Why it matters: ALS drug development has produced far more failures than approvals, and no treatment can currently stop or reverse the disease. For Novartis, the setback also comes amid a difficult stretch for its pipeline: pelacarsen missed its Phase 3 primary endpoint on Sept. 4, and del-desiran, the lead drug from its Avidity Biosciences takeover, failed four days later.
Zoom in: VHB937 was designed to stabilize and activate TREM2, a receptor on microglia, in the hope of making the cells more protective of motor neurons. ASTRALS tested the antibody in patients with early-stage ALS without selecting them for a particular causal mutation or biomarker.
- The trial gave VHB937 or placebo for 40 weeks to 251 people within two years of their first symptoms. Its 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.
- Novartis has released no numerical data. Detailed findings are due at the 37th International Symposium on ALS/MND in Amsterdam on Dec. 9-11.
The big picture: French biotech Axoltis Pharma added another setback on Sept. 15 when 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 needs prospective confirmation.
- Amylyx’s AMX0035 went further: after reaching the market in the U.S. and Canada, the drug missed its primary and secondary endpoints in the 664-patient Phase 3 PHOENIX trial in 2024, prompting Amylyx to withdraw it from the market.
- Genetically targeted approaches can fail too. 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 shows the other side. The SOD1-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.
An outside view: “We learn from every trial,” Merit Cudkowicz, a prominent ALS expert and a professor of neurology at the 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.”
- “Precision neurotherapeutics is really critical in ALS,” Cudkowicz said, 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.
TREM2 context: Alector’s AL002, a TREM2 antibody that binds a different domain, failed Phase 2 in Alzheimer’s in 2024. Guggenheim Securities analysts wrote in June that TREM2 is better validated in Alzheimer’s than ALS.
What’s next: Among a wider set of late-stage ALS bets worldwide, two European programs stand out: Dutch Prilenia and Barcelona-based Ferrer are enrolling patients in the global Phase 3 PREVAiLS trial of pridopidine, while French biotech AB Science is preparing an authorized confirmatory Phase 3 trial of masitinib. Novartis’ Phase 2 Alzheimer’s study of VHB937 also remains underway.
Bottom line: ASTRALS leaves TREM2 unproven in ALS. But after decades of setbacks, there is growing hope that a meaningful treatment breakthrough may be close. “The field is ripe for major breakthroughs,” Cudkowicz added.
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