PLN-74809 Well Tolerated, Showing Effectiveness in Phase 2a Trial

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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The experimental oral therapy PLN-74809 was overall well tolerated in people with idiopathic pulmonary fibrosis (IPF) participating in the Phase 2a INTEGRIS-IPF trial, according to new data announced by its developer, Pliant Therapeutics.

The data also indicated that PLN-74809 was able to slow lung function decline when given with or without current IPF standard-of-care therapies.

“The results from INTEGRIS-IPF are impressive, with PLN-74809 demonstrating a favorable safety profile and treatment effect both on and off standard of care therapy,” Lisa Lancaster, MD, professor of medicine at Vanderbilt School of Medicine and the principal investigator of INTEGRIS-IPF, said in a press release.

The main part of the INTEGRIS-IPF study (NCT04396756) included 90 people with IPF, ages 40 and older. About 80% of them were on current standard-of-care therapies, with a roughly even mix of those on Esbriet (pirfenidone) and Ofev (nintedanib).

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Enrollment Complete for Phase 2 Trial Testing Anti-fibrotic PLN-74809

Participants were randomly assigned to one of three doses of PLN-74809 (40, 80, or 160 mg), or a placebo, taken daily for 12 weeks (about three months). The study’s main goals were to assess its safety, tolerability, and pharmacological properties.

PLN-74809 was well tolerated at all three doses, according to Pliant, with no deaths or treatment-related serious side effects reported. Of the 67 patients on PLN-74809, all but two completed the 12-week study. Pliant did not specify the reason for the two discontinuations, but said neither were due to treatment side effects.

Pharmacological data were generally consistent with earlier research on the treatment, which is designed to reduce fibrosis, or tissue scarring, by blocking the activity of certain protein receptors called integrins. PLN-74809 was recently given fast track designation in the U.S.

The INTEGRIS-IPF study assessed forced vital capacity (FVC), a standard lung function measure that indicates how much air a person can forcibly exhale after a deep breath, and Quantitative Lung Fibrosis imaging (QLF), which assesses the extent of lung fibrosis based on imaging tests.

The average decline in FVC over 12 weeks was 74.1 mL for patients on placebo. For all patients given PLN-74809, the decline was of just 15.1 mL — an 80% relative reduction.

Compared with placebo, the average FVC decline was 38% lower in the 40 mg dose group and 66% lower in the 160 mg dose group. In the 80 mg dose group, there was a slight increase in FVC — 24.6 mL — compared with the study’s start. A treatment effect was observed in all groups with and without standard-of-care therapy.

“Data from the INTEGRIS-IPF trial exceeded our expectations exhibiting a favorable safety and tolerability profile and a treatment effect on FVC, the current registrational endpoint in IPF,” Éric Lefebvre, MD, chief medical offer of Pliant, said.

The proportion of patients with a percent predicted FVC decline of 10% or higher — a risk factor for disease progression and death in those with IPF — was 17.4% for patients on a placebo. For patients on PLN-74809, the proportion in the 40, 80, and 160 mg groups was 18.2%, 8.7% and 4.5%, respectively.

“The dose-dependent reduction observed in the proportion of patients experiencing a decline in percent predicted FVC of [at least] 10% underscores the potential of this novel investigational therapy to advance the treatment of IPF,” Lefebvre said.

The average change in QLF was 1.15% in the placebo group, compared with 3.15%, 0.70%, and 0.00% in the 40, 80, and 160 mg groups, respectively. Higher QLF values indicate more fibrosis, suggesting there was less fibrosis when PLN-74809 was given at higher doses. Consistently, the proportion of patients whose QLF scores improved or remained stable was higher in the 80 and 160 mg dose groups compared with the placebo group.

The data also demonstrated the levels of two markers of collagen production — PRO-C3 and PRO-C6 — that had been previously associated with IPF progression were reduced in patients given PLN-74809.

“I am very encouraged by the Phase 2 results from INTEGRIS-IPF. IPF studies are challenging, as large samples sizes are usually required to detect a treatment effect. The IPF patient community is in desperate need of new drugs given the limited treatment options currently available,” Lancaster said.

Pliant announced an addition to the study earlier this year, which will entail testing a higher dose of PLN-74809 (320 mg/day) for at least six months in about 28 IPF patients. Interim 12-week data from this group are expected early next year, the company said.

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