Phase 2 Randomized Double-Blind Placebo-Controlled Study of VHB937 in Amyotrophic Lateral Sclerosis Patients Over 40 Weeks with Open-Label Extension

The primary objective of this study is to compare the **efficacy** of VHB937 versus placebo on a composite endpoint of permanent assisted ventilation (PAV) free survival and function during the double-blind (DB) epoch in patients with **Amyotrophic Lateral Sclerosis (ALS)**. This objective is clinically relevant as it aims to determine the potential of VHB937 to improve survival and functional outcomes in ALS, a progressive neurodegenerative disease with limited treatment options.

Secondary objectives include: - Assessing the efficacy of VHB937 on functional decline, respiratory function decline, and a biomarker of neurodegeneration in both DB and open-label extension (OLE) epochs. - Evaluating the safety and tolerability of VHB937. - Comparing the efficacy of VHB937 versus placebo on survival endpoints in the DB epoch. - Assessing the efficacy of early versus delayed administration of VHB937 on survival endpoints. - Evaluating changes in ALS condition, quality of life (QoL), and the pharmacokinetics (PK) and immunogenicity (IG) of VHB937 in DB and OLE epochs.

The clinical trial involves a total of **134 participants** diagnosed with **Amyotrophic Lateral Sclerosis (ALS)**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific criteria, including a diagnosis of sporadic or familial ALS using the revised El Escorial criteria, with the onset of ALS symptoms within the past 24 months. The general health status of participants requires a Slow Vital Capacity (SVC) of at least 60% of the predicted capacity and an ALSFRS-R total score of 30 or higher. Participants may be treated or untreated with standard of care (SoC) therapy for ALS, provided they meet stabilization requirements if treated. The trial population includes individuals who are able and willing to travel to the study site, with or without assistance. The selection process ensures a diverse representation of the ALS patient population, including vulnerable groups, to comprehensively assess the efficacy of VHB937 compared to placebo.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy of VHB937 in patients with **Amyotrophic Lateral Sclerosis (ALS)**. The trial is structured in a parallel group format and spans a duration of 40 weeks, followed by an open-label extension. The primary objective is to compare the efficacy of VHB937 versus placebo on a composite of permanent assisted ventilation-free survival and function. The trial will employ the Combined Assessment of Function and Survival (CAFS) as the primary analysis method, with the primary endpoint being the composite of PAV-free survival and change in ALSFRS-R from baseline to week 40.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, ALS diagnosis, and functional capacity. Following randomization, participants will attend regular follow-up visits throughout the double-blind phase to monitor efficacy and safety parameters, including adverse events, laboratory data, and vital signs. The end-of-study visit will occur at the conclusion of the double-blind phase, or earlier if the participant experiences significant adverse events or other conditions necessitating early termination. The expected length of participant involvement is up to 40 weeks for the double-blind phase, with an additional period for those continuing into the open-label extension.

Inclusion criteria require participants to be 18 years or older, with a diagnosis of sporadic or familial ALS as per the revised El Escorial criteria. Participants must have an ALSFRS-R total score of 30 or higher and a Slow Vital Capacity (SVC) of at least 60% of the predicted capacity. Exclusion criteria are not specified in the provided data. The trial is anticipated to start recruitment in February 2025, with an estimated end date in April 2029. Participants will receive either VHB937 or a placebo, administered intravenously as a concentrate for solution for infusion. The trial will assess secondary endpoints such as changes in ALSFRS-R total score, SVC, and neurofilament light concentration, as well as safety and tolerability measures.

The clinical trial involves the administration of **VHB937**, a **monoclonal antibody** developed by Novartis Pharma AG. VHB937 is provided as a **concentrate for solution for infusion**. The pharmaceutical form is specifically designed for **intravenous** administration. The dosing regimen is based on a milligram per kilogram (**mg/kg**) body weight basis, although the exact dosage and frequency are not specified in the provided data. The maximum treatment period for VHB937 is set at 100 days. The trial aims to evaluate the efficacy of VHB937 in patients with **Amyotrophic Lateral Sclerosis (ALS)**, focusing on a composite of permanent assisted ventilation-free survival and function.

The study also includes a **placebo** group, which receives a placebo concentrate for solution for infusion, designed to match the administration form of VHB937. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered in the same manner as VHB937, via intravenous infusion, to ensure consistency in the administration process across all study participants. The use of a placebo control is critical in assessing the true efficacy of VHB937 by providing a baseline for comparison.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints over specified timeframes. The primary endpoint is the composite of permanent assisted ventilation (PAV)-free survival and change in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score. This will be analyzed using the Combined Assessment of Function and Survival (CAFS) method from baseline to week 40 of the double-blind (DB) phase.

Secondary endpoints include the ALSFRS-R total score, Slow Vital Capacity (SVC) as a percentage of predicted normal value, and the ratio to baseline in Neurofilament Light (NfL) concentration in serum. These will be measured from baseline to week 40 of the DB phase or until death or PAV, whichever occurs first, and from baseline to week 100 of the open-label extension (OLE) phase or until death or PAV, whichever occurs first. Additional secondary endpoints involve safety and tolerability parameters, time to death, time to event (death or PAV), and changes in quality of life (QoL) as measured by the Amyotrophic Lateral Sclerosis Assessment Questionnaire-5 (ALSAQ-5), EuroQoL 5 Dimension 5 Level (EQ-5D-5L), and the 12-item Short Form Health Survey (SF-12).

Other assessments include the Clinician and Patient Global Impression of change in functional ability and ALS symptom severity (CGI-C and PGI-C), pharmacokinetics (PK) in serum and cerebrospinal fluid (CSF), and the presence of anti-VHB937 antibodies in serum. These parameters will be collected and analyzed at various time points, including up to week 40 of the DB phase and up to week 100 of the OLE phase, with specific measurements for CSF at week 12 of the DB phase.