LY3873862 / Eli Lilly - LARVOL DELTA

Deficiency of SARM1 attenuates neuronal injury and improves neurological performance in a photothrombotic stroke model. (PubMed, Mol Brain) - "FK866 and DSRM-3716, two recently reported pharmacological inhibitors of SARM1, failed to alleviate brain injury in mice with stroke. Our findings demonstrate that SARM1 deficiency attenuates ischemic neuronal injury and improves neurological performance post PTI, suggesting that the SARM1 signaling pathway could serve as a potential therapeutic target for stroke in the future."

Journal • Cardiovascular • CNS Disorders • Inflammation • Ischemic stroke • Vascular Neurology • TNFA

SARM1 inhibitor LY3873862 as neuroprotective treatment in ALS: design of a proof-of-concept trial regimen in the HEALEY ALS Platform Trial (ALS-MND 2025) - "We will test if the oral SARM1 inhibitor LY3873862 is safe and prevents or delays ALS progression in a proof-of-concept trial regimen in the HEALEY ALS Platform Trial."

NEFL

Targeting SARM1 NAD hydrolase for therapy of cardiometabolic diseases by regulating mitophagy and mitochondrial respiration (AHA 2025) - "Genetic (KO mice) or pharmacologic (DSRM-3716) inhibition of SARM1 was employed... SARM1 is a therapeutic target to fine-tune mitophagy and protect mitochondria in cardiometabolic disease."

Cardiovascular • Genetic Disorders • Heart Failure • Metabolic Disorders • Obesity • CTSD • HIF1A • RAB5A

SARM1 INHIBITION LIMITS AXONAL DEGENERATION INDUCED BY KAINIC ACID-INDUCED EXCITOTOXICITY (PACTALS 2025) - "We also used a small molecule inhibitor of SARM1, DSRM-3716... SARM1 limits KA-induced axon degeneration in iPSC-derived neuronal cultures. However, further optimization of our models is required, and it appears that SARM1 inhibition is insufficient in arresting neurodegeneration in all contexts, such as organophosphate exposure. We are also extending this work to identify novel approaches to inhibiting SARM1."

Amyotrophic Lateral Sclerosis • CNS Disorders

Developing an in vitro model of Wallerian degeneration using an immortalised human DRG-derived cell line (NeuPSIG 2025) - "Chemotherapeutic agents and vacor induce dose- and time-dependent neurotoxicity in an immortalised human DRG cell line. Pharmacological inhibition of SARM1 confers neuroprotection in this human cellular model of WD."

Preclinical • CNS Disorders • Neuralgia • Peripheral Neuropathic Pain • NEFL

A Study of LY3873862 in Healthy Participants (clinicaltrials.gov) - P1 | N=84 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion

A Study of LY3873862 in Healthy Participants (clinicaltrials.gov) - P1 | N=84 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed

Quantification of SARM1 activity in human peripheral blood mononuclear cells. (PubMed, bioRxiv) - "Our results reveal that SARM1 agonist pyrinuron, also known as Vacor, activates a dose-dependent increase in cAPDR and the cADPR:ADPR ratio that is arrested when paired with SARM1 inhibitor DSRM-3716. Various changes in secondary metabolites were also characterized and reported herein. Overall, these findings demonstrate that human PBMCs have detectable SARM1 activation potential and could be leveraged as a clinical readout of SARM1 expression and activity across diverse disease contexts."

Journal • CNS Disorders • Metabolic Disorders

Onset of CIPN delayed through SARM1 inhibition in human NerveSim preclinical drug-discovery platform (Neuroscience 2024) - "We demonstrated the ability to induce peripheral neuropathy in vitro with the chemotherapeutic vincristine (VinC) and to delay CIPN onset through SARM1 inhibition with compounds NB-7, DSRM-3716, and WX-02-37...Ephys proved to be the most sensitive of the assays by repeatedly detecting functional dysregulation before neurodegeneration analysis detected morphological dysfunction. The ability to multiplex longitudinal Ephys data with morphological, molecular biology, and next-generation sequencing data in hNS makes it a powerful platform for neurotoxicity screening and drug discovery."

Preclinical • CNS Disorders • Pain

A Study of LY3873862 in Healthy Participants (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Dec 2024 ➔ Jun 2025 | Trial primary completion date: Dec 2024 ➔ Jun 2025

Trial completion date • Trial primary completion date

Inhibiting the SARM1-NAD+ axis reduces oxidative stress-induced damage to retinal and nerve cells. (PubMed, Int Immunopharmacol) - "Here, we employed the SARM1 NADase inhibitor DSRM-3716 and established a glucose oxidase (GOx)-induced oxidative stress cell model...Additionally, JNK simultaneously serves as both an upstream and downstream regulator in the SARM1-NAD+ axis, regulating retinal cell pyroptosis and neurite injury. Thus, this study provides new insights into the pathological processes of retinal cell oxidative stress and identifies potential therapeutic targets for retinal neurodegenerative diseases."

Journal • CNS Disorders • Metabolic Disorders

A Study of LY3873862 in Healthy Participants (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Jan 2024 ➔ Dec 2024 | Trial primary completion date: Jan 2024 ➔ Dec 2024

Trial completion date • Trial primary completion date

Impacts of H O , SARM1 inhibition, and high NAm concentrations on Huntington's disease laser-induced degeneration. (PubMed, J Biophotonics) - "SARM1 inhibition seems to result in protection from neuronal degeneration while hydrogen peroxide has been implicated in oxidative stress and axonal degeneration. The effects of laser-induced axonal damage in wild-type and HD dorsal root ganglion cells treated with NAm, hydrogen peroxide (H O ), and SARM1 inhibitor DSRM-3716 were investigated and the cell body width, axon width, axonal strength, and axon shrinkage post laser-induced injury were measured."

Journal • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Huntington's Disease • Movement Disorders

Phenotypic and functional models of chemotherapy induced peripheral neuropathy using scalable human induced pluripotent stem cell derived sensory neurons (Neuroscience 2023) - "In a phenotypic study, we treated human induced pluripotent stem cell-derived sensory neurons (hiPSC-SN) that are functionally and molecularly similar to primary DRG with four chemotherapy drugs (bortezomib, oxaliplatin, paclitaxel, and vincristine) in dose response with and without pre-treatment of the SARM1 inhibitor DSRM-3716. When co-treated with gabapentin after 48 hours, there was a rescue effect where spike train parameters returned to control levels. Together, these findings demonstrate the ability to phenotypically and functionally screen CIPN-related and potential neuroprotective compounds in human nociceptors in high throughput systems."

CNS Disorders • Pain

Autohcs: automated ai-based scoring of dose-response high-content neuroprotectant screens. (Neuroscience 2023) - "Our analysis found that, when neurons were pretreated with the neural protectant SARM1 inhibitor DSRM-3716, the harmful phenotypes induced by these compounds were significantly lessened...This also makes it both user-friendly and extremely flexible to researcher needs. AutoHCS directly addresses the need for automation, objectivity, speed, and versatility in neuroprotectant research and development."

Neuroprotectant • CNS Disorders

A Study of LY3873862 in Healthy Participants (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Apr 2023 ➔ Mar 2024 | Trial primary completion date: Apr 2023 ➔ Mar 2024

Trial completion date • Trial primary completion date