SAR448851 / Sanofi - LARVOL DELTA

Aβ-Overlapping Ectodomain Binding of the Clinical-Stage TREM2 Agonist VG-3927. (PubMed, bioRxiv) - "Consistently, Aβ induced a rightward shift in the VG-3927 dose-response curve in a Jurkat TREM2-DAP12 NFAT reporter assay and attenuated VG-3927-induced phospho-SYK signaling. Together, these findings support the presence of a previously unrecognized ectodomain interaction mode for VG-3927 and suggest that amyloid-associated ligand occupancy may modulate TREM2 agonist activity within the AD microenvironment."

Journal • Alzheimer's Disease • CNS Disorders • Targeted Protein Degradation • APOE • SYK

UNLOCKING THE POTENTIAL OF TREM2: VG-3927 AS A NOVEL THERAPEUTIC FOR ALZHEIMER'S DISEASE (ADPD 2026) - "VG-3927 represents the first small molecule TREM2 agonist that reprograms microglia through a unique molecular glue mechanism, achieving robust activation in preclinical disease-relevant contexts. These findings support the potential for a differentiated therapeutic modality that harnesses microglial protective functions, overcoming limitations of antibody-based strategies, and warrant further investigation of VG-3927 as a compelling candidate for AD."

Alzheimer's Disease • Amyloidosis • CNS Disorders • Targeted Protein Degradation • GFAP • TREM2

Structure-Based Virtual Screening Identifies TREM2-Targeted Small Molecules that Enhance Microglial Phagocytosis. (PubMed, ChemMedChem) - "The top hit, EN020, exhibited a KD of 14.2 µM (MST) and 35.9 µM (SPR), and significantly enhanced microglial phagocytosis in BV2 cells, outperforming the known TREM2 agonist VG-3927. A preliminary structure-activity relationship (SAR) study, including synthetic and catalog-derived analogs, highlighted a narrow tolerance for scaffold modifications, with only T2V002 retaining partial TREM2 binding affinity. This work identifies EN020 as a novel small-molecule TREM2 modulator with functional activity, providing a framework for rational optimization toward potential AD therapeutics."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders

The TREM Receptor Family in Cardiovascular Diseases: Functions, Mechanisms and Therapeutic Perspectives. (PubMed, Int Immunopharmacol) - "The TREM family constitutes a pivotal immunoregulatory axis in CVD, with the TREM1/TREM2 balance critically determining inflammatory burden and tissue outcomes. Targeting this family, particularly through dual strategies of TREM1 inhibition and TREM2 activation, represents a promising frontier for immunomodulatory therapy in CVD. Overcoming challenges related to ligand identification, cellular specificity, and species divergence will be crucial for successful clinical translation."

Journal • Review • Atherosclerosis • Cardiomyopathy • Cardiovascular • Coronary Artery Disease • Hematological Disorders • Infectious Disease • Inflammation • Ischemic stroke • Myocardial Infarction • Septic Shock • Thrombosis

Synergistic Potential of TREM2 Agonists and Exercise Training in Alzheimer’s Disease. (PubMed, Am J Physiol Endocrinol Metab) - "Pharmacologic TREM2 agonists, such as AL002, DNL919, and VG-3927, enhance microglial survival, plaque compaction, and mitochondrial respiration in AD models, although clinical efficacy may depend on disease stage and metabolic fitness...Both aerobic and resistance exercise activate TREM2-dependent signaling pathways to reduce neuroinflammation and support synaptic integrity. Collectively, these findings highlight TREM2 as a central immunometabolic regulator and suggest that combining TREM2-targeted therapeutics with exercise may offer a synergistic strategy to slow neurodegeneration in AD."

Journal • Review • Alzheimer's Disease • CNS Disorders • Inflammation • Metabolic Disorders • TREM2

Structure-Based Virtual Screening Identifies TREM2-Targeted Small Molecules that Enhance Microglial Phagocytosis. (PubMed, bioRxiv) - "The top hit, EN020 , exhibited a KD of 14.2 µM (MST) and 35.9 µM (SPR), and significantly enhanced microglial phagocytosis in BV2 cells outperforming the known TREM2 agonist VG-3927 . A preliminary structure-activity relationship (SAR) study, including synthetic and catalog-derived analogs, highlighted a narrow tolerance for scaffold modifications, with only T2V002 retaining partial TREM2 binding affinity. This work identifies EN020 as a novel small molecule TREM2 modulator with functional activity, providing a framework for rational optimization toward potential AD therapeutics."

Journal • Alzheimer's Disease • CNS Disorders

Discovery of a Small Molecule TREM2 Agonist with Improved In Vitro Pharmacokinetic Profile and Validated Target Engagement. (PubMed, ACS Med Chem Lett) - "We report the discovery of C1, a racemic structural analog of the clinical-stage TREM2 agonist VG-3927...Docking studies suggest a potential binding mode for C1 within TREM2's extracellular domain, revealing key interactions. These attributes establish C1 as an accessible and pharmacokinetically favorable lead compound with strong potential for developing TREM2-targeted therapies."

Journal • PK/PD data • Preclinical • Alzheimer's Disease • CNS Disorders

Press Release: Sanofi completes the acquisition of Vigil Neuroscience, Inc. (Sanofi Press Release) - "Sanofi announces the completion of its acquisition of Vigil Neuroscience, Inc. ('Vigil'). This acquisition strengthens Sanofi’s early-stage pipeline in neurology with VG-3927, a novel, oral, small-molecule TREM2 agonist, which will be evaluated in a phase 2 clinical study in patients with Alzheimer’s disease. In addition, the acquisition of Vigil’s preclinical pipeline will further strengthen Sanofi’s research in various neurodegenerative diseases...Under the terms of the acquisition agreement, Sanofi and Vigil have agreed to the following: Sanofi acquired all outstanding common shares of Vigil for $8 per share in cash at closing, representing an equity value of approximately $470 million (on a fully diluted basis); In addition, Vigil’s shareholders received a non-transferrable contingent value right (CVR) per Vigil share, which entitles its holder to receive a deferred cash payment of $2, conditioned upon the first commercial sale of VG-3927."

M&A • Alzheimer's Disease

Discovery of an Achiral Small Molecule TREM2 Agonist with Improved Pharmacokinetic Profile and Validated Target Engagement. (PubMed, bioRxiv) - "Here, we report the discovery of C1 , an achiral structural analog of VG-3927 -the first small molecule TREM2 agonist to enter clinical development...Docking studies suggested a potential binding mode of C1 at the extracellular domain of TREM2, revealing key polar and hydrophobic interactions. These findings position C1 as a synthetically accessible and pharmacokinetically favorable lead for the development of TREM2-targeted therapies."

Journal • PK/PD data • Alzheimer's Disease • CNS Disorders

Sanofi acquires Vigil to advance Alzheimer's drug VG-3927 toward clinical trials (Chosun Biz) - "French pharmaceutical company Sanofi announced on the 22nd (local time) that it has acquired U.S. company Vigil Neuroscience for about $470 million (approximately 650 billion won). With this acquisition, Sanofi secured the oral drug candidate 'VG-3927,' which is a TREM2 agonist. TREM2 is a receptor protein found in myeloid cells that functions to detect damage to microglia in the central nervous system and brain."

M&A • Alzheimer's Disease • CNS Disorders • Tauopathies And Synucleinopathies

VG-3927, Small Molecule TREM2 Agonist (GlobeNewswire) - "The Company plans to advance a once-daily oral dose of 25 mg that fully engages the desired pharmacology and expects to initiate the Phase 2 trial in the third quarter of 2025."

New P2 trial • Alzheimer's Disease

PHASE 1 SINGLE AND MULTIPLE ASCENDING DOSE STUDY OF VG-3927 (NOVEL ORAL TREM2 AGONIST) IN HEALTHY VOLUNTEERS AND ALZHEIMER'S DISEASE (ADPD 2025) - "Conclusions This is the first clinical study assessing VG-3927 in HV, elderly, and patients with AD. Initial findings support continued development of VG-3927 as a potential once-daily oral therapy for AD."

Clinical • P1 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Targeted Protein Degradation • TREM2

KEY MODALITY-SPECIFIC PHARMACOLOGICAL FEATURES UNDERSCORE THE INNOVATIVE POTENTIAL OF SMALL MOLECULE TREM2 AGONISTS IN AD CLINICAL DEVELOPMENT (ADPD 2025) - "Conclusions Small molecule TREM2 agonists possess favorable mechanistic and functional repertoires in AD modeling states, extending the targeting capacity of TREM2 immunotherapy. Collectively, such distinct characteristics highlight the unique pharmacological potential of the small molecule TREM2 agonist VG-3927 to more fully realize the transformative opportunity of TREM2 therapeutics for AD with the additional clinical advantage of oral dosing."

Clinical • Alzheimer's Disease • Amyloidosis • CNS Disorders • TREM2

VG3927-02.101: A Phase 1 Study of VG-3927 in Healthy Adults and Patients With Alzheimer's Disease (clinicaltrials.gov) - P1 | N=123 | Completed | Sponsor: Vigil Neuroscience, Inc. | Enrolling by invitation ➔ Completed

Trial completion • Alzheimer's Disease • CNS Disorders

Vigil Neuroscience Reports Positive Data from its Phase 1 Clinical Trial Evaluating VG-3927 for the Potential Treatment of Alzheimer’s Disease (GlobeNewswire) - P1 | N=108 | NCT06343636 | Sponsor: Vigil Neuroscience, Inc. | "Demonstrated a favorable safety and tolerability profile across all cohorts...All related adverse events were mild or moderate in severity and self-resolving without drug discontinuations. No serious AEs were reported. Highly brain penetrant with a favorable and predictable PK profile that supports once-daily dosing. Achieved robust and dose-dependent reduction of sTREM2 of up to approximately 50% in the cerebral spinal fluid (CSF) demonstrating a strong PK/PD relationship, sustained target engagement and TREM2 agonist activity...Vigil expects to provide additional data in an oral presentation at the AD/PD 2025 International Conference on Alzheimer’s and Parkinson’s Disease...Based on the Phase 1 results and preclinical profile of VG-3927, the Company plans to advance a once-daily oral dose of 25mg that fully engages the desired pharmacology and expects to initiate the Phase 2 trial in the third quarter of 2025."

New P2 trial • P1 data • Alzheimer's Disease

Drug Development. (PubMed, Alzheimers Dement) - "VG-3927 represents the first potent, selective small molecule TREM2 agonist able to favorably tune human microglia activation and impart a broadly neuroprotective profile across preclinical model systems. Initial PKPD studies have confirmed brain penetrance and pharmacological activity in CNS; an ongoing clinical study aims to further interrogate the potential of VG-3927 as an AD modifying therapeutic with transformative potential as an orally bioavailable treatment."

Journal • Alzheimer's Disease • Amyloidosis • CNS Disorders • APOE

Drug Development. (PubMed, Alzheimers Dement) - "VG-3927 represents the first potent, selective small molecule TREM2 agonist able to favorably tune human microglia activation and impart a broadly neuroprotective profile across preclinical model systems. Initial PKPD studies have confirmed brain penetrance and pharmacological activity in CNS; an ongoing clinical study aims to further interrogate the potential of VG-3927 as an AD modifying therapeutic with transformative potential as an orally bioavailable treatment."

Journal • Alzheimer's Disease • Amyloidosis • CNS Disorders • APOE

Drug Development. (PubMed, Alzheimers Dement) - "The ongoing Phase 1 study will assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of VG-3927 in healthy volunteers and is expected to inform subsequent development in AD."

Clinical • Journal • Alzheimer's Disease • CNS Disorders • Targeted Protein Degradation • TREM2

Phase 1, First-in-human, Single and Multiple Ascending Dose Study of a Novel Orally Administered TREM2 Agonist (VG-3927) in Healthy Volunteers: Interim Results (CTAD 2024) - No abstract available

Clinical • P1 data

Vigil Neuroscience Announces FDA Has Removed Partial Clinical Hold on VG-3927 (GlobeNewswire) - "Vigil Neuroscience, Inc...announced that the U.S. Food and Drug Administration (FDA) has removed the partial clinical hold on its ongoing Phase 1 clinical trial of VG-3927. The FDA’s decision was based on a complete response submitted by the Company....The Company plans to report the complete Phase 1 clinical data, including data from the AD patient cohort, in the first quarter of 2025."

FDA event • P1 data • Alzheimer's Disease • CNS Disorders

Vigil Neuroscience Reports Second Quarter 2024 Financial Results and Provides Business Update (GlobeNewswire) - "VG-3927, Small Molecule TREM2 Agonist...The Company plans to report the complete Phase 1 clinical data, including data from the AD patient cohort, in the first quarter of 2025...R&D expenses for the second quarter ended June 30, 2024, were $15.5 million, compared to $14.9 million for the same period in 2023. This increase was driven by advancing VG-3927 Phase 1 clinical development and headcount-related costs to support the Company’s continued growth."

Commercial • P1 data • Alzheimer's Disease • CNS Disorders

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 (GlobeNewswire) - P1 | N=90 | NCT06343636 | Sponsor: Vigil Neuroscience, Inc. | "Vigil Neuroscience, Inc...announced interim data from its ongoing Phase 1 clinical trial of VG-3927 in healthy volunteers. Collectively, the interim safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profile supports continued clinical development of VG-3927 as a potential once-daily oral therapy for AD....VG-3927 demonstrated a predictable PK profile that is supportive of once-daily dosing. In the SAD and MAD cohorts, VG-3927 achieved a robust and sustained decrease of sTREM2 in the CSF. VG-3927 also showed an increase in osteopontin/secreted phosphoprotein 1 (SPP1), a biomarker associated with neuroprotective microglia, after repeat dosing."

P1 data • PK/PD data • Alzheimer's Disease • CNS Disorders

Vigil Announces Upcoming Presentations on its Small Molecule TREM2 Agonist VG-3927 at the 2024 Alzheimer's Association International Conference (GlobeNewswire) - "Vigil Neuroscience, Inc...today announced one oral and two poster presentations highlighting its oral small molecule VG-3927 at the 2024 Alzheimer's Association International Conference (AAIC) taking place on July 28-August 1, 2024 in Philadelphia, Pennsylvania and virtually."

Clinical protocol • Preclinical • Alzheimer's Disease • CNS Disorders

Characterization of the first TREM2 small molecule agonist, VG-3927, for clinical development in Alzheimer's disease (AAIC 2024) - "VG-3927 represents the first potent, selective small molecule TREM2 agonist able to favorably tune human microglia activation and impart a broadly neuroprotective profile across preclinical model systems. Initial PKPD studies have confirmed brain penetrance and pharmacological activity in CNS; an ongoing clinical study aims to further interrogate the potential of VG-3927 as an AD modifying therapeutic with transformative potential as an orally bioavailable treatment."

Clinical • Alzheimer's Disease • Amyloidosis • CNS Disorders • APOE

Design of a Phase 1, First-in-human, Randomized, Double-blind, Placebo-controlled, Single and Multiple Ascending Dose Study of a Novel Orally Administered TREM2 Agonist (VG-3927) in Healthy Volunteers (AAIC 2024) - "The ongoing Phase 1 study will assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of VG-3927 in healthy volunteers and is expected to inform subsequent development in AD."

Clinical • P1 data • Alzheimer's Disease • CNS Disorders • Targeted Protein Degradation • TREM2