FDA Removes Partial Clinical Hold on VG-3927 for Microglial Dysfunction in Alzheimer Disease

Ivana Magovčević-Liebisch, PhD, JD

(Credit: Vigil)

According to a recent announcement, the FDA has removed a partial clinical hold on Vigil Neuroscience’s ongoing phase 1 trial (NCT06343636) assessing its investigational therapy VG-3927 to treat common neurodegenerative diseases associated with microglial dysfunction, with an initial focus on patients with Alzheimer disease (AD), based on a complete response submitted by the company. The company noted that it plans to report the complete phase 1 trial data, including findings from the AD patient cohort, in the first quarter of 2025.¹

As part of the phase 1 trial, the company also announced that it has initiated dosing of the cohort of patients with AD, which included some participants who carried triggering receptor expressed on myeloid cells 2 (TREM2) or other disease-related variants, to investigate the biomarker response of VG-3927 following a single dose. Vigil Neuroscience anticipates using these data to inform the development strategy for subsequent and larger clinical studies evaluating VG-3927 for AD.

"We are pleased with the resolution of the partial clinical hold – a decision that was supported by non-clinical and clinical data from our ongoing Phase 1 trial. The removal of the hold provides us the best opportunity to explore the full pharmacology of VG-3927 as a potentially novel, next generation therapy for those living with Alzheimer’s disease," Ivana Magovčević-Liebisch, PhD, JD, president and chief executive officer at Vigil, told NeurologyLive^®. "As a first-in-class, orally available and highly CNS penetrant small molecule TREM2 agonist, we believe VG-3927 has the potential to become a next-generation therapy for AD."

In July 2024, the company reported interim data from its ongoing phase 1 single- and multiple-ascending dose (SAD/MAD) clinical trial assessing VG-3927 in healthy volunteers. As of June 30, 2024, the trial had enrolled 80 healthy volunteers, of which 60 received VG-3927 across multiple SAD and MAD cohorts. All told, the findings demonstrated that the safety and tolerability profile observed in individual doses in 6 SAD and 2 MAD cohorts supported continued clinical development of VG-3927 as a potential once-daily oral therapy in AD.²

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"As a first-in-class, orally available and highly CNS penetrant small molecule TREM2 agonist, we believe VG-3927 has the potential to become a next-generation therapy for AD. It has several exciting and special features that differentiate it from current approaches," Magovčević-Liebisch addded. "First, as a TREM2 agonist, VG-3927 has the potential for greater efficacy over Abeta antibodies. With VG-3927, microglia can respond to a broad range of pathologies and types of damage beyond just Abeta plaques. VG-3927 also acts in concert with natural TREM2 ligands and synergizes for increased maximal effect."

In the phase 1 trial with healthy volunteers, findings showed that VG-3927 had a predictable pharmacokinetic profile supportive of once-daily dosing. In both dosing cohorts, VG-3927 achieved a robust and sustained reduction of sTREM2 in the cerebrospinal fluid of participants. The therapy also showed an increase in osteopontin/secreted phosphoprotein 1, a biomarker associated with neuroprotective microglia, after repeat dosing. An effect on soluble Colony Stimulating Factor 1 Receptor, a microglial trophic factor, has not been observed to date. In terms of safety, all adverse events were considered mild or moderate in severity and resolved without intervention with no serious adverse events reported to date.

"By focusing the neuroprotective action of microglia to the immediate site of CNS damage, we believe VG-3927 has the potential for improved safety by providing a wider therapeutic window versus existing approaches," Magovčević-Liebisch said. "Finally, a molecule that is dosed orally once daily is a favorable modality for both a monotherapy and any future combination regimens and has benefits for patient access and convenience."

REFERENCES
1. Vigil Neuroscience Announces FDA Has Removed Partial Clinical Hold on VG-3927. News Release. Vigil Neuroscience. Published September 17, 2024. Accessed January 3, 2024. https://investors.vigilneuro.com/news-releases/news-release-details/vigil-neuroscience-announces-fda-has-removed-partial-clinical
2. Vigil Neuroscience Announces Interim Data from its Ongoing Phase 1 Clinical Trial Evaluating VG-3927 in Healthy Volunteers Supporting Continued Development in Alzheimer’s Disease. News Release. Vigil Neuroscience. Published July 24, 2024. Accessed January 3, 2024. https://investors.vigilneuro.com/news-releases/news-release-details/vigil-neuroscience-announces-interim-data-its-ongoing-phase-1