Dr Paul Frohna Details Plans for Further Research on ENV-101 for IPF

The ENV-101 phase 2a trial for idiopathic pulmonary fibrosis (IPF) focused on assessing safety, lung function, and fibrosis, with plans for further trials, combination therapies, and strategies to manage adverse effects.

While at the American Thoracic Society (ATS) 2024 International Conference, Paul Frohna, MD, PhD, PharmD, chief medical officer for Endeavor BioMedicines, sat down to highlight the primary and secondary end points of the ENV-101 phase 2a trial for idiopathic pulmonary fibrosis (IPF). He also explained future research plans, which involve testing lower doses and combination therapies with standard care, addressing challenges like adverse effects through nonpharmacologic strategies, and moving forward with larger trials to replicate initial positive results and secure funding for FDA approval.

Frohna contributed to the research on ENV-101 presented at the ATS 2024 International Conference. In a prior interview, he explained the hedgehog inhibitor’s mechanism of action, results from the trial, and potential side effects of the treatment.

This transcript has been lightly edited for clarity.


What were the primary and secondary end points measured in the ENV-101 phase 2a trial?

Our phase 2a trial in IPF was a randomized, double-blind, placebo-controlled trial with the overall objective of characterizing the safety in IPF patients who weren't on the background standards of care. We've never tested this drug outside of oncology, so it was really important to understand how safe and tolerable this medication was in patients. Beyond the safety, we also looked at lung function, characterized by the forced vital capacity, as well as looking into the effects of overall fibrosis that can be quantified by high-resolution computed tomography (CT) on chest CT scans of these patients.

Are there plans to explore higher dose ranges or combination therapies with ENV-101 to potentially achieve even greater improvements in lung function?

I think our dose that we picked for the first trial—the phase 2a—was the top dose that we plan to test, and from here on forward, we plan to look at lower doses to try to maximize the benefit vs the risk in these patients. We intend to also evaluate it in combination with standard of care, so pirfenidone and nintedanib will be allowed, but that will be up to the investigators to decide on a patient-by-patient basis whether it's the right thing for those patients to continue or to switch on to ENV-101 by itself.

What are the biggest milestones and challenges that Endeavor BioMedicines anticipates on the path to commercialization of ENV-101?

I think the biggest milestone is the phase 2a trial we just completed, and having demonstrated proof of concept that's got everybody very excited about, not only us but investors and, we hope, the pulmonary fibrosis communities since we're sharing the data at ATS. And then the next phases of development is just now proving that what we saw over a 3-month trial can be replicated in a larger trial with more patients over a longer period of time. Once we get there, I think then it's just going to be an ability to raise enough money to do these very long, larger trials that the FDA requires for approval.

What strategies do you see for mitigating these adverse effects in future development of ENV-101 or similar drugs targeting the Hedgehog pathway?

Yeah, that's a good question. There are some recommended strategies that the dermatologists in the basal cell cancer field use around the altered taste. People will try different recipes; they tried zinc supplementation, which can enhance the ability of tastebuds to sense and taste foods, so we're going to try to incorporate that into the trial. For hair loss, there are some medications that are available for topical use, like minoxidil, that can be applied to reduce the appearance of hair loss. And then, with respect to muscle cramps, what's been most effective to date in our trials is just simple stretching, monitoring fluid intake, and electrolytes to ensure patients stay well hydrated because there weren't really any patients who required pharmacologic therapy for the muscle cramps. So, it's more about getting them in tune to recognize them and then modulating them with these nonpharmacologic therapies.

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