MW151-101: First-in-human Study of MW151

Study Overview
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Brief Summary
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MW01-2-151SRM (=MW151), a small molecule, is being developed for the treatment of cognitive disorders. The development program is based on nonclinical evidence that MW151 improves neurocognitive outcomes in animal models of radiation-induced cognitive impairment, Alzheimer's disease, and other central nervous system (CNS) disorders. The present study will provide safety and pharmacokinetic (PK) information on single ascending doses to support decisions for continued clinical development.

Detailed Description
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The primary objective of this trial is to assess the safety and tolerability of single ascending doses of MW151 when administered orally to healthy adults. Subjects will be screened prior to inpatient admission. Subjects will be admitted to the inpatient clinic on the day prior to dosing (Day -1) and will remain in the unit until discharge on Day 3. A follow-up visit will be done on Day 7. A single dose of study drug or placebo will be administered on Day 1. Healthy adult female subjects will be randomly assigned to one of 5 dose cohorts (8 subjects each). Each subject will receive a single dose of MW151 (10-160mg) or placebo under fasted conditions. Following a review of safety and tolerability data for the first 24 hours of dosing in each cohort (including reported adverse events (AEs), physical examination findings, clinical laboratory results, vital signs, and electrocardiograms (ECGs), the remaining 6 subjects will be randomized in a 5:1 ratio. Dosing of the remaining subjects in a cohort may proceed after review of sentinel subject safety data collected during the first 24 hours of dosing and determination that no stopping rules are met. The remaining subjects in each cohort will be dosed sequentially, not simultaneously.

Official Title
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A Phase 1a, Double-Blind, Randomized, Placebo-Controlled Single Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetic Profile of MW151 Administered Orally to Healthy Volunteers

Conditions
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Drug Toxicity

Intervention / Treatment
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* Drug: Placebo
* Drug: MW151, 10mg
* Drug: MW151, 20mg
* Drug: MW151, 40mg
* Drug: MW151, 80mg
* Drug: MW151, 160mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide written informed consent In good health as determined by medical history, physical exam, laboratory examinations, ECG, and vital signs. Weight >50kg BMI <34 kg/m2. ECG without clinically significant pathologic abnormalities and with QTcF <450 ms - Systolic BP ≤ 150 mmHg and diastolic BP ≤ 90 mmHg at screening No suicidal ideation, as demonstrated by a score of 0 on the Columbia Suicide Severity Rating Scale (C-SSRS). Women who are neither pregnant (negative pregnancy test) nor nursing, and are either: surgically sterile, postmenopausal with last natural menses greater than 24 months, or premenopausal and agrees to use and acceptable form of birth control during the study and for 1 month after dosing. Adequate venous access for blood draws. Exclusion Criteria: Any unstable chronic medical condition requiring interventional treatment that might increase the risk to the subject or confound interpretation of safety observations. Subjects who are considered stable and who have been receiving stable treatment for medical condition for > 3 months may be considered with approval of medical monitor. Evidence of active infection requiring antibiotic therapy within 14 days prior to dosing. Medical history of vasculitis or any autoimmune disease excluding seasonal allergic rhinitis and childhood history of atopic dermatitis. History of any treatment for cancer within the past 2 years, other than basal cell or squamous cell carcinoma of the skin. Seropositive for human immunodeficiency virus (HIV). History of acute/chronic hepatitis B or C and/or carriers of hepatitis B Clinically significant abnormalities in screening laboratory tests Over-the-counter and herbal medications are prohibited within 10 days prior to study dosing (with exception of calcium/vitamin D supplements and ocular medications at the discretion of the Investigator). Stable doses (> to 3 months of stable dose) of prescription medications are allowed with the approval of the medical monitor (birth control medications are allowed without medical monitor approval). Subjects should not be on non-steroidal anti-inflammatory drugs or immunosuppressive drugs within 10 days prior to dosing. Use of known CYP450 CYP1A2, CYP2D6 or CYP3A4 inhibitors or inducers within 14 days of dosing or planned use during the study. Use of an investigational drug, vaccine, device, or blood product within 3 months prior to dosing in this study. Any disorder that could interfere with the absorption, distribution, metabolism or excretion of drugs (e.g. small bowel disease, Crohn's disease, celiac disease, or liver disease.) Psychiatric history of current or past psychosis, bi-polar disorder, clinical depression, or anxiety disorder requiring chronic medication within the past 5 years. History of substance abuse including alcohol within the past 5 years. Smoker. Current substance or drug dependence confirmed by positive urine drug screen at screening visit or Day -1 admission. Current alcohol abuse confirmed by positive breathalyzer at screening visit or Day -1 admission. History of serious head injury as determined by the site investigator or designee. Chronic kidney disease (defined as the presence of any degree of proteinuria on urine analysis and/or an eGFR of <60 ml/min using the MDRD formula). Any reason or opinion of the investigator that would prevent the subject from participation in the study. Inability to follow the instructions or an unwillingness to cooperate with study procedures. Has donated more than 500 mL of blood within the last month prior to dosing.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose-escalation study.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants will receive placebo. | Drug: Placebo<br>* Matched placebo administered orally<br>|
| Experimental: Dose 1<br>Participants will receive 10 mg of MW151. | Drug: MW151, 10mg<br>* 10 mg MW151, 1 x 10mg capsule administered orally<br>|
| Experimental: Dose 2<br>Participants will receive 20mg of MW151. | Drug: MW151, 20mg<br>* 20 mg MW151, 1 x 20mg capsule administered orally<br>|
| Experimental: Dose 3<br>Participants will receive 40mg of MW151. | Drug: MW151, 40mg<br>* 40 mg MW151, 2 x 20mg capsule administered orally<br>|
| Experimental: Dose 4<br>Participants will receive 80mg of MW151. | Drug: MW151, 80mg<br>* 80 mg MW151, 1 x 80mg capsule administered orally<br>|
| Experimental: Dose 5<br>Participants will receive 160mg of MW151. | Drug: MW151, 160mg<br>* 160 mg MW151, 2 x 80mg capsule administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Drug-related Serious Adverse Events. | Percentage of participants experiencing drug-related serious adverse events from the start of study drug administration up to 7-day follow-up. | Seven days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Drug Concentration (Cmax) | Peak serum concentration of MW151. | predose, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, 24h and 36h post-dose | 
| Time to Maximum Drug Concentration (Tmax) | Time required to reach the maximum serum concentration of MW151. | predose, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, 24h and 36h post-dose | 
| Overall Drug Exposure (AUC) | Overall drug exposure (h*ng/mL) determined by calculating the area under the curve (AUC) from a plasma drug concentration-time curve. | predose, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, 24h and 36h post-dose | 
| Drug Half-Life (T1/2) | Time at which the concentration of MW151 is at half the maximum concentration. | predose, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, 24h and 36h post-dose | 
| Elimination Rate Constant (Kel) | Fraction of MW151 eliminated per unit of time (mathematical determination). | predose, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, 24h and 36h post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cognitive disorder, pharmacokinetics, MW151, MW01-2-151SRM, PK, dose escalation