verdiperstat (BHV-3241) / AstraZeneca, Biohaven - LARVOL DELTA

Verdiperstat in Amyotrophic Lateral Sclerosis: Results From the Randomized HEALEY ALS Platform Trial. (PubMed, JAMA Neurol) - P2/3 | "Results demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS. Clinical Trial Identifiers: NCT04297683 and NCT04436510."

Clinical • Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Inflammation • Insomnia • Sleep Disorder • MPO

Microglial suppression by myeloperoxidase inhibitor does not delay neurodegeneration in a mouse model of progressive multiple sclerosis. (PubMed, Exp Neurol) - "Remarkably, verdiperstat did not affect adaptive immunity, neutrophils invasion as well as mitochondrial derangement in the spinal cords of immunized mice. Data suggest that microglia suppression is not sufficient to prevent disease evolution, corroborating the hypothesis that immune-independent components drive neurodegeneration in progressive MS."

Journal • Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • Metabolic Disorders • Movement Disorders • Multiple Sclerosis • Multiple System Atrophy • Parkinson's Disease • MPO

Targeting Myeloperoxidase to Reduce Neuroinflammation in X-Linked Dystonia Parkinsonism. (PubMed, CNS Neurosci Ther) - "Collectively, our results suggest that MPO inhibition mitigates oxidative stress and may provide a novel therapeutic strategy for XDP treatment."

Journal • CNS Disorders • Dystonia • Inflammation • Movement Disorders • Parkinson's Disease • MPO

Myeloperoxidase limits tumor-associated neutrophils mediated immunosuppression in pancreatic cancer (AACRPanCa 2024) - "Additionally, treatment with the MPO-specific inhibitor Verdiperstat also delayed tumor growth...These data suggest that loss of MPO in TANs has decreased immunosuppressive functions resulting in increased cytotoxic and activated T cells and NK cells with increased memory response within the tumor microenvironment. Our results demonstrate the contribution of MPO in regulating tumor progression, TAN immunosuppression, and immune cell infiltration using an orthotopic PDAC model."

IO biomarker • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD4 • CD8 • GZMB • IL2RA • MPO

Targeting myeloperoxidase to reduce neuroinflammation in X-linked dystonia parkinsonism. (PubMed, medRxiv) - "Collectively, our results suggest that MPO inhibition mitigates oxidative stress and may provide a novel therapeutic strategy for XDP treatment. MPO activity is increased in XDP post-mortem prefrontal cortex.MPO activity is increased in cellular models of XDP.MPO increases reactive oxygen species (ROS) in vitro.Inhibiting MPO mitigates ROS in XDP.The MPO inhibitor, verdiperstat, dampens ROS suggesting a potential therapeutic strategy for XDP."

Journal • CNS Disorders • Dystonia • Inflammation • Movement Disorders • Parkinson's Disease • MPO

Prediction of the Liver Safety Profile of a First-in-Class Myeloperoxidase Inhibitor Using Quantitative Systems Toxicology Modeling. (PubMed, Xenobiotica) - "Subsequent Phase 3 clinical trials found that ALT elevations in the verdiperstat treatment group were generally similar to those in the placebo group. This validates the DILIsym simulation results and demonstrates the power of QST modeling to predict the liver safety profile of novel therapeutics."

Journal • CNS Disorders • MPO

Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis. (PubMed, Muscle Nerve) - "Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials."

Clinical • Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

HEALEY ALS Platform Trial - Master Protocol (clinicaltrials.gov) - P2/3 | N=1500 | Active, not recruiting | Sponsor: Merit E. Cudkowicz, MD | Recruiting ➔ Active, not recruiting

Enrollment closed • Amyotrophic Lateral Sclerosis • CNS Disorders

HEALEY ALS Platform Trial - Regimen B Verdiperstat (clinicaltrials.gov) - P2/3 | N=167 | Completed | Sponsor: Merit E. Cudkowicz, MD | Active, not recruiting ➔ Completed | Trial completion date: Apr 2023 ➔ Dec 2022

Trial completion • Trial completion date • Amyotrophic Lateral Sclerosis • CNS Disorders

HEALEY ALS Platform Trial - Master Protocol (clinicaltrials.gov) - P2/3 | N=1500 | Recruiting | Sponsor: Merit E. Cudkowicz, MD | Trial completion date: Dec 2025 ➔ Apr 2026 | Trial primary completion date: Apr 2025 ➔ Jul 2025

Trial completion date • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders

HEALEY ALS Platform Trial - Master Protocol (clinicaltrials.gov) - P2/3 | N=1200 | Recruiting | Sponsor: Merit E. Cudkowicz, MD | N=800 ➔ 1200 | Trial completion date: Dec 2023 ➔ Dec 2025 | Trial primary completion date: Apr 2023 ➔ Apr 2025

Enrollment change • Trial completion date • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders

Inhibition of myeloperoxidase enhances immune checkpoint therapy for melanoma. (PubMed, J Immunother Cancer) - "MPO contributes to ICT resistance in established melanoma. Repurposing MPO-specific inhibitors may provide a promising therapeutic strategy to enhance ICT response."

Journal • Immune Modulation • Melanoma • Oncology • Solid Tumor • CD4 • MPO

Introduction to Veri-T: A Phase 1 Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of Verdiperstat in Patients with svPPA Due to FTLD-TDP (AAIC 2022) - No abstract available

Clinical • P1 data • Frontotemporal Lobar Degeneration

Introduction to the Veri-T trial: A Phase 1 Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of Verdiperstat in Patients with svPPA Due to FTLD-TDP (CTAD 2022) - P1 | "The Veri-T trial examines the safety, tolerability and pharmacokinetic properties of verdiperstat in svPPA and explores novel pharmacodynamic biomarkers and outcome measures that could be employed in future efficacy studies targeting sporadic FTLD-TDP."

Clinical • P1 data • Alzheimer's Disease • Frontotemporal Lobar Degeneration • Immunology • MPO • NEFL • TARDBP

New developments and opportunities in drugs being trialed for amyotrophic lateral sclerosis from 2020 to 2022. (PubMed, Front Pharmacol) - "Six were tested in phase 1 studies, 31 were in phase 2 studies, three failed in phase 3 studies and stopped further development, and the remaining 13 drugs were being tested in phase 3 studies, including methylcobalamin, masitinib, MN-166, verdiperstat, memantine, AMX0035, trazodone, CNM-Au8, pridopidine, SLS-005, IONN363, tofersen, and reldesemtiv. Among them, five drugs, including methylcobalamin, masitinib, AMX0035, CNM-Au8, and tofersen, have shown potent therapeutic effects in clinical trials. Recently, AMX0035 has been the third medicine approved by the FDA for the treatment of ALS after riluzole and edaravone."

Journal • Review • Amyotrophic Lateral Sclerosis • CNS Disorders • Gene Therapies

Veri-T-001: Veri-T: A Trial of Verdiperstat in Patients With svPPA Due to TDP-43 Pathology (clinicaltrials.gov) - P1 | N=64 | Recruiting | Sponsor: Peter Ljubenkov, MD | Trial completion date: Dec 2027 ➔ Sep 2026 | Trial primary completion date: Dec 2026 ➔ Jun 2026

Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration

Biohaven Provides Update From Pivotal Phase 2/3 Trial with Verdiperstat in Amyotrophic Lateral Sclerosis (Healy ALS Platform Trial) (PRNewswire) - P2/3 | N=800 | HEALEY ALS (NCT04297683) | “Biohaven Pharmaceutical Holding Company Ltd...announced results from a focused analysis of treatment with verdiperstat in the HEALEY ALS Platform Trial in amyotrophic lateral sclerosis (ALS)….Verdiperstat did not statistically differentiate from placebo on the prespecified primary efficacy outcome, disease progression measured by the ALS Functional Rating Scale-Revised and survival, nor the key secondary efficacy measures during the 24-week study period. Initial analysis of safety data was consistent with the overall profile of verdiperstat from prior clinical trial experience. Additional analyses are ongoing, and complete study results will be presented at an upcoming scientific meeting.”

P2/3 data • Amyotrophic Lateral Sclerosis • CNS Disorders

Safety and Efficacy of Verdiperstat, a Novel Myeloperoxidase Inhibitor, in MSA (MDS Congress 2022) - P3 | "Verdiperstat was generally well tolerated but did not separate from placebo on primary and secondary endpoints. Trends toward reduced global and regional brain atrophy were observed. Ongoing analyses of subgroups and biomarkers may provide further insight into the effects of MPO inhibition with verdiperstat on neurodegeneration in MSA."

Clinical • CNS Disorders • MPO

Effect of Verdiperstat on Microglial Activation in Well-characterized MSA Patients (clinicaltrials.gov) - P1 | N=19 | Completed | Sponsor: Brigham and Women's Hospital | Active, not recruiting ➔ Completed | Trial completion date: Jun 2022 ➔ Jan 2022 | Trial primary completion date: Jun 2022 ➔ Jan 2022

Trial completion • Trial completion date • Trial primary completion date • CNS Disorders • Hypotension • Movement Disorders • Multiple System Atrophy • Parkinson's Disease

M-STAR: Study of BHV-3241 in Subjects With Multiple System Atrophy (clinicaltrials.gov) - P3 | N=336 | Completed | Sponsor: Biohaven Pharmaceuticals, Inc. | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Movement Disorders • Multiple System Atrophy

Verdiperstat attenuates acute lung injury by modulating MPO/μ-calpain/β-catenin signaling. (PubMed, Eur J Pharmacol) - "Moreover, MPO inhibition resulted in lower μ-calpain activation and lower β-catenin in the nucleus. Our cumulative results suggest that verdiperstat alleviates ALI by strengthening VE-cadherin and claudin 5 through the inhibition of MPO/μ-calpain/β-catenin activation."

Journal • Acute Lung Injury • Multiple System Atrophy • Respiratory Diseases • CDH5 • CLDN5 • MPO

Veri-T-001: Veri-T: A Trial of Verdiperstat in Patients With svPPA Due to TDP-43 Pathology (clinicaltrials.gov) - P1 | N=64 | Recruiting | Sponsor: Peter Ljubenkov, MD | Not yet recruiting ➔ Recruiting

Enrollment open • Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration

BIOHAVEN REPORTS FOURTH QUARTER AND FULL YEAR 2021 FINANCIAL RESULTS AND RECENT BUSINESS DEVELOPMENTS (PRNewswire) - “Completed enrollment of verdiperstat arm of pivotal HEALEY ALS trial – In November 2021, the Company announced that approximately 160 individuals with Amyotrophic Lateral Sclerosis (‘ALS’) were enrolled in the verdiperstat treatment arm of the pivotal HEALEY ALS Platform Trial….Topline results for verdiperstat in the treatment of ALS are anticipated in mid-2022.”

P2/3 data • Amyotrophic Lateral Sclerosis • CNS Disorders

HEALEY ALS Platform Trial - Master Protocol (clinicaltrials.gov) - P2/3 | N=800 | Recruiting | Sponsor: Merit E. Cudkowicz, MD | Active, not recruiting ➔ Recruiting

Enrollment open • Amyotrophic Lateral Sclerosis • CNS Disorders

HEALEY ALS Platform Trial - Master Protocol (clinicaltrials.gov) - P2/3 | N=800 | Active, not recruiting | Sponsor: Merit E. Cudkowicz, MD | Recruiting ➔ Active, not recruiting | Trial completion date: Nov 2022 ➔ Dec 2023 | Trial primary completion date: Mar 2022 ➔ Apr 2023

Enrollment closed • Trial completion date • Trial primary completion date • Amyotrophic Lateral Sclerosis • CNS Disorders