Work Stops on Fezagepras, or PBI-4050, as Potential IPF Treatment

Liminal BioSciences is stopping the clinical development of its investigative oral therapy fezagepras (PBI-4050) for idiopathic pulmonary fibrosis (IPF), based on interim pharmacological data from a Phase 1 clinical trial testing it at ascending doses in healthy volunteers.

The decision comes less than a month after the company announced plans to launch a Phase 2 trial in early 2022 to test fezagepras in people with IPF.

While Liminal, formerly known as Prometic Life Sciences, did not fully disclose the reasons behind this decision in its press release, the company stated that no dose-limiting adverse events or other potential safety concerns related to the experimental therapy were observed to date.

Fezagepras is an anti-inflammatory and anti-fibrotic small molecule that works by modulating the activity of multiple receptors, including FFAR1 and PPAR alpha , that are involved in metabolic, inflammatory, and fibrotic (scarring) processes.

Previous studies in mouse models of pulmonary fibrosis showed the experimental therapy reduced the levels of scarring-promoting molecules, resulting in a significant alleviation of the disease. Fezagepras was also shown to regulate several cell types involved in fibrosis.

These positive preclinical data prompted the launch of an open-label, Phase 2 clinical  trial (NCT02538536) that evaluated fezagepras’ safety and effectiveness in 40 IPF patients, ages 40 and older.

Participants recruited at six Canadian sites received four oral capsules of fezagepras (200 mg each) daily for three months. One group took fezagepras by itself, another in combination with Esbriet (pirfenidone), and the third in combination with Ofev (nintedanib). Both Esbriet and Ofev are approved oral treatments for IPF.

Results from the trial, completed in January 2017, showed that patients receiving fezagepras alone or in combination with Ofev had stable lung function after three months. In contrast, a significant progressive decline in lung function was seen in those taking fezagepras plus Esbriet.

Fezagepras was generally well-tolerated, both when given alone or as part of a combination therapy.

The investigational therapy also had a favorable pharmacokinetic profile (the therapy’s movement into, through, and out of the body), except when combined with Esbriet, where it appeared to degrade faster. This likely indicated the two treatments interacted in a way that lowered their effectiveness, potentially explaining the lack of benefits seen for this specific combination.

In December 2020, Liminal launched a placebo-controlled Phase 1 clinical trial (NCT04695041) in the U.K. to evaluate the safety, tolerability, and pharmacokinetics of multiple ascending doses of fezagepras in healthy volunteers.

The goal was to test daily dose exposures higher than those evaluated in previous Phase 2 trials, specifically doses ranging between 1,200 to 2,400 mg, administered in the form of oral capsules taken between one to three times daily for 14 days.

Results were expected to guide selection of fezagepras’ optimal dose and dosing frequency for anticipated future trials, including a proof-of-concept Phase 2 trial in IPF patients.

Now, based on an initial analysis of the trial’s interim pharmacokinetic data, Liminal decided to stop developmental work on fezagepras in treating both IPF and hypertriglyceridemia.

Hypertriglyceridemia is a condition characterized by increased blood levels of triglycerides, the most abundant fatty molecules in the body. A Phase 1/2 trial in people with this condition was also planned for next year.

Liminal will continue to evaluate the trial’s results until its completion, and will decide on its next steps and other potential indications for further development of fezagepras once the full data becomes available.

Fezagepras was designated an orphan drug in both the U.S. and Europe, and given fast track designation in the U.S. for the treatment of IPF. All are meant to speed its development and regulatory review.