- Preclinical presentation highlights key, modality specific, pharmacological differentiations of VG-3927 - 
- First presentation of topline clinical data from Phase 1 SAD/MAD trial of VG-3927 for the potential treatment of Alzheimer’s disease (AD) -

WATERTOWN, Mass., April 02, 2025 (GLOBE NEWSWIRE) -- Vigil Neuroscience, Inc. (Nasdaq: VIGL), a clinical-stage biotechnology company committed to harnessing the power of microglia for the treatment of neurodegenerative diseases, today presented data highlighting its oral small molecule program, including its lead clinical candidate VG-3927, in two oral presentations at the AD/PD™ 2025 International Conference on Alzheimer’s and Parkinson’s Diseases being held April 1 – April 5 in Vienna, Austria.

“We are thrilled to showcase our preclinical and Phase 1 data on VG-3927 at AD/PD™,” said Ivana Magovčević-Liebisch, Ph.D., J.D., President and Chief Executive Officer of Vigil. “Today’s two presentations highlight the unique potential of VG-3927 as an orally bioavailable, highly potent and CNS penetrant small molecule TREM2 agonist and provide the complete dataset from the positive Phase 1 results that we announced earlier this year. Collectively, VG-3927's favorable safety, tolerability, PK and PD profile support the advancement of this program as a differentiated next-generation therapeutic candidate that may go beyond what is possible with amyloid-based therapies to also target other, unaddressed contributors of disease progression in AD. We are looking forward to progressing VG-3927 as the first and only oral, once-daily, clinical-stage small molecule TREM2 agonist into Phase 2 development in the third quarter of this year.”

Oral presentation by Christian Mirescu, Ph.D., Senior Vice President, Neuroimmunology: Small Molecule TREM2 Agonists as Next-Generation Therapeutics for Alzheimer’s Disease 
Date and Time: Wednesday, April 2, 2025, 3:20 PM – 3:35 PM (CET) 
Session: TREM2, Microglia: From Mechanisms to Potential Treatments

Key highlights from this presentation demonstrated:

• VG-3927 is an orally bioavailable small molecule TREM2 agonist that has high specificity for membrane-bound TREM2 versus soluble TREM2 (sTREM2), which leads to increased access to the therapeutic site of action.
• VG-3927 shows a unique, synergistic activation of TREM2 with endogenous TREM2 ligands such as aggregated amyloid-beta (Aβ) that is expected to drive enhanced potency and specificity in regions of pathology.
• New data in 5xFAD plaque-burdened mice illustrate that small molecule TREM2 agonism enhances microglial uptake of both Aβ and Tau supporting the broad efficacy potential of the TREM2 agonist approach to go beyond targeting a single driver of AD pathology.
  

“In addition to the existing evidence supporting TREM2 as a therapeutic target in AD, our continued interrogation of VG-3927 has demonstrated that by activating TREM2, we can engage the brain’s immune system to counter multiple pathologies,” said Christian Mirescu, Ph.D., Senior Vice President, Neuroimmunology of Vigil. “By promoting microglial uptake of both Aβ and Tau, this program has the potential to be a transformative treatment option in AD as a once-daily oral therapy.”

Oral presentation by Petra Kaufmann, M.D., F.A.A.N., Chief Medical Officer: Phase 1 Study of VG-3927, A Novel Oral TREM2 Agonist 
Date and Time: Wednesday, April 2, 2025, 3:35 PM – 3:50 PM (CET) 
Session: TREM2, Microglia: From Mechanisms to Potential Treatments

Key highlights from the presentation:

• The Phase 1 trial of 115 participants provided a comprehensive and robust dataset evaluating healthy volunteers, elderly participants and a cohort of AD patients.
• VG-3927 demonstrated a favorable safety and tolerability profile across all cohorts with no serious adverse events.
• All treatment-related adverse events (AEs) were mild or moderate and self-resolving.
• VG-3927 showed a predictable and dose-dependent pharmacokinetic (PK) profile that supports once-daily dosing. These data demonstrated that VG-3927 has high CNS penetrance with an estimated cerebral spinal fluid (CSF) to unbound plasma ratio of 0.91.
• PK and sTREM2 reduction observed in the single dose AD cohort was consistent with healthy volunteers and the reduction in sTREM2 was similar across evaluated TREM2 and ApoE genetic variants supporting development in AD across genotypes.
• PK and sTREM2 reduction observed in the multiple ascending dose (MAD) elderly cohort was consistent with healthy volunteers.
• At the 25 mg dose, VG-3927 achieved the maximum sTREM2 reduction in the CSF of approximately 50%.
• PK/PD data support the selection of a 25 mg once-daily oral dose for the Phase 2 trial in AD patients.

“Our extensive preclinical and Phase 1 data give us confidence that VG-3927 is a highly CNS penetrant molecule that effectively engages TREM2, harnessing the neuroprotective capabilities of microglia,” said Petra Kaufmann, M.D., F.A.A.N., Chief Medical Officer of Vigil. “By targeting TREM2, we believe VG-3927 can reduce neuroinflammation and promote microglial health to address the underlying AD pathology. We are committed to advancing this program with the goal of providing a new and differentiated therapeutic option for individuals affected by AD that may improve the treatment paradigm and patient outcomes.”

About the Phase 1 Trial
The Phase 1 single and multiple ascending dose (SAD/MAD) trial assessed the safety, tolerability, PK, and PD of VG-3927 across 14 cohorts. As part of this trial, the Company evaluated 8 SAD cohorts of healthy volunteers up to a 140 mg dose and 4 MAD cohorts of healthy volunteers up to a 50 mg dose. The trial also included an elderly cohort and a single dose cohort of 11 AD patients, including some participants who carry TREM2 or other genetic risk factors for AD. The trial enrolled a total of 115 participants. Eighty-nine (89) participants received VG-3927, including 34 who were 55 years of age and older.

About VG-3927

VG-3927 is a potent orally bioavailable small molecule TREM2 agonist. Its novel mode of action as both an agonist and a positive allosteric modulator (PAM) may amplify functional responses around sites of pathology leading to strong modulation of microglia and potentially greater neuroprotection. VG-3927 is designed to enhance protective microglial responses to aggregated amyloid and tau without increasing inflammation. In contrast to antibody TREM2 agonists, VG-3927 maximizes receptor activation and microglial function because it does not bind to sTREM2, which may increase its access to the site of therapeutic action in AD. Additionally, VG-3927 does not have an Fc (fragmented crystallizable region) domain, which engages elements of the immune system that have been associated with increased risk of amyloid-related imaging abnormalities (ARIA). Collectively across preclinical and clinical data, these key differentiators create a compelling profile for VG-3927 as an investigational next-generation therapy for the treatment of AD.

About Vigil Neuroscience

Vigil Neuroscience is a clinical-stage biotechnology company focused on developing treatments for both rare and common neurodegenerative diseases by restoring the vigilance of microglia, the sentinel immune cells of the brain. Vigil is utilizing the tools of modern neuroscience drug development across multiple therapeutic modalities in its efforts to develop precision-based therapies to improve the lives of patients and their families. Iluzanebart, Vigil’s lead clinical candidate, is a fully human monoclonal antibody agonist targeting triggering receptor expressed on myeloid cells 2 (TREM2) in people with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare and fatal neurodegenerative disease. Vigil is also developing VG-3927, a novel small molecule TREM2 agonist, to treat common neurodegenerative diseases associated with microglial dysfunction, with an initial focus on Alzheimer’s disease (AD).

Forward-Looking Statements

This press release includes certain disclosures that contain “forward-looking statements” of Vigil Neuroscience (“Vigil” or the “Company”) that are made pursuant to the safe harbor provisions of the federal securities laws, including, without limitation, express or implied statements regarding: the Company’s strategy, business plans and focus; the potential therapeutic benefit of the Company’s product candidates, including VG-3927; the progress and timing of the clinical development of Vigil’s programs, including the expected progress and timing to advance VG-3927 into a Phase 2 clinical trial in the third quarter of 2025; and beliefs about observations made analyzing preclinical study and clinical trial data to date, including with respect to VG-3927. Forward-looking statements are based on Vigil’s current expectations and are subject to inherent uncertainties, risks and assumptions that are difficult to predict. Factors that could cause actual results to differ include, but are not limited to, risks and uncertainties inherent in the development of product candidates, including the conduct of research activities and clinical trials; whether results from prior preclinical studies and clinical trials will be predictive of the results of subsequent preclinical studies and clinical trials; and the timing and content of additional regulatory information from the FDA; as well as the risks and uncertainties identified in the Company’s filings with the Securities and Exchange Commission (SEC), including Vigil’s Annual Report on Form 10-K for the year ended December 31, 2024 and any subsequent filings Vigil makes with the SEC. Forward-looking statements contained in this announcement are made as of this date, and Vigil undertakes no duty to update such information except as required under applicable law. Readers should not rely upon the information on this page as current or accurate after its publication date.

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Investor Contact:
Leah Gibson
Vice President, Investor Relations & Corporate Communications
Vigil Neuroscience, Inc.
lgibson@vigilneuro.com 

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CTD Comms, LLC
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