Amyotrophic lateral sclerosis Nervous System Diseases
Conditions
Interventions
VRG50635 is a PIKfyve inhibitor. In each cohort in part 1, 6 subjects will receive VRG50635 and 2 subjects will receive a placebo. In part 2, 8 subjects will receive VRG50635 and 2 subjects will recei
each subject will receive a placebo and VRG50635 for 28 days with a washout of 2 weeks in between.
Dose range Part 1:
Cohort 1: 60mg
Cohort 2: 120mg
Sponsors
Verge Genomics
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion criteria for Parts 1 and 2: 1. Healthy male or female aged between 18 to 65 years old at screening (inclusive) 2. For male and female subjects of childbearing potential: Subjects and their spouse/partners who are of childbearing potential must use highly effective contraception when engaging in sexual activity consisting of 2 forms of birth control (1 of which must be a barrier method such as latex or polyurethane condoms) starting at screening and continue throughout the clinical study period, and for 90 days after the final study drug administration. 3. For males: Subject must not donate sperm starting at screening and throughout the clinical study period, and for 90 days after the final study drug administration. Inclusion criteria for Part 3: 1. Diagnosis of laboratory-supported probable, probable, or definite (sporadic) amyotrophic lateral sclerosis (ALS) according to the El Escorial World Federation of Neurology revised research diagnostic criteria (Ludolph et al. 2015) 2. Aged between 18 and 80 years old 3. 5 years or less since the onset of ALS symptoms 4. Forced vital capacity (FVC) =50% predicted value 5. Able to swallow medication for the duration of the study (in the opinion of the investigator)
Exclusion criteria
Exclusion criteria: Exclusion criteria for Parts 1 and 2: 1. History of clinically significant hematological, renal, neurologic, pancreatic, gastrointestinal, hepatic, cardiovascular, psychological, pulmonary, metabolic, endocrine, immunological, allergic disease, or other major disorders 2. Current significant medical or psychiatric condition 3. Evidence of clinically significant hepatic or renal impairment in the opinion of the investigator, including alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5 the upper limit of normal (ULN) or bilirubin > 1.5ULN. Patients with Gilbert syndrome without evidence of hepatic impairment may be enrolled. 4. Poor peripheral venous access 5. A lifetime history of suicidal behavior or suicidal ideation as determined by a positive response (‘’Yes’’) to either question 4 or question 5 of the C-SSRS at screening 6. For part 2 only: Subjects not eligible for lumbar puncture (anti-coagulation, anti-aggregation or blood coagulation pathologies, recent spine surgery, acquired or congenital spine malformation, clinical signs of intracranial hypertension, cutaneous infection at the punction site) Exclusion criteria for Part 3: 1. Amyotrophic lateral sclerosis (ALS) patients with a known mutation in the SOD1 or C9orf72 gene 2. Tracheotomy and/or ventilator-dependent (or daily use of non-invasive ventilation = 22 hours for 7 consecutive days) 3. After percutaneous gastrostomy (PEG) operation 4. Subjects not eligible for lumbar puncture (anti-coagulation, anti-aggregation or blood coagulation pathologies, recent spine surgery, acquired or congenital spine malformation, clinical signs of intracranial hypertension, cutaneous infection at the punction site)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part 1 Single ascending dose: 1. Assessment of: 1.1. Adverse events (AEs) measured by collecting the number of AEs, the intensity, relationship with the study drug and chronicity, continuously throughout the study 1.2. Vital signs, evaluations of systolic and diastolic blood pressure, pulse rate, respiratory rate (only predose, 0.5h, 1.5h, 24h) and temperature at screening, Day -1, predose and postdose at 0.5h, 1.5h, 2h, 24h, 48h and at follow-up (FU) 1.3. Electrocardiograms (ECGs) measured in triplicate at screening, predose and postdose at 0.5h, 1.5h, 4h, 7h, 24h, 48h and at FU. The ECG parameters assessed will include heart rate, PR, QRS, QT and QTcF. 1.4 Physical examinations, including neurological examination, at screening predose, 48h postdose and at FU 1.5. Suicidal ideation and behaviour measured using the Columbia Suicide Severity Rating Scale (C-SSRS) at screening, Day -1, and 48h postdose 1.6. Laboratory safety tests, including chemistry, hematology, coagulation and glucose at screening, Day-1, 24h (no Coagulation), 48h, at FU Part 2 Multiple ascending doses 2. Assessment of: 2.1. Adverse events (AEs) measured by collecting the number of AEs, the intensity, relationship with the study drug and chronicity, continuously throughout the study 2.2. Vital signs, evaluations of systolic and diastolic blood pressure, pulse rate, respiratory rate (only predose, Day 2 and Day 4) and temperature at screening, Day -1, predose and postdose on Day 1 (2h and 5h), Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9 and at FU 2.3. ECGs measured in triplicate at screening, Day -1, predose and postdose on Day 1 (2h and 5h), Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 9 and at FU. The ECG parameters assessed will include heart rate, PR, QRS, QT and QTcF. 2.4. Phys | — |
Secondary
| Measure | Time frame |
|---|---|
| Part 1 Single ascending dose: Characterize plasma and urine pharmacokinetics (PK) of VRG50635 and active metabolite VRG50648. PK parameters include Tmax, Tlag, Cmax AUC(0-last), AUC (0-inf) and T1/2. Urine PK parameters include cumulative total amount excreted in urine and cumulative percentage of dose in urine. Plasma PK timepoints: predose and postdose: 0.5h, 1h, 1,5h, 2h, 4h, 7h, 10h, 24h, 34h, 48h; Urine PK timepoints: Predose, 0-6h, 6-24h, 24-36 hours, 36-48 hours (cohorts 2, 3, 4, 5 and 6) Characterize plasma PK of VRG50635 and VRG50648 after high-fat meal. PK parameters include Tmax, Tlag, Cmax AUC(0-last), AUC (0-inf) and T1/2. Plasma PK timepoints: predose and postdose: 0.5h, 1h, 1,5h, 2h, 4h, 7h, 10h, 24h, 34h, 48h. Part 2 Multiple ascending doses Characterize plasma and cerebrospinal fluid (CSF) PK of VRG50635 and VRG50648. PK parameters include Tmax, Tlag, Cmax AUC(0-last), AUC (0-inf) and T1/2. CSF PK parameters include concentrations and plasma/CSF ratio. Plasma PK timepoints: pre-dose and 0.5, 1, 1.5, 2, 4, 7, 10 h post-dose; pre-dose sample on Days 2, 3, on Day 4 prior to CSF sample, 5; on Day 6 predose and on Day 7, pre-dose, 0.5, 1, 1.5, 2, 4, 7 and 10 h following the last dose; on Day 8, 24h after the last dose; on Days 9 and 10, 48 and 72 h after the last dose. CSF sample timepoint: Day 4, 2 hours post-dose. Part 3 ALS Characterize plasma and CSF PK of VRG50635 and VRG50648. PK parameters include Tmax, Tlag, Cmax AUC(0-last), AUC (0-inf) and T1/2. CSF PK parameters include concentrations and plasma/CSF ratio. Plasma PK timepoints: pre-dose and 0.5, 1, 1.5, 2, 4, 9, 12 h post-dose; predose on Day 2 (44); pre-dose sample on Days 7 (50), 14 (57) and 28 (71); and 0.5, 1, 1.5, 2, 4, 9, 12 hours post-dose on Day 28 (71) and a 24 hours post-dose sample on Day 29 (72). On days -1, 28 and 71 a PK sample will be taken directly after CSF sampling. CSF sample t | — |
Countries
Netherlands
Contacts
Public ContactLars Smit
Outcome results
None listed