Novartis drops ALS drug lifonebart after Phase 2 trial misses key goals

Novartis AG has stopped developing experimental amyotrophic lateral sclerosis treatment VHB937, also known as lifonebart, after a mid-stage clinical trial failed to meet both its primary and secondary objectives. The company confirmed the decision to Reuters after earlier reports from Endpoints News and Bloomberg, marking another setback during an unusually difficult period for the Swiss pharmaceutical company’s research pipeline.

The Phase 2 trial enrolled 251 people with early-stage ALS whose symptoms had begun within the previous two years. Lifonebart was designed to stabilise TREM2, a protein involved in immune regulation, inflammation and the clearance of cellular waste in the brain. The failure is important because TREM2 has attracted interest as a neurological drug target, but successful clinical validation has remained elusive.

What happened in the Novartis lifonebart ALS trial?

The study evaluated whether VHB937 could improve outcomes for patients with amyotrophic lateral sclerosis, a progressive neurodegenerative disease that destroys nerve cells controlling voluntary muscles.

Novartis concluded that the programme should be discontinued after the drug failed both the principal efficacy measure and secondary trial objectives. Reuters reported that the company subsequently confirmed it was ending development of VHB937 for ALS.

The result does not mean the TREM2 biological pathway has been definitively disproven across every neurological disease. Novartis is separately evaluating lifonebart in Alzheimer’s disease, and ClinicalTrials.gov indicated that the mid-stage Alzheimer’s study was continuing to recruit patients when Reuters reported the ALS decision.

That separation matters because a drug can fail in one disease while still retaining a rationale in another, particularly when patient biology and endpoints differ materially.

Why has TREM2 been difficult for drug developers?

TREM2 is associated with microglia, immune cells that play an important role in maintaining the brain’s environment. Researchers have investigated whether modifying TREM2 activity could change inflammation, immune response and clearance of damaged material in neurodegenerative diseases.

The scientific logic has been compelling enough to attract several drug developers, but clinical results have been difficult. Alector reported in 2024 that one of its experimental TREM2 programmes failed in a mid-stage study, providing an earlier warning that translating the biology into measurable patient benefit would be challenging.

ALS itself has proved exceptionally difficult for drug development. The disease can progress differently between patients, and treatments must demonstrate clinically meaningful changes against a rapidly worsening condition.

That combination means disappointing results are common even when preclinical science appears promising.

Why is the VHB937 failure more important after Novartis’ other setbacks?

The timing magnifies the investor impact.

Reuters noted that Novartis recently suffered a Phase 3 failure involving cardiovascular drug pelacarsen, followed by another late-stage disappointment involving delpacibart etedesiran in myotonic dystrophy type 1. Novartis also halted eight of 10 studies involving its rap-cel cell therapy programme after three patient deaths, creating an unusually concentrated series of clinical challenges.

Pelacarsen was particularly significant because investors had viewed drugs targeting elevated lipoprotein(a) as a potentially important new cardiovascular market. Novartis said the Lp(a)HORIZON Phase 3 trial lowered Lp(a) but failed to achieve the primary objective of reducing major cardiovascular events compared with placebo.

The HARBOR Phase 3 study of del-desiran similarly failed its primary endpoint in myotonic dystrophy type 1, although Novartis said secondary and exploratory measures showed evidence of activity and that it would examine the complete dataset before deciding on the programme’s future.

One drug failure is routine in pharmaceutical research. Several high-profile setbacks occurring close together can alter expectations around pipeline productivity and future revenue replacement.

Does Novartis have a broader growth problem?

Novartis remains a large, profitable pharmaceutical company with multiple established growth products, so a sequence of trial disappointments should not be equated with an immediate deterioration of the entire business.

The challenge concerns the future portfolio. Large pharmaceutical companies must continually replace revenues as older drugs face competition and patents expire, which means pipeline assets and acquisitions are central to long-term valuation.

Novartis has invested aggressively in cardiovascular disease, neuroscience and RNA-based medicines. It has also used acquisitions to obtain new technology and development programmes, increasing investor attention on whether those investments ultimately generate commercial products.

The company maintained its five-year sales growth guidance following the recent del-desiran failure, suggesting management does not currently view the setbacks as sufficient to alter its overall financial outlook.

How did Novartis shares react to the ALS setback?

Novartis’ U.S.-listed shares were marginally higher when Reuters reported the decision, indicating the ALS discontinuation itself did not trigger a major immediate selloff. That reaction probably reflects the programme’s relative importance compared with larger late-stage assets and the fact that investors had already absorbed several pipeline disappointments during September.

Earlier failures have generated more visible market reactions. Novartis shares fell more than 3% following the pelacarsen cardiovascular result because investors had attached substantial commercial value to the programme.

The contrast demonstrates how pharmaceutical markets differentiate between pipeline failures rather than reacting equally to every clinical setback.

What should investors watch next in the Novartis pipeline?

Upcoming data from acquired and internally developed programmes will become increasingly important because Novartis needs positive readouts to rebalance sentiment around research execution.

The Alzheimer’s trial involving lifonebart will also be worth monitoring because it could determine whether the TREM2 mechanism retains value for Novartis outside ALS. Continued development does not imply that the Alzheimer’s study will succeed, but it prevents the ALS failure from automatically closing the entire programme.

More broadly, Novartis will need to demonstrate that its portfolio can absorb unsuccessful trials without undermining medium-term growth.

Drug development is inherently built around attrition, but investors eventually judge pharmaceutical research not by how many programmes enter trials but by how consistently successful products emerge from them.