A Phase 1, First-in-human, Randomized, Double-blind, Placebo-controlled, Single and Multiple Ascending Intravenous Dose Study of a novel TREM2 agonist (VGL101) in Healthy Volunteers (HVs) (S14.004)

Abstract

<h3>Objective:</h3> To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VGL101 in healthy adult participants after both single- (SAD) and multiple-ascending dose (MAD) administration. <h3>Background:</h3> VGL101 is a fully human monoclonal antibody targeting TREM2, in development for the treatment of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare, progressive, debilitating neurodegenerative disorder. TREM2, a receptor expressed on microglia in the brain is critical to microglial function in health and in disease. The activation of TREM2 by VGL101 is expected to enhance microglia function and neural tissue repair mechanisms regulated by microglia thereby slowing disease progression in ALSP. <h3>Design/Methods:</h3> The Phase 1 study has enrolled 74 HVs in several cohorts at doses up to 40mg/kg SAD and 20mg/kg MAD or placebo. Safety was assessed by the incidence of adverse events (AEs), changes in vital signs, laboratory tests, ECGs, and clinical evaluations. VGL101 serum and CSF PK and the PD of CSF soluble TREM2 (a marker of microglia target engagement) were characterized across single and multiple doses. <h3>Results:</h3> VGL101 demonstrated a favorable safety and tolerability profile at studied doses. Adverse events were mild, did not require intervention and resolved spontaneously. To date, there are no reports of SAEs or clinically meaningful abnormalities in vital signs, laboratory parameters or ECGs. VGL101 demonstrated approximately dose proportional peripheral pharmacokinetics with half-life supporting monthly dosing and brain penetration typical of IgG1 monoclonal antibodies. Dose and time dependent reduction in sTREM2 levels in the CSF was observed demonstrating CNS target engagement for VGL101. <h3>Conclusions:</h3> VGL101 demonstrated a favorable safety, PK profile and confirmation of CNS target engagement in healthy volunteers. The Phase 1 data supports further clinical development of VGL101 in ALSP. <b>Disclosure:</b> Dr. Papapetropoulos has received personal compensation for serving as an employee of Vigil Neuroscience . Dr. Papapetropoulos has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Acadia. Dr. Papapetropoulos has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Ventus Therapeutics Inc. Dr. Papapetropoulos has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Adamas Pharmaceuticals. Dr. Papapetropoulos has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Lipocine Inc. Dr. Papapetropoulos has stock in Vigil Neuroscience. Dr. Papapetropoulos has stock in Adamas. Dr. Papapetropoulos has stock in Lipocine. Andreas Meier has received personal compensation for serving as an employee of Voyager Therapeutics. Andreas Meier has received personal compensation for serving as an employee of Biogen. Mr. O’Mara has received personal compensation for serving as an employee of VIgil Neuroscience, LLC. Mr. Marsh has received personal compensation for serving as an employee of Vigil Neuroscience, Inc.. Mr. Marsh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Vigil Neuroscience, Inc.. Dr. Neelon has received personal compensation for serving as an employee of BridgeBio. Dr. Neelon has received personal compensation for serving as an employee of Vigil NeuroScience. An immediate family member of Dr. Neelon has received personal compensation for serving as an employee of Crisper Therapeutics. An immediate family member of Dr. Neelon has received personal compensation for serving as an employee of Mana Therapeutics. Dr. Neelon has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for BridgeBio. Dr. Neelon has stock in BridgeBio. Dr. Neelon has stock in VigilNeuro Science. An immediate family member of Dr. Neelon has stock in Cripser Therapeutics. An immediate family member of Dr. Neelon has stock in Mana Therapeutics. Dr. Neelon has received intellectual property interests from a discovery or technology relating to health care. Dr. Rajagovindan has received personal compensation for serving as an employee of Biogen. Dr. Rajagovindan has received personal compensation for serving as an employee of Vigil. Dr. Rajagovindan has stock in Biogen. Dr. Rajagovindan has stock in Vigil . Dr. Thackaberry has received personal compensation for serving as an employee of Vigil Neuroscience. Dr. Thackaberry has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Samsara Biocapital. Dr. Thackaberry has stock in Vigil Neurosciences. Dr. Stiles has received personal compensation for serving as an employee of Vigil Neuroscience. Dr. Stiles has received personal compensation for serving as an employee of Vertex Pharmaceuticals.