Deupirfenidone showed an 80.9% treatment effect compared to placebo at the higher dose studied, while pirfenidone had a 54.1% treatment effect versus placebo.


RT’s Three Key Takeaways:

  1. PureTech Health announced positive results from the ELEVATE IPF phase 2b trial, evaluating deupirfenidone (LYT-100) in patients with idiopathic pulmonary fibrosis (IPF).
  2. The ELEVATE IPF trial demonstrated a dose-dependent response with deupirfenidone, showing a treatment effect at both doses compared to placebo.
  3. Following these phase 2b results, PureTech plans to discuss the data with regulatory authorities and continue to develop deupirfenidone.

Clinical-stage biotherapeutics company PureTech Health plc announced positive results from ELEVATE IPF, a phase 2b randomized, double-blind, active- and placebo-controlled, dose-ranging trial evaluating deupirfenidone (LYT-100) at two dose levels three times a day over 26 weeks in patients with idiopathic pulmonary fibrosis (IPF).

“The ELEVATE IPF trial broke new ground in phase 2 trial design in IPF. This was the first time that a new therapy (deupirfenidone) has been evaluated alongside one of the two existing standard-of-care treatments (pirfenidone),” says Toby Maher, MD, PhD, professor of medicine and director of interstitial lung disease at Keck School of Medicine, University of Southern California, Los Angeles, and lead investigator in the ELEVATE IPF trial, in a release. 

He continues, “Deupirfenidone 825 mg [three times a day] reduced lung function decline to near-physiologic levels over 26 weeks and had an effect size, compared with placebo, that was approximately 50% greater than that seen with pirfenidone. Deupirfenidone has the potential to offer patients a highly effective and tolerable treatment option. These are extremely exciting results from a phase 2b trial, and I am very enthusiastic about the continued development of deupirfenidone.”

Treatment Effect and Trial Results

Participants in the trial were randomized 1:1:1:1 to receive deupirfenidone 550 mg, deupirfenidone 825 mg, pirfenidone 801 mg (the US Food and Drug Administration-approved dose), or placebo three times a day for 26 weeks, and had the option to enroll in an ongoing, open-label extension study. The two doses of deupirfenidone were chosen based on PureTech’s phase 1 data, which showed that a 550 mg three times a day dose of deupirfenidone provided approximately equivalent drug exposure to pirfenidone, 801 mg three times a day.

The trial achieved its primary endpoint based on the prespecified Bayesian analysis, with a 98.5% posterior probability. This means there is a 98.5% probability that the pooled deupirfenidone arms were superior to placebo in slowing the rate of lung function decline in people with IPF, as measured by forced vital capacity (FVC) at 26 weeks. The trial also successfully demonstrated a dose-dependent response.

The rate of FVC decline at week 26 with:

  • deupirfenidone 825 mg three times a day compared to placebo was statistically significant (-21.5 mL vs -112.5 mL, respectively; p=0.02) and represents a robust treatment effect of 80.9% as a monotherapy; for context, the level of six-month natural decline in lung function as measured by FVC expected in healthy adults over 60 years old is approximately -15.0 mL to -25.0 mL. 
  • pirfenidone 801 mg three times a day showed a treatment effect of 54.1% compared to placebo (-51.6 mL vs -112.5 mL, respectively), which is consistent with previously reported pirfenidone clinical trial data.

Secondary Endpoint and Statistical Significance

The trial also achieved its key secondary endpoint based on a prespecified Bayesian analysis, with a posterior probability of 99.6%. This means that there is a 99.6% probability that the pooled deupirfenidone arms were superior to placebo in slowing the rate of lung function decline in people with IPF, as measured by the forced vital capacity percent predicted (FVCpp) from baseline to week 26. 

While FVCpp and FVC (the primary endpoint) are both measures of lung function, FVCpp accounts for key patient characteristics (age, sex, height, race) and therefore normalizes the results at the patient level. Deupirfenidone 825 mg three times a day also demonstrated a benefit on this endpoint compared to placebo that was statistically significant (-0.43 vs -3.43, respectively; p=0.01).

 Placebo Three Times a Day(N=65)Pirfenidone801 mg Three Times a Day(N=61)Deupirfenidone 550 mg Three Times a Day(N=65)Deupirfenidone 825 mg Three Times a Day(N=63)
Change from Baseline in FVC (mL) over 26 Weeks (SE)-112.5 (27.84)-51.6 (29.13)-80.7 (29.32)-21.5 (28.86)
Difference in FVC (mL) vs. Placebo (95% CI) 60.9(-18.3, 140.0)31.8(-47.6, 111.2)91.0†(12.2, 169.7)
Change from Baseline in FVCpp (%) over 26 Weeks (SE)-3.43 (0.842)-1.46 (0.881)-1.81 (0.886)-0.43 (0.872)
Difference in FVCpp (%) vs. Placebo (95% CI) 1.97(-0.42, 4.37)1.62(-0.78, 4.02)3.00†(0.62, 5.38)
†Statistically significant at 0.05 level; p values are two-sided and have not been corrected for multiplicity.

“Our goal in developing deupirfenidone is to offer better outcomes to people living with IPF. The adoption and adherence of currently approved antifibrotics has been limited by a tradeoff between efficacy and tolerability, specifically related to gastrointestinal adverse events. This prevents many patients from initiating treatment or maintaining optimal therapeutic doses and, in turn, achieving the best possible outcomes,” says Eric Elenko, PhD, president and co-founder of PureTech, in a release “I could not be more pleased that deupirfenidone showed a favorable tolerability profile at both doses evaluated and—most importantly—has demonstrated the potential to offer patients enhanced efficacy at the higher dose.”

Safety and Tolerability Profile

Both doses of deupirfenidone were generally well-tolerated in the trial. The overall number of patients experiencing any gastrointestinal-related adverse events was similar across the deupirfenidone 825 mg three times a day and pirfenidone 801 mg three times a day arms. Deupirfenidone 825 mg three times a day demonstrated a favorable tolerability profile compared to pirfenidone 801 mg three times a day, with a lower percentage of patients reporting key gastrointestinal adverse events that occurred in ≥5% of participants in at least one arm: nausea (20.3% vs 27.0%), dyspepsia (14.1% vs 22.2%), diarrhea (7.8% vs 11.1%), constipation (4.7% vs 6.3%) and vomiting (1.6% vs 3.2%). The only key gastrointestinal adverse events increase observed was abdominal pain (14.1% vs 7.9%). 

There were five deaths in the pirfenidone arm, two deaths in the placebo arm, and one death in each of the deupirfenidone arms. None of the deaths was deemed to be treatment-related.

Next Steps and Ongoing Development

Overall, 187 out of 257 patients completed the trial: 43 out of 63 patients in the pirfenidone 801 mg three times a day arm; 42 out of 65 patients in the deupirfenidone 550 mg three times a day arm; 50 out of 64 patients in the deupirfenidone 825 mg three times a day arm; and 52 of 65 patients in the placebo arm.

Of those who completed the trial, 170 patients (more than 90%) opted to enroll in an ongoing open-label extension evaluating the two doses of deupirfenidone. To date, preliminary data support a durable treatment effect and a consistent tolerability profile with deupirfenidone 825 mg. Across the randomized trial and open-label extension, the longest treatment duration with deupirfenidone 825 mg three times a day is 79 weeks and with deupirfenidone 550 mg three times a day is 81 weeks.

“These data are remarkable, particularly for a monotherapy, and if supported by a phase 3 trial would represent a step change in the treatment of IPF,” says Bharatt Chowrira, PhD, JD, CEO of PureTech, in a release. “At PureTech, our approach is centered on identifying simple and elegant solutions to big problems that underlie tremendous patient need, and we are proud that our R&D engine has generated another potentially transformative treatment. We are committed to the rapid advancement of deupirfenidone, with the goal of delivering a new standard of care to patients while generating value for our shareholders.”

PureTech intends to discuss the phase 2b results with regulatory authorities to align on the appropriate path forward. Additional data from this trial will be presented at a future forum.

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