Admilparant's Split Dose Result: Novel Mechanism Validated, Dose-Response Anomaly Clouds Regulatory Path

Bristol Myers Squibb's Admilparant Shows Mixed Phase 3 Results in IPF

Bristol Myers Squibb’s LPA1 antagonist, admilparant, met its primary endpoint in a Phase 3 idiopathic pulmonary fibrosis (IPF) study at the 60-mg dose, demonstrating a statistically significant improvement in patients’ absolute change in forced vital capacity (FVC) from baseline at week 52. However, the higher 120-mg dose failed to achieve statistical significance on the same measure, leading to mixed analyst reactions. Despite the high-dose miss, the low-dose win is considered potentially sufficient for regulatory approval, with analysts estimating significant future sales for admilparant in IPF. BMS plans to engage with health authorities for regulatory submissions, with detailed results expected at a future medical meeting.

• The ALOFT-IPF Phase 3 trial demonstrated that Bristol Myers Squibb's admilparant met its primary endpoint at the 60-mg dose, showing a statistically significant improvement in absolute change in forced vital capacity (FVC) from baseline at week 52 in patients with idiopathic pulmonary fibrosis. Conversely, the higher 120-mg dose failed to achieve statistical significance on this same measure. This lack of a clear dose-response relationship has raised questions among analysts regarding the drug's overall profile, despite the positive outcome for the lower dose.
• Admilparant was reported to be well-tolerated across both 60-mg and 120-mg doses in the ALOFT-IPF study, with discontinuations due to adverse events comparable to placebo. This addresses previous concerns about liver safety, following an earlier report of a patient death due to multi-organ failure after acute liver injury in the broader ALOFT program. An adjudication committee determined this death, which occurred in the 120-mg arm, was unlikely related to the study treatment, alleviating some of the safety overhang.
• Analysts view the success of the 60-mg dose as potentially sufficient to support regulatory approval for admilparant in idiopathic pulmonary fibrosis, derisking the submission path for Bristol Myers Squibb. William Blair estimates admilparant sales for IPF could reach $1.3 billion by 2032, highlighting the drug's novel mechanism and non-overlapping toxicities with current therapies as positive for combination approaches. The company plans to engage with health authorities for planned regulatory submissions, with full data presentation anticipated at a future medical meeting.

Admilparant's ALOFT-IPF Phase 3: A Mixed Efficacy Picture

Two recent phase 2 trials of admilparant (BMS-986278), an oral lysophosphatidic acid receptor 1 antagonist, evaluated the drug in parallel cohorts of patients with idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). In the randomized, double-blind, placebo-controlled phase 2 study (NCT04308681), 278 patients with IPF and 125 with PPF were randomized 1:1:1 to 30 mg admilparant, 60 mg admilparant, or placebo twice daily for 26 weeks. Rates of change in percentage of predicted FVC over 26 weeks for IPF were −2.7% (placebo), −2.8% (30 mg), and −1.2% (60 mg); for PPF they were −4.3% (placebo), −2.9% (30 mg), and −1.1% (60 mg). 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 companion post-hoc analysis of the same study assessed time to disease progression — defined as a composite of relative decline of ≥10% in percentage of predicted FVC, acute exacerbation, all-cause hospitalization, and all-cause mortality — and found that 60 mg admilparant delayed time to disease progression compared with placebo 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]). On safety, diarrhea occurred at similar frequencies in admilparant arms versus placebo, transient Day 1 postdose blood pressure reductions were observed in all arms but were greater with admilparant, and treatment discontinuations due to adverse events were similar across IPF arms and lower with admilparant (2.5% [30 mg]; 0% [60 mg]) versus placebo (17.1%) in the PPF cohort.

The ISABELA 1 and ISABELA 2 trials evaluated ziritaxestat, a novel autotaxin inhibitor, in patients with IPF across 26 countries. Both were identically designed phase 3 randomized clinical trials in which 525 patients (ISABELA 1) and 781 patients (ISABELA 2) were randomized 1:1:1 to 600 mg ziritaxestat, 200 mg ziritaxestat, or placebo once daily on top of local standard of care for at least 52 weeks. The primary outcome was the annual rate of FVC decline at week 52. In ISABELA 1, the least-squares mean annual rate of FVC decline was −124.6 mL (95% CI, −178.0 to −71.2 mL) with 600 mg ziritaxestat versus −147.3 mL (95% CI, −199.8 to −94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, −52.3 to 97.6 mL]); in ISABELA 2, the corresponding figures were −173.8 mL (95% CI, −209.2 to −138.4 mL) with 600 mg versus −176.6 mL (95% CI, −211.4 to −141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, −46.9 to 52.4 mL]). There was no benefit with ziritaxestat versus placebo for key secondary outcomes. Both trials were terminated early after an independent data and safety monitoring committee concluded that the benefit-to-risk profile no longer supported continuation. All-cause mortality in ISABELA 2 was 9.3% with 600 mg ziritaxestat, 8.5% with 200 mg ziritaxestat, and 4.7% with placebo.

The INTEGRIS-IPF trial evaluated bexotegrast (PLN-74809), an oral, once-daily investigational dual integrin inhibitor, in a phase 2a multicenter study in which participants with IPF were randomized to receive 40 mg, 80 mg, 160 mg, or 320 mg bexotegrast or placebo once daily, with or without background IPF therapy (pirfenidone or nintedanib), for at least 12 weeks. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs); bexotegrast was well tolerated, with similar rates of TEAEs in the pooled bexotegrast and placebo groups (62/89 [69.7%] and 21/31 [67.7%], respectively). Diarrhea was the most common TEAE, predominantly in participants also receiving nintedanib. Exploratory efficacy analyses showed a reduction in FVC decline over 12 weeks compared with placebo, a dose-dependent antifibrotic effect on quantitative lung fibrosis extent by imaging, and a decrease in fibrosis-associated biomarkers with bexotegrast versus placebo.

LPA1 Antagonism: Validated Mechanism in a Crowded IPF Pipeline

Several LPA1 (lysophosphatidic acid receptor 1) antagonists beyond admilparant have been evaluated or are in development for IPF, sharing the same mechanism of selectively blocking LPAR1 to exert antifibrotic effects. The clinical and preclinical landscape includes compounds that have advanced to Phase 2 trials, been halted due to safety findings, or are supported by robust preclinical data.

BMS-986020 produced hepatobiliary toxicity in its Phase 2 trial — including elevated ALT, AST, and ALP, cholecystitis, and increased plasma bile acids — attributed to inhibition of hepatic bile acid efflux transporters (BSEP, MRP3, MRP4) and mitochondrial dysfunction, mechanisms determined to be compound-specific rather than class-related, as equipotent LPA1 antagonists BMS-986234 and BMS-986278 (admilparant) did not replicate these findings.

LPA1 Antagonism: A New Chapter in IPF Therapy

The positive Phase 3 results for Bristol Myers Squibb's admilparant at the 60-mg dose represent a crucial step forward in the challenging landscape of idiopathic pulmonary fibrosis (IPF) treatment. For years, pirfenidone and nintedanib have been the primary antifibrotic agents, demonstrating efficacy in slowing the relentless decline in forced vital capacity (FVC), a critical measure strongly associated with mortality in pulmonary fibrosis. However, these therapies do not halt disease progression, and the need for novel, more effective, and better-tolerated options remains high.

Admilparant, as a lysophosphatidic acid receptor 1 (LPA1) antagonist, offers a distinct mechanism of action. Previous research has highlighted LPA signaling as fundamental in fibrotic diseases, and earlier LPA1 antagonists faced safety challenges that admilparant (BMS-986278) appears to have overcome, showing a favorable safety profile in earlier studies. The statistically significant improvement in FVC at the 60-mg dose validates this novel pathway and positions admilparant as a strong candidate for regulatory approval. This could provide clinicians with an important new tool, potentially expanding the therapeutic arsenal for patients with IPF and other progressive fibrotic interstitial lung diseases (PF-ILD), where it also showed promise in Phase 2.

However, the mixed dose response, with the 120-mg dose failing to achieve significance, introduces considerations. This raises questions about the optimal dosing strategy and whether a higher dose could have offered greater efficacy or if an efficacy ceiling exists. Furthermore, while admilparant offers a novel approach, it will enter a market with established therapies and emerging competitors like nerandomilast, which has shown similar efficacy with potentially better tolerability. Therefore, clear differentiation based on its unique mechanism, safety profile, and long-term benefits will be paramount for its successful integration into clinical practice. The full long-term safety and tolerability data from the Phase 3 program will be critical in shaping physician confidence and patient adoption.