Sanofi's Oral TREM2 Agonist SAR448851 Advances to Phase 2 TREMHANCE Trial in Early Alzheimer Disease

The design of TREMHANCE, a phase 2 study evaluating SAR448851, an investigational oral small-molecule triggering receptor expressed on myeloid cells 2 (TREM2) agonist, in early Alzheimer's disease (AD) was presented at the 2026 Alzheimer's Association International Conference (AAIC) in London.¹ The trial is in final planning, with enrollment expected to begin in 2026, and represents the first phase 2 evaluation of an oral CNS-penetrant TREM2 agonist specifically designed for AD.

Led by Catherine Mummery, MD, PhD, Professor of Clinical Neurology at the Dementia Research Centre at University College London, the presentation brought together investigators from institutions including Washington University in St. Louis, Lund University, Amsterdam University Medical Center, and Sanofi.

Phase 1 Findings and Mechanism

SAR448851 targets TREM2, a receptor predominantly expressed on microglia in the CNS, where it regulates microglial survival, proliferation, phagocytosis, and inflammatory signaling. Loss-of-function TREM2 variants, including the R47H mutation, significantly increase AD risk in humans, and TREM2 knockout in preclinical models worsens amyloid plaque accumulation, tau pathology, and neuroinflammation. SAR448851 is designed to activate TREM2 and shift microglia toward a neuroprotective state, promoting clearance of amyloid and tau pathology.¹

In phase 1, SAR448851 demonstrated a favorable safety profile with no serious adverse events or treatment discontinuations, high CNS penetration, and dose-dependent target engagement evidenced by up to 50% reduction in CSF soluble TREM2 (sTREM2), a validated pharmacodynamic marker of TREM2 activity.¹ Preclinical studies in relevant AD models showed potent and selective TREM2 agonism resulting in microglial engulfment of amyloid and tau.

READ MORE: Anti-Tau Agent Diranersen Slows Cognitive Decline Across Multiple Endpoints in Phase 2 CELIA Trial, Biogen to Advance to Phase 3

SAR448851 was originally developed as VG-3927 by Vigil Neurosciences, which Sanofi acquired in May 2025 for approximately $470 million specifically to add the compound to its neurology pipeline.² The phase 1 program completed in February 2025 before the acquisition closed.

TREMHANCE Trial Design

TREMHANCE is a multicenter, randomized, double-blind, placebo-controlled phase 2 study with an open-label extension.¹ Participants aged 55 to 85 years with MCI due to AD or mild AD dementia, confirmed by cerebral amyloid pathology, a Clinical Dementia Rating (CDR) of 0.5 to 1.0, and a Mini-Mental State Examination (MMSE) score of 20 or above, will be randomized 1:1 to receive oral SAR448851 or placebo for 48 weeks. All participants will then receive SAR448851 during a 48-week open-label extension.

The primary endpoint is change from baseline to week 48 in plasma phosphorylated tau 217 (p-tau217), reflecting the trial's focus on capturing the drug's downstream effect on tau pathology as a surrogate of disease modification. Key secondary endpoints include CSF and plasma biomarkers, neuroimaging, and safety. The biomarker-centric primary endpoint is a notable design choice, positioning TREMHANCE as a proof-of-mechanism study rather than a clinical outcomes study, consistent with the drug's stage of development.

Landscape Context

The TREMHANCE design comes as the TREM2 agonism field grapples with mixed results. AL002, a humanized TREM2 agonistic monoclonal antibody developed by Alector, failed to meet its primary endpoint of change in Clinical Dementia Rating-Sum of Boxes score in a phase 2 trial published in Nature Medicine in March 2026, despite demonstrating sustained CSF target engagement.³ The study also reported MRI changes resembling amyloid-related imaging abnormalities (ARIA) as the most frequent adverse events, a complication not anticipated with a TREM2 agonist given that the mechanism does not directly target amyloid. The investigators suggested the ARIA signal may reflect microglial activation-mediated clearance of amyloid.

SAR448851's oral, small-molecule approach offers potential advantages over antibody-based TREM2 agonists, including reliable blood-brain barrier penetration without the complex pharmacokinetics of intravenous biologics. Whether small-molecule TREM2 agonism can achieve the sustained, sufficient target engagement needed to translate microglial activation into clinical benefit remains the central question TREMHANCE is designed to address.

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REFERENCES
1. Mummery C, Watson D, Cummings J, et al. TREMHANCE: a phase 2 study to evaluate the efficacy and safety of TREM2 agonist SAR448851 in early Alzheimer's disease. Abstract presented at: Alzheimer's Association International Conference (AAIC); July 2026; London, United Kingdom.
2. Sanofi to acquire Vigil Neuroscience, Inc., adding a new investigational medicine to treat Alzheimer's disease to the neurology pipeline. News release. Sanofi. May 22, 2025. Accessed July 16, 2026. https://www.sanofi.com/en/media-room/press-releases/2025/2025-05-21-23-15-31-3086232
3. Mummery CJ, Bhatt J, Lai RYK, et al. The TREM2 agonistic antibody AL002 in early Alzheimer's disease: a phase 2 randomized trial. Nat Med. 2026. doi:10.1038/s41591-026-04273-1. https://doi.org/10.1038/s41591-026-04273-1