ALOFT Hepatotoxicity Signal Leaves Admilparant's Benefit-Risk Case Unresolved Before Q4 2026 Readout

BMS Reports Liver Injury Events in Phase 3 Lung Disease Program

Bristol Myers Squibb (BMS) has amended the protocol for its Phase 3 ALOFT clinical program testing the pulmonary fibrosis candidate admilparant, following reports of multiple liver injury cases, including one death. The company stated that the study remains blinded, making the direct cause of these events unclear. This disclosure has caused unease among investors in Contineum Therapeutics, which is developing a similar product, due to concerns about potential class-wide effects. Despite the issues, an independent data monitoring committee has recommended that the trial continue, with a key readout for the ALOFT-IPF study in idiopathic pulmonary fibrosis expected in Q4 2026.

• BMS confirmed a "limited number" of liver events in the Phase 3 ALOFT program, mostly mild and transient, often linked to other medical conditions or concomitant medications. One death occurred due to multi-organ failure after acute liver injury, but its direct association with admilparant remains unconfirmed as the company is still blinded to treatment assignments.
• The protocol amendment by BMS led to a sharp decline in Contineum Therapeutics' shares, as investors feared a potential class-wide effect on lysophosphatidic acid receptor 1 (LPA1-R) inhibitors. However, Contineum's CEO and analysts downplayed these concerns, citing differences in molecular makeup and dosage for their rival therapy, PIPE-791.
• Despite the reported liver injury events, the independent data monitoring committee for the ALOFT program has regularly reviewed unblinded data and recommended the trial's continuation. A new committee has also been established to specifically investigate potential liver injuries, with the crucial Phase 3 ALOFT-IPF study readout for idiopathic pulmonary fibrosis still anticipated in the fourth quarter of 2026.

Current Treatment Guidelines for Idiopathic Pulmonary Fibrosis

Nintedanib and pirfenidone represent the established pharmacological standard of care for IPF, both approved by the FDA in 2014 on the basis of positive phase 3 trials and conditionally recommended in the 2015 ATS/ERS/JRS/ALAT Clinical Practice Guideline. Monotherapy with either agent remains the mainstay of pharmacological treatment, with long-term studies confirming acceptable safety and tolerability for both. Real-world comparative data indicate that mean annual FVC decline was -1.74% with pirfenidone and -2.38% with nintedanib, with no statistically significant difference between therapies, and overall survival across up to six years of follow-up was 4.18 years with no significant between-group difference (nintedanib 4.55 years; pirfenidone 3.81 years; p = 0.159). Given equivalent efficacy profiles, treatment selection is guided by individual clinical characteristics rather than comparative effectiveness. Immunosuppressive regimens — including prednisone, azathioprine, and N-acetylcysteine — are contraindicated in IPF; the PANTHER-IPF trial demonstrated that exposure to this combination was associated with a hazard ratio of 2.84 (95% CI, 1.02–7.87; P = 0.045) for the composite endpoint of death, lung transplantation, hospitalization, or FVC decline, particularly in patients with short leukocyte telomere length.

Non-pharmacological interventions are integral to the multidisciplinary management of IPF. Oxygen therapy is indicated for patients with resting, nocturnal, or exertional hypoxemia, and pulmonary rehabilitation — encompassing supervised exercise and patient education — has demonstrated short-term improvements in exercise tolerance, though long-term effects on dyspnoea and health-related quality of life are inconsistent. Immunisation against influenza, pneumococcus, and SARS-CoV-2 is considered essential given the elevated risk of infection-related morbidity and mortality. Management of gastro-esophageal reflux disease is also included among guideline-recommended interventions. Data from the US IPF-PRO Registry (n = 727) indicate that guideline implementation remains suboptimal in clinical practice, with referral for pulmonary rehabilitation achieved in only 19.5% of eligible patients and referral for lung transplant evaluation in only 22.3%, with implementation more likely in patients with greater disease severity.

For patients with progressive disease refractory to medical therapy, lung transplantation offers a potential survival advantage and timely referral is recommended. International guidelines advise referral to a transplant centre once the diagnosis of IPF is established, as the survival benefit of transplantation in IPF is well documented. Disease progression is defined by a decline in forced vital capacity (FVC) ≥ 10% from baseline, decline in diffusing capacity of the lungs for carbon monoxide, or increased fibrosis on high-resolution computed tomography (HRCT); a histological pattern of usual interstitial pneumonia (UIP) is recognised as a risk factor for progression, and real-world data confirm that disease progression correlates significantly with a probable UIP pattern on HRCT (p = 0.006). Enrollment of patients into trials of novel therapies — including agents targeting the ATX/LPA pathway, CTGF, pentraxin-2, αvβ6 integrin, and galectin-3 — is considered best current practice, as it offers access to potentially more effective treatments while the field continues to evolve.

LPA1 Antagonists: Navigating Liver Safety in IPF Development

Idiopathic pulmonary fibrosis (IPF) remains a devastating, progressive lung disease, leaving patients with limited therapeutic options. While approved antifibrotics like pirfenidone and nintedanib have demonstrated efficacy in slowing lung function decline, the search for novel, safe, and more effective treatments continues. Lysophosphatidic acid receptor 1 (LPAR1) antagonists have emerged as a promising class, with preclinical studies showing antifibrotic effects in models of lung fibrosis.

However, the recent disclosure from Bristol Myers Squibb regarding liver injury cases, including one fatality, in its Phase 3 ALOFT program for the LPAR1 antagonist admilparant, casts a significant shadow over this therapeutic avenue. This is not an isolated incident; existing evidence points to a prior LPAR1 antagonist, BMS-986020, being discontinued in Phase 2 due to hepatobiliary toxicity. While non-clinical data at the time suggested this toxicity was compound-specific, the recurrence of such serious events with admilparant raises critical questions about the predictability of preclinical models and the potential for a broader, albeit nuanced, class effect.

For BMS, the independent data monitoring committee's recommendation to continue the trial suggests a perceived favorable risk-benefit balance or a belief that these events are manageable. This implies a strong commitment to the drug's potential, but the path forward will undoubtedly involve heightened vigilance and potentially adaptive monitoring strategies. For other companies developing similar LPAR1 antagonists, such as Contineum Therapeutics, this event creates a significant overhang. Investors and regulators will now scrutinize these programs with increased intensity, potentially leading to more rigorous safety requirements, extended development timelines, or even a re-evaluation of their pipelines.

Ultimately, the ongoing ALOFT trial will be pivotal. Should admilparant demonstrate robust efficacy with a manageable safety profile, it could still offer a valuable new mechanism for IPF patients, particularly those intolerant to existing therapies. However, the specter of liver toxicity means that any potential approval would likely come with stringent label warnings, mandatory liver function monitoring, and careful patient selection, shaping its role within the evolving IPF treatment landscape. The balance between therapeutic innovation and patient safety remains paramount in this challenging disease area.