Verge launches Phase 1 trial to test PIKfyve inhibitor therapy in ALS
VRG50635 proof-of-concept study to enroll sporadic and familial ALS patients
Verge Genomics has launched a proof-of-concept trial to test whether VRG50635, its oral PIKfyve inhibitor therapy, can be used as a potential treatment for people with amyotrophic lateral sclerosis (ALS).
The Phase 1b study will assess the safety and tolerability of escalating doses of VRG50635 — which works by blocking a protein called PIKfyve — in people with sporadic and familial types of ALS.
In addition to using traditional measures of ALS progression, the trial will employ digital devices to objectively evaluate disease-relevant changes in patients — including changes in mobility, breathing, and sleeping — which may help detect disease progression and treatment responses much earlier than with conventional physician rating scales.
“Incorporating cutting-edge technology into our ALS proof-of-concept study is a necessity born from the urgent unmet need to efficiently study promising therapeutics for people battling this devastating disease,” Diego Cadavid, MD, Verge’s chief medical officer, said in a company press release.
This “will make it possible to collect dense amounts of unbiased, objective disease-relevant data to properly assess the safety, tolerability, and potential efficacy, including dose-response, early in clinical development,” Cadavid added.
Trial of VRG50635 PIKfyve inhibitor to use digital tools in testing
ALS is characterized by progressive damage to motor neurons, which are the specialized nerve cells that control voluntary movements. This damage results in muscle weakness and wasting, leading patients to experience progressively worsening issues with mobility and balance, breathing, and speaking.
VRG50635 is designed to slow ALS progression and potentially extend survival in patients by helping motor neurons clear out the toxic protein aggregates, or clumps, that contribute to nerve cell damage.
This PIKfyve inhibitor, which blocks the protein, was identified as a potential treatment target in ALS by Verge’s artificial intelligence (AI) platform ConVERGE. This platform goes through large amounts of biological data from people with a given disease to identify novel therapeutic targets, and then predicts new drugs with a higher probability of clinical success.
PIKfyve’s function in ALS was described in a landmark 2018 study. Researchers showed that blocking this protein increased the number of lysosomes, which are cellular organelles that break down faulty or unwanted molecules, and are essential to prevent the accumulation of toxic proteins.
Given that lysosomes are faulty in ALS, inhibiting the activity of PIKfyve could restore their function and improve the clearance of toxic protein clumps, it was thought.
Those discoveries led to the development of VRG50635.
Initiating our proof-of-concept study marks another important milestone for Verge and further demonstrates that by leveraging our AI-enabled platform in combination with patient data using a novel study design we are able to more efficiently discover and develop potential drugs for deadly diseases like ALS.
The therapy has been shown to extended survival of nerve cells from ALS patients and in models of motor neuron degeneration. It also was deemed safe and well tolerated at multiple doses in healthy volunteers who participated in a Phase 1 clinical trial (ISRCTN14792372). In these participants, the therapy showed a pharmacological profile that supported once-daily dosing.
“Initiating our proof-of-concept study marks another important milestone for Verge and further demonstrates that by leveraging our AI-enabled platform in combination with patient data using a novel study design we are able to more efficiently discover and develop potential drugs for deadly diseases like ALS,” said Alice Zhang, MD, PhD, Verge’s co-founder and CEO.
In ALS clinical trials, disease progression is often measured with physician-rated scales, such as the ALS Functional Rating Scale Revised (ALSFRS-R). However, these can only be measured in clinical appointments, meaning there’s only scarce data to monitor disease progression. Such scales also tend to relate poorly to treatment responses.
To address that, Verge will use digital devices to measure changes in functionality in the patients’ own homes. The company also announced in December it would use Modality.AI, a computer-based tool for automated assessments of language and speech patterns, in the trial.
The platform uses machine learning to analyze what patients say and how they say it. It does not require specialized equipment and can be done using home devices like smartphones and laptops. According to Verge, this can deliver more precise and comprehensive insights into how VRG50635 may benefit ALS patients.
Other clinicians voiced their support for the VRG50635 study.
“I applaud Verge for creating a bold proof-of-concept design that incorporates cutting-edge technology and scientific innovation in their efforts to create groundbreaking therapies for ALS,” said Angela Genge, MD, director of the ALS Centre of Excellence for Research and Patient Care, at the Montreal Neurological Institute-Hospital.