Experts debate use of dual biologics to treat severe asthma
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Key takeaways:
- Individual biologics have specific targets, including IgE, IL-4, IL-5 and TSLP, potentially complementing each other.
- Safety data on the use of multiple biologics is lacking, while cost remains a factor as well.
WASHINGTON — A debate at the American Thoracic Society International Conference changed some minds about whether providers could or should combine and overlap biologic treatments to treat severe asthma.
Before the speakers began making their cases for and against these combinations, a poll administered via the meeting’s mobile app found that 67% of the audience agreed that biologics could be combined and overlapped, whereas 33% disagreed.
The case for combination
“I think it’s doable. I think we already do it,” Monica Kraft, MD, Murray M. Rosenberg Professor of Medicine and system chair of the department of medicine at the Icahn School of Medicine at Mount Sinai, said during her presentation.
“Now, do we have data to support us? We’re in the middle of it. We’re getting some. So, we’re just in this early phase,” she continued. “I get this question all the time from people who take care of patients.”
Kraft noted that the six biologics available to treat severe asthma address different targets. Omalizumab (Xolair; Genentech, Novartis) is designed for IgE. Reslizumab (Cinqair, Teva Respiratory) and mepolizumab (Nucala, GSK) target IL-5.
Also, benralizumab (Fasenra, AstraZeneca) targets IL-5R. Dupilumab (Dupixent; Sanofi Genzyme/Regeneron) targets IL-4R alpha. Tezepelumab (Tezspire, Amgen/AstraZeneca) targets thymic stromal lymphopoietin, or thymic stromal lymphopoietin (TSLP).
“They’re all opening the airway, which is wonderful,” Kraft said. “They’re complementary to each other. It only lends itself to the concept that combining them makes sense.”
Now recruiting, PREDICTUMAB will study the magnitude and prediction of response to omalizumab and mepolizumab among adults with severe asthma. Kraft called it the first head-to-head, randomized controlled study to compare the efficacy of two biologics.
Patients eligible for both therapies will be randomly assigned to begin treatment with one of these biologics. Based on clinical response, patients will continue with that therapy or switch to the other one. The study is expected to wrap up by December 2024.
In the meanwhile, Kraft said, an algorithm is available to determine whether patients should receive a single biologic or a combination of treatments when they have asthma and a concomitant atopic disease.
“If your patient has atopic dermatitis and severe asthma, then dupilumab could be a great first choice,” Kraft said. “Potentially, if they have allergy, you may be able to treat asthma with a second biologic, depending on biomarkers, and that would be perfectly legal to do.”
Kraft also recommended mepolizumab for patients with eosinophilic granulomatosis with polyangiitis, or EGPA.
“But for nasal polyps, that’s where you can actually think about combinations,” she said.
Dupilumab is a first-line treatment for polyps, Kraft said, with omalizumab to treat childhood-onset asthma or mepolizumab to treat adult-onset asthma.
Blood eosinophil counts, fractional exhaled nitric oxide levels and sensitivities to environmental allergens may guide the use of multiple biologics among patients with asthma and comorbidities as well, Kraft continued.
“You can think about this algorithm in a patient who you have already treated for their other [type 2 inflammation-related] comorbid disease, and it’s perfectly legal to do that,” Kraft said.
However, Kraft noted that approximately 60% of patients with severe eosinophilic asthma have partial or failed responses to T2-targeted therapies because patients qualify for more than one therapy.
“We know this because blood eosinophils alone, as you saw from the algorithm, is not really a distinguisher,” she said. “There were a lot of alternative agents, so therefore they overlap in their efficacy and their function, so it makes sense to think about combining them.”
Further, Kraft described a woman with severe asthma, allergic rhinitis and severe atopic dermatitis who experienced improved outcomes with omalizumab and dupilumab.
Another woman with severe persistent eosinophilic and allergic asthma and multiple atopic comorbidities was receiving omalizumab alone for 10 years with some success before seeing greater improvements with the addition of mepolizumab, which later was switched to benralizumab.
A similar case of a man with severe persistent eosinophilic and allergic asthma with multiple atopic comorbidities saw minimal benefits with omalizumab before adding mepolizumab and then switching to benralizumab and dupilumab, tolerating these various combinations of biologics well.
In addition to improved outcomes, the second and third patients were weaned off oral steroids.
“I’d be very interested to find out how they did long-term,” Kraft said.
Kraft concluded that combined and overlapping biologics can be well tolerated while delivering improved outcomes in severe asthma. These strategies may be cost-effective as well, she added, despite the high price tags on these drugs.
“Dual biologics may actually save funds when we’re talking about entire hospitalizations, and therefore you could justify dual therapy,” Kraft said. “I hope you agree combining biologics makes sense.”
The case against combination
While there are no guidelines for combining biologics in asthma, there is some evidence against it, Praveen Akuthota, MD, ATSF, professor of clinical medicine, pulmonary and critical care medicine, University of California, San Diego, said during his presentation.
Akuthota cited a study of itepekimab (Sanofi/Regeneron Pharmaceuticals), which targets IL-33, in treating moderate to severe asthma. Percentages of patients who experienced a loss of asthma control included 41% of those on placebo, 27% of those on both itepekimab and dupilumab, 22% of those on itepekimab alone and 19% of those on dupilumab alone.
“This particular combination did not work,” Akuthota said.
These biologics may have different targets, he continued, but those targets all occupy the same space by targeting T2, which is why there was no increase in efficacy.
“These are overlapping and connected pathways, so you’re not necessarily getting much bang for your buck out of overlapping any of these agents,” Akuthota said. “Potentially even more modern strategies like anti-TSLP and anti-IL-33 strategies.”
As a result, Akuthota continued, the Global Initiative for Asthma and National Asthma Education and Prevention Program guidelines have not recommended combining or overlapping biologics to treat asthma.
Despite their apparent success, Akuthota said, there was nothing in Kraft’s studies explicitly recommending the use of dual biologics. Meanwhile, he continued, other algorithms for choosing a biologic to treat asthma only use one biologic at a time.
In addition to the costs involved with multiple biologics, Akuthota called safety a concern as well, especially since the study on itepekimab only had 73 or 74 patients in each of its subgroups.
“I don’t think that’s really enough to make any major decisions,” Akuthota said, adding that overall, safety remains a major unknown in combining biologics.
As a result overall, Akuthota said, he concluded that providers should not use dual biologics to treat asthma.
“There’s a lack of evidence,” he said. “Targets are overlapping. Major guidelines don’t support it. It costs a ton, and there’s safety unknowns.”
The final vote
Once the debate concluded, 42% of the audience agreed that biologics could be combined and overlapped in treating severe asthma, and 58% disagreed.