BMS Dual Phase III Win Masks Distinct Risk Profiles Across Two Novel Mechanisms

BMS Achieves Pivotal Phase 3 Wins in IPF and GEP-NETs

Bristol Myers Squibb (BMS) announced positive results from two pivotal Phase III trials. The ALOFT-IPF trial for admilparant, an LPA1 antagonist for idiopathic pulmonary fibrosis (IPF), met its primary endpoint, with the 60mg dose showing statistically significant improvement in forced vital capacity (FVC) over 52 weeks and a well-tolerated safety profile. Concurrently, the ACTION-1 trial for RYZ101 (225Ac-DOTATATE) in gastroenteropancreatic neuroendocrine tumours (GEP-NETs) demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS) in patients who had progressed on Lu177-based therapy, maintaining a consistent safety profile. BMS plans to engage with regulatory authorities for both therapies.

• In the Phase III ALOFT-IPF trial (NCT06003426), BMS's oral LPA1 antagonist, admilparant, achieved its primary endpoint. The 60mg dose significantly improved absolute change in forced vital capacity (FVC) after 52 weeks compared to placebo. The drug exhibited a well-tolerated safety profile, with low adverse event-related discontinuations and no liver concerns, addressing prior protocol amendments. These results are crucial for IPF patients seeking effective and tolerable treatment options.
• The Phase III ACTION-1 trial (NCT05477576) for RYZ101 (225Ac-DOTATATE), developed by BMS subsidiary RayzeBio, showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for GEP-NET patients who had progressed on Lutetium-177-based therapy. This marks the first Phase III success for an alpha-isotope-based targeted radiopharmaceutical therapy. RYZ101 also holds FDA Orphan Drug Designation, supporting its expedited development and planned regulatory submissions.
• The positive admilparant data is poised to be a significant driver in the global IPF market, which is projected to grow from $2.8 billion to $6 billion by 2026 with an 8.2% CAGR. BMS plans comprehensive data evaluation and regulatory submissions for admilparant. Additionally, the company anticipates topline results in early 2027 for the Phase III ALOFT-PPF trial (NCT06025578) in progressive pulmonary fibrosis, further expanding its lung disease portfolio.

Admilparant's Efficacy and Safety in ALOFT-IPF

Several recent studies have characterized the efficacy and safety of antifibrotic agents in idiopathic pulmonary fibrosis (IPF) across both clinical trial and real-world settings. The INPULSIS-ON open-label extension trial evaluated long-term nintedanib treatment in patients who had completed the phase III INPULSIS trials, with a median exposure of 44.7 months (range 11.9–68.3). The safety profile was consistent with that observed in INPULSIS, with diarrhoea remaining the most frequent adverse event — reported at 60.1 events per 100 patient-years in patients who continued nintedanib and 71.2 events per 100 patient-years in patients who initiated nintedanib. Progression of IPF was the adverse event most frequently leading to permanent discontinuation, affecting 12% of patients continuing nintedanib and 14% of those initiating it. The event rate of major adverse cardiovascular events was 3.6 per 100 patient-years in patients continuing nintedanib and 2.4 per 100 patient-years in those initiating it, with no new safety signals identified over long-term use.

In the real-world setting, the PROOF registry — an observational study enrolling 277 IPF patients across eight centres in Belgium and Luxembourg — assessed longitudinal clinical outcomes in patients treated with pirfenidone. Among the pirfenidone-treated population (N = 233, 84.1%), mean percent predicted FVC was 81.2% (SD 19.0) at Month 0 and 78.3% (SD 25.0) at Month 24, while mean percent predicted DLco was 47.0% (SD 13.2) and 45.0% (SD 16.5) at the same time points, respectively. Rates of ≥10% absolute decline in percent predicted FVC and ≥15% absolute decline in percent predicted DLco over 24 months were 31.0% and 23.2%, respectively. Mean time from registry inclusion to death was 31.0 (SE 0.9) months. Regarding tolerability, 12.9% of patients had a temporary dose discontinuation, 31.8% had a temporary dose reduction, and only 4.3% permanently discontinued pirfenidone due to an adverse drug reaction.

The prospective, observational PASSPORT study further characterised the long-term safety of pirfenidone in a real-world population of 1,009 patients (99.7% with IPF), with a median pirfenidone exposure of 442.0 days. Overall, 73.4% of patients experienced adverse drug reactions (ADRs), most commonly nausea (20.6%) and fatigue (18.5%), and ADRs led to treatment discontinuation in 28.7% of patients after a median of 99.5 days. Gastrointestinal symptoms (38.3%) and photosensitivity reactions/skin rashes (29.0%) were the most commonly reported ADRs of special interest. Older age and female sex were identified as factors associated with early treatment discontinuation due to an ADR. Findings were consistent with the known safety profile of pirfenidone, with no new safety signals observed.

Admilparant's Place in the Evolving IPF Landscape

The IPF treatment landscape has undergone meaningful expansion beyond the established standard-of-care agents pirfenidone and nintedanib, both of which slow FVC decline but carry tolerability burdens that frequently necessitate dose reduction or discontinuation. A real-world comparative cohort study of 292 patients treated between 2017 and 2023 found no significant difference in long-term efficacy between the two agents, though dose reduction was markedly more frequent with nintedanib (59.3%) than pirfenidone (16.9%), with patients on nintedanib carrying a 4-fold higher risk of dose reduction. Critically, dose adjustment did not significantly affect clinical outcomes in either group. Against this backdrop, the approval of nerandomilast (Jascayd) by the FDA in October 2025 represents the most consequential regulatory milestone of the period. As a first-in-class selective PDE4B inhibitor developed by Boehringer Ingelheim, nerandomilast elevates intracellular cyclic adenosine monophosphate in inflammatory and structural lung cells, suppressing pro-inflammatory cytokines and fibroblast activation through a mechanism distinct from existing antifibrotics.

The phase 3 FIBRONEER-IPF trial, enrolling 1,177 patients of whom 77.7% were receiving background nintedanib or pirfenidone, demonstrated that nerandomilast significantly reduced FVC decline at week 52. Adjusted mean FVC changes were -114.7 ml (95% CI, -141.8 to -87.5) in the 18 mg twice-daily group and -183.5 ml (95% CI, -210.9 to -156.1) in the placebo group, yielding an adjusted difference of 68.8 ml (95% CI, 30.3 to 107.4; P<0.001). The 9 mg twice-daily dose also met the primary endpoint, with an adjusted difference versus placebo of 44.9 ml (95% CI, 6.4 to 83.3; P=0.02). Diarrhea was the most frequent adverse event, reported in 41.3% of the 18 mg group and 31.1% of the 9 mg group versus 16.0% with placebo, though serious adverse events were balanced across groups. Full follow-up data from FIBRONEER-IPF further showed that nerandomilast 18 mg twice daily was associated with a numerically lower risk of death (hazard ratio 0.66 [95% CI, 0.41–1.08]), though the composite endpoint of time to first acute exacerbation, hospitalization for respiratory cause, or death did not reach statistical significance. In parallel, the FIBRONEER-ILD trial demonstrated that nerandomilast also significantly reduced FVC decline in progressive pulmonary fibrosis, with an adjusted difference of 67.2 ml (95% CI, 31.9 to 102.5; P<0.001) for the 18 mg dose versus placebo.

Beyond nerandomilast, the phase 2 data for admilparant (BMS-986278), an oral LPA1 antagonist, have added further momentum to the pipeline. In a randomized, double-blind, placebo-controlled phase 2 trial (NCT04308681) enrolling parallel IPF (n=278 randomized) and PPF (n=125 randomized) cohorts, 60 mg admilparant twice daily produced rates of FVC change over 26 weeks of -1.2% in IPF and -1.1% in PPF, versus -2.7% and -4.3% with placebo, respectively. Treatment differences between 60 mg admilparant and placebo were 1.4% (95% CI, -0.1 to 3.0) for IPF and 3.2% (95% CI, 0.7 to 5.7) for PPF. A post-hoc analysis further showed that 60 mg admilparant delayed time to disease progression in both cohorts (IPF: hazard ratio 0.54 [95% CI, 0.31–0.95]; PPF: hazard ratio 0.41 [95% CI, 0.18–0.90]). In contrast, pamrevlumab, a fully human monoclonal antibody targeting connective tissue growth factor, failed to demonstrate a statistically significant benefit in the phase 3 ZEPHYRUS-1 trial, with no significant between-group difference in absolute FVC change from baseline to week 48 (mean between-group difference 70 ml [95% CI, -60 to 190 ml]; P=0.29). Collectively, these data illustrate a pipeline maturing toward mechanism-specific, upstream-targeting agents, with nerandomilast now establishing a new therapeutic class and admilparant supporting further phase 3 evaluation.

Dual Clinical Wins Signal New Eras in Fibrosis and Neuroendocrine Cancer

Bristol Myers Squibb's recent announcement of positive Phase III results for two distinct therapies marks a significant moment for patients battling idiopathic pulmonary fibrosis (IPF) and advanced neuroendocrine tumors. These dual clinical wins underscore a strategic advancement in addressing areas of high unmet medical need, leveraging novel mechanisms and cutting-edge therapeutic modalities.

For IPF, admilparant, an oral lysophosphatidic acid receptor 1 (LPAR1) antagonist, has demonstrated statistically significant improvement in forced vital capacity (FVC) over 52 weeks. This is particularly impactful given that current IPF treatments primarily slow disease progression and are often associated with notable side effects. Admilparant's mechanism of action, targeting an upstream signal initiation point in fibrosis, represents a shift towards more specific, mechanism-based inhibition, with the potential for true disease modification. Earlier studies have shown it reduces circulating biomarkers associated with epithelial injury and fibrosis, further supporting its antifibrotic effects. While the 60mg dose was well-tolerated, continued vigilance regarding long-term safety, including transient blood pressure reductions observed in earlier phases, will be important as it moves towards regulatory review and broader clinical use.

Simultaneously, the ACTION-1 trial for RYZ101 (225Ac-DOTATATE) in gastroenteropancreatic neuroendocrine tumours (GEP-NETs) has delivered compelling data. This targeted alpha therapy (TAT) showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for patients who had progressed on prior 177Lu-DOTATATE therapy. This is a critical development for a patient population with limited options after standard beta-emitting radioligand therapy failure. Alpha emitters like 225Ac-DOTATATE offer higher potency and specificity, capable of inducing more complex double-stranded DNA breaks, which can translate to enhanced therapeutic efficacy. However, as a newer modality, long-term safety data for 225Ac-DOTATATE are still accumulating, with some evidence pointing to potential adverse effects such as subclinical hypothyroidism. Additionally, while generally promising, the presence of bone metastases has been associated with poorer overall survival in some patients receiving 225Ac-DOTATATE, suggesting that patient selection and combination strategies may be crucial for optimizing outcomes.

These results position BMS to potentially introduce two impactful therapies, diversifying its portfolio and reinforcing its commitment to addressing challenging diseases with innovative solutions. The successful development of both a novel small molecule for fibrosis and an advanced radioligand therapy for cancer highlights a robust and multifaceted research and development strategy.