Boehringer Bids To Go Beyond Slowing IPF

The family-owned German group is the market leader in idiopathic pulmonary fibrosis with Ofev but the big-selling drug has significant side effects and only slows, but does not stop, the progression of the disease. It is hoping that the Phase III-ready compound BI 1015550 will offer a significant improvement.

Source: Boehringer Ingelheim

 

Boehringer Ingelheim GmbH markets one of the two drugs approved for idiopathic pulmonary fibrosis (IPF) in Ofev but has high hopes that its new treatment could actually stop the lung-scarring disease rather than just slowing it down.

The German group has unveiled positive Phase II data at the American Thoracic Society meeting in San Francisco on BI 1015550, an oral phosphodiesterase 4B (PDE4B) inhibitor. The results, also published in the New England Journal of Medicine, showed a reduction in the rate of lung function decline in patients with IPF receiving BI 1015550 versus patients on placebo, both with or without background approved antifibrotics, namely Boehringer's Ofev (nintedanib) or Roche Holding AG's Esbriet (pirfenidone).

The primary endpoint of the trial was the change from baseline in forced vital capacity (FVC), the maximum amount of air measured in mL that can be forcibly exhaled from the lungs after fully inhaling at week 12. The median changes in FVC in patients who were not on approved antifibrotics were +5.7 mL for BI 1015550 and -81.7 mL for placebo.

In those patients already on therapy, the changes in FVC were +2.7 mL for BI 1015550 and -59.2 mL in the placebo arm. Boehringer said the data suggested there was over 98% probability that its therapy was superior to placebo in slowing down the worsening of lung function in IPF patients.

Toby Maher of the Keck School of Medicine at USC, Los Angeles, and a co-investigator on the study, told Scrip that it was "a great achievement in 2014 to have not one but two drugs approved that slowed IPF down and have genuinely made a difference. The next step forward is to try and stop the disease progressing because, unfortunately, my patients still die from IPF, even though they have access to antifibrotic drugs."

The Phase II data on BI 1015550, which was granted breakthrough therapy designation by the US Food and Drug Administration in February this year, are "very exciting and hold the prospect that we might be able to shift the dial further in an important direction," he said, noting that the key conclusion is "seeing the effect of the drug not just on its own, but also in combination with existing therapy. It's one thing to show the therapy works as monotherapy but, in reality, any new drug is going to be used in combination with existing treatments and we see a clear added benefit."

The trial also met its secondary endpoint, demonstrating that BI 1015550 showed acceptable safety and tolerability in IPF patients over 12 weeks. Diarrhoea was the most frequently reported adverse event (30.6% in patients receiving background antifibrotic and 16.7% in those not receiving it) and all of these events were reported as non-serious.

However, Mather acknowledged that "unfortunately, it seems with all these treatments that there is no free lunch and we do see the trade-off of side effects." He pointed out that "phosphodiesterase inhibitors are reasonably well known from the COPD field," where roflumilast and cilomilast are approved therapies, "but with this drug being more specific than some of the others, hopefully it's going to be much better tolerated."

In the combination groups, "it's sitting on top of Ofev and Esbriet that already cause gastrointestinal side effects, so it will be important for us to see in Phase III studies exactly how big an impact that has, that remains to be defined," Maher added. Boehringer confirmed to Scrip that the late-stage program is set to start over the summer.

He said: "If this were a trivial disease we were trying to treat, then diarrhea might be considered a showstopper for any drug. Given the IPF outcomes and how deadly the disease is, the risk;benefit analysis does change somewhat and we've had a lot of success with the existing drugs in working with patients to find ways to overcome the side effects."

Maher noted that in later phase studies, "once people have confidence that the drug actually has a positive benefit, everyone tries harder to ensure that patients stay on treatment and we find mitigation strategies. I would hope that as we learn how to use it, we may find better ways of dealing with any gastrointestinal side effects in particular and I'd be optimistic that it's manageable."

Other Phase III Assets For IPF

There is a fair bit of late-stage activity in the clinic for IPF, headed by FibroGen, Inc.'s Bristol Myers Squibb Company-partnered pamrevlumab, an anti-connective tissue growth factor (CTGF) monoclonal antibody, United Therapeutics Corporation's Tyvaso (inhaled treprostinil), which is already approved for pulmonary hypertension associated with interstitial lung disease, and Promedior, Inc./Roche's recombinant human pentraxin-2 drug RG6354.

However, there have been some high-profile setbacks in the field, notably for Boehringer itself. In November 2020, a pact with South Korea's Bridge Biotherapeutics, Inc. to develop BBT-877, a small-molecule inhibitor of autotaxin for IPF and various other fibrotic diseases, was terminated amid concerns over toxicity. Worries about toxicity also led to the termination of Galapagos NV’s same-class ziritaxestat in February 2021. (Also see "Bridge Biotherapeutics Rebounds After IPF Deal Roller Coaster Ride" - Scrip, 9 Feb, 2022.)  (Also see "Ziritaxestat Failure Could Spell End For Gilead/Galapagos Pact" - Scrip, 11 Feb, 2021.)

Maher is hoping that "as many of these drugs as possible succeed in Phase III and get through to approval. My vision of success for IPF treatment mirrors what we've seen in pulmonary hypertension, a similarly complex and deadly disease where we now see combination therapy with different drugs targeting different pathways."

With Ofev and Esbriet, "we have a fairly broad range of molecular targets without us really knowing exactly what either of the drugs is doing to have their therapeutic effect," he said. These new candidates "should open up the possibility of more personalized medicine approaches, a bit like the oncology field so we can better identify which patients are going to be responders."

Ofev is a big earner for Boehringer despite its safety issues and sales grew by 25.8% to €2.5bn in 2021. Esbriet also sells well but Roche reported Q1 2022 sales of CHF241m, down by 6% and it could decrease further very soon: Sandoz Inc. has just launched at-risk the first generic version of pirfenidone in the US, while PureTech Health plc is also advancing LYT-100, a modified version of Esbriet.  (Also see "Sandoz Launches First US Pirfenidone At-Risk After Court Triumphs" - Generics Bulletin, 12 May, 2022.)  (Also see "PureTech Takes On Roche With Improved IPF Drug" - Scrip, 6 Jan, 2022.)