Exploring Nerandomilast's Value in the Complex IPF Treatment Landscape

Idiopathic pulmonary fibrosis (IPF) remains a challenging and progressive disease with significant unmet needs and high mortality rates, despite the availability of 2 approved antifibrotic treatments. In this interview, Martin Kolb, MD, PhD, professor of medicine at McMaster University, delves into the complexities of IPF treatment and explore how nerandomilast, a new PDE4B inhibitor, could offer a valuable alternative by targeting different pathways involved in disease progression.

According to Kolb, “by adding blockage of a different pathway to the ones that we currently block, we might achieve, hopefully, a more profound impact on disease progression.”

Kolb also serves as a pulmonary physician and director of research at the Firestone Institute for Respiratory Health at St. Joseph’s Healthcare, as well as Jack Gauldie Boehringer Ingelheim Chair in Interstitial Lung Disease.

Transcript

What are some of the challenges and unmet needs in treating IPF?

IPF is by definition a progressive disease, and the untreated mortality rate is about 40% to 50%. Now, we have 2 antifibrotic drugs available which have clearly had an impact on many people, but not all. On average, there's still quite a few people who either don't tolerate the drugs or they just partially respond or they don't respond at all, that's why the overall survival rate is still way worse than what we like to see. So, there is a big need to get drugs that help on top of existing drugs, and drugs that are alternatives to the ones that we have because they are not tolerated or they don't work. So, there's a lot of need for this field.

How does nerandomilast differ from current antifibrotic treatments, and what are some advantages of its mechanism of action?

It's a PDE4B inhibitor, and I'll emphasize a few differences. One is that we have worked with PDE4 inhibitors for a while for other diseases, and that means there is a pretty solid understanding of the safety of this drug class. PDE4B is something that is less expressed in the intestinal system, which means things like diarrhea are probably less of a problem for this PDE4B instead of the PDE4 inhibitors.

It affects 2 elements in wound healing. The one is fibrosis, so it interferes with fibroblast proliferation and scar formation driven by fibroblasts for one, and the other part is that it also has a built-in anti-inflammatory effect. And we know that, while IPF is not the prototypical inflammatory disease, there is still some kind of immune activation going on, and it would certainly be a little bit different to other antifibrotic drugs that primarily focus on the fibrosis only. It's still mainly an antifibrotic drug from the concept that we pursue here, but it has a few added elements that could become beneficial, particularly for diseases that have a concomitant inflammatory component such as progressive pulmonary fibrosis.

Why is it challenging to treat IPF with a single drug, and how might nerandomilast contribute to the treatment of this disease?

It's a complex disease, and 1 drug will never hit it all. There are different components and they are active at different times in an individual patient's journey; they are different in the different spaces of the lungs. You may have areas that have one biology more active, and other areas a different one, so it's unlikely that one single drug will ever have a profound impact on all patients because it's such a kind of multifaceted biology.

I wouldn't necessarily say that nerandomilast and that pathway that's targeted is better than the others—we'll have to find out with the clinical trials—but it certainly is different from the others, and that's why it is valuable, similar to other approaches currently, because it's not a biology that is currently catered to by pirfenidone or nintedanib. So, it's different and makes it valuable, and you would hope that by adding blockage of a different pathway to the ones that we currently block, we might achieve, hopefully, a more profound impact on disease progression.