Major , Jonathan I. Silverberg, MD, PhD, said during a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations that had been slated for the annual meeting of the American Academy of Dermatology, which was canceled due to the COVID-19 pandemic.
Dr. Jonathan I. Silverberg
“In the next 2-3 years, we may have nine new treatments approved for atopic dermatitis,” said Dr. Silverberg, director of clinical research and contact dermatitis at the University.
All nine medications he discussed are either in ongoing pivotal phase 3 randomized controlled trials or have completed their phase 3 developmental programs. “This is not theoretical; these are things you’re going to be using in your toolbox imminently,” he stressed.
Oral JAK inhibitors
The Janus kinase (JAK) pathway is the intracellular signaling mediator that interacts with extracellular inflammatory cytokines, including interleukin-4, -13, and -31, which are familiar to dermatologists because they’re targeted by potent biologic monoclonal antibody therapies. For example, IL-4 goes through JAK1 and 3, while IL-31 signals through JAK1 and 2.
“You really need to know the key JAK and STAT pathways involved in atopic dermatitis because it will help you determine the selectivity of the agents you’re going to be using,” the dermatologist advised.
Three oral, once-daily JAK inhibitors – abrocitinib, upadacitinib, and baricitinib – are in an advanced stage of development.
“Upadacitinib and abrocitinib may be the two most potent options coming to market soon for us to be thinking about,” Dr. Silverberg said.
Abrocitinib: Three positive phase 3 studies featuring this selective JAK1 inhibitor have been completed in adults with moderate to severe atopic dermatitis (AD). The most recent, JADE COMPARE, featured a head-to-head randomized comparison of abrocitinib and the injectable IL-4/IL-13 inhibitor dupilumab. The results of this 837-patient study haven’t yet been formally presented at a conference because of the COVID-19 pandemic. However, Pfizer recently announced that abrocitinib at 200 mg/day achieved significantly greater improvements than dupilumab (Dupixent) in the coprimary endpoints of skin clearance as reflected in an Investigator’s Global Assessment (IGA) score of 0 or 1 (that is, clear or almost clear) and disease extent based upon 75% reduction from baseline in Eczema Area and Severity Index (EASI 75) at 12 weeks. The same was true at 16 weeks.
Also, a significantly larger proportion of abrocitinib-treated patients achieved at least a 4-point reduction in itch severity as measured using the Peak Pruritus Numerical Rating Scale at week 2. The company plans to file for regulatory approval later this year.
The JADE COMPARE data are exciting because of a pressing unmet need for treatment options that are even more powerful than dupilumab, Dr. Silverberg said.
Upadacitinib: This is selective JAK1 inhibitor is not as far along in the developmental pipeline as abrocitinib, but the efficacy appears to be comparable. In a phase 2 study of 126 adults with moderate to severe AD, upadacitinib at the top dose of 30 mg/day achieved efficacy results Dr. Silverberg deemed “quite extraordinary,” with a rate of IGA score of 0 or 1 of 50% at 16 weeks and an EASI 75 response rate of 69%. Those findings numerically eclipsed results seen in an earlier phase 3 pivotal trial for dupilumab, in which the IGA 0/1 rate was 37% and EASI 75 was 48%, albeit with the caveat that cross-trial comparisons must be taken with a large grain of salt.
Baricitinib: Multiple phase 3 studies of this JAK 1/2 inhibitor have reported positive results. At the top dose of 4 mg/day, baricitinib appears to be less effective than dupilumab in its earlier pivotal trials.