In the phase 2b ELEVATE-IPF trial, deupirfenidone 825 mg 3 times daily (TID) slowed the rate of forced vital capacity (FVC) decline by 91.0 mL compared with placebo over 26 weeks in patients with idiopathic pulmonary fibrosis (IPF).¹
“These results support further evaluation of deupirfenidone as a treatment option for patients with IPF in a phase 3 trial,” wrote Toby M. Maher, MD, PhD, from Keck Medicine of USC, and colleagues.
Deupirfenidone is a selectively deuterated analog of pirfenidone designed to retain pharmacodynamic activity while altering pharmacokinetic exposure and tolerability. Pirfenidone and nintedanib have been available since 2014, but dose-limiting gastrointestinal, neurologic, and cutaneous adverse effects contribute to low treatment uptake and frequent discontinuation.
Deupirfenidone Efficacy in the ELEVATE-IPF Trial
ELEVATE-IPF was a 4-arm, randomized, double-blind, active- and placebo-controlled phase 2b trial conducted at 87 sites across 14 countries that evaluated 2 deupirfenidone doses against both placebo and an active pirfenidone comparator to assess efficacy and tolerability. In total, 257 antifibrotic-naive patients, or patients off nintedanib for ≥ 6 months, were randomized 1:1:1:1 to deupirfenidone 550 mg TID, deupirfenidone 825 mg TID, pirfenidone 801 mg TID, or placebo. The primary endpoint was the rate of change in FVC at 26 weeks, analyzed using a Bayesian model with dynamic borrowing of historical placebo data from the ASCEND, INPULSIS, and TOMORROW trials.
The posterior mean FVC change was -110.71 mL (95% CI, -148.75 to -70.98) for placebo and -48.42 mL (95% CI, -87.66 to -9.04) for pooled deupirfenidone arms, a difference of 62.29 mL (95% CI, -6.13 to 115.73; posterior probability of superiority, 0.985). In frequentist analysis, deupirfenidone 825 mg reduced FVC decline versus placebo by an adjusted mean difference of 91.0 mL (95% CI, 12.2 to 169.7; P =.02), and time to IPF progression was significantly delayed (HR, 0.439; 95% CI, 0.255 to 0.756; P =.0023).
Deupirfenidone Secondary Endpoints and Safety in IPF
A parallel analysis of FVC percent predicted (FVCpp) supported the primary result: placebo declined by an adjusted mean of -3.43 versus -0.43 for deupirfenidone 825 mg, a difference of 3.00 (95% CI, 0.62 to 5.38; P =.01). A numerical dose response was observed, with deupirfenidone 825 mg showing a smaller adjusted FVC decline (-21.5 mL) versus the 550 mg dose (-80.7 mL), though the comparison did not reach significance. The pirfenidone active-control arm also outperformed the placebo numerically (adjusted mean difference, 60.9 mL; 95% CI, -18.3 to 140.0; P =.13), consistent with the effect size seen in the pivotal ASCEND trial and supporting internal validity.
Gastrointestinal events were the most common adverse events across active arms, occurring in 52.4% of the pirfenidone group, 35.4% of the deupirfenidone 550 mg group, and 53.1% of the deupirfenidone 825 mg group, versus 24.6% with placebo. Photosensitivity occurred at similar rates with pirfenidone (7.9%) and deupirfenidone 825 mg (7.8%). Treatment discontinuation due to adverse events occurred in 12.3% (placebo), 17.5% (pirfenidone), 24.6% (deupirfenidone 550 mg), and 18.8% (deupirfenidone 825 mg), with no deaths considered related to study drug.
Given the dose-response pattern observed between deupirfenidone 550 mg and 825 mg, the 825 mg dose has been selected for phase 3 development, with dose modification permitted to manage tolerability. Study sponsor PureTech Health has proposed a head-to-head superiority trial of deupirfenidone 825 mg versus pirfenidone 801 mg to generate additional comparative efficacy and safety data.¹
“These results support further evaluation of deupirfenidone as a treatment option for patients with IPF in a phase 3 trial,” investigators concluded.
References
Maher TM, Hamblin MJ, Choi WI, et al. Deupirfenidone compared with pirfenidone and placebo in idiopathic pulmonary fibrosis (ELEVATE-IPF): a phase 2b randomized placebo-controlled trial. Am J Respir Crit Care Med. 2026;212(8):1761-1769. doi:10.1093/ajrccm/aamag155
Maher TM, Molina-Molina M, Russell AM, et al. Unmet needs in the treatment of idiopathic pulmonary fibrosis-insights from patient chart review in five European countries. BMC Pulm Med. 2017;17(1):124. Published 2017 Sep 15. doi:10.1186/s12890-017-0468-5
