Dr Paul Frohna Discusses Promising Results of Novel Hedgehog Inhibitor for IPF


Promising results from a phase 2 trial of ENV-101, a novel hedgehog inhibitor, showed improvement in lung function and reduction of fibrosis in patients with idiopathic pulmonary fibrosis, said Paul Frohna, MD, PhD, PharmD.

Paul Frohna, MD, PhD, PharmD, chief medical officer for Endeavor BioMedicines discussed ENV-101, a hedgehog inhibitor and the benefits it has on patients with idiopathic pulmonary fibrosis. Frohna contributed to research presented at the American Thoracic Society (ATS) 2024 International Conference titled, "ENV-101, A Novel Hedgehog Inhibitor, Increases Lung Function, and Reduces Lung Fibrosis: Results From a Idiopathic Pulmonary Fibrosis: Results From a Randomized, Double-blind, Placebo-controlled Phase 2 Trial," where he addressed the trial methods, results, and explains how this effects current treatment methods for patients.

As a chief medical officer for Endeavor BioMedicines, Frohna creates and leads departments in charge of candidate selection, investigational new drug/clinical trial authorization filings, phase 1 to 3 clinical trials, and global development partnerships. His expertise lies in designing and launching clinical and translational programs for a variety of therapies, including biologics, small molecules, and stem cells across a multitude of therapeutic areas.

ATS 2024 is being held May 17-22 in San Diego, California. See the rest of our coverage of the meeting.


ENV-101 targets the Hedgehog pathway. Can you elaborate on the specific mechanisms by which it inhibits this pathway and how this inhibition is expected to halt the progression of IPF?

ENV-101 binds to the smoothened receptor, which is a key component of the Hedgehog pathway. By blocking that receptor, you initially shut off the signaling through the overall Hedgehog pathway. The key driver of idiopathic pulmonary fibrosis is thought to be the Hedgehog pathway, which is overactive for some unknown reason and ends up driving the activation and proliferation of myofibroblasts, which are the responsible cell in the lung, which lays down extracellular matrices, pulls the lungs into an abnormal configuration, and ultimately leads to progressive disease in lung fibrosis.

Clinical trials often have unexpected results. What surprised you most about the phase 2a trial results for ENV-101, and will those surprises inform the design of future trials?

I think we were surprised on multiple fronts and really from the efficacy and effects on lung fibrosis. Over just a short period of time of 3 months, we saw dramatic improvements in lung function as well as dramatic reductions in fibrosis that was measurable on the chest CTs in these patients—something that had not been shown previously. So I think it really kind of over exceeded our expectation by quite a bit.

The safety and tolerability I think we're pretty much what we expected because this drug is part of a class of agents that is approved for the treatment of certain types of cancer. They've seen similar side effects, which are mostly about tolerability, not really about true safety events.

Were there any observed side effects, and how do they compare with current treatment options for IPF?

The most common side effects were those associated with a class of hedgehog inhibitors which includes loss of taste or altered taste called dysgeusia. We have some patients who have some alopecia, so thinning or loss of some hair. Finally, there's a number of patients that end up having some muscle spasms and cramps.

Overall, this is a very different safety profile from the approved agents of nintedanib and pirfenidone which really focused on [gastrointestinal] tolerability—so, nausea and diarrhea, are real big problems in those patients—as well as rash and even sometimes elevations in liver enzymes, which can necessitate discontinuation of those medications.

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