BI 1015550 Slows IPF Lung Function Decline in Phase 2 Clinical Trial

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Boehringer Ingelheim’s experimental oral therapy, BI 1015550, slowed lung function decline in people with idiopathic pulmonary fibrosis (IPF), regardless of whether they were receiving approved anti-scarring therapies, according to final data from a Phase 2 clinical trial.

“As the global market leader in pulmonary fibrosis, we have the ambition to go beyond slowing down disease progression and hope to one day provide a cure for this chronic debilitating condition,” Carinne Brouillon, member of the board of managing directors and head of the Human Pharma unit at Boehringer Ingelheim, said in a press release.

“The Phase 2 results reinforce our confidence in BI 1015550, which will be accelerated into a pivotal Phase 3 program,” Brouillon said.

The upcoming Phase 3 trial (NCT05321069) is expected to start in August and enroll up to 642 adult patients, ages 40 and older, without exacerbations, or sudden episodes of disease worsening, in the three months prior. Clinical site locations have not yet been disclosed.

“We will work with regulatory agencies and scientific communities to potentially bring the next generation of treatments to people living with pulmonary fibrosis as quickly as possible,” Brouillon said.

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The Phase 2 trial’s findings were detailed in the study, “Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis,” published in The New England Journal of Medicine. They were also recently presented at the 2022 American Thoracic Society (ATS) International Conference in San Francisco, May 13–18.

BI 1015550 is an orally available molecule designed to specifically block the activity of phosphodiesterase 4B (PDE4B), an enzyme involved in inflammation. PDE4B suppression has been associated with anti-inflammatory and anti-scarring, or anti-fibrotic, effects.

As such, BI 1015550 may help reduce the fibrosis and inflammation that mark IPF and other progressive fibrosing interstitial lung diseases (ILDs). ILDs are a group of more than 200 diseases characterized by progressive lung tissue scarring.

Early this year, the therapy received breakthrough therapy designation for IPF from the U.S. Food and Drug Administration (FDA), which is expected to speed its clinical development and regulatory review.

A Phase 2 trial (NCT04419506) evaluated BI 1015550’s safety and effectiveness with IPF, alone or combined with approved anti-fibrotic therapies, in 147 IPF patients, ages 40 and older. Eligible patients had a forced vital capacity (FVC) of at least 45% of the predicted value and no IPF exacerbation within the previous four months.

FVC is a lung function measure that refers to the maximum amount of air a person can forcibly exhale after a deep breath.

Participants, recruited at 90 sites across 22 countries, were randomly assigned to receive oral tablets of either 18 mg of BI 1015550 or a placebo, taken twice daily for 12 weeks (about three months). Patients were separated based on their background use or no use of approved anti-fibrotic therapies.

The study’s main goal was to assess FVC changes. Safety was evaluated as a secondary goal through the percentage of patients with side effects during the treatment period and one subsequent week of follow-up.

Most patients were men with a mean age of about 70. The patients who had used anti-scarring therapies had lived with an IPF diagnosis for about two years longer and had a lower FVC (about 70% vs. 80%) than those not using such medications.

Results showed the trial met both its goals, with BI 1015550 being superior to a placebo at preventing or slowing lung function decline, and being generally safe and well tolerated.

Specifically, BI 1015550-treated patients not on approved anti-fibrotics showed a median increase of 5.7 mL in FVC after three months, while those on a placebo experienced a 81.7 mL reduction — corresponding to a difference of 88.4 mL.

A slightly milder effect — a group difference of 62.4 mL — was observed for patients already taking anti-scarring therapy, with those given BI 1015550 showing a 2.7 mL in FVC increase and those on a placebo having a 59.2 mL drop.

In both patient groups, the probability of BI 1015550 being superior to a placebo at slowing worsening lung function was greater than 98%.

The proportion of patients reporting any side effect was higher with BI 1015550 than with a placebo, regardless of background use of anti-fibrotic therapy. However, the rates of serious or severe side effects were similar between the BI 1015550 groups and the placebo groups.

The most frequently reported side effect was diarrhea, which was most commonly mild in severity. No new safety concerns were identified.

A total of 13 patients, 10 of whom were on antifibrotic therapies, discontinued BI 1015550 treatment due to side effects, most commonly gastrointestinal problems.

While the combination with approved anti-fibrotic medications “seems to be feasible despite an overlap in the gastrointestinal side-effect profile,” a comprehensive characterization of BI 1015550’s safety profile, alone or as combined therapy, “in a larger patient population over a longer duration in a phase 3 trial is warranted,” the research team wrote.

There were two deaths during the study, one related to COVID-19 and the other thought to be associated with an IPF exacerbation and vasculitis (blood vessel inflammation), but this was not confirmed by an independent monitoring data committee.

Given that PDE4 suppressors have been previously linked to vasculitis, “it will be important to evaluate vasculitis as an adverse event of special interest in phase 3 trials of BI 1015550,” the researchers wrote.

“These encouraging, early data showed treatment with BI 1015550 slowed the rate of lung function decline in patients who were not on approved antifibrotics, as well as those who were taking existing antifibrotic therapy,” Luca Richeldi, MD, PhD, the trial’s principal investigator, said. Richeldi is a professor of respiratory medicine at the Catholic University of Sacred Heart, in Rome, Italy.

Boehringer Ingelheim also plans to launch another Phase 3 trial (NCT05321082) to test the therapy in people with progressive fibrosing ILDs other than IPF.