At ENCALS, Commitment to Understanding the Cause of ALS and Developing Effective Treatments

By Diego Cadavid, M.D, FAAN, FANA, Chief Medical Officer

As a practicing neurologist, long-time clinical investigator and Chief Medical Officer at Verge Genomics, I’ve been committed to the pursuit of identifying and developing potential novel therapeutics that could help improve the lives of people with serious neurological diseases of high unmet need such as amyotrophic lateral sclerosis (ALS). I’m just back from the European Network to Cure Amyotrophic Lateral Sclerosis (ENCALS) annual meeting in Barcelona, Spain. I joined several hundred researchers, investigators and clinicians who are deeply committed to advancing the scientific understanding of the cause of ALS and to developing safe and effective therapies that one day could slow down or stop its relentless progression. 

At ENCALS, Verge presented, for the first time, results of the first-in-human Phase 1 clinical trial of VRG50635, an orally administered, investigational PIKfyve inhibitor small molecule being developed as a potential disease-modifying treatment for people with the sporadic and familial forms of ALS. My company discovered PIKfyve as a novel ALS drug target using data derived from diseased human tissues using artificial intelligence (AI). New approaches to discovering targets that have the potential to slow or stop this horrible disease are long overdue. It is estimated that at any given time in the United States alone, there are some 30,000 people living with ALS and in urgent need of disease-modifying treatments.

In our first-in-human trial – the critical first step in the drug development process – VRG50635 was well tolerated when given to healthy adult volunteers after both single and repeated administrations up to the maximum planned doses, with favorable pharmacokinetics showing relevant exposures with once-daily oral dosing.

The results provide important and novel supportive information to advance VRG50635 into its first clinical trial in people with ALS. Verge discovered PIKfyve, a novel ALS drug target, using our all-in-human, AI-powered platform, referred to as CONVERGE™. VRG50635 is one of the first drugs entirely discovered and developed from an AI-enabled platform to enter clinical trials and was advanced from discovery to clinic in just four years. This is much faster than industry standards.

With these data in hand, Verge is looking forward to initiating a proof-of-concept study later in 2023, in people with sporadic and familial ALS. This study has been designed to generate the high-quality data needed to efficiently and robustly determine as soon as possible whether PIKfyve inhibition with VRG50635 has the potential to be the first disease-modifying treatment for all forms of ALS.

My colleagues, collaborators and partners are now diligently planning the ALS proof-of-concept study for VRG50635. It plans to use an innovative design that can provide – faster and with greater confidence – all the important information needed to determine whether VRG50635 should be advanced into a registrational trial. The study carefully balances the key needs to evaluate both safety and efficacy at different drug exposures while having strong power to enable robust decisions on relevant efficacy biomarkers.

We are keenly aware of the very high unmet need for safe and effective disease-modifying treatments for ALS. People affected by the disease cannot wait. We should do everything possible to identify promising drug targets, develop novel drug candidates and rapidly advance them into preclinical and clinical evaluations. Verge is doing this not only with our AI-enabled target discovery platform, CONVERGE, based on molecular characterization of affected disease tissues, but also by implementing novel, efficient, robust and informative proof of concept study design with informative endpoints. We are focused relentlessly on patients. In the planned ALS proof-of-concept study, we are implementing, for the first time in ALS clinical trials, a battery of digital health technology assessments to measure ALS’s key neurological impairments frequently and precisely. These include the continued evaluation of mobility, breathing and sleep while in patients’ homes.  

The time is now to improve how we identify and evaluate novel promising drug targets for ALS and how we test novel compounds in clinical trials to rapidly and robustly identify the most promising ones to advance toward potential approval. We’re looking forward to initiating VRG50635’s proof-of-concept clinical trial later this year. The recently completed Ph1 study in healthy volunteers just presented at ENCALS strongly supports advancing VRG50635 into testing in people with ALS. Using cutting-edge drug target discovery technologies, a highly innovative proof-of-concept clinical trial design, and with the support and invaluable involvement of patients, their families and investigators and their staff, we are getting ready to investigate whether PIKfyve inhibition with VRG50635 has the potential to become the first disease modifying treatment for all forms of ALS.