): 30.26 ng-H / mL Table 15. MR32 Individual BFB-520 Plasma Concentrations and Parameters MR32 BFB-520 PLASMA CONCENTRATIONS ' and AUCo'tlH.flo.Wl Hsurs- 1-BFB-528 2-BFB-823 3-BFB-52G 5-BFB-630 6-8FB-529 7-BFB-528 3-BFB-828 9-BF8-520 10-8FB-5Z9 11-BFB-520 12-BFB-523 13-BFB-520 0 0,06 8.00 8.00 3.60 0,60 0,08 0,06 0.00 0.60 0.09 0,00 9,00 C25 9.08 0,08 8.00 8.60 0,60 9,00 0,06 0.00 0.00 0.09 0,00 9,00 0,5 9.08 0,08 8.00 8.60 0.60 9,08 9,00 0.00 0.00 3.89 0.60 9,00 1 0.58 0,54 8.00 8.30 0.53 9,32 0,28 1.01 0.60 9.79 0,56 0,28 3,5 3,25 0.35 8.58 3.3S 0,72 9,61 0,76 1.28 0.42 1.26 1.10 0,50 2 1.24 0,35 6.80 8.62 0,92 9,89 0,58 242 0.50 1.41 1,23 0.36 2,5 1.41 0,75 8.37 8.89 1.18 9,88 0,34 216 1.19 1.69 1.78 0,79 2 1 37 0.34 8.39 1.13 4,56 1,12 1,16 3.33 1.58 1.83 1,63 0,74 3,5 1 73 1,03 6.81 1.25 1,44 1,28 1,28 291 1.57 1.81 1.04 0,34 4 2.03 0,38 8.38 1.33 1.65 1,21 1,28 230 1.65 1.77 2,27 0,95 5 1.91 1.18 1.09 0.50 1.64 1,18 1,97 255 297 2.09 1,61 1,03 £ 1,81 1.08 8.83 3.63 1,76 9,96 1,98 223 3.12 1.34 1.73 1,10 7 1*1 0,95 8.99 8.30 1,40 9.94 0,38 225 2.91 2.19 1,16 1.01 8 4.09 0,92 8.71 8.79 1.60 1,01 1,18 2S3 3.12 1.83 1.42 :.08 10 1.27 1.08 1.09 3.63 1.69 9,73 1,73 1.97 276 2.4S 1,44 1,01 12 0.73 1,28 8.50 8.84 1,39 9,56 1,42 1.07 212 2.83 1.26 0,71 14 0.88 1,08 3.62 1.67 1.30 9,75 1,48 263 2.35 2.74 1,37 0,55 IS 0,3? 0,85 0.54 9.65 035 9.58 1.23 1,75 1,53 1.65 1.93 6.51 23 1.42 0.8S 0,48 9.58 0,91 3.86 0.70 1.29 0 8? :.40 8.95 6.41 24 0,8* 0.39 0.35 900 0.25 3.77 0.47 0,67 0.70 0,58 6.53 6.36 28 3.8$ 0,80 0,31 9.06 0,30 3.44 0.00 6,45 0 48 0.37 8.33 6.81 32 0.42 0.80 0,60 9.06 0,00 3.35 0.30 0.09 028 9.06 8.96 6.81 38 0,00 0.80 0.00 900 0.90 3.00 0.30 0,00 0.06 0,06 8.00 6.81 48 0.80 0,80 0,00 9.06 0,00 3.06 0.00 0,80 9.00 0,06 6,00 3.80 £8 0.82 0.80 0,60 9.06 0,00 3.06 0.30 0,09 008 0,06 8.00 6.00 72 •>.<•0 0,00 0.08 0.00 6,00 9.89 9.00 0.00 0.60 6.89 0.60 9.00 Wax ng:mi 2.9 1.2 1,1 1,4 <5 1.2 1.7 3.3 3.1 2,7 2.2 11 Tmax H 4,0 12.8 10,0 4,0 s,o 4,9 13.0 3.0 8.3 149 4,0 6.0 AUC0-t 34 7 20.1 16.7 15.3 27.2 22 6 248 44.9 47.2 46.7 34.5 28 5 2024219717   13 Sep 2024 Table 16. MR32 Mean BFB-520 Plasma Concentrations and Parameters MR32 »32 BFB-523 PLASMA CONCENTRATIONS and AUCo-t Hours MEAN Sd Sm CV% 0 8,00 0,25 8,00 3,5 8,00 1 0,42 3.2S 0,23 88,42 1.5 8,81 0.33 0,23 41,48 2 1,04 0.51 0,36 48,77 3,5 1,21 3,45 0,36 37,88 3 1,48 8,58 0,46 46,84 3.5 1,49 8,58 0,43 38,35 4 1,55 8,48 0,48 31,28 5 1,50 3,57 0,54 42,38 S 1,55 8, 69 0,85 44,45 7 1,44 8,68 0,57 47,23 8 1,51 8,75 0,57 49,53 to 1,48 8,58 0.53 44,31 12 1,21 8,63 0,46 52,49 14 1,40 8,7? 0,68 54,91 IS 1,81 0,44 0,36 43.42 20 8,85 0.34 0,27 48.36 24 8,50 8,22 3.18 44,3S 28 8,35 8,28 0.18 75,95 32 8,15 8,:28 0.21 188,74 38 8,85 8,18 0.88 348,41 48 8,00 68 8,30 72 8,00 Max 1,91 3,80 0,65 41,65 Tmax H 6,S2 3,65 3.68 82,84 AUCO-t H.ng / mi 38.28 11,35 9,43 37,51

[00343] See Figure 9.

[00344] GR-01 - 12 subjects (cross-over)

[00345] Geo Mean     1.77 ng / mL 2024219717   13 Sep 2024 AUC(o-tau): 27.48 ng H ml. Relative Bioavailability versus MR32: F% Ci!iax: 80.48%, F% AUQo-tau): 96.1% Table 17. GR-01 Individual BFB-520 Plasma Concentrations and Parameters GRG1 GR61 BFS-528 PLASMA CONCENTRATIONS {ngrwJJ and AUCo-t tHngl'mQ Hours 1-BFB-52G 2-BFB-520 3-BFB-520 5-BFB-520 9-8FB-526 7-BFB-520 8-BFS-520 9-BFB-520 10-8FB-526 11-BFB-520 12-BFB-5Z0 13-896-528 0 0.05 0,00 0,00 0.80 0.00 0.30 0,60 0..00 3.80 6.80 0,.60 0.68 0,25 0.G9 0,00 0,00 0.00 6.00 0.30 0,60 0..00 0.80 6.86 0,.60 0.60 0.5 0.G9 0,00 0,00 0.00 6.00 0.30 0,60 0..00 0.80 6.80 0,.60 0.60 0.G9 0,00 0,00 0.00 6.00 0.30 0,60 0.,00 0.80 6.00 0..60 0,98 1.5 0.G9 0,00 0,00 0.00 0.00 0.30 0,60 0,00 0.80 6.00 0..60 0,90 2 0.G9 0,00 0,28 0.00 0.00 0.30 0,60 0,00 0.80 6.26 0..60 0,90 2.5 9.89 0,50 0,43 0.00 0.00 0.30 0,30 0,00 0.46 6.60 0,.28 0,90 3 0.42 0,71 0,45 0.44 0.00 0.29 0,60 0,80 0.63 9.86 0,.53 0,38 3.5 0.54 1G0 0,50 0.47 0.00 0,38 0,57 126 0.74 1.00 0,.89 0,48 4 0:54 1.04 0.49 G..63 0.35 0,38 0.45 141 109 129 G.72 6.51 5 101 0.98 0.30 G.72 0.62 0,51 0.75 156 113 145 0.98 6.81 $ 107 107 0.43 0.78 0,83 0,54 0.85 1.47 0,85 119 6.72 6.84 7 126 1^3 0,57 0,92 0,93 0,51 0.88 1.47 0,71 147 6.74 0.86 8 117 107 0,44 HO 103 0.8* 0,76 ISO 1.37 1.63 1,.60 0,74 10 0.98 0.88 1.23 0,77 0.33 1.28 1 72 184 132 137 6.99 12 0;5S 0.77 0.85 130 0,68 0.32 0.91 146 174 078 2.28 108 14 ICO 0.37 0.72 -173 0,74 0,43 1.24 184 182 Ml 1.11 105 1S ICO 0.71 0.83 180 0,51 0.43 1.09 149 ISO 1.24 111 6.95 20 0,59 0.70 0.63 -166 0,67 0.40 0.71 ITS 113 144 11? 6.88 24 0,57 0.31 0.43 0.85 0,5O 0.00 0.39 131 •>.57 165 0.99 6.58 28 0,72 0.26 0.5G 0.86 0,59 0.00 0.28 115 •>.92 1 27 0.98 6.58 32 0,33 0.00 0.23 0.30 0,48 0,44 0.80 0.87 •>.62 068 0.28 6.43 35 0,29 0.00 0.OG 0.00 0,38 1,10 0.80 0.26 •>.0'> 051 0.00 6.42 48 0,00 0.00 0.G0 0.00 0,60 0,33 0.80 0.06 •>.0'> 060 0.00 6.06 85 0,00 0.00 0.00 0.00 0,60 0,50 0.80 0.06 •>.0'> OGO 0.00 6.06 72 0,00 0.00 0.00 0.00 0.06 6.06 O.GG 0.60 0.00 6.06 G.OG 0.66 Max ng / mi 12 13 0,3 is 10 1.1 13 13 18 16 2.3 11 Tmax H 7.0 7,8 16.0 16.0 8.0 38,6 10,0 8.0 10.0 8.0 12,6 12,9 AUCO-t R-ng^rn! 23,5 18,6 16.1 313 19.7 19,6 19,6 43,8 36.1 40.6 33,7 27,9 F AUG 67,7 ?2,5 96.3 204.6 72.3 83,5 79,2 97,8 76.5 86.9 37,7 98,6 F Cmax 59.0 107.4 75.8 131,0 586 90.8 73.6 54.0 58.8 59 7 99.5 97.5 2024219717   13 Sep 2024 Table 18. GR-01 Mean BFB-520 Plasma Concentrations and Parameters GR01 GR81 BFB-520 PLASMA CONCENTRATIONS and AUCo-s Hours MEAM Sd Sm CV% 0 0.08 0.25 0.00 0,5 0,00 1 0.00 ts 3,00 2 0.04 0,1$ 9,87 233,68 2,5 0,22 0,25 8,22 112.01 3 0,49 0,23 0,17 45,9$ 3,5 0,85 0.35 8,27 53,37 4 0,77 0,36 0.31 47,35 5 0.89 9.36 0,29 40,77 £ 0.3? 0,2$ 0,:22 33,50 7 0,94 0 35 0,28 37,58 8 1,07 0.39 0,29 36,81 to 1 .16 8,45 0,36 46,79 12 1.04 0.55 0,43 53.43 14 1,11 0 42 0,31 37,58 IB 1.08 0.45 0,34 41.52 20 0,86 0 43 0,38 452$ 24 0.63 9.36 0,28 57.32 28 0,63 0 36 0,26 57,90 32 0,37 0.23 0,18 60,48 38 0,25 0 33 0,25 133,52 48 0.03 o,os 0,05 346,41 60 0.00 72 0,00 Max ng / ml 1,43 8,43 0,37 30.06 Tmax H 12,50 6,04 5.08 64.32 AUCO-t H.ng / ml 27,46 9,46 8,07 34,41 F AUC $8,10 35.77 18,95 37,22 F Cmax 80,48 24,60 2S 65 30,58

[00347] See Figure 10.

[00348] GR-02 - 12 subjects (cross-over)

[00349] Geo Mean 1.13 ng / mL 2024219717   13 Sep 2024 AUC(o-tau): 27.53 ng H ml. Relative Bioavailability versus MR32: F% Ci!iax: 69.48%, F% AUQo-tau): 88.46% Table 19. GR-02 Individual BFB-520 Plasma Concentrations and Parameters GROS GR32 BFB-520 PLAS >MA CONCENTRATIONS and AUCo-t tH.nofwfl Hours 1-SFB-520 2-BFE-S26 3-BFB-520 4-8FB-52C 5-BFS-S26 7-EFB-520 8-SFB028 S-BFB-S26 K-SFB02O 11BFB026 12-EFB-529 13-BFB-S20 14-BF&026 0 0,00 0.00 O.CO 6,00 000 900 60S 9.00 003 0.69 C,X 800 3.60 8.25 ¢.96 8.00 0.00 8.X 8.39 903 8.X* ¢.60 908 O.X 0.69 9,90 6,89 ¢,30 0.80 8.00 ¢,00 0.98 3.69 900 0,98 6.89 900 6.X 009 9.96 ■: ¢,80 0.00 3.00 000 9.98 8,89 000 ¢.39 609 900 8.X 009 9 06 1.5 8.00 8.00 0 00 O.K' 0.30 908 0.00 600 003 000 0.00 0.90 3,60 2 0.30 0.00 0,00 C0O 0.08 0.69 9,00 0.90 0.00 000 O.X 0.00 006 2.5 ¢,59 3.00 008 609 9.00 0,80 009 9.X 009 0.00 c,x 009 9.44 3 3.89 000 8.X 8.39 9 03 8.X ¢.60 903 8.26 0.69 0.93 6,60 5,5 ¢,80 0.00 8.00 ¢,00 0.96 8,69 900 0.90 009 002 O.X 000 9.76 4 ¢.33 8.00 0,80 008 9,93 609 008 ¢.30 009 0.6? 8,27 609 1.08 5 ¢.35 8.09 000 O.K' 8.32 903 8.X 6.27 9,27 1.37 0.35 0.35 6,75 6 ¢.53 0.38 8.00 ¢,00 0,49 3,69 9,00 0,25 0.42 1.47 60S ¢.45 975 7 ¢04 0.29 0,80 000 9.41 0,28 009 9.2" 009 1.64 8,49 308 0.73 $ 8,47 3.32 008 8,25 607 9.23 8.X 6 St 9,42 1,85 007 009 3,?§ 48 ¢,47 0.33 3.25 ¢.38 792 8,34 900 0,74 001 1.62 112 107 <14 12 O.S3 0.00 0,41 0,52 0,94 605 0.35 ¢,74 1.23 2.25 C,X 109 103 14 1,96 3.33 0.51 8,X 109 90S 0,41 ¢.90 L2S 2.45 1.20 MS 205 IS 1.31 0,33 3.5* ¢.62 1.46 3,52 9 87 126 102 2 38 13“ 103 231 SC 1,03 0.64 0,75 60S 105 0.76 0.26 1.43 0,71 2.42 104 000 109 24 8,31 3.44 0.55 0,49 G.75 9.55 O.X 608 9,61 1.75 1,39 009 604 28 ¢07 0.4? 8.50 ¢,56 9.48 102 900 193 003 1.74 104 007 9.58 32 0.82 0.34 8.21 602 9,00 1,14 009 1.83 1,21 0.70 0,59 801 302 36 8,47 3.32 008 0,X 6.39 90S O.X 605 9,64 0,41 0,32 0,46 606 48 ¢.27 0.90 3.80 ¢.80 9.93 0,80 900 0,90 009 008 8.X 809 906 80 0.00 0.00 0,00 6.X 600 908 O.X ¢.60 003 009 0,08 0.90 3,60 72 8.93 3.09 000 8,X 6,39 9 03 O.X ¢,69 903 800 0.69 0,93 609 <1 60 0,8 0,7 14 1.2 0,4 14 40 2.4 10 12 20 Tma< H 20,0 20.0 20.0 14,0 16,0 28.0 14,9 200 12.0 140 200 14,0 160 AUCQ-1 Hng / mJ 30.0 11.5 12.3 12.5 23.8 60 31,9 314 61.4 38,8 320 43.5 F AUG 960 57.0 73 3 910 80,3 195.2 24. S 71,1 660 131.5 1120 115.5 142 7 F Cmax 53.1 53.3 722 46.2 “90 196.6 230 420 410 860 723 1040 1208 2024219717   13 Sep 2024 Table 20. GR-02 Mean BFB-520 Plasma Concentrations and Parameters GR02 GRM BFB-520 PLASMA COtiCEMTRATfOMS snc AUCo-t H®urs MBAN SO Sm C¥% 0 8.00 0,25 0,00 as a® t 0,00 1.5 0,00 2 0,00 2.5 0,03 0,13 0,87 37528 3 0,07 0,20 0,13 280,02 3,5 an 0,27 0,19 254,72 4 0,21 0,40 0,29 191,24 5 0,31 8,40 0,27 130,19 6 0,39 0,42 0,28 186.,04 7 0,44 0,45 8,38 102,76 8 0,52 0,49 0,31 94,19 18 0,68 0,51 8,41 75,52 12 5,9-8 0,85 0,51 75,73 14 1,07 0,70 0,53 65,38 16 1,11 0,59 8,54 61,68 28 1,08 0,89 0,47 55,93 24 0,77 8,45 9,31 59,86 28 0,88 0,45 0,34 55,61 32 0,5'7 8,41 0,33 71,69 38 8 30 8,35 0,24 92,16 48 0.02 0,09 66 8.00 72 0,00 Max ng / mi 1,27 0,83 0,47 49,77 Tmax H 17,54 4,48 3,58 25,42 AUC1M 27.53 15.59 12.05 58,88 FAUC 88,46 33.92 27.56 38,35 F Cmax 69,48 29,58 24,00 42,86

[00351] See Figure 11. 2024219717   13 Sep 2024 Table 21. Comparison of MR32, GR-01, and GR-02 BFB-520 Plasma Concentrations. MR32 GR81 and GROS Sfean SFB-520 Plasma Concentrations Hours MR32^ean GRG1-Mean GR02-Mean 0 3,00 8,80 8,00 0.25 0,80 8,85 0,80 0.5 8.80 8,00 0,80 1 0,42 8,00 0,80 1.5 9,81 0,60 3,80 2 1,04 0,34 3,00 2.5 1 2$ 0.22 8,03 3 1.45 0,40 8,07 2.5 1,46 8,85 0,11 4 1,55 8,77 0,21 5 1,5$ 8,89 0,31 6 1,55 8,87 0,30 7 1,44 8,94 3,44 8 1,51 1,07 8,52 10 1,48 1,10 8,88 12 •$ 1,84 8,SO 14 1.40 1,11 1,37 ■38 1,01 1,06 111 20 0.85 0,$6 1,06 24 0.50 0,83 0,77 2S 0.35 0.83 0,80 32 8,15 0.37 0,57 38 8.85 8,25 0,30 48 0.80 0,03 0,82 €8 3,80 8,08 0,80 72 0,80 8,00 0,80 CMax nc'mi 1,S 1,4 1,27 Tmax H 8,8 12,5 17,5 AUCO-8 §.7 4.5 1,65 AUC5-12 H.ng / mi 15,4 8,8 4.4 AUCC< H-ngM 30.3 27,5 27,5 F AUC REF 96,1 88,5 F Cmax REF 80,5 6$ .5

[00352] See Figure 12. 2024219717   13 Sep 2024 Table 22. Comparison of MR32, GR-01, and GR-02 BFB-520 Plasma Concentrations - Rates of Increase and Decrease. MR32 GR01 and GR02 Mean BFB-520 Plasma Cone. Rates of increase and Decrease (nq / mh / H Hours MR32-RATE GR01-RATE GR02-RATE 0 0,90 0,00 0,00 0,25 0,00 0,00 0,00 0,5 0,90 0,00 0,00 1 0.84 0,00 0,00 1,5 0,77 0.00 0,00 2 0,46 0,09 0,00 2,5 0,34 0,35 0,07 3 0,49 0,54 0,07 3,5 0,97 0,31 0,07 4 0,11 0,24 0,20 5 0,04 0,13 0,10 6 OjOG 0,03 0,08 7 0,00 0,07 0,04 8 0,07 0,13 0,08 18 0,90 0,01 0,08 12 0,90 0,00 0,11 14 0,10 0,04 0,09 16 0,90 0,00 0,02 20 0,00 0,00 0,00 24 0,90 0,00 0,00 28 0,00 0,00 0,01 32 0,90 0,00 0,00 36 0,00 0,00 0,00 Wax (ng / mSJ / H 0,84 0,54 0,20 Time of VMax 1,00 3,00 4,00 TE8T7MR32 REF 0.64 0.24

[00353] During each time interval (dt) the plasma concentration (Cp) of BFB-520 increases or decreases. From t=0 to Tmax, the rate of increase Vmax = d(Cp) / dt. After the Vmax, the rates are decreasing. SeeFigurel3. 2024219717   13 Sep 2024 Example 10: Predicted Plasma Concentrations of MIN-101 and BFB-520 at Steady State in MR32 and GR-01 Tablets (32 and 64 mg) Table 23. Predicted Plasma Concentrations of MIN-101 at Steady State in MR32 and GR-01, 32 mg Tablets »R22 and SKH     WM81 at S^aeiy-State Rasma          taaW HOUPS SR32S8 GWJ S$ 72 3,33 6,45 72,8 9X5 90 73 22,62 8,38 7X5 2X74 6,96 74 26,78 44,23 74,.5 37,44 46,9? 75 24,39 26,59 7X5 22,54 28,89 76 2X86 29,58 77 33,38 48,91 78 403 45,38 79 13,34 13,96 88 14X9 12,8-5 S3 :3 43 13,53 84 43,86 44,92 86 19,97 13,83 88 8,34 12,32 93 4,44 5,75 93 3,32 6,46 XMaaSS 27,1 20,9 3,32 MS TmaxSS H 2,58 3,5 AUC72-M HjjgiW 282,8 287,6 F MX REF 98,3 F Caiax REF 7'0

[00354] See Figure 14. 2024219717   13 Sep 2024 Table 24. Predicted Plasma Concentrations of BFB-520 at Steady State in MR32 and GR-01, 32 mg Tablets v"’ •.>         >       < :■ SlisSSssS: si SHisssv-SlsHf SS >! sasss HOURS ^R33SS GR81 SS 72 948 848 724 9,44 843 73 @;81 848 734 145 8,57 74 145 3.53 74,5 1,48 8,72 75 1,78 8,97 754 1,71 1,18 7« 1,83 142 77 1,74 1,27 7S 148 1,21 75 144 144 SC 148 148 S3 1,53 1,31 84 148 1,23 S£ 1,41 145 88 143 143 33 §35 143 35 845 8.88 CMaxSS 1,89 1,49 9,58 0,98 TmaxSS H 4.00 8,08 AUC72-9S 29,1 26,3 F AVC REF MS REF 77,2

[00355] See Figure 15. 2024219717   13 Sep 2024 Table 25. Predicted Plasma Concentrations of MIN-101 at Steady State in MR32 and GR-01, 64 mg Tablets ^R32 and GR81 64 mg at S&ady- Sisis wm* Ptesma CwKamtaitions (saWI) HOURS W32SS GRfllSS 72 ^84 «,S8 72,5 18,3^ 12,48 73 ¢5,34 12,88 73,5 53,47 13,83 74 53,55 23,45 74.5 54,28 33,84 75 48,77 41,18 45,07 41,77 76 43,33 41,17 77 48,78 37,82 78 33,85 35,83 7S 28,88 27,92: ®8 23,78 25,S3 82 28,87 27,88 84 27,31 25,85 88 21,84 27,81 88 18,48 24,84 92 8,88 13,48 8,84 12,93 CMaxSS agM 54,28 41,77 6,84 12,53 TmassSS H 2,58 3,50 AUC72-&8 H.ng,W 585,2 577,6 5 AUC REF MJ F Cm REF 7«

[00356] See Figure 16. 2024219717   13 Sep 2024 Table 26. Predicted Plasma Concentrations of BFB-520 at Steady State in MR32 and GR-01, 64 mg Tablets AG 84 34       8? <54 -333« W32SS GR81 SS 72 08 1,32 72,6 5.38 1,27 73 MS 1,38 73.5 2.,31 1,13 74 2,88 4,IS 74,5 2,88 1,45 75 3,48 1,9:3 75,5 3,41 2,18 78 3,78 2,84 7? 3,4« 2,54 73 03 2^1 78 3,«7 2,48 88 3,32 2,83 82 3,85 2,82 84 3,54 3,57 85 2,83 2,48 88 2,85 3,37 §3 2,85 08 1,32 C^axSS. 3J9 2,92 C^inSS 0,99 1,32 TswaxSS H 4,SO 8,00 A0C72-&5 HaWm? 58,1 52,8 F AUC REF 90,8 F C®a;< REF 77.2

[00357] See Figure 17. Example 11: Predicted Plasma Concentrations of MIN-101 and BFB-520 at Steady State in MR32 and GR-02 Tablets (32 and 64 mg) 2024219717   13 Sep 2024 Table 27. Predicted Plasma Concentrations of MIN-101 at Steady State in MR32 and GR-02, 32 mg Tablets arsd GR^              st Steadi-State Plasma           tRa« HOURS SSR32SS GR92 SS 72 3,52 3,2« ^,5 8,68 7.63 73 22,62 7,46 73,5 .^,74 7,23 74 26,78 7,37 74,5 27.34 3,32 75 24.33 6.22 75,5 22.34 18,37 76 2MS 12,88 77 23,38 11,87 78 46,83 IMS 7S 13,34 6,74 St! IMS 18,58 82 13.49 18,66 34 43,86 4538 85 w? 13,87 S3 8,24 12,66 82 4,44 7,47 65 3,32 M? C^sskSS agM 27.1 15,4 CMsaSS 3.32 7.17 TmssSS H 2,50 12 AUC72-S6 H.h.^ 292,S 24S:3 F AUG REF 84.0 F Cmat REF 5C7

[00358] See Figure 18. 2024219717   13 Sep 2024 Table 28. Predicted Plasma Concentrations of BFB-520 at Steady State in MR32 and GR-02, 32 mg Tablets SR 82 U8O-S28 O SOsssy-OOS® HOURS 54R32SS GSW S$ 72 8.55 0JS 72,5 8,44 6,73 73 04 0,72 73,5 8 4 5 0,87 74 1,35 0,83 74,5 ■MS <3.85 75 1,78 <3.83 75,5 8,78 <3.83 78 8,89 8,84 77 8 74 6,75 78 8,S3 0,78 75 8,54 ©,7S 58 1,85 8,89 82 8,53 <3,03 84 8,28 8,30 88 8,48 8.22 88 8,83 8,33 82 8,85 M3 M 8,55 0.79 1,89 1,23 C&inSS 0,58 0,78 TsaaxSS H 4,80 16> AUC72-S5 29,1 23,6 F AUC REF §1,4 F REF £4.§

[00359] See Figure 19. 2024219717   13 Sep 2024 Table 29. Predicted Plasma Concentrations of MIN-101 at Steady State in MR32 and GR-02, 64 mg Tablets S82 84 mg aS St ea^'-Ststs HOURS MR32SS GR&2 SS 72 8,64 «,53 IS 73:,6- 53,47 U,45 74 53,55 t4,78 74,5 54,28 t«,§4 7 g 48,77 18,44 7 b 4^7S z43 & 23J5 78 3XSS 33.SS 38,58 18,48 88 23,75 21,12 82 28,97 21,32 84 2731: 33,77 88 31,34 27,73 83 5 8.43 24,18 S2 8sS9 14,35 $8 S.S4 fSsSS C®ax$S 54,28 38,77 C^StaSS 8,84 14,35 TmoSS H 2,58 12,00 AUS 72-98 585,2 49®,g F AUC REF 85,2 F €m«i REF 56,7

[00360] See Figure 20. 2024219717   13 Sep 2024 Table 30. Predicted Plasma Concentrations of BFB-520 at Steady State in MR32 and GR-02, 64 mg Tablets 83 84 8F7S-878 tW HOURS MR32SS W SS w 1,58 72,5 8,8-8 1,52 73 •M3 1,43 72.5 2,31 1,35 ?$ 2,68 M 74,5 2,36 1.25 75 3,46 1.25 7§,5 3,4-1 1,2? 78 3,79 2,67 7? 3,48 1,58 78 3,33 1,57 79 3,97 1,5? 88 3,32 2,28 82 3.M 1,83 84 2.5-i 2,4« 8g 2,53 2,44 88 2,85 2,45 §2 •ms 2,25 SS W 1.58 3,79 2,45 Q,§9 1,58 TsmxSS H 4,00 15,50 AUC72-88 58,1 47,4 F AUC REF F Cmsx REF GO

[00361] See Figure 21.

[00362] Examples 12-15 detail an evaluation of the PK profile of the GR-01 formulation in healthy CYP2D6 EM male and female subjects in fed and fasted states (or predictions thereof). Subjects who completed part 1 of the study (evaluation of the PK profile of MIN-101 and its metabolite BFB-520 in the GR-01, GR-02, and MR32 formulations) returned and received a further single oral dose of GR-01 under fed or fasted conditions to allow the assessment of food 2024219717   13 Sep 2024 effect by comparison of the PK properties to those obtained in part 1 (Examples 9-12). There was a wash-out period of 14 ± 2 days after part 1. Example 12: In Vivo Pharmacokinetic Analysis of MIN-101 in CR GR-01 Tablets in Subjects in Fed versus Fasted States, (tau = 72 h)

[00363] Fed State - 12 subjects (cross-over)

[00364] Geo Mean Cmax: 19.70 ng / mL

[00365] Tmax: 12.00 H AUQo-tau): 269.19 ng-H / mL Table 31. CR GR-01 Individual MIN-101 Plasma Concentrations and Parameters (Fed State) GROi 1 FED «1N-191 PtA.SMACONCEKTRATK>HS 6MtAyC»-l tH.r.Q.T^O 1-MIN-151 2-MSN-191 s-wh-isi 31 7-^-451 S-MHS-SOi Sl-MIN-m 12-MW-lOi 134OM61 3 SA'S 8,.56 3.00 sao 0,00 8.83 ■5.88 8.33 5 30 a so 6.86 AGO 0.3S S 08 OjOO okso ¢,58 W 8.03 8.83 5.^0 no, ft -tlft A86 $ 5 SA'S 8,.56 3,00 <w ¢,50 8.83 0.88 8.08 5.80 6.85 6 .46 ft -Oft •: S 08 3,00 okso ¢,50 W 0.88 ¢.-08 5.80 6.85 6.86 8,68 :> -5 S .38 0,05 5.00 8A8 8.,::8 8,03 8.03 8.08 5.85 6.85 6 .46 ft -Oft 2 6,86 9.56 9.69 9.08 8,08 8,08 8,03 8.-08 5.80 6.85 6.86 8,68 2;S S .38 0,05 A > 6 -0,98 ¢,::8 8,03 8.03 0,08 0.80 6,88 3,66 0.30 .) 0.05 has 9.98 8,08 8,08 8,03 0.60 8.08 SS8 SA'S 0.11 V 5,05 0,05 11f9G ¢,08 8,08 8,08 0,03 0,08 8.80 6,88 3,66 ?,91 4 5.05 0.00 44.38 3,05 0,08 0,39 8,30 0,60 8.08 6.88 3,66 S,33 5 5,05 9.56 12,6$ 23.02 8,08 <2,?s 0,03 0.60 8.53 8-88 8.38 0^4 $ 0,05 5S.4S 13..78 ■13,78 0,08 1SA1 SA'S 0,60 23.85 6.88 3,66 S>< -¼ - 0.00 1S.?3 12.05 10,32 0,6« 11,96 8,5'0 0,60 <8.18 13,03 8.38 4 ' 4 0,05 5,3'3 5.55 0,08 ■t S.fiS SA'S 0.60 <7.78 14,58 0.38 VI ■Mj! 3.89 11 ,32 0.30 7,57 8,00 25,10 <4,88 11.23 OxSO 0x80 ■52 35,56 6.4 0.71 3.41 15.3-: 1 ..-52 0.30 0.35 44.32 13,3? 24.02 12-48 ■54 12,3.3 3M 7,25 2.54 1 1,.-3 <3.51 0x80 5.32 18.33 17<4? 12,72 0,85 10 14.89 3.72 10,6< ES5 0,72 6,59 0.30 0,30 20.47 13.36 ? J5A S.32 2« 7,14 4.5' 4..0 0.52 S,?5 9,42 4214 s20 11.74 11 14.96 4,23 2* 9,7 5 2,1 2 o.os 12^5 5,57 W4 30-78 USS 18,33 28,27 0.75 28 7,17 £.40 4.43 0.80 18Z5S S,£9 5,31 15.53 5.53 7.53 2-1,55 4,34 32 2.5¾ 2.84 0.80 19.52 3,49 2,32 10.20 3-,47 3-44 14,1? 2.32 30 S.97 1,81 ■MV ¢,35 2,10 0x82 3.35 1,58 1.55 5x78 2,42 4g ws 0.30 3.80 0.80 1,87 0,87 8.30 <\8J ¢,58 0,4? 6,54 0,S0 86 0.00 0.00 aso. 5.8« 0.83 0,33 8.30 0.60 8,M 0.08' 8x38 0.35 72 0.00 0.00 3.85 0.80 0.30 0,59 8,30 0.60 808 6 58 8.38 c a<i OS 0 •isa 14,4 2$ .0 ■ROS 18,8 •RIS 38.S 23.8 17.5 283 42,4 1 if5 4.-5 5,9 12.8 8.8 34.3 34.8 0x0 14,6 21,6 12.8 K.KgJn’d 305.0 577,2 241.3 ■138,5 34? A 272,-0 52,2 SO', 3 3S?x7 383'S 444.8 218,2 F Al.”.- 158,3 03..¾ 124,3 35,9 133.3 1 SO. 2 4'A< 102.8 13V '5.5 •ISM ?4,4 r Crrs a* 1 74. ? 37 A 115,8 114.2 127,4 131.S Si:xS 100.1 -iSM 65.5 53.8 87.? 2024219717   13 Sep 2024 Table 32. CR GR-01 Mean MIN-101 Plasma Concentrations and Parameters (Fed State) GP51 GRW FED WH-W PLASMA eOHCEHTRAUQRS a«® AUCo-t Hoars MEAK Sd C^4 8,25 09 6,5 oe 1 9,69 15 09 2 9,80 2,5 07 1,95 1,84 349,41 3 1,44 3.53 2,48 245,39 5,5 4,55 w 2,59 238,14 4 1,78 4 42 2,94 248,88 5 4,77 7,77 5,27 152,96 6 7,.74 O 3,96 116,41 7 7,77 7,71 §,91 98,36 s 6.35 £959 8,95 183.,82 1® 7,53 04 5,26 91.54 12 13,75 8,54 6,71 §9,§3 14 9,3® 5,54 4,§6 58,68 IS 9,88 §,54 3,85 32. V 29 7.94 3,83 3,13 §5,69 24 16,71 09 8,31 84,8§ 25 8,28 8,79 5,27 61,78 32 5,.22 4,39 3,56 82,42 35 2,83 2,17 1,78 78,52 48 9,71 8,52 8,39 73,23 85 9,1 S 0.22 6,18 133,11 72 9,83 8,99 6,95 346,41 CSax 29,89 7,48 5,91 35,63 Tmax H 12,59 7,85 §,98 61,18 280$ 197,53 85.11 39,95 5 AUC 95,34 36,15 23.93 38,68 F Cssjax 195,97 31,46 2332 28,81

[00366] See Figure 22

[00367] Fasted State - 12 subjects (cross-over)

[00368] Geo Mean Cmax: 18.82 ng / mL

[00369] Median Tmax: 4.50 H 2024219717   13 Sep 2024 AUC(o-tau): 284.52 ng-H / mL Table 33. CR GR-01 Individual MIN-101 Plasma Concentrations and Parameters (Fasted State) GR9 EASTER 1EA« Wb'Mt 1Pf A8WA rrW / FNTEATKlfift mo* 'i>-1 01.110.806 2-31174-181 NM 84-484 <-WtN-<:3< S-NW-KI ;-NUM31 8-MW-K1 S-fcNN-<<'1 <GW1W-181 144.W-184 ■12'-M!W-19t 13-^114-191 8 5(1K' 8,56 8,8« 8.88 8,88 3.8C- 8,-38 C%39 ■3 f«> 3 $9 8.2S 5% 53 9,53 8,48 8 / 43 s.es IW 8.8« 8,38 8,89 3.3-1 8 $8 $.5 5%*S 5,43 8,48 S / X" 3,s<- 3,88 SS$ •N8>> 3.83 ti 11-3 5,81 1 9.58 $.53 5,43 8,48 3,43 8,e<- 3,88 ¢,81- 4,22 3,8$ 5 9-3 8.88 4.5 ■>.<■8 3.53 5.23 8,48 8,33 9,88 3,38 9.88 8A2 8.93 <793 .798 2 3.83 5,42 19^8 2.58 8,33 9,88 ■13,23 1388 8.71 IK ¢,43 5.14 2,5 <5.55 $2,52 12.14 4.38 9.4-5 -13.42 388 <? 79 24.1? 23,38 7,82 < 7.35 17,33 1<;4i? 13,58 5.39 12,73 -11.M 24.92 12.33 28.86 28,88 18.13 3-,5 <5.55 13.37 12.31 5-32 18,53 18,94 28,13 < 3.89 28.75 24,8'1 13,13 4 25,53 13,5$ 5,23 11,38 1N23 8,84 22,9’1 17,-34 24.78 22,88 •11,35 * 1?r->S 1724 5.5S 14,88 1N31 8,44 ■14,98 •17,95 12,52 21.48 12,88 12,59 S 18,2$ 44 / 1 8,85 13.14 •13.39 $.88 12,38 <1.72 7-82 19,24 5.84 <8.42 7 9<:1 41,33 5,28 12.82 -13.84 4.71 <1,51 < 3.95 8,78 i 7.53 3,.- 2 3.85 $ 7.29 5.54 1:-1.18 <$,51 ■>.51 8.1S 18.-53 < 3.39 14.½ 5;92 9.52 <%• 4.3%' M-> <2,38 1:-1.1-3 <>18 2.74 18,48 17.98 18 85 8.$S 13 / 19 IS 59 52 3.45 5.5$ <3.22 24,18 7,2'4 >.<■$ 13,22 -8.93 <3.31 11 .<5 13.34 •13.47 14 12.17 1872 12.81 1773 7,12 2,52 13,85- ■12,92 <4.42 11.87 28,32 4.38 18,38 8.3S <2,55 18-58 «,48 5.18 7.48 11.25 < 3.43 13 '39 1--,44 S:85 2$ 5.54 3.88 4,89 5,38 4,35 2.85 2.44 7.88 8.52 SJ3 592 3.23 84 5.5.? 1.84 N2< 4.75 8.3< 2.3$ 2.98 ^2,21 3.9’8 13.97 3 / 13 788 i® 4.3? 1,84 3, <4 2.55 3,-31 2,35 1.47 7.4? 3.79 IS 31 $.54 5.58 32 3.5$ 1.5<j 2,73 1.18 3,85 9.88 5.58 2,7$ 7.5-9 ■>.57 3.48 3® 2.37 1.34 <\S4 2.14 12.25 6.$$ 1.88 5,54 3 73 ’>.>? 1.48 4« 1.33 3,73 3.25 8,39 2,94 2.58 -14-8 9.89 8,38 8,5-5 8.88 1 74 Sv 3.81' 3,2$ 3.84 <’.34 1,33 1.Cv 84-8 9.89 8,35 8 -N7 8.58 •>.45 72 3.8%' ¢.59 3.84 <’.34 4,41 $.44 84-8 9.88 :* i'-r. '1 -V< 9-93 •1 CNsis' rvj.'tw 33.¾ H,S 13 7 28,2 15,8 12.8 1$.< 28,3 <9,1 3<i.7 23.3 <3.7 Tmsz H 4,5 3.5 13.4 12,4 8.4 3.-> 18.8 3.5 18.3 3 8 3» £,-> AilCS-t H n^r.: 35 TS 14R3 324.1 334,7 282.8 257.3 213,¾ .387^ 239.7 439-4 279-8 28.7,-3 2024219717   13 Sep 2024 Table 34. CR GR-01 Mean MIN-101 Plasma Concentrations and Parameters (Fasted State) GR81 GSW PASTES PLASMA 3 ON CENTS ATI Of. S ®R«AUCo-t MEAN 5«? cv% & 9,80 §,80 §,80 9,25 §,80 9,8® a,s& §,80 166 0,80 9,89 8,80 0,80 1 §,35 1,22 6,55 348,41 O 3,25 3,7? 1,85 228,78 2 5,75 5,57 4.07 98,91 2,5 33,73 7,48 5,45 S3,OS 3 15,54 7,84 §,8S 58,45 3.5 304 7,91 5, §8 43.58 4 15,89 5,88 5,27 38,89 5 14,62 4,89 3.28 31,47 8 11,35 4,37 3,38 39,78 7 103 3,53 2,84 34,53 8 9,30 3,53 3,25 401 TS 19,69 S. 39 4,42 59,45 12 11,26 4,96 3,48 41,34 ^$4 33,78 4,87 3,33 38,73 18 38,58 4,87 3, S§ 48,81 28 5.48 2.33 1,.85 42,48 24 5,57 3.38 2,58 SS,31 28 2,8§ 2,94 78,S7 32 3,18 2,08 1,58 SO.*® 36 2,42 3.33 2,95 137,59 48 8,77 8,S2 8,77 118,51 SB 8,38 3,51 8,48 171,48 72 845 9,24 8,28 159,83 ■19,59 5,74 4,81 29,39 Tmsx H §,80 3,43 3,95 57, IS AUC8-1 254,52 80,83 41,48 21,38

[00370] See Figure 23 2024219717   13 Sep 2024 Table 35. CR GR-01 Mean MIN-101 Plasma Concentrations and Parameters (Fed versus Fasted State) FOOS EFFECT WWt Hasmss Ce»eentra1s«>»s Hours GRS1FED GRO3 FASTED <5 9,89 <>.25 9,89 0,.6 8,98 5,83 1 1.5 0,88 vs 3 8,88 5,75 2,5 §,57 «.71 3 3,44 45,54 3,5 1,55 4 V4 4 V« 4539 5 4.77 14,82 6 7,74 41,35 7 7,77 19,33 8 8,38 V® 18 7,58 18,8S 12 13,79 11,25 14 S,38 TVS 10 8,88 18,53 29 7,.94 5,49 24 18,71 5,5? 28 8,28 3,S§ 32 5,22 3,1 S 3® 2,83 2,42 4« §.71 8,77 88 0,18 9,33 72 9.33 8. S3 38, S IV Tf»s3.x H 12,5 v AUC34 203,2 284,5 8 AUC 85,44 REF F Cmax ■?W7 REF

[00371] Relative bioavailability of MIN-101 in GR-01 formulation in fed versus fasted states: F% Cmax: 108.97% 2024219717   13 Sep 2024 F% AUC(o-tau): 95.14%

[00372] See Figure 24 Example 13: In Vivo Pharmacokinetic Analysis of BFB-520 in CR GR-01 Tablets in Subjects in Fed versus Fasted States, (tau = 72 h)

[00373] Fed State - 12 subjects (cross-over)

[00374] Geo Mean Cmax: 1.54 ng / mL

[00375] Median Tmax: 18.00 H AUC(o-tau): 30.12 ng-H / mL Table 36. CR GR-01 Individual BFB-520 Plasma Concentrations and Parameters (Fed State) GR01 ___________________________GRC1FFD___555 -522 PLASMA                 tn-rmil ami              ___________________________ How* 2-SFB-528 O-BFB-526 5-BFB-536 8-BF5572 7-BF&-820 6SF8-528 S-BFE-528 48-5FS-522 41-3F8-520 12-SF&-520 10-388-526 £: ?5? 656 6.32 MS 3.66 050 656 8.82 8,80 0,60 858 8.08 0,.26 ?5? 656 6.32 MS 3.60 050 656 8.88 8,00 0,60 858 8,08 85? 656 6.32 252 2,60 656 656 '3.82 8,60 050 858 8.08 4 3,2? 656 6.32 252 2,60 656 656 '3.82 8,60 050 858 8.08 5,5 3,23 656 6.32 252 3.60 050 656 8.88 8,00 0,00 858 8.08 2 3,23 656 6.32 2fS2 0.,60 050 656 652 853 ■0,60 8,28 8.08 3,23 656 6.32 252 0,60 656 6.86 '3.82 8,60 ■050 858 8.08 3 3,26 5,.35 6.32 353 350 6.36 656 '3.82 8,60 ■050 858 8.08 3,5 3,23 656 6.32 253 0.,60 050 656 8.88 8,00 0,60 858 8.08 4 3,23 656 6.48 253 0.,60 050 656 6.82 853 ■0,60 8,28 8.27 5 3,23 656 654 252 0,20 052 6.86 8.88 8,60 ■0,60 858 853 S 6,26 5.45 6.7S W 3.80 156 656 8.88 8,30 ■0,60 858 854 .? 3,23 656 ■1.32 25^ 0,60 1,28 656 8.88 4,10 <50 &58 858 & 3,23 <56 6.32 253 0,60 1,53 656 6.82 4,54 1,77 8,28 8.4.3 16 3,23 156 6.72 45? 0,20 1,44 656 8.84 4,87 858 8.07 42 1,4? 5,32 6.62 3J8 8,75 1,82 656 1.14 4,80 M: 158 8.07 34 15? 6.46 6.62 2r52 a, $7 2,28 656 ■1.54 2,6S 2,53 1,08 853 1$ 4,80 5.75 5J8 353 3.87 4.80 656 MS 3.-43 2.28 655 ME 26 2.3? M* 2,24 6.26 155 2.15 050 143 3.,08 256 65.3 0,72 24 2.35 058 656 1.82 4.1E 0,60 255 1,08 158 ■155 0,44 26 4,14 3,,43 M3 6.26 1.75 3,13 854 248 1,43 153 456 0,56 32 2,.32 5,.35 M* 656 1.01 652 25? 255 8,74 658 1.36 0,43 36 2.32 e:55 2.,26 656 355 6,52 0,20 MS 8,08 353 656 0,34 4? 2,.32 3,53 2.,26 6..26 3.05 652 050 0,20 8,06 353 6.86 0,60 30 2.32 5,53 2.26 6.36 656 55 3,:63 0,80 8,08 353 6.86 0,60 72 3,23 656 6.32 2,32 0.20 0,23 656 656 8.30 0,60 &58 8,08 Max <5 15 15 1,1 45 25 0,8 2,8 2.4 2.7 15 65 Tmax H 44.6 <2,5 ?5 -i<s3 26.8 145 285 245 26,8 26,8 235 4 £5 AUC8A HmgOoJ 24,4 175 165 8.2 34,6 w 46.2 455 55,8 .34.4 235 r AUC <34.2 §4,2 -1425 285 4 77,5 230,2 34,5 142.5 1285 4375 482,1 82,8 F Cmax <58,1 8« 132.8 SS.3 1-S.1 33,4 1S3.8 S23.4 ■HS3.S SS.5 7S,i 2024219717   13 Sep 2024 Table 37. CR GR-01 Mean BFB-520 Plasma Concentrations and Parameters (Fed State) GR81 GR81 FED BFB-528 PLASMA CONCEMTRABOS S    A0€®4 Hobcs MEA& O Sm 8 OS «,25 9,89 9,5 08 1 9,89 09 OS 40^781 & w 09 M® siOS'Wl 2 O® 09 o® 2,5 8,88 08 OS ^©^<8i 3 8,88 OS 08 4EW.J6? 15 M3 OS os :348,41 4 08 MS OS 244,57 5 OS O® os 150® 8 8,35 M3 OS 128,88 7 9,54 03 ■8,48 OO 8 07 8,68 SO: 02,84 19 9,73 Ck&S :8,54 88,88 ■12 W 9,53 8,43 52,83 W 02 OS 54,14 ■is OS 07 8,59 1'08 29 04 o§ ■w F5JS 24 O1 04 77,24 28 os 9,72 ■158 508 32 8,83 M3 8,48 750 38 9,42 o® :8,34 85,« 48 9,82 69 9,88 72 9,88 Max ngiW OS 9,73 8,SI 43,32 Issas H 05 7,5S 9.42 41,41 AUCS-t 302 18,25 13,82 53,88 F AUG «1,58 505 37,75 43,74 F Etna* 1202 48,85 38,65 38,83

[00376] See Figure 25

[00377] Fasted State - 12 subjects (cross-over)

[00378] Geo Mean Cmax: 1.32 ng / mL

[00379] Median Tmax: 12.5 H 2024219717   13 Sep 2024 AUC(o-tau): 27.48 ng-H / mL Table 38. CR GR-01 Individual BFB-520 Plasma Concentrations and Parameters (Fasted State) GRU BF522C PLASWX Xv^EENT!^^           and Atf£X4 iHn-a 28: Hours S-BF8>-S20 2-BF&-S25 S-EFB-520 1SFB233 1&F5223 7-8FB22S 1BFE223 $-BF&-SX •X-&FB-520 11-SFB225 S2-SFB-52C •D-BFE-SiC I? S,X< 8,13 13¾ 0,3¾ 1<2 0X2 0.0ft 103 ft >X‘ ft .CO 8 CO 0X0 125 S / X IMv ISO 18¾ K2 0.0ft 10ft ft 03 ¢,08 ft SO 8,33 18:¾ Is 1X< 10« 13¾ <‘X2 0X2 0.0ft 103 S,'X‘ ft.CO ICO 110 0,8¾ 0.03 0.08 10ft 8,00 3?X> 3.8¾ 103 vj'y 1,5 ix< 8.1.' 10« 13¾ K'0 0X2 0.0ft 103 S?X ft.CO ICO 110 2 ISO 3.1.' 125 0,8¾ 108 0.08 10ft 8,00 3,!X ISO 103 0.00 15 l‘X 8.52 143 13¾ 102 OX-8 0,0ft s,os 5,48: ft 20 12& 18» 8.42 8.71 '3.45 0,44 0X2 128 10ft 820 323 ISO 122 0.38 3.5 3,54 1.1.' 13¾ 02 7 0.08 1,38 4 47 125 3.74 1.8¾ 130 X v,S4 104 «3.45 103 822 0 30 145 t,4< 4X« < 2S 1’2 151 s 131 oxs 138 172 3,52 181 175 120 1.13 1.45 ft,OS 101 8 137 1« ’ 143 8,75 18.3 024 ISO ■1,47 ft.05 ■528 8X0' 8.84 7 lift <2 & 13T 1S5 113 1S< 0,5ft 1.-47 ft 71 ■1 47 8,74 ISO a MT 107 144 ■It 3 4,03 028 1.7ft <20 1.37 12ft 1,3b 0,74 to ISO 0,35 0.08 •123 1?7 323 12# 1,72 124 122 137 S.ftl 42 0.S5 177 155 <00 8,80 0.82 024 '1.43 3-74 178 2,28 1.80 14 134 0,07 173 8.74 0.48 1.24 ■> .54 1..02 4 '51 1,11 1.8'5 4¾ 4,0ft 17 < 1S3 1,38 8.51 0.4.3 1X2 '1.43 1.08 <24 1,1:1 135 3S 103 1?8 1S3 IS? 827 0.4ft 0.71: ■: .73 •t .1S 1,44 M7 ISO JH 1O.‘ sai 143 025 8.5'3 0.80 0.3ft ■t,3< ft.5? 1S5 8.13 ISO 3ft ft,72 32 $ $2¾ 8,S5 8.5ft 0.8ft 0.0ft ■t,ts ft «'2' 1.27 1S5 8. SO 32 «.33 xw 1,25 130 lift 0.44 0,0ft ft 07 ft 32$ 8,28 0.43 3ft sfx 323 133 8,30 8.3:3 '5ft 0.0ft ft,28 ft.'X 322 iso 82? 4ft S / X< 323 10¾ 8.30 113 0.13 0,0ft ft 03 S.'X: ft SO IflO 180 3ft srx 323 13¾ 8,30 8.80 0.80 0,0ft ft.03 •1'38 3f2 8., 38 180 73 ISO 111 >3.03 3.83 ft X 3 08 ■138 130 ■3.8ft 0X3 ft.OS ft aft Mac op-'ml ■13 32 <2 IQ 1.3 12 42 ft.3 1,4 Twax M 7.3 72 10 S ■18,3 32 318 <02 0.8 13ft 2.0 ■12.S Tift AvCft-t H.ngi.'raJ 23.5 ■tie 117 313 53.7 110 312 432 38 1 43.8 3.3.7 37 \ 2024219717   13 Sep 2024 Table 39. CR GR-01 Mean BFB-520 Plasma Concentrations and Parameters (Fasted State) GRM GSM BF8-526 PIASSM CO WCEKTRAItaiiS sad Hoots Sm CW 8 ya 8,25 08 3,5 OS 1 OS 1,5 03 2 8,84 8,18 8,87 233,68 2,5 3,22 05 02 112..81 3 8,48 03 847 45,89 3,5 9,65 05 8,2? 50? 4 07 O 8,31 47.35 5 8,88 8,38 8,23 43,77 8 07 6.29 02 33,59 7 04 05 08 37,58 8 1,67 0'3 8,28 301 38 1,38 8,45 8,38 49,79 32 04 S.5S 8,43 53,43 34 1,11 02 8,31 37,58 IS OS ■8,45 8,34 41.52 26 OS 8,43 8,38 45^6 24 03 8,38 8,28 57,32 28 8,63 8,36 OS 57,98 32 07 03 8,48 68,48 38 8,25 03 8,25 133,52 43 O 8.69 8,85 348,41 §6 W 72 8,88 ft ax TtgM 03 03 8,37 38,9« Trsiax H 12,58 04 OS §4,32 A«£S4 H,ag<W 27,48 06 8,87 34,41 F AUC 1.3 38,77 18,95 57,22 F Cmax 808 24,sa 28.65 38,56

[00380] See Figure 26 2024219717   13 Sep 2024 Table 40. CR GR-01 Mean BFB-520 Plasma Concentrations and Parameters (Fed versus Fasted State) GR91 GB9t 876-526 PLASMA and AV Co 4 Hours MEAH Sf? 0 9.¢9 8,25 8,68 8,5 w 1 8,.58 V 09 2 8,84 MS 8,97 233,98 2,5 9,22 8,25 8,32 112,81 3 8,48 ■03 07 409 05 8,35 8,27 53,37 4 9.77 9.36 8,31 47,35 S O'? 6,36 09 46,77 6 8,8? ■OS 6,22 33,53 ?' 04 OS 8,25 37,53 8 07 8,39 8,3S 38,81 to w 9,45 8,36 49,79 12 04 8,55 8,43 53,43 14 4,11 8,42 8,31 37,58 18 08 6,34 41,52 20 9,96 SO 8,38 45,39 24 03 9,36 8,28 57,32 28 9,83 8,38 8,38 57,98 32 07 03 8,18 96,48 30 8,25 03 8,25 0.52 48 03 6,86 05 346,41 88 9,69 72 9.59 Max 1,43 6,43 8,37 36,88 Tmax H 12,58 8,94 5,98 64,32 AUCO 27,43 6,46 3,8? 34,41 F AVC SO 8 35,77 105 37,32 F >vsx oOS 24,86 20$ 39,56

[00381] Relative bioavailability of BFB-520 in GR-01 formulation in fed versus fasted states: F% Cmax: 121.32% 2024219717   13 Sep 2024 F% AUC(o-tau): 111.58%

[00382] See Figure 27 Example 14: Predicted Food Effect on Plasma Concentrations of MIN-101 and BFB-520 at Steady State in GR-01 Tablets (32 mg)

[00383] Determination of elimination slopes from the mean plasma concentrations time curves before numerical computations.

[00384] MIN-101 Fed State: Ke = 0.119 / H Fasted State: Ke = 0.082 / H

[00385] BFB-520: Fed State: from 14 H to 28 H during the flip flop phase Ke = 0.014 / H; post absorption Ke = 0.233 / H Fasted State: from 14 H to 28 H during the flip flop phase Ke = 0.005545 / H; post absorption Ke = 0.1586 / H 2024219717   13 Sep 2024 Table 41. Predicted Plasma Concentrations of MIN-101 at Steady State in GR-01, 32 mg Tablets (Fed and Fasted states) GR01 82mg FED and FASTED &W-W1 at Steady-State &W181 Plasma Concentrations (n^mij HOURS GR91 FED SS GR81 FASTED SS 72 11,45 8,45 72,5 10 JO OJO 73 109 8,39 73,5 9,59 8,9S 74 8.95 11,23 74,5 9,00 16,97 75 9,39 20,59 75,5 9,94 208 75 10,40 28,58 77 11,04 18,91 78 13,38 15,38 79 12,71 13,96 80 103 12,95 82 11,04 13,53 84 18,70 14.02 §5 11,53 106 88 10,57 12,32 92 8,89 8.75 95 105 MS CMmSS ngAnl TS,7 20,S CfcSS 09 mb TmaxSS H 12,00 3,5 AUC72-96 H.ng / mJ 283,8 287,8 F ADC $1,7 REF F Cmax 80,0 REF

[00386] See Figure 28. 2024219717   13 Sep 2024 Table 42. Predicted Plasma Concentrations of BFB-520 at Steady State in GR-01, 32 mg Tablets (Fed and Fasted states) GR01 32mg FED and FASTED BFB-520 at Steady-State BFB^20 Plasma Cence»tratiens (ng / mO HOURS GR01 FED SS GR01 FASTED SS 72 1.33 0,56 72,5 1,02 0,64 73 1,01 0,62 73.5 w 0,68 74 9,88 0,63 74.5 0,93 873 £ 3 75,5 1,80 i :1 1,18 76 1,25 1,41 77 1,13 1,38 78 1,28 1,33 79 1,46 1,38 80 1,51 1,45 82 1.26 1,37 84 1.43 1.28 86 1,43 1,26 88 1,21 1,19 92 1,18 1,82 86 1,83 0,88 CMaxSS ng / ml 1,51 1,45 C^mSS 1,03 0,85 TmaxSS H 8,0-0 8,00 AUC72-96 Hmg / nd 29,5 27.0 F AUC 199,4 REF F Cm ax 103.7 REF

[00387] See Figure 29. 2024219717   13 Sep 2024 Example 15: Predicted Food Effect on Plasma Concentrations of MIN-101 and BFB-520 at Steady State in GR-01 Tablets (64 mg)

[00388] Determination of elimination slopes from the mean plasma concentrations time curves before numerical computations.

[00389] MIN-101 Fed State: Ke = 0.119 / H Fasted State: Ke = 0.082 / H

[00390] BFB-520: Fed State: from 14 H to 28 H during the flip flop phase Ke = 0.014 / H; post absorption Ke = 0.233 / H Fasted State: from 14 H to 28 H during the flip flop phase Ke = 0.005545 / H; post absorption Ke = 0.1586 / H 2024219717   13 Sep 2024 Table 43. Predicted Plasma Concentrations of MIN-101 at Steady State in GR-01, 64 mg Tablets (Fed and Fasted states) GR01      FED and FASTED SUN-161 at Steady-State Plasma Concentrations HD a RS GROf FED SS GR01 FASTED SS 72 22,91 1230 72,5 21,41 12,48 73 20,17 12,66 73,5 19,81 13,93- 74 17,91 22,48 74,5 18,80 33,94 75 18,78 41,16 75,5 18,88 41,77 76 20.92 41,17 77 22,08 37,82 78 26,88 30tS6 79 25,42 27,.92 eo 23,65 25^6 62 22,08 27,88 84 33,41 28,05: 86 23,85 27,61 88 21,14 24,64 §2 16,17 13,49 S6 22,91 12.93 CNEaxSS ug / nd 33,41 41,77 CiMinSS 16,17 12,93 TmaxSS H 12,00 3,50 AUC72-98 527,5 577,6 F AHC 91,3 REF F C max 30,0 REF

[00391] See Figure 30. 2024219717   13 Sep 2024 Table 44. Predicted Plasma Concentrations of BFB-520 at Steady State in GR-01, 64 mg Tablets (Fed and Fasted states) GR01     FED and FASTED BFB-520 at Steady-State BFB-520 Pk tsma Eoncentratkos HOURS GR01 FED SS GR01 FASTED SS 72 2,95 1,32 72,5 2,04 1,28 73 2,92 1,24 73,5 2,98 1,21 74 1,99 1,28 74,5 1,97 1,58 75 1,35 2,99 75,5 1,03 2,37 78 2,50 2,82 77 2,27 2,77 78 2,57 2,88 79 212 2,78 80 3,01 2,91 ®2 2,51 2,75 84 2,87 2,57 86 2,88 2,52 S3 2,42 2,37 82 2,38 2,83 :98 238 1,32 C^axSS ng / ml 3,01 2,11 C&lmSS 2,06 1,32 TmaxSS H 8,00 8,.00 AUv / 2-W H.ngiml 59,0 54,1 F AUC 109,1 REF F Cmax 103,7 REF

[00392] See Figure 31. Example 16: Description of 32 mg gastro-resistant CR tablet (GR01 / B-32 mg) 2024219717   13 Sep 2024

[00393] The CR GR-01 / B tablets are supplied as round (diameter 10 mm and R=10) tablets, free from visual defects. Each tablet contains 32 mg of Compound (I). The complete statement of the components and quantitative composition of CR GR-01 / B tablet is given in Table 45. Table 45: Composition of CR GR-01 / B 32mg tablet Com ponent / lngred lent IIIM mg / tablet % (wM MIN-1011 38.40 12.09 Hypromellose (METHOCEL™ K100LV CR) 30.00 9.45 Hypromellose (Methocel™ KI OOM CR) 72.00 22.67 Microcrystalline Cellulose 96.67 30.42 Lactose 60.00 18.89 Silica Colloidal Anhydrous 1.50 0.47 Magnesium stearate 1.50 0.47 Eudragit L30D55 15.0 4.72 Plasacryl HTP20 2.55 0.80 Total 317.62 100.00 1 Salt correction factor of 1.2 applied Example 17: Description of 64 mg gastro-resistant CR tablet (GR-01 / B-64 mg)

[00394] The CR GR-01 / B tablets are supplied as round (diameter 10 mm and R=10) tablets, free from visual defects. Each tablet contains 64 mg of Compound (I). The complete statement of the components and quantitative composition of CR GR-01 / B tablet is given in Table 46. Table 46: Composition of CR GR-01 / B 64mg tablet C ompmi ent / In gred lent GR-0l / B-64mg mg / tablet % fw / w) MIN-1011 76. 8 24.14 Hypromellose (METHOCEL™ K100LV CR) 30.00 9.45 Hypromellose 72.00 22.67 2024219717   13 Sep 2024 (Methocel™ KI OOM CR) Microcrystalline Cellulose 77.40 24.37 Lactose 40.80 12.85 Silica Colloidal Anhydrous 1.50 0.47 Magnesium stearate 1.50 0.47 Eudragit L30D55 15.0 4.72 Plasacryl HTP20 2.55 0.80 Total 317.55 100.00 1 Salt correction factor of 1.2 applied 179445285 v2 2024219717   13 Sep 2024 via EFS: June 21, 2018                            Cooley Docket No. MNRV-017 / 001WO (323191-2227) Example 18: Comparison of GR-01 32 mg Tablet, GR-01 / B 32 mg Tablet, and GR-01 / B 64 mg Tablet Table 47:Tablet Composition : GR01 vs GR01 / B Com pan entd ngredienf GROL32mg mg / tablet % (w / w) »i Sublet mg / fahfet % (Ww) MIN-1011 38.40 12.09 38.40 12.09 76.8 24.14 Hypromellose (Metolose® 90SH 100 SR) 30.00 9.45 Hypromellose (METHOCEL™ K100LV CR) 30.00 9.45 30.00 9.45 Hypromellose (Methocel™ K100M CR) 72.00 22.67 72.00 22.67 72.00 22.67 Microcrystalline Cellulose 95.10 29.95 96.60 30.42 77.40 24.37 Lactose 60.00 18.89 60.00 18.89 40.80 12.85 Silica Colloidal Anhydrous 1.50 0.47 1.50 0.47 1.50 0.47 Magnesium stearate 3.00 0.94 1.50 0.47 1.50 0.47 Eudragit L30D55 15.0 4.72 15.0 4.72 15.0 4.72 Plasacryl HTP20 2.55 0.80 2.55 0.80 2.55 0.80 Total 317.55 5.53 317.55 100.00 317.55 100.00 1 Salt correction factor of 1.2 applied 179445285 v2 122 2024219717   13 Sep 2024 Example 19: Stability Data Experiments: Comparison of GR-01 and GR-01 / B 32 mg Tablets

[00395] “Impurity A,” “2-isomer,” and “PMIC” refer to impurities from the manufacturing process for MIN-101. Table 48: Stability data at 25 °C / 60% RH Product Name: Strength: Storage Condition: MIN-101 25 ?C / 60% RH Product Manufacturer: Amatsi Aquitaine API Manufacturer: PCAS Container Closure: TEKNIFLEX® VPOA 10200 and aluminum blister packs Stability Interval (Months) Test Initial 1 3 6 9 12 GR01 tablets Related Sub. (%) Impurity A <LOQ 0.02 0.03 0.04 0.03 <LOQ 2-isomer <LOQ <LOQ <LOQ 0.02 <LOQ <LOQ PMIC 0.08 0.13 0.18 0.20 0.24 0.26 Unspecified imp. <0.1% each <0.1% each RRT0.67 : 0.11 RRT0.67 : 0.12 RRT0.67 : 0.12 RRT0.67 : 0.15 Total impurities 0.15 0.29 0.46 0.51 0.52 0.59 GR01 / B tablets Related Sub. (%) Impurity A ND ND ND ND 2-isomer 0.07 0.07 0.07 0.07 PMIC 0.09 0.11 0.15 0.16 Unspecified imp. <0.1% each <0.1% each <0.1% each <0.1% each Total impurities 0.26 0.29 0.37 0.38 2024219717   13 Sep 2024 Table 49: Stability data at 40°C / 75% RH Product Name: Strength: Storage Condition: MIN-101 32mg 40°C / 75% RH Product Manufacturer: Amatsi Aquitaine API Manufacturer: PCAS Container Closure: TEKNIFLEX® VPOA 10200 and aluminum blister packs Test Stability Interval (Months) Initial 1 3 6 GR01 tablets Related Sub. (%) Impurity A 2-isomer PMIC Unspecified imp. Total impurities <LOQ <LOQ 0.08 <0.1% each 0.15 0.04 <LOQ 0.27 RRT0.67 = 0.12 0.57 0.06 <LOQ 0.44 RRT0.67 : 0.18 0.94 0.08 <LOQ 0.77 RRT0.67 : 0.24 1.46 GR01 / B tablets Related Sub. (%) Impurity A 2-isomer PMIC Unspecified imp. Total impurities ND 0.07 0.09 <0.1% each 0.26 ND 0.07 0.23 <0.1% each 0.51 ND 0.07 0.34 RRT0.67 : 0.11 0.71 ND 0.06 0.52 RRT0.67 : 0.15 1.00 2024219717   13 Sep 2024 Example 20: In Vitro Dissolution Specifications for GR-01 / B Tablets Table 50: Specifications for GR-01 / B tablets Test Method Acceptance Criteria Dissolution (%) 2 hours 4 hours 8 hours 16 hours HPLC Report results (±10%) 0.0 % 24.1% 59.2% 88.6% Example 21: Description of 32 mg gastro-resistant CR tablet (GR-01 / C-32 mg)

[00396] The CR GR-01 / C tablets are supplied as round (diameter 10 mm and R=10) tablets, free from visual defects. Each tablet contains 32 mg of Compound (I). The complete statement of the components and quantitative composition of CR GR-01 / C tablet is given in Table 51. Table 51: Composition of CR GR-01 / C 32mg tablet ComponeiH / lng^ IIM mg / tablet % (w / w) MIN-1011 38.40 12.11 Hypromellose (METHOCEL™ K100LV CR) 30.00 9.45 Hypromellose (Methocel™ KI OOM CR) 72.00 22.67 Microcrystalline Cellulose 95.10 29.95 Lactose 60.00 18.89 Silica Colloidal Anhydrous 1.50 0.47 Magnesium stearate 3.00 0.94 Eudragit L30D55 15.0 4.72 Plasacryl HTP20 2.55 0.80 Total 317.55 100.00 2024219717   13 Sep 2024 Example 22: Description of 64 mg gastro-resistant CR tablet (GR-01 / C-64 mg)

[00397] The CR GR-01 / C tablets are supplied as round (diameter 10 mm and R=10) tablets, free from visual defects. Each tablet contains 64 mg of Compound (I). The complete statement of the components and quantitative composition of CR GR-01 / C tablet is given in Table 53. Table 53: Composition of CR GR-01 / C 64mg tablet Comp (men t / l ngredien t G1U(H / O64mg mg / tablet % (w / w) MIN-1011 76.8 24.19 Hypromellose (METHOCEL™ K100LV CR) 30.00 9.45 Hypromellose (Methocel™ KI OOM CR) 72.00 22.67 Microcrystalline Cellulose 75.90 23.91 Lactose 40.80 12.85 Silica Colloidal Anhydrous 1.50 0.47 Magnesium stearate 3.00 0.94 Eudragit L30D55 15.0 4.72 Plasacryl HTP20 2.55 0.80 Total 317.55 100.00 EQUIVALENTS AND INCORPORATION BY REFERENCE

[00398] The dosage forms, compositions and methods of the disclosure have been described herein by reference to certain preferred embodiments. However, as particular variations thereon will become apparent to those skilled in the art, based on the disclosure set forth herein, the disclosure is not to be considered as limited thereto.

[00399] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure 2024219717  15 Nov 2024 belongs. In the specification and claims, the singular forms also include the plural unless the context clearly dictates otherwise.

[00400] It is to be understood that at least some of the descriptions of the disclosure have been simplified to focus on elements that are relevant for a clear understanding of the disclosure, while eliminating, for purposes of clarity, other elements that those of ordinary skill in the art will appreciate may also comprise a portion of the disclosure. However, because such elements are well known in the art, and because they do not necessarily facilitate a better understanding of the disclosure, a description of such elements is not provided herein.

[00401] Further, to the extent that a method does not rely on the particular order of steps set forth herein, the particular order of the steps recited in a claim should not be construed as a limitation on that claim.

[00402] All patents, patent applications, references and publications cited herein are fully and completely incorporated by reference as if set forth in their entirety. Such documents are not admitted to be prior art to the present disclosure.

[00403] Any reference to publications cited in this specification is not an admission that the disclosures constitute common general knowledge in Australia.

[00404] The term “comprise” and variants of the term such as “comprises” or “comprising” are used herein to denote the inclusion of a stated integer or stated integers but not to exclude any other integer or any other integers, unless in the context or usage an exclusive interpretation of the term is required.

Claims

1. A gastro-resistant, controlled release dosage form, comprising:about 19 to about 29% w / w of 1H-isoindol-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, hydrochloride, hydrate (1:1:2) (roluperidone hydrochloride);about 4 to about 14% w / w of a first hypromellose;about 17 to about 27% w / w of a second hypromellose;about 19 to about 29% of a first filler;about 8 to about 18% w / w of a second filler;about 0.1 to about 4% w / w of a glidant;about 0.1 to about 4% of a lubricant;about 1 to about 10% w / w of a polymeric controlled release agent; andabout 0.5 to about 5% w / w of an anti-tacking agent.

2. The gastro-resistant, controlled release dosage form of claim 1, wherein the dosageform comprises 64 mg of 1H-isoindol-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, hydrochloride, hydrate (1:1:2) (roluperidone hydrochloride).

3. The gastro-resistant, controlled release dosage form of claim 1 or 2, wherein the firstfiller and second filler are selected from the group consisting of microcrystalline cellulose, lactose monohydrate, sucrose, glucose, and sorbitol.

4. The gastro-resistant, controlled release dosage form of any one of claims 1-3, whereinthe glidant is silica colloidal anhydrous, starch, or talc; and / or the lubricant is magnesium stearate, stearic acid, or vegetable stearin.

5. The gastro-resistant, controlled release dosage form of any one of claims 1-4, whereinthe glidant is silica colloidal anhydrous.

6. The gastro-resistant, controlled release dosage form of any one of claims 1-5, whereinthe lubricant is magnesium stearate.2024219717   17 Sep 20267.     A gastro-resistant, controlled release dosage form, comprising:about 7 to about 17% w / w of 1H-isoindol-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, hydrochloride, hydrate (1:1:2) (roluperidone hydrochloride);about 4 to about 14% w / w of a first hypromellose;about 17 to about 27% w / w of a second hypromellose;about 25 to about 35% of a first filler;about 13 to about 23% w / w of a second filler;about 0.1 to about 4% w / w of a glidant;about 0.1 to about 4% of a lubricant;about 1 to about 10% w / w of a polymeric controlled release agent; and about 0.5 to about 5% w / w of an anti-tacking agent.

8. The gastro-resistant, controlled release dosage form of claim 7, wherein the dosageform comprises 32 mg of 1H-isoindol-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-, hydrochloride, hydrate (1:1:2) (roluperidone hydrochloride).

9. The gastro-resistant, controlled release dosage form of claim 7 or 8, wherein the firstfiller and second filler are selected from the group consisting of microcrystalline cellulose, lactose monohydrate, sucrose, glucose, and sorbitol.

10. The gastro-resistant, controlled release dosage form of any one of claims 7-9, wherein the glidant is silica colloidal anhydrous, starch, or talc; and / or the lubricant is magnesium stearate, stearic acid, or vegetable stearin.

11. The gastro-resistant, controlled release dosage form of any one of claims 7-10, wherein the glidant is silica colloidal anhydrous.

12. The gastro-resistant, controlled release dosage form of any one of claims 7-11, wherein the lubricant is magnesium stearate.

13. A method of treating negative symptoms in a subject comprising orally administeringto the subject the gastro-resistant, controlled release dosage form of any one of claims 1-12.2024219717   17 Sep 202614. The method of claim 13, wherein the gastro-resistant, controlled release dosage form is administered once daily.

15. The method of claim 13 or 14, wherein the subject has a diagnosis of schizophrenia.

16. Use of the gastro-resistant, controlled release dosage form of any one of claims 1-12in the manufacture of a medicament for treating negative symptoms in a subject.

17. The use of claim 16, wherein the medicament is formulated for use once daily administration.

18. The use of claim 16 or 17, wherein the subject has a diagnosis of schizophrenia.

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