Admilparant slows lung function decline in IPF, progressive PF
Key takeaways:
- Admilparant vs. placebo resulted in smaller decreases in percent-predicted FVC at 26 weeks in two types of pulmonary fibrosis.
- Use of background antifibrotics did not change this finding.
Receiving admilparant, an oral lysophosphatidic acid receptor 1 antagonist, for 26 weeks lowered percent-predicted FVC decline in idiopathic and progressive pulmonary fibrosis, according to study results.
Admilparant (Bristol Myers Squibb), previously known as BMS-986278, was granted FDA breakthrough therapy designation for patients with progressive pulmonary fibrosis (PPF) in October 2023.
“In this first phase 2 study to evaluate antifibrotic treatment in parallel IPF and PPF cohorts, 60 mg admilparant slowed lung function decline and was safe and well tolerated,” Tamera J. Corte, BSc, MBBS, FRACP, PhD, consultant respiratory physician and director of interstitial lung disease in the department of respiratory medicine at Royal Prince Alfred Hospital, and colleagues wrote.
In a randomized, double-blind, placebo-controlled phase 2 trial published in American Journal of Respiratory and Critical Care Medicine, Corte and colleagues analyzed 276 adults with IPF to determine the impact of twice-daily 30 mg admilparant (n = 91; mean age, 69.5 years; 84.6% men; 70.3% white) and 60 mg admilparant (n = 93; mean age, 68.8 years; 74.2% men; 68.8% white) vs. placebo (n = 92; mean age, 69 years; 82.6% men; 70.7% white) on lung function decline, as well as safety at 26 weeks.
Researchers also investigated these outcomes in 123 adults with PPF. In this set of patients, 40 (mean age, 71.4 years; 57.5% men; 67.5% white) received the twice-daily 30 mg admilparant dose, 42 (mean age, 67.9 years; 52.4% men; 76.2% white) received the twice-daily 60 mg admilparant dose and 41 (mean age, 68.8 years; 48.8% men; 75.6% white) received placebo.
As Healio previously reported, a 2023 European Respiratory Society International Congress presentation found that receiving admilparant for 26 weeks lowered the rate of percent-predicted FVC (ppFVC) decline in PPF.
Additionally, 26-week admilparant slowed time to disease progression in IPF, according to a presentation of a post hoc analysis at the 2024 American Thoracic Society International Conference.
The IPF cohort included 67% of patients on background antifibrotics. The PPF cohort included 37% of patients on background antifibrotics, and some patients in this cohort had immunosuppressant use (30 mg, 13%; 60 mg, 12%; placebo, 15%).
No patients from the PPF 60 mg group discontinued treatment due to an adverse event, whereas one patient from the PPF 30 mg group and seven patients from the PPF placebo group stopped treatment for this reason.
The study noted that a comparable proportion of patients from each group in the IPF analysis discontinued treatment by reason of an adverse event (30 mg, nine patients; 60 mg, six patients; placebo, nine patients).
Compared with the 60 mg dose of admilparant in the IPF analysis, researchers found a greater decrease in ppFVC among patients receiving placebo at 26 weeks (placebo, –2.7% vs. 60 mg, –1.2%), revealing a treatment difference of 1.4% (95% CI, –0.1 to 3). In contrast, ppFVC decline was similar in the 30 mg admilparant group and the placebo group (–2.8% vs. –2.7%).
Switching to the PPF analysis, researchers found larger decreases in ppFVC among patients receiving placebo vs. both admilparant doses at 26 weeks (placebo, –4.3% vs. 30 mg, –2.9% vs. 60 mg, –1.1%), revealing a treatment difference of 3.2% (95% CI, 0.7-5.7) between 60 mg and placebo.
“Further studies are needed to understand why 30 mg admilparant had a treatment effect in the PPF cohort but not in the IPF cohort,” Corte and colleagues wrote.
Notably, in both analyses, patients assigned admilparant continued to show less decline in ppFVC compared with the placebo group regardless of use of background antifibrotics.
Among the three treatment groups of patients with IPF, the rate of one or more treatment-emergent adverse events was highest among those receiving placebo (80.4%), followed by those receiving the 30 mg dose (75.8%) and those receiving the 60 mg dose (74.2%).
In slight contrast, the rate of one or more treatment-emergent adverse events among patients with PPF was highest in the 30 mg group (82.5%), followed by the placebo group (78%) and the 60 mg group (66.7%).
Researchers reported nine total deaths due to treatment-related adverse events in the IPF treatment groups — two in the placebo group, three in the 30 mg group and four in the 60 mg group. In the PPF analysis, none of the patients in either of the admilparant groups died, whereas three patients from the placebo group died.
According to the study, the most frequent treatment-emergent adverse event in each of the treatment groups in both the IPF and PPF analyses was diarrhea. When divided into patients using vs. not using background antifibrotics, researchers found a higher proportion of patients on background antifibrotics experiencing this event in the IPF analysis (using vs. not using antifibrotics: 30 mg, 13% vs. 7%; 60 mg, 13% vs. 7%; placebo, 16% vs. 3%) and the PPF analysis (30 mg, 13% vs. 16%; 60 mg, 13% vs. 4%; placebo, 40% vs. 0%).
In terms of blood pressure, researchers reported larger transient drops among patients receiving admilparant vs. placebo following dosing on day 1.
“These findings support further evaluation of admilparant as a therapeutic option for patients with IPF and PPF in phase 3 trials,” Corte and colleagues wrote.
Perspective
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There remain only two FDA-approved medications for the treatment of IPF — pirfenidone and nintedanib — with no new therapies approved in over a decade. Beyond scleroderma-associated ILD and IPF, ILDs with PPF have only one FDA-approved treatment: nintedanib.
While these antifibrotic treatments can slow progression of disease, they are not curative, and they do not completely halt progression. Additionally, treatment with these drugs can often be limited by adverse effects. Therefore, there is an urgent need for additional safe and efficacious treatments for both IPF and PPF. This clinical trial was unique in examining a new antifibrotic treatment in parallel IPF and PPF cohorts.
This was a phase 2 randomized control trial of admilparant, a second-generation lysophosphatidic acid receptor 1 antagonist, which found that compared with placebo, 60 mg admilparant reduced the rate of decline in FVC percent predicted in both the IPF and PPF cohorts, supporting further study of this drug in phase 3 trials. Furthermore, although the clinical trial of a first-generation lysophosphatidic acid receptor 1 antagonist, BMS-986020, had to be stopped early due to hepatobiliary adverse events, there were lower rates of serious adverse events and treatment discontinuations due to adverse events in the admilparant arms of this study compared with placebo. This is an important finding since treatment discontinuation due to side effects is relatively common with both nintedanib and pirfenidone.
While these results are promising, I remain cautiously optimistic. Within the last 2 years, there were three drugs — ziritaxestat, zinpentraxin alfa and pamrevlumab — with promising phase 2 data that failed to show efficacy in the treatment of IPF in larger phase 3 trials. However, in this trial, it is encouraging that admilparant was found to slow progression in two cohorts (IPF and PPF) and that this effect was consistent with or without background antifibrotic use for both cohorts.
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