Upadacitinib Clears Atopic Dermatitis Faster Than Dupilumab

Laird Harrison

April 23, 2021

An oral Janus kinase 1 (JAK1) inhibitor, upadacitinib (Rinvoq), relieves the symptoms of atopic dermatitis (AD) better than dupilumab (Dupixent), researchers say.

"The differences between the two drugs were more pronounced when we looked at higher levels of improvement," said Andrew Blauvelt, MD, MBA, president of the Oregon Medical Research Center, in Portland, Oregon.

Upadacitinib also causes a different set of adverse reactions than dupilumab, he told Medscape Medical News.

Blauvelt presented the findings from the Heads Up trial at the International Society of Atopic Dermatitis (ISAD) 2021 Annual Meeting.

The results of the phase 3 study suggest that upadacitinib, if approved for AD, will provide clinicians with another treatment option for patients who don't get adequate relief from either topical medications or dupilumab or who find these treatments difficult to use.

In 2017, dupilumab became the first systemic drug approved by the US Food and Drug Administration (FDA) specifically for AD, although systemic steroids and other immunosuppressant drugs are sometimes prescribed. A monoclonal antibody delivered by subcutaneous injection, dupilumab binds to interleukin-4 (IL-4) receptors to block signaling pathways involved in AD. It is now approved for treatment of patients aged 6 years and older who have moderate to severe AD.

Upadacitinib is a small molecule that inhibits JAK1, which is thought to modulate multiple cytokines involved in AD, including IL-4, IL-13, IL-31, IL-22, and thymic stromal lymphopoietin. Two other JAK1 inhibitors, baricitinib and abrocitinib, are also being investigated as systemic treatments for AD.

In 2019, upadacitinib received FDA and European Commission approval for the treatment of rheumatoid arthritis at a dose of 15 mg once daily. Phase 3 trials of upadacitinib in atopic dermatitis, rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, Crohn's disease, ulcerative colitis, giant cell arteritis, and Takayasu arteritis are ongoing.

In Heads Up, the researchers randomly assigned 344 adults with moderate to severe AD to receive dupilumab and 348 to receive upadacitinib. Patients taking upadacitinib received 30 mg once daily. Patients who received dupilumab received an initial dose of 600 mg at the baseline visit followed by 300 mg every other week. The patients who received dupilumab also took placebo pills; those who received upadacitinib were also given placebo injections.

More of the patients who received upadacitinib experienced improvements by every measure used, including an Eczema Area and Severity Index (EASI-75) response (defined as an improvement of at least 75%) and Worst Pruritus Numerical Rating Scale (NRS). EASI-75 response at week 16 was the primary outcome of the study.

Table. Week 16 Outcomes

Outcome measure Dupilumab, 300 mg (n = 344) Upadacitinib, 30 mg (n = 348)
EASI-75, % 61 71
EASI-90, % 39 61
EASI-100, % 8 28
Percent change from baseline in worst pruritus NRS, % -49 -67
Worst pruritus NRS improvement ≥4, % (dupilumab, n = 336) (upadacitinib, n = 340) 36 55

"Another significant difference between the two drugs was the onset of action," said Blauvelt. "Upadacitinib worked much faster than dupilumab." At week 2 of the trial, 44% patients who were taking upadacitinib had achieved EASI-75, vs 18% of those taking dupilumab.

At week 16, the most common adverse events were acne for the upadacitinib group and conjunctivitis for the dupilumab group. Serious adverse events occurred in 2.9% of patients who received upadacitinib and in 1.2% of patients who received dupilumab.

Serious infections were reported infrequently in both treatment groups: 1.1% with upadacitinib, and 0.6% with dupilumab. One patient taking upadacitinib died from bronchopneumonia associated with influenza A.

Rates of laboratory abnormalities were higher in the upadacitinib group than in the dupilumab group, although the overall rates for lab abnormalities were generally below 5% in the upadacitinib group. Blood test monitoring is required for patients taking upadacitinib when used for rheumatoid arthritis.

"I predict there will be places in clinical practice for both drugs, given the variety of clinical scenarios that clinicians face," Blauvelt said. "For example, there may be patients very interested in taking a pill and not a shot. They may also be comfortable with blood test monitoring required for follow-up. Lastly, they may want a drug that works fast to improve their skin disease. On the other hand, there may be patients who are uncomfortable with the potential side effects of upadacitinib and want to go on dupilumab, which does not require blood tests."

An advantage of upadacitinib that is becoming clear from this and other studies is its versatility, Jonathan I. Silverberg, MD, PhD, MPH, associate professor of dermatology and director of clinical research and contact dermatitis at George Washington University, Washington, DC, said in an interview.

Because the drug is likely to be available in both 15-mg and 30-mg doses, has a quick onset, does not affect immunogenicity as much as dupilumab, and is taken once per day, it might be used in a variety of ways, he said. A low dose can be used initially to avoid side effects. The dose can then be increased if patients need it. Alternatively, a high dose may be used initially to quickly control symptoms, after which a lower dose can used for maintenance.

"That really allows us to tailor therapy to the individual needs of patients," he said. "And that's an exciting concept. But of course, with all of that, we have to factor in this issue of the risk-benefit ratio."

The study was sponsored by AbbVie. Blauvelt is a scientific consultant and clinical investigator for AbbVie Regeneron/Sanofi. Silverberg is also a consultant to AbbVie and Regeneron.

International Society of Atopic Dermatitis (ISAD) 2021 Annual Meeting: Abstract PT29. Presented April 19, 2021.

Laird Harrison writes about science, health and culture. His work has appeared in magazines, newspapers , and online publications. He is at work on a novel about alternate realities in physics. Harrison has taught writing at San Francisco State University, UC Berkeley Extension and the Writers Grotto. Visit him at lairdharrison.com or follow him on Twitter: @LairdH.

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