In AD Biologics Debate, Therapy Choice Is Just Half of the Battle

Capping off a special day-long dermatology program, 2 specialists in pediatric allergy and immunology and a lone dermatologist held a lively and spirited “debate” about the preferred treatment for atopic dermatitis (AD) during this year’s American College of Allergy, Asthma & Immunology Scientific Meeting.

With several new AD treatments on the horizon in the year or two ahead, the late-afternoon session called “Battle of the Biologics” discussed the pros and cons of the biologic dupilumab (Dupixent) vs the oral class of drugs known as Janus kinase 1 (JAK1) inhibitors.

Both presenters, one making the case for dupilumab and the other for JAK inhibitors (both of whom have received honoraria or consulting fees for the drugs mentioned), were challenged at the end to figure out how to present these concepts in an average 7-minute clinic visit with their patients, assuming they practiced shared decision-making.

The Case for Dupilumab

Mark Boguniewicz, MD, FACAAI, pediatric allergist and immunologist at National Jewish Health, began the discussion with what he viewed as the most positive benefits of dupilumab (Dupixent) over JAK inhibitors, which include attacking the underlying type 2 inflammation in not only AD but also asthma and chronic rhinosinusitis with nasal polyposis.

Dupilumab, an injectable biologic that works on the interleukin 4 (IL-4) and IL-13 pathways, is also being studied in eosinophilic esophagitis; last week, drugmakers Regeneron Pharmaceuticals and Sanofi announced the biologic met primary end points in a phase 3 trial for that use.

He quickly reviewed findings from a recently published study, of which he was lead author, that assessed dupilumab's impact on asthma and sinonasal conditions in adult patients with moderate to severe AD in 4 randomized, double-blinded, phase 3 placebo-controlled trials.

In LIBERTY AD SOLO 1, SOLO 2, CHRONOS, and CAFÉ, 2444 patients received placebo, dupilumab 300 mg every 2 weeks, or dupilumab 300 mg weekly. In CHRONOS and CAFÉ, patients received concomitant topical corticosteroids.

In the studies, 83% had 1 or more atopic diseases besides AD; 30% had asthma and 48% had sinonasal conditions.

Besides evaluating AD signs and symptoms, the post hoc analysis also assessed Asthma Control Questionnaire-5 (ACQ-5) scores in those with asthma; the Sino-Nasal Outcome Test-22 (SNOT-22) scores were used to assess patients with sinonasal conditions.

Results showed that dupilumab worked on all 3 diseases simultaneously. At week 16, ACQ-5 scores improved by 0.27 for placebo and 0.59 for dupiliumab; SNOT-22 scores improved by 5.1 for placebo and 9.9 for dupiliumab.

Results were similar for patients with AD and both conditions, said Boguniewicz.

Getting to one of the main points of the debate—safety—Boguniewicz noted that unlike some JAK inhibitors, there is no “black box” warning about the possible risks of cancer, infections, or cardiovascular effects.

“The label says no lab requirements, so we don't have a scary box warning like some other treatments, and that's really important when you sit down and do that shared decision-making with your patients because you don't have to spend, not just that clinic time, but certainly the next patient and the next patient and the next patient time trying to explain to your patient about the warnings and precautions that some of the other treatments are likely to have,” he said.

The Case for JAK Inhibitors

Boguniewicz was followed by Jonathan Silverberg, MD, PhD, MPH, associate professor of dermatology and director of clinical research and patch testing, George Washington University School of Medicine and Health Sciences.

Asking that Boguniewicz’s slides be returned to the screen, Silverberg ran through them to present the case for oral JAK inhibitors, which work on more pathways than dupilumab; besides IL-4 and IL-13, they also target IL-22, IL-31, interferon gamma, and possibly others.

The first JAK inhibitor for AD, ruxolitinib cream, was approved in September by the FDA. Oral therapies are still under investigation; this summer, the FDA did not meet a July approval date for Pfizer’s abrocitinib (PF-04965842). Other potential therapies include baricitinib (Incyte and Lilly) and upadacitinib (Abbvie).

“You can do almost anything with them because of the tremendous flexibility,” Silverberg said of the drugs. “We expect a deeper response by targeting more cytokines.”

In addition, JAK inhibitors work faster than dupliumab, sometimes within hours compared with a week or weeks later, Silverberg said.

Another shift that has come about in trials of these small molecule inhibitors, he said, is to aim for helping patients become itch free instead of just seeing their itch reduced, or being 100% clear of lesions instead of just 75% clear.

"Why should we settle for partial response?" he asked.

While safety concerns are real, Silverberg also said he thought that some were “overblown” particularly in the short-term, up to 16 weeks, as studied in the trials. Long term, they can be managed, such as through dose reductions or even drug holidays, he said.

But What About Patients?

However, both Boguniewicz and Silverberg were leaving out another important part of the discussion, said the clinician who wrapped up the session.

“I am here to represent our patients,” said David R. Stukus, MD, FACAAI, a professor of clinical pediatrics in the Division of Allergy and Immunology and director of the Food Allergy Treatment Center at Nationwide Children's Hospital in Columbus, Ohio.

Using the example of biologics for asthma by referring to a 2019 review article, Stukus said the field has been here before, and made a few points:

• The current pricing structure for these therapies is not cost effective. “You must seriously consider a drop in the price,” he suggested.
• In asthma, clinicians should use biomarkers before starting biologic therapy and to monitor response to treatment. “Are we there yet with atopic dermatitis? I would argue no," he said.
• While clinicians may have issues with the analyses performed by the Institute for Clinical and Economic Review, Stukus implored the audience to be “thoughtful” about how they prescribe these therapies; as allergists, they are already not as thoughtful as they should be when using biologics for asthma in terms of selecting the right patients and conducting monitoring, he said.

Comparing asthma and AD, he noted that patients with AD, while having similar quality-of-life issues, are not having hospitalizations or emergency department visits in the same way as patients with asthma, making the case for cost-effectiveness with these newer therapies even more important.

“The fight is just now beginning on behalf of our patients,” he said.

Furthermore, he challenged Boguniewicz, Silverberg, and the audience to think about how they would go about explaining all of these factors that go into a treatment choice via shared decision-making with a patient on a busy clinic day.