Sanofi to Acquire Vigil Neuroscience for $470 Million, a 246% Premium, to Advance Oral TREM2 Agonist VG-3927 for Alzheimer’s Disease

On May 22, Sanofi announced that it had reached an acquisition agreement with Vigil Neuroscience to purchase all outstanding shares of Vigil at a prepayment of $8 per share, representing a premium over the latter's closing price on Wednesday.Premium 246%. Sanofi stated that the enterprise value of this transaction is$470 million (approximately 3.386 billion yuan), far higher than Vigil's current market value of approximately $115 million.。

This acquisition is aimed at obtainingOral Small Molecule Agonist Targeting TREM2 Expressed in Myeloid CellsVG-3927，Indications include neurodegenerative diseases such as Alzheimer's disease (AD), with a Phase II clinical trial for AD scheduled to commence in the second half of the year.

The transaction is expected to be completed in the third quarter of 2025.Bruce Booth, Atlas Ventures, and CEO Ivana Magovčević-Liebisch have signed voting and support agreements in favor of the transaction. The shares subject to these agreements account for approximately...Total Number of Issued Common Shares16.2%。

In addition, shareholders of Vigil Neuroscience will receive a non-transferable contingent value right (CVR) for each share of the company's stock.. That is, after VG-3927 achieves its first commercial sale, Vigil shareholders willEntitled to a deferred cash payment of $2。Based on the upfront cash portion, potential or valuable payments of this transaction,The total market capitalization may reach approximately US$600 million.

In June 2024, Sanofi made a strategic investment of $40 million in Vigil Neuroscience, which included preferential negotiation rights for exclusive licensing, granting, or transferring rights related to the research, development, manufacturing, and commercialization of VG-3927. Based on this transaction, Sanofi will further enhance its early clinical pipeline in the field of neurology.

TREM2 is a unidirectional transmembrane immune receptor of the immunoglobulin superfamily, consisting of three parts: a transmembrane domain, an extracellular domain, and an intracellular region. Under physiological conditions, TREM2 activity is limited to specific tissues, such as microglia in the brain and macrophages in peripheral areas. TREM2 is involved in various biological processes, including cell survival, lipid metabolism, phagocytosis, and inflammatory responses. In pathological states, the TREM2 signaling pathway becomes an immune signaling hub that senses and inhibits tissue damage.

In the central nervous system, TREM2 mainly affects cholesterol and phospholipid metabolism and can promote the transformation of microglia into disease-associated phenotypes. In neurodegenerative diseases such as Alzheimer's disease, the dysregulation of microglial activation leads to plaque accumulation, chronic inflammation, and neurodegeneration in the central nervous system.

Research has proven that,Activation of TREM2 can promote the migration of microglia to the injury site, enhance their phagocytosis, proliferation, and survival abilities, and achieve neuroprotective functions.Therefore, TREM2Targets help prevent neurodegeneration associated with neurodegenerative diseases.

In fact, multiple MNCs have already targeted this point, but have successively encountered clinical setbacks and terminated development:

DNL919 co-developed by Takeda/DenaliDNL919 is a TREM2-targeting monoclonal antibody. In the phase 1 study, moderate and reversible hematological effects were observed as safety signals at the highest tested dose, indicating a narrow therapeutic window for DNL919 in the AD patient population. In August 2023, Takeda and Denali announced the termination of DNL919's development.

AbbVie and Alector Co-develop Monoclonal Antibody AL002,This collaboration project comes from AbbVie in 2017.An upfront investment of $205 million. In November 2024, the AL002 study failed to meet the primary and secondary endpoints of the INVOKE-2 Phase 2 trial, showing no significant impact on disease progression or biomarkers, and development was announced to be terminated.

As of now, there are only three TREM2 projects in the CNS indication that remain in the clinical stage:

Novartis Self-Developed Monoclonal Antibody VHB937, currently under applicable treatmentAmyotrophic Lateral Sclerosis (ALS)Phase II clinical stage;

Amgen Originated, Licensed toVigil Neuroscience's Monoclonal Antibody VGL101 (Iluzanebart), applicable toLeukoencephalopathy with Axonal Spheroids and Pigmented Glial Cells (ALSP)——One of the most common types of adult-onset inherited leukodystrophy. VGL101Currently in Phase II clinical trials, and has received FDA Orphan Drug and Fast Track designations. However, this timeSanofiThe acquisition did not include this pipeline, and VGL101 will be returned to Amgen.

The third item, which is the protagonist of this transactionVG-3927，Is the only one in the above pipelineOral Small Molecule TREM2 Agonist。As a small molecule agonist with strong oral bioavailability, VG-3927 differs significantly from previous antibody agonists and can achieveOnce daily dosing。

VG-3927 is designed to enhance the protective response of microglia to aggregated amyloid and tau, without increasing inflammatory responses. Based on itsNovel Modes of Action for Agonists and Positive Allosteric Modulators (PAMs), mayAmplify the effect of VG-3927 at the lesion site, therebyStrongly modulates microglia and may enhance neuroprotectionClinical and preclinical data showVG-3927 further demonstrates its neuroprotective effects by activating microglial cells downstream of the TREM2 signaling pathway.

Since VG-3927 does not bind to sTREM2, this therapy canMaximizing receptor activation and microglial function,This may increase its chances of reaching AD lesions. In addition, VG-3927Without Fc Domain, a domain associated with elements linked to an increased risk of amyloid-related imaging abnormalities (ARIA) in the immune system.

Phase I clinical study results show that the therapy hasHigh Brain Penetrability, and inAchieved in cerebrospinal fluid (CSF)Up to approximately 50%FreeTREM2Significant dose-dependent reduction, demonstrating a robust PK/PD relationship, sustained target binding capability, and TREM2 agonist activity.

At the same time, the PK characteristics and reduction of sTREM2 observed in the AD patient cohort were consistent with those in healthy volunteers, regardless of the patients' TREM2 or ApoE genotype. This result will supportDevelopment of VG-3927 in AD Patients with Different Genotypes.Similarly, in the elderly cohort, the observed PK and sTREM2 reductions were consistent with those in healthy volunteers.

The first quarter of 2025,AstraZeneca Announces Full Exit from CNS Field, Shifting Resources to Core Areas like Oncology and Metabolic Diseases, at the same timeTerminated multiple neuroscience projects, including the Alzheimer's drug MEDI1814, which had been in collaboration with Eli Lilly for many years, and MEDI0618 for the treatment of migraines.、MEDI7352 for osteoarthritis pain and diabetic neuropathy.

In fact, AstraZeneca's choice is also Pfizer, Amgen, Merck, etc.The choice of many MNCs. Over the past decade, dozens have successively scaled down or withdrawn from the CNS battlefield, while坚守者 like Biogen alsoExploring the next R&D and performance anchor point.High Risk and Long Cycle of CNS，As with the exploration of the TREM2 target, setbacks and progress go hand in hand.

That said, the dawn has never faded. In the highly attended field of Alzheimer's disease, Leqembi, the Aβ antibody jointly developed by Biogen and Eisai, received full FDA approval for marketing in 2023, becoming the first fully approved Alzheimer's drug by the FDA in 20 years. In July 2024, the second Aβ antibody, donanemab from Eli Lilly, also received FDA approval for marketing.

Sanofi is one of the few companies that continues to increase its investment.In April 2022, collaborated with Terran Biosciences to obtainTwo Late-Stage Central Nervous System (CNS) Global Exclusive Rights for Pipeline Asset Development and CommercializationThese two therapies have led to four Investigational New Drug (IND) applications and more than 104 clinical studies involving over 15,000 subjects with CNS indications. In terms of self-developed products, although...Venglustat (Parkinson's Disease) and Oditrasertib(amyotrophic lateral sclerosis) has been terminated, but frexalimab (multiple sclerosis) has overcome the "death curse" of Phase II clinical trials and reached the primary endpoint.

Another company that continues to increase its investment is Roche.——In the direction of Alzheimer's disease, Roche's two Aβ monoclonal antibody drugs, gantenerumab and crenezumab, showed unsatisfactory clinical performance and their development was terminated. However, Trontinemab, a bispecific antibody targeting Aβ/TfR, is still under research and has demonstrated the ability to cross the blood-brain barrier along with impressive clinical data.

Since 2024, Roche has shown a high level of attention to gene therapy in the CNS field.In August, Genentech reached a licensing agreement worth nearly $2 billion with Sangamo Therapeutics to develop intravenously administered gene therapies for neurodegenerative diseases, including AD. Its AAV capsid demonstrated strong ability to cross the blood-brain barrier in non-human primate models.

In October, a collaboration was reached with Dyno Therapeutic, a developer of AI-powered gene therapy platforms, involving a $50 million upfront payment and potential total payments exceeding $1 billion, to develop next-generation adeno-associated virus (AAV) vector gene therapies for neurological diseases. This marks the second collaboration between the two parties, following their partnership since 2020 to develop next-generation AAV vectors for neurological disorders and liver-targeted gene therapies, with a potential collaboration value exceeding $1.8 billion.

Almost simultaneously with Sanofi's official announcement, on May 21, Genentech announced its collaboration with Orionis Biosciences once again.Development of Monovalent Molecular Glue New Drugs Based on AI-Driven Proprietary Platform, including a $105 million upfront payment and a potential total transaction value exceeding $2 billion.In September 2023, the two parties collaborated for the first time to discover new small molecule drugs for challenging targets in disease areas including oncology and neurodegenerative diseases.

From monoclonal antibodies, bispecific antibodies to small molecule agonists, gene therapies, molecular glues, and further to AI-driven AAV capsid design platforms and novel drug discovery platforms, CNS innovative drugs continue to advance under the joint promotion of cutting-edge technologies and clinical controversies.