Drugs to treat atopic dermatitis are at the top of the FDA’s dermatology list. Biologics and PDE4 inhibitors show promise in the treatment of AD. Approval is still needed for the use of biologics to treat AD in pediatric patients.
Dr. KircikWhen it comes to the sheer number of products in the pipeline for dermatology, targeting atopic dermatitis nearly tops the list.
“For the first time, we now will have biologics to treat moderate-to-severe atopic dermatitis,” says Leon Kircik, M.D., a clinical associate professor of dermatology at Icahn School of Medicine at Mount Sinai in New York City and Indiana University Medical Center in Indianapolis.
Dupilumab (Regeneron/Sanofi) is a monoclonal antibody that downregulates interleukin-4 (IL-4).
“This will be the first FDA-approved biologic for atopic dermatitis. IL4 and IL 13 are major cytokines that play an important role in atopic dermatitis. Dupilumab inhibits the signaling of IL4 and IL13 by blocking the IL 4 receptor alpha,” says Dr. Kircik, with an indication of moderate-to-severe atopic dermatitis in adults age 18 and older.
Dipilumab received FDA approval on March 28, 2017. (https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm549078.htm)
In an interview with Dermatology Times after his presentation on atopic dermatitis at February’s 2017 South Beach Symposium in Miami Beach, Fla., Dr. Kircik says the efficacy of dupilumab has been shown to be about 38% of patients in two Phase 3 trials achieving a score of 0 or 1 (clear or almost clear) on the 5-point Investigator’s Global Assessment (IGA).
There were two different dosing regimens: every week and every other week. “However, there was no difference in efficacy between the two cohorts,” Dr. Kircik says.
Two adverse events associated with dupilumab are injection site reactions and conjunctivitis.
“But there is also concern about exacerbation of atopic dermatitis,” Dr. Kircik notes. “Studies demonstrate anywhere from 10% to 16% of patients experience exacerbation of their atopic dermatitis. This may be an issue that requires further investigation.”
Next: Other biologics
Among the biologics in development is nemolizumab (Chugai), an IL-31 receptor antagonist, for which Dr. Kircik was an investigator for a Phase 2 study. “We now know that IL 31 is considered to be responsible for the development of pruritus in humans. This drug inhibits the itch pathway, which is very important in atopic dermatitis,” he says.
The decrease of pruritus on the visual analogue scale (VAS) was approximately 60% over 12 weeks for nemolizumab. There were also several different dosing regimens tested in the clinical study. The two highest doses -- 0.5 mg/kg and 2 mg/kg -- had similar efficacy results.
Similarly, lebrikizumab (Roche) is an IL-13 inhibitor in early phase studies. “Lebrikizumab is also being investigated for asthma, so if the drug is approved, you can kill two birds with one stone, because most children have both asthma and atopic dermatitis,” observes Dr. Kircik, medical director of Skin Sciences PLLC in Louisville, Ky.
One recently approved topical phosphodiesterase type 4 (PDE4) inhibitor to treat mild-to-moderate atopic dermatitis is crisaborole ointment (applied twice daily).
“Crisaborole is a boron-based molecule and is approved all the way down to 2 years of age,” says Dr. Kircik, who participated in all the FDA studies of the drug.
“This novel drug is going to address the concerns of parents who do not want to use topical steroids on their children because this is a nonsteroidal drug,” Dr. Kircik says.
Approximately 32% of patients achieved clear or almost clear status with a 2-grade improvement on Investigator Static Global Assessment (ISGA). The incidence of pruritus also decreased over 29 days, with 63% of patients showing an improvement in pruritus.
A second topical PDE4 inhibitor, OPA-15406 (Otsuka), is pending FDA approval. “Only Phase 2 studies are completed for this ointment (also applied twice daily),” Dr. Kircik conveys.
Two different concentrations of the drug (0.3% and 1.0%) were tested in the clinical trial. “However, only one (1.0%) of the two doses showed a statistically significant difference against the vehicle at 29 days,” Dr. Kircik says. “For the dose that did, though, the clear or almost clear rate with 2-grade improvement was roughly 20%, and just clear or almost clear rate on IGA was about 30% at day 29.”
A third topical PDE4 inhibitor, cerdulatinib (Dermavant), is an ointment as well, and is currently undergoing a Phase 2 study.
On the other hand, the oral antihistamine bilastine (FAES Farma) is approved only in Canada. “This is the only antihistamine without any sedative effect,” Dr. Kircik says. Total symptom score reduction over 28 days is roughly 4.6. “But the most important feature of bilastine is that it does not cause sleepiness,” he says.
Most biologics in the pipeline, targeting IL-13 and IL-31, are being studied for adult patients (age 18 and above). “However, the need is in the pediatric population, because atopic dermatitis is more of a pediatric disease than an adult disease,” Dr. Kircik says.
Dr. Kircik expects some day that biologics will be indicated for children, too.
Disclosures: Dr. Kircik is a consultant, an adviser or an investigator for Pfizer, Anacor, Galderma, Chugai and Amgen.