Shifting the Treatment Paradigm of Severe Asthma With Novel Biologics - Episode 13

PATHWAY/NAVIGATOR Trials for Tezepelumab

, , ,

Geoffrey Chupp, MD, and Nicola Hanania, MD, MS, review the phase 2 PATHWAY trial and the phase 3 NAVIGATOR trial details for tezepelumab in patients with severe, oral corticosteroid-dependent asthma.

Reynold Panettieri, Jr, MD: Geoff, how about you tell us a little bit about NAVIGATOR, the 2 patents of pathway trial, and some of the pivotal trial data that it’s reading out? It’s an exciting time, and these are ringing out in our international conferences very shortly. Could you punctuate some of those, Geoff?

Geoffrey Chupp, MD: Yeah. I think that the PATHWAY and NAVIGATOR trials were part of the anti-TSLP [thymic stromal lymphopoietin] pivotal trial program. Both were published in the New England Journal of Medicine as recently as 2 days ago for the NAVIGATOR study. Phase 2 of the PATHWAY study looked at patients with severe uncontrolled asthma. But as the criteria that we’ve discussed—regardless of their biomarker, phenotyping, as T2 [type 2 asthma] high or low T2—data shows really robust reductions in exacerbation rates over the course of the trial. What was very exciting about this trial, which has held up in NAVIATOR for the first time for a biologic, is that patients with both high T2 and low T2, by biomarker status, have very strong responses in terms of exacerbation reduction. So there’s less of a stratification by both blood eosinophil levels and FeNO [exhaled nitric oxide] in the patient’s response to the drug in terms of exacerbation reduction. I think it makes sense, from a mechanistic standpoint, because of the broader effects that TSLP has on both T2 and non-T2 inflammatory responses, to expect this response in the clinic. It holds up very nicely in both PATHWAY as well as NAVIGATOR. The other nice thing, as you discussed with blood eosinophil levels, is that we see biomarkers decrease with treatment of the drugs. For example, FeNO levels drop very nicely after treatment.

Reynold Panettieri, Jr, MD: One of the fascinating stories is when you’re on teze [tezepelumab], IgE levels drop. If you don’t use it, you can’t use IgE as a biomarker—pharmacodynamic biomarker, of course—with the use of reslizumab [Cinqair]. But you can see a decrease with teze and the filament. What we’re seeing now is this effect on the allergic phenotype, which is quite interesting, I think, and certainly valuable. Nic, were you excited by the New England Journal of Medicine paper?

Nicola Hanania, MD, MS: Absolutely. I think this type of target may open new doors for patients who we have in our clinic at Baylor College of Medicine in Houston, Texas, with borderline or 92-type inflammation. Even in those patients who are already on biologics that are targeted to inflammation are not doing well or not responding. And then some are naive. I see that there are 3 patient populations that, such as tezepelumab, may work. Obviously, we need to start doing it because real-life studies, as you know, are much more informative than clinical trials. I believe that there’s good, robust data on efficacy and safety in that type of patient population by just looking at the data from clinical trials. It’s a broader biologic than the ones we have right now. Obviously, there’s still room for all of these biologics to be used. The big question, the big elephant in the room, is: Who do we start first? Which one? Going back to our previous discussion, do we need to phenotype if this drug works in both using affiliate monies and affiliate allergic, non-allergic? Or why bother? I don’t know if we’re still there or if we’re there yet. But I think it’s a very interesting advancement to what we have right now.

Reynold Panettieri, Jr, MD: I think surprisingly, in their trial, when you look at the oral corticosteroid ability of teze, there were arithmetic directions to outcomes that made sense. But they didn’t quite hit the 0.05 significance. That appeared to be because the placebo responded to treatment. These are tricky studies. Aren’t they, Sid?

Sidney Braman, MD: Yeah. I think so. I talked to the company a couple of weeks ago, and they expressed the same frustration. But I thought that in future studies, they may be larger numbers. It may come out. But I don’t think that’s going to be a big negative. I don’t think we’re not going to use a drug because of a trial that didn’t show the immediate response that they’d hoped for. 

Reynold Panettieri, Jr, MD: Yeah. I’ll go back to what Nic had said. The real-world evidence where you’re going to take the drug and put it into other patients that aren’t homogeneous regarding their attributes, really tells the tale that the stewards vary. That may not get onto the label unless they do it vs placebo. On the other hand, from real-world experience, I know for a fact that with the use of omalizumab [Xolair], I was able to spare people of corticosteroid burden. Now it’s not in the label.

Nicola Hanania, MD, MS: The other issue, Rey, is the medication’s efficacy on comorbidities. Obviously, we want to see more data on atopic dermatitis, nasal polyps, and chronic rhinosinusitis. As I mentioned earlier, 1 of the decision-making factors in my mind is to look at the whole picture—not just the asthma. Most asthmatics with severe disease have other teaching comorbidities that I would like to target. I think it would be nice to see what happens to patients with those comorbidities targeting TSLP.

Reynold Panettieri, Jr, MD: Thank you for watching this HCP Live® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your inbox. It comes to you wherever you’re at: on your phone, in your office, or in your home. I want to thank everyone and our sponsors for this wonderful opportunity. Have a wonderful day and be safe. Thank you.

Transcript Edited for Clarity