IPF Therapy PLN-74809 Well-tolerated, Suppresses Pro-fibrotic Signals, Phase 1b Trial Shows

IPF Therapy PLN-74809 Well-tolerated, Suppresses Pro-fibrotic Signals, Phase 1b Trial Shows

Idiopathic pulmonary fibrosis (IPF) oral treatment candidate PLN-74809 can prevent the activation of the pro-fibrotic protein TGF-beta by up to 70% in healthy volunteers, according to final results of a Phase 1b trial.

Being developed by Pliant Therapeutics, PLN-74809 is a small molecule and selective inhibitor of the alphavbeta6 and alphavbeta1 integrins — two types of protein that mediate cell adhesion and are specific to tissues implicated in fibrosis (scarring).

By blocking these integrins, this investigational inhibitor is thought to be able to prevent the activation of TGF-beta, a pro-fibrotic molecule that controls important cellular mechanisms, including cell differentiation and growth, which underlie the progression of IPF.

Preclinical studies in animal models confirmed that PLN-74809 could prevent the growth of fibrotic tissue in the lungs by blocking TGF-beta.

In a previous Phase 1a study in 71 healthy volunteers receiving 10 to 75 mg of PLN-74809, the therapy was also well-tolerated, with its stability in the body potentially supporting once-daily dosing.

More recently, the researchers conducted a randomized, double-blind study to compare two PLN-74809 doses — 20 mg and 40 mg — to a placebo, given over seven days to 18 healthy volunteers.

Researchers evaluated the potential treatment’s safety and pharmacokinetics — its absorption, distribution, metabolism and excretion in the body. They also determined its ability to ease TGF-beta activation, as assessed via the levels of the phosphorylated (or activated) form of the SMAD2 protein in immune cells called macrophages found in the lung’s tiny air sacs, or alveoli.

Besides showing that PLN-74809 has on-target biological activity in humans, the trial revealed the plasma concentrations needed to therapeutically suppress activation of TGF-beta with a once-daily dose. This information will help Pliant design the upcoming Phase 2a trials in IPF patients, expected to start in the second half of this year.

All participants who achieved the targeted blood exposure levels of PLN-74809 after seven days experienced 50% or greater reductions in TGF-beta activation compared to before the treatment. As for safety, only mild adverse events were observed, and no treatment-related side effects were reported.

“We’re pleased to report that PLN-74809 has shown human proof of mechanism by inhibiting [TGF-beta] activation in the lungs of healthy volunteers,” Éric Lefebvre, MD, Pliant’s chief medical officer, said in a press release.

“We believe PLN-74809 may disrupt the fibrosis pathway and affect disease progression in patients with IPF,” added Lefebvre, who further noted the continued positive safety, tolerability, and pharmacokinetic results of the experimental treatment.

PLN-74809 received orphan drug designation by the U.S. Food and Drug Administration in August 2018 for the treatment of IPF.

Beyond IPF, Pliant is planning to test PLN-74809 in other fibrotic diseases, including primary sclerosing cholangitis, a chronic disorder characterized by inflammation and fibrosis within the bile ducts that gradually damages the liver.

José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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