Shifting the Treatment Paradigm of Severe Asthma With Novel Biologics - Episode 12
Nicola Hanania, MD, MS, and Sidney Braman, MD, discuss tezepelumab as an emerging biologic suitable for patients with both T2 and non-T2 driven asthma.
Reynold Panettieri Jr, MD: Let’s transition. The alarmin cytokines was a perfect setup. TSLP, IL-33, IL-25: these are cytokines, liberated by the epithelium after injury—virus, toxic, allergic—that then rain down into the effector cells. I imagine that epithelial muscle interaction really doesn’t need other players, because many of these receptors are found on the muscle. You could have an uncoupling of airway inflammation from asthma, or airway hyperresponsiveness or bronchoconstriction, which wasn’t really recognized before. Everything was felt to be but IL-33 or TSLP can directly affect the muscle and excitation-contraction coupling [actin and myosin binding]. I don’t need another immunocyte to transmit that signal. Nic, do you want to discuss tezepelumab? This is really exciting. This is a new biologic. It’s not out. It’s still in development, but the phase 3 trials are going on and they’re encouraging. What excites you, Nic?
Nicola Hanania, MD, MS: Everything you said excites me. This light at the end of the tunnel for these patients that we see every day keeps us going and keeps the hopes up. We talked about smooth muscles, which also is something that is of interest to me. But another very important structural set of cells in the airway that has been focused on is the airway epithelium. The airway epithelium is like the scene of the crime. The exposures—allergen, microbes, smoke, pollutants—are the first hit to the airway, so the airway epithelium has been the focus of potentially new drugs. Because of this, alarmins—these are the cytokines you mentioned, Rey—including the thymic stromal lymphopoietin, which is TSLP, interleukin 33, and interleukin 25. These are the alarmins, which are important epithelial cytokines that drive inflammatory cascade down to the different pathways that we talked about: not only the T2 pathway but the non-T2 pathway. In fact, emerging data suggest that TSLP can play a key role in not only allergic inflammation but eosinophilic inflammation and, potentially, neutrophilic inflammation.
Which really makes you think, “Why do we even need to phenotype? We give this blanket type of block, this type of cytokine.” Tezepelumab is 1 of these more advanced monoclonal antibodies that blocks TSLP. There are several others: anti–IL-33, inhaled TSLP. Tezepelumab is an injectable subcutaneous monoclonal antibody that’s given for patients with severe asthma, in the hope that it blocks T2 inflammation. We’re going to talk more about clinical trials. Some of these clinical trials show that it blocks non-T2 signals as well. It’s certainly something that has been a long time in the making, and I’m hoping we’ll see the clinical outcomes, at least in our clinic. We know there are clinical studies that suggest that tezepelumab is good in its efficacy and safety.
Reynold Panettieri Jr, MD: Sid, any comments on Nic’s observations?
Sidney Braman, MD: Yeah. One other thing that we know about asthma is that if there’s a virus around, and they catch that rhinovirus, or respiratory syncytial virus, or even severe influenza, they’re going to have an exacerbation. It’s really well known that the virus stays around in the nose and throat longer. The viral shedding lasts much longer. We know that not only are the viral symptoms worse, but this causes more severe exacerbations. We also know that these viruses attack the epithelium. This is really 1 of the exciting aspects of the alarming story—the antialarming, like the anti-TSLP. Will they begin to show some effect on the other viral-induced respiratory exacerbation of asthma? There’s probably some reason to think so.
Reynold Panettieri Jr, MD: Yeah. The concept of the viral-mediated or toxic-mediated airway inflammation, which then extends exacerbations, is relatively straight insensitive too. We use steroids, of course, with an exacerbation. Don’t get me wrong, but these are not the ones that are weakly resolved; not like a typical allergic exposure exacerbation. Those people really respond to steroids quickly. We see the viral, or the toxicant, patients languish a bit as we eventually get bored treating them with steroids and we taper them off. So you raised some really important points.
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Transcript Edited for Clarity