A Study of VRG50635 in Participants With Amyotrophic Lateral Sclerosis (ALS)

A Phase 1b, Open-Label, Multiple Ascending Dose, Multicenter Study of VRG50635 in Participants With Sporadic and Familial Amyotrophic Lateral Sclerosis Followed by Long-Term Treatment

The primary purpose of this study is to evaluate the safety and tolerability of VRG50635 in participants with ALS.

Study Overview

• Status: Terminated
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: VRG50635

Detailed Description

This is a Phase 1b, open-label, within-participant, multiple ascending dose, multicenter study of VRG50635 in participants with sporadic amyotrophic lateral sclerosis (sALS) and familial amyotrophic lateral sclerosis (fALS). Part 1 is a pre-treatment run-in period to establish the mean baseline based on repeated measurements of all biomarkers in eligible participants prior to initiating dosing with VRG50635. In Part 2, the safety, tolerability, PK, and efficacy of VRG50635 will be evaluated using a within-participant multiple ascending dose scheme. In Part 3, the long-term tolerability, safety, and efficacy of VRG50635 will be evaluated at the highest tolerated dose.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Flemish Brabant
    • Leuven, Flemish Brabant, Belgium
      • UZ Leuven
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • The Neuro - Montréal Neurological Institute-Hospital
    • Montreal, Quebec, Canada, H3A 2B4
      • Stan Cassidy Centre for Rehabilitation (Horizon NB)
• Finland
  • Eastern Finland
    • Kuopio, Eastern Finland, Finland, FI-70210
      • University of Eastern Finland, Brain Research Unit
  • Uusimaa
    • Helsinki, Uusimaa, Finland, FI-00029
      • Helsinki university hospital
  • Western Finland
    • Turku, Western Finland, Finland, FI-20520
      • Turku University Hospital
• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • University Medical Center Utrecht

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Provide written informed consent and be willing and able to comply with the requirements of the study protocol.
2. Must be ≥ 18 and ≤ 75 years of age at the time of signing the informed consent form (ICF).
3. Have a diagnosis of ALS according to the Gold Coast Diagnostic Criteria.
4. Have either sporadic amyotrophic lateral sclerosis (sALS) or familial amyotrophic lateral sclerosis (fALS).
5. Treatment Research Initiative to Cure ALS (TRICALS) risk profile > -6.00 and < -2.00.
6. Have slow vital capacity (SVC) ≥ 60% of the predicted value.
7. Have a score of 3 or 4 on Item #3 (Swallowing) of the Harmonized ALS Functional Rating Scale-Revised (ALS-FRS-R). Participants with a score of 3 can be enrolled with the Sponsor's approval only if they are able to safely swallow capsules.
8. Have a body weight ≥ 45 kg and body mass index (BMI) ≥ 18 kg/m2.
9. Participants of childbearing potential are eligible to participate if they are not pregnant or breastfeeding and agree to use one highly effective method of contraception, if sexually active, for the duration of the study through 90 days after the last study drug administration. Participants must not donate eggs for the duration of study through 90 days after the last dose of study drug.
10. Participants capable of producing sperm and their partners of childbearing potential must agree to use condoms and one highly effective method of contraception, respectively, for the duration of the study through 90 days after the last study drug administration. Participants must not donate sperm for the duration of study through 90 days after the last dose of study drug.
11. Be able and willing to undergo measurement of at-home mobility using contactless sensors connected to the internet.
12. Be able and willing to have clinic or at-home visits during the study.

Exclusion Criteria:

1. Have active psychiatric disease, substance abuse, neuromuscular weakness other than ALS, or any other medical condition that, in the opinion of the Investigator, might confound the results of the study or interfere with the intake or absorption of the study drug or participation for the full duration of the study.
2. Have a history of unstable or severe cardiac, pulmonary, neurological, oncological, hepatic, or renal disease or another medically significant illness other than ALS precluding their safe participation in this study.
3. Have a history of substance use disorder or illicit drug use in the last year (medically prescribed or over-the-counter cannabis use is allowed, if legal in the country).
4. Have a history of serious infection (e.g., pneumonia, septicemia) ≤ 4 weeks of Screening; infection requiring hospitalization or treatment with intravenous (IV) antibiotics, antivirals, or antifungals within 4 weeks of Screening; or chronic bacterial infection (e.g., tuberculosis) deemed unacceptable as per the Investigator's judgment.
5. Had major surgery ≤ 4 weeks before Screening.
6. Be currently taking or planning to take strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers.
7. Be currently taking or have discontinued treatment with riluzole < 4 weeks before Screening. Participants who have been taking a stable dose of riluzole for ≥ 4 weeks are eligible if they remain on the same dose throughout the duration of the study.
8. Be taking Radicava (administered orally or IV as approved in the participant's country), Relyvrio, any other approved standard of care treatment, or tauroursodeoxycholic acid (TUDCA) as a dietary supplement administered for < 4 weeks prior to Screening or on a schedule of treatment different from the approved standard schedule of treatment. Participants who have completed ≥ 4 weeks of treatment before Screening are eligible if they plan to continue treatment at a stable dose throughout the duration of the study.
9. Have an active malignancy or history (≤ 1 years prior to enrollment) of solid, metastatic, or hematologic malignancy. Exception: basal cell carcinoma in situ of the skin that has been adequately treated.
10. Be diagnosed with long QT syndrome. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes) should be discussed with and approved by the study medical monitor prior to enrollment.
11. Have a prolonged corrected QT interval using Fridericia's formula (QTcF) at the Screening visit ECG > 450 ms for male participants and > 470 ms for female participants.
12. Have an active SARS-CoV-2 infection or positive COVID-19 test at Screening.1
13. Have one or more of the following laboratory test abnormalities at Screening: (a) Positive hepatitis C virus (HCV) antibodies with confirmation by HCV-RNA polymerase chain reaction (PCR) reflex testing; (b) Positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Note: If a participant is negative for HBsAg but positive for HBcAb, the participant is eligible if the participant tests positive for the antibody to HBsAg reflex testing.
14. Have uncontrolled seizures.
15. Have a documented history of attempted suicide within 6 months prior to the Screening visit, or suicidal ideation of category 4 or 5 on the screening Columbia-Suicide Severity Rating Scale (C-SSRS), or be at significant risk for suicide, in the opinion of the Investigator.
16. For participants of childbearing potential, be pregnant or breastfeeding.
17. Have received a live vaccine within 14 days before Screening.
18. Be concurrently participating in any other interventional clinical study or have received treatment with another investigational drug within 4 weeks or 5 half-lives of the investigational agent before the Screening visit, whichever is longer. Participation in observational studies is allowed.
19. Have received stem cell or gene therapy for ALS at any time in the past.

20. At the Screening visit, have one or more of the following:

    1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3.0 × upper limit of normal (ULN)
    2. Bilirubin > 1.5 × ULN, unless the participant has documented Gilbert syndrome (isolated bilirubin > 1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is < 35%)
    3. Serum albumin < 3 g/dL
    4. Hemoglobin < 9.0 g/dL
    5. Platelets < 30,000/μL
    6. Estimated glomerular filtration rate < 90 mL/min/1.73 m2 (Modification of Diet in Renal Disease [MDRD])

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: VRG50635; The study drug is VRG50635 200 mg oral capsules. VRG50635 will be administered as oral capsules once daily in the morning after a low-fat meal, approximately 30 minutes prior to VRG50635 administration. Following administration there is a 5 to 6-hour restriction period where participants should consume only low-fat food.	Drug: VRG50635; Part 1, no study drug will be administered. Part 2, the starting dose is 400 mg for 8 weeks (Treatment Period 1) and doses will be escalated to 600 mg for 8 weeks (Treatment Period 2) and 800 mg for 8 weeks (Treatment Period 3). Part 3, each participant will continue receiving treatment with the highest tolerated dose achieved in Part 2 for up to 40 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Participants with Treatment-emergent Adverse Events (TEAEs)	Up to 80 weeks
Number of Participants with Clinical Laboratory Evaluation Abnormalities	Up to 80 weeks
Number of Participants with Vital Sign Abnormalities	Up to 80 weeks
Number of Participants with Electrocardiogram (ECG) Abnormalities	Up to 80 weeks
Number of Participants with Physical Examination Abnormalities	Up to 80 weeks
Number of Participants with Neurological Examination Abnormalities	Up to 80 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Maximum Observed Concentration (Cmax)	Up to 80 weeks
Area Under the Concentration-time Curve (AUC)	Up to 80 weeks
Time to Maximum Observed Concentration (tmax)	Up to 80 weeks
Change from Baseline in Plasma Levels of Neurofilament Light Chain (NfL) as Measured by Immunoassay	Baseline, up to 80 weeks
Time to Disease Progression	Up to 80 weeks
Change in Harmonized ALS Functional Rating Scale-Revised (ALS-FRS-R) Score	Up to 80 weeks

Collaborators and Investigators

• Sponsor: Verge Genomics
• Investigators: Study Director: Diego Cadavid, MD, Verge Genomics

Publications and helpful links

General Publications

• Hung ST, Linares GR, Chang WH, Eoh Y, Krishnan G, Mendonca S, Hong S, Shi Y, Santana M, Kueth C, Macklin-Isquierdo S, Perry S, Duhaime S, Maios C, Chang J, Perez J, Couto A, Lai J, Li Y, Alworth SV, Hendricks E, Wang Y, Zlokovic BV, Dickman DK, Parker JA, Zarnescu DC, Gao FB, Ichida JK. PIKFYVE inhibition mitigates disease in models of diverse forms of ALS. Cell. 2023 Feb 16;186(4):786-802.e28. doi: 10.1016/j.cell.2023.01.005. Epub 2023 Feb 7.
• Shi Y, Lin S, Staats KA, Li Y, Chang WH, Hung ST, Hendricks E, Linares GR, Wang Y, Son EY, Wen X, Kisler K, Wilkinson B, Menendez L, Sugawara T, Woolwine P, Huang M, Cowan MJ, Ge B, Koutsodendris N, Sandor KP, Komberg J, Vangoor VR, Senthilkumar K, Hennes V, Seah C, Nelson AR, Cheng TY, Lee SJ, August PR, Chen JA, Wisniewski N, Hanson-Smith V, Belgard TG, Zhang A, Coba M, Grunseich C, Ward ME, van den Berg LH, Pasterkamp RJ, Trotti D, Zlokovic BV, Ichida JK. Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat Med. 2018 Mar;24(3):313-325. doi: 10.1038/nm.4490. Epub 2018 Feb 5.

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2024
• Primary Completion (Actual): July 7, 2025
• Study Completion (Actual): July 7, 2025

Study Registration Dates

• First Submitted: December 18, 2023
• First Submitted That Met QC Criteria: January 10, 2024
• First Posted (Actual): January 22, 2024

Study Record Updates

• Last Update Posted (Estimated): December 15, 2025
• Last Update Submitted That Met QC Criteria: December 5, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: ALS; Familial Amyotrophic Lateral Sclerosis; Sporadic Amyotrophic Lateral Sclerosis; VRG50635
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Metabolic Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Motor Neuron Disease; Nutritional and Metabolic Diseases; Amyotrophic Lateral Sclerosis; Amyotrophic lateral sclerosis 1
• Other Study ID Numbers: VGCS-50635-002; 2023-506509-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No