Biomarkers in Shifting the Treatment Paradigm of Asthma - Episode 12
Thomas Casale, MD: What about pulmonary functions, FEV1 [forced expiratory volume in first second of expiration]? Do you ever use a biologic to...reduce exacerbations but also to see if this 1 works on FEV1? And if so, which ones do you think have a better response?
Stanley Goldstein, MD: Could I answer that question, Tom?
Thomas Casale, MD: You can answer any question you want.
Stanley Goldstein, MD: If you really look at pulmonary function as an endpoint, the issue is that we’re stuck getting approval for these products, and they’re all approved based upon exacerbations. At this point, if you really wanted to improve this person’s lung function and they don’t have a history of exacerbations, you’re not going to be able to use them clinically.
That brings up an important point. Are we using these biologics too late? We know...there may be better response in patients when treating them early on with the biologic if you feel they have difficult-to-treat asthma, even when they’re not having exacerbations.
If you look at the different biologics, there’s no question that there is lung function change or improvement. If you look at omalizumab, the 2 studies that were done for the pivotal studies, no significant improvement in lung function. However, one has to understand that those clinical studies were done 17-18 years ago, and the design was completely different than the studies that have been done with anti—IL-5 that came out 4 years ago. There are studies over the course of these 17 years that look at the continuum, and you do see improvement in lung function, even with omalizumab. You see ability to decrease oral corticosteroids and inhaled corticosteroids with omalizumab.
If you look at mepolizumab, it had improvement in lung function that was statistically better in their quality-of-life study, and it was mixed data with respect to the other studies.
Reslizumab, as mentioned, had a good improvement in lung function, and benralizumab also had good improvement in lung function. Related to the change in eosinophils, the higher the eosinophils, the better improvement in lung function, as you find with dupilumab. My sense is that they all work very similarly, even though the data are compartmentalized at this point in time. I think they all can result in improvement in lung function. However, it’s picking them at the right time.
Thomas Casale, MD: Geoff, do you agree with that?
Geoffrey L. Chupp, MD: I do think that there are definitely differences between the drugs in terms of their effects on lung function. As we know from the trial data, which is not head to head, there were differences between the effects, some of which suggest that receptor blockade might be better on lung function compared to soluble mediator blockade.
I am moving more and more toward thinking about lung function as a primary parameter to move patients to a biologic because I think, especially in some patients, I’ve had older patients with asthma who have some exercise limitation but don’t have a lot of exacerbations. This is a key factor in their quality of life. I’ve had good success with all agents. I think it’s definitely an important thing, and I think we know on the horizon that 1 of the major unmet needs in terms of phenotypes in asthma is irreversible loss of lung function or nonreversible decrements in FEV1. That if we can restore to normal in some of these patients, it will dramatically improve their lives.
Michael E. Wechsler, MD, MMSc: I think the response with regard to the biologics in terms of lung function is heterogeneous across patients. Some patients will have a very robust improvement in lung function, and other patients may not. I think that tells us important facts about the underlying biology in a given individual, and it may reflect in some individuals who have eosinophilic asthma the mucus that may be associated with it. Similarly, some patients may have IL-4— or IL-13–mediated asthma with mucus production in the airways, mucosal edema, airway inflammation that may be IL-13 or IL-4 driven. All these play an important role. You can target these patients with these biologic therapies and get a sense of what’s driving the underlying pathophysiology and what might be driving the decrements in lung function in that given individual. It could be multifaceted, and many different pathways could be involved in a given individual.
What we’ve seen is that the more pathways you target, the more likely you are to achieve greater benefits in terms of lung function. Similar to exacerbations, the higher the eosinophil counts, the greater the improvement in lung function if you try to ablate the eosinophils.
Transcript Edited for Clarity