Novartis Halts ALS Program After VHB937 Misses Primary and Secondary Endpoints in Phase 2 ASTRALS Trial
核心洞察
Novartis discontinued development of VHB937 (lifonebart (搜索)) after the Phase 2 ASTRALS trial in early-stage ALS missed both primary and secondary endpoints.
The 251-patient trial tested the TREM2 (搜索)-stabilizing monoclonal antibody or placebo for 40 weeks, with no numerical data released by the company.
The setback adds to a difficult pipeline stretch for Novartis, following Phase 3 misses for pelacarsen and del-desiran and halted rap-cel studies.
Novartis has discontinued development of VHB937, also known as lifonebart (搜索), after the investigational monoclonal antibody failed to meet both its primary and secondary endpoints in the Phase 2 ASTRALS trial in amyotrophic lateral sclerosis (搜索) (ALS). The company confirmed the decision in an emailed statement, following earlier reports by Endpoints News and Bloomberg News.
The trial evaluated the efficacy and safety of VHB937 in participants with early-stage ALS within two years of symptom onset. According to clinicaltrials.gov, ASTRALS enrolled 251 patients globally and completed recruitment in 2025. Participants received VHB937 or placebo for 40 weeks.
Trial Design and Endpoints
ASTRALS was designed to assess whether VHB937 could slow disease progression in ALS, a rapidly debilitating neurodegenerative condition with limited treatment options. The primary endpoint combined survival without permanent ventilation and change on the ALS Functional Rating Scale-Revised, which scores everyday tasks such as walking, speaking and breathing.
The study did not select patients for a particular causal mutation or biomarker, testing the antibody in a broadly defined early-stage population. Novartis has released no numerical data from the trial. Detailed findings are due to be presented at the 37th International Symposium on ALS/MND in Amsterdam on December 9-11, 2026.
Mechanism: Targeting TREM2
VHB937 was designed to stabilize and activate TREM2 (搜索), a receptor on microglia that helps regulate immune responses, inflammation and waste clearance in the brain. The goal was to make these cells more protective of motor neurons.
TREM2 (搜索)-directed drug development has proven difficult. Alector's AL002, a TREM2 antibody that binds a different domain, failed Phase 2 in Alzheimer's disease (搜索) in 2024, and in 2024 the company also reported that an experimental drug failed in a mid-stage trial. Guggenheim Securities analysts wrote in June that TREM2 is better validated in Alzheimer's than in ALS. Novartis continues to study VHB937 in Alzheimer's disease, with a Phase 2 trial still underway and recruiting patients.
A Broader Pipeline Reckoning
The ALS halt is the latest in a series of setbacks for Novartis this year. These include an earlier disappointment for a closely watched heart drug, last week's late-stage failure of a muscle-wasting drug, and the halt of eight of 10 studies for its rap-cel cell therapy this month after three patient deaths. Pelacarsen missed its Phase 3 primary endpoint on Sept. 4, and del-desiran, the lead drug from the company's Avidity Biosciences takeover, failed four days later. The developments have intensified investor scrutiny of the company's pipeline.
Novartis said it will continue supporting all participants as they complete their involvement in the trial. The company acknowledged the disappointment felt across the ALS community, including patients, families, investigators and advocacy groups, and emphasized its ongoing commitment to advancing scientific understanding of neurodegenerative diseases. It extended gratitude to trial participants, caregivers, researchers, clinical sites and ALS organizations.
A Field Defined by Failure — and Isolated Successes
ALS drug development has produced far more failures than approvals, and no treatment can currently stop or reverse the disease. The ASTRALS result follows other recent disappointments. French biotech Axoltis Pharma (搜索) reported on Sept. 15 that NX210c missed the prespecified biomarker endpoint in its 82-patient Phase 2 SEALS trial; post-hoc analyses suggested slower functional decline, but the stronger signal came at the lower dose and requires prospective confirmation.
Amylyx's AMX0035 reached the market in the U.S. and Canada before missing its primary and secondary endpoints in the 664-patient Phase 3 PHOENIX trial in 2024, prompting the company to withdraw it from the market. Genetically targeted approaches have also failed: Wave Life Sciences' WVE-004, developed for C9orf72-associated ALS and frontotemporal dementia, substantially reduced its poly(GP) biomarker but showed no clinical benefit, leading Wave to discontinue the program in 2023.
Biogen's tofersen illustrates a different path. The SOD1 (搜索)-targeted drug missed the main functional endpoint in its pivotal study but won accelerated FDA approval in 2023 based on lower neurofilament light, with longer follow-up providing supportive clinical evidence.
"We learn from every trial," Merit Cudkowicz, a prominent ALS expert and a professor of neurology at Harvard Medical School, told European Biotechnology. "As we understand more about the underlying biology of ALS, the treatments in development will have greater likelihood of success."
Cudkowicz said precision neurotherapeutics is critical in ALS, but added that some treatments could still work broadly because ALS also contains mechanisms shared across most patients. She cited TDP-43 biology, which several early-stage programs are attacking in different ways, including VTx-002 from Dutch biotech VectorY (搜索).
Late-Stage Bets Remain
Among a wider set of late-stage ALS programs worldwide, two European efforts stand out. Dutch Prilenia (搜索) and Barcelona-based Ferrer (搜索) are enrolling patients in the global Phase 3 PREVAiLS trial of pridopidine, while French biotech AB Science (搜索) is preparing an authorized confirmatory Phase 3 trial of masitinib. Alector remains one of the notable companies pursuing therapies for neurodegenerative diseases, including programs targeting ALS-related pathways.
Novartis shares traded between $121.57 and $170.46 over the past year. The stock closed Wednesday's trading at $138.70, up 0.06%, and stood at $139.44 in pre-market trading, up 0.53%.