The Changing Treatment Landscape of IPF and PPF: Toby Maher, MD, PhD

For a decade, the standard of care for idiopathic pulmonary fibrosis (IPF) has been limited to 2 antifibrotic therapies: nintedanib and pirfenidone, each with distinct mechanisms of action and often-challenging tolerability profiles. The recent approval of nerandomilast adds a welcome third option to the armamentarium, Toby Maher, MD, PhD, professor of clinical medicine and director of Interstitial Lung Disease at the Keck School of Medicine at the University of Southern California, told The American Journal of Managed Care® (AJMC®).

Toby Maher, MD, PhD | Image credit: Keck School of Medicine

In progressive pulmonary fibrosis (PPF), nerandomilast is a promising second option, with only nintedanib previously approved for the condition. In this interview, Maher discusses each therapy's mechanism of action and how the FIBRONEER-IPF (NCT05321069) and FIBRONEER-ILD (NCT05321082) trials support the use of nerandomilast in IPF and PPF.

This transcript has been lightly edited.

AJMC: Nerandomilast is the first preferential PDE4B inhibitor for IPF. Can you explain how this mechanism differs from historic standard-of-care therapies?

Maher: With the existing 2 drugs, we have a rough idea how they work. Nintedanib is something called a multi-tyrosine kinase inhibitor. Tyrosine kinases are cell surface receptors through which growth factors like VEGF (vascular endothelial growth factor), platelet-derived growth factor, and connective tissue disease growth factor signal through. For pirfenidone, we have slightly less idea how it works, but we know it influences growth factors like TGF-β and TNF-α. Nerandomilast is a PD4B inhibitor, and we have a slightly better idea of what it's doing. We know that PD4 is an important sort of intracellular signaling mechanism that drives things like fibroblast proliferation. It drives collagen production by fibroblasts. It also has a role in inflammation and in vascular health as well. By targeting this one intracellular pathway, we know that we're having effects on multiple mechanisms that play a role in the development and progression of fibrosis.

AJMC: How should clinicians interpret the key efficacy and safety end points in the FIBRONEER-IPF trial in the context of previous landmark studies for IPF?

Maher: First off, it's worth saying this was the first positive trial in 10 years. In 2014, when we had 2 drugs approved at exactly the same time, it suddenly seemed like we'd worked out how to find new treatments for IPF. The last 10 years have reminded us how difficult it is, so I don't think we should underestimate the importance of a positive trial. Having a third option available to treat these diseases is critically important.

One key takeaway is that nerandomilast does look to be better tolerated than the 2 existing treatments, and I think that's an important step change. The other thing that's worth recognizing with the trial is that nerandomilast was, for 80% of patients, an additional treatment. It was being used on top of either nintedanib or pirfenidone, so this is the first time that we've also been able to contemplate the possibility of combination therapy for IPF.

I think the trial opens up a number of options: nerandomilast as a standalone treatment for IPF—particularly in patients who've been unable to tolerate existing treatments—or potentially as add-on therapy for patients who've deteriorated despite existing treatments. There [are] several important take-homes from the study. We now have a third treatment, we have the potential for combination treatment, and we have a drug that looks like it's better tolerated than existing treatments.

AJMC: For a newly diagnosed patient, how do you see nerandomilast fitting into the current treatment paradigm?

Maher: For a newly diagnosed patient, they now have a choice of 3 drugs, and whilst there might not be anything to separate them on efficacy, I do think the tolerability is an important step change. If money is not a problem, that would probably make nerandomilast the first choice for most patients.

AJMC: Are there any patient characteristics that make someone a particularly good candidate for nerandomilast?

Maher: We’re still digging into the clinical trial data to understand whether there are specific subgroups of patients that benefit, but I do think in the FIBRONEER-ILD study, what was very striking [were] the benefits in the secondary end points: reductions in hospitalization, acute exacerbations and death in patients with progressive pulmonary fibrosis, and when we've seen some of the subgroups presented at European Respiratory Society and other meetings, it does look like the patients with autoimmune lung disease derive particularly striking benefits in terms of those secondary end points, so maybe patients with a combination of autoimmune or inflammatory driven disease and pulmonary fibrosis may be the ones that benefit most from treatment.

AJMC: How does the safety profile of nerandomilast compare with the current standard of care, and how might this impact long-term compliance?

Maher: I've generally considered pirfenidone and nintedanib to be safe, but they do cause significant tolerability problems. Pirfenidone tends to cause bloating, upper gastrointestinal disturbance, and photosensitive rash. Nintadenib tends to cause diarrhea, particularly with fecal urgency, and, to a lesser extent, nausea; and certainly for nintedanib, we also know that there is potential for hepatotoxicity, so we must monitor liver function tests as well. With nerandomilast, we saw a slight increase in diarrhea with treatment, but we didn't see the sort of fecal urgency that we see with nintedanib, and that, in my experience—that need to go to the toilet, and if you don't go to the toilet, then accidents might happen—is what has stopped people from taking nintedanib. I'm optimistic that the diarrhea won't really be much of a problem with nerandomilast.

The need not to monitor liver function tests is also important. It's always a concern for physicians that patients might not come back for blood tests, but blood tests must be followed up and the results kept an eye on. Not having to do regular blood monitoring actually reduces the burden of treatment quite considerably.