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
Frequently Asked Questions
What is deupirfenidone being studied for?
Deupirfenidone, a deuterated analog of pirfenidone, is in phase 2b development for idiopathic pulmonary fibrosis (IPF) to slow lung function decline while aiming for improved tolerability versus pirfenidone.
How does deupirfenidone differ from pirfenidone?
Deupirfenidone replaces 3 hydrogen atoms with deuterium in the methyl group of pirfenidone, preserving pharmacodynamic activity while altering its pharmacokinetic profile and plasma exposure.
What did the ELEVATE-IPF trial show?
Deupirfenidone 825 mg TID reduced 26-week FVC decline by 91.0 mL versus placebo (P =.02) and delayed time to IPF progression (HR, 0.439; P =.0023), with a safety profile similar to pirfenidone.
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
