COPENHAGEN – The nonsteroidal phosphodiesterase-4 inhibitor crisaborole aced all Food and Drug Administration–required efficacy and safety endpoints as a topical treatment for atopic dermatitis, according to results from a pair of pivotal phase III randomized trials.
“This is a fairly rapidly effective treatment,” explained Dr. Mark G. Lebwohl, who presented the findings at the annual congress of the European Academy of Dermatology and Venereology. “It has a favorable safety profile and has been studied in patients as young as 2 years of age. It may represent a new, safe, and efficacious treatment for patients 2 years of age and older with mild to moderate atopic dermatitis.”
Atopic dermatitis (AD) experts have long complained of a major unmet need for new, safe, and effective topical agents for AD, a condition that affects an estimated 18%-20% of children and 2%-10% of adults. Current treatment options all have drawbacks.
Topical steroids, long a treatment mainstay, are viewed by many parents with phobic mistrust of safety. And both FDA-approved topical calcineurin inhibitors carry black box warnings of possible cancer risk.
The two pivotal phase III studies, identical in design, included a total of 1,522 patients aged 2 years through adulthood with mild to moderate AD. Roughly 60% of patients had moderate disease, as defined by an Investigator’s Static Global Assessment (ISGA) score of 3 on a 0-4 scale; the other 40% had mild AD. The mean involved body surface area was 18%.
Participants were randomized two to one to crisaborole ointment 2% b.i.d. or vehicle for 28 days. Physicians assessed patients at baseline on day 1 of the study and again on days 8, 15, 22, 29, and 36. The primary endpoint was the proportion of patients on day 29 who had an ISGA of 0 or 1 – clear or almost clear – as well as at least a 2-point improvement from baseline on that scale.
In one of the trials, that endpoint was achieved in 32.8% of the crisaborole group, compared with 25.4% of controls.
“That 25% placebo response is actually fairly typical for atopic dermatitis studies,” according to Dr. Lebwohl, professor and chairman of the department of dermatology at Mount Sinai School of Medicine, New York.
In the other study, 31.4% of the crisaborole group and 18% of controls achieved the primary endpoint. In both studies, the difference was statistically significant in favor of topical crisaborole.
There were two prespecified secondary endpoints. One was time to treatment success, as defined by clear or almost clear. A “striking” significant difference between the study arms appeared as early as the first assessment, just 1 week into the trial, Dr. Lebwohl observed.
The other secondary endpoint was the FDA’s former efficacy standard, which required being clear or almost clear without the additional need for at least a 2-point ISGA improvement. That endpoint was achieved by 51.7% and 48.5% of crisaborole-treated patients in the two studies, compared with 40.6% and 29.7% of controls. Again, both differences were statistically significant.
No treatment-related serious adverse events occurred in either study. Mild application-site pain was slightly more common in the crisaborole-treated patients. But the rate of study discontinuations because of adverse events was identical between the crisaborole and control groups, at 1.2%. No differences in laboratory values, ECGs, or vital signs were noted between the two groups.
Dr. Lebwohl explained that boron is an essential element in crisaborole. The boron stimulates an increase in cyclic adenosine monophosphate levels, which in turn results in a steep reduction in production of inflammatory cytokines, including interleukins-4, -2, and -31, as well as tumor necrosis factor-alpha.
One audience member asked if it’s possible that crisaborole acts systemically rather than topically, given that patients averaged 18% body surface area involvement, and such a large area of damaged skin could conceivably allow the topical agent ready access to the circulation.
Dr. Lebwohl replied that systemic absorption of the drug was minor. “If you break down the results into patients with very low body surface areas – the lowest was 5% – those patients improved as well. So, I think it would be unlikely that this was a systemic effect.”
Anacor, which is developing the drug as a treatment for AD and other skin diseases, plans to file for marketing approval during the first half of 2016.
Anacor sponsored the two pivotal phase III randomized trials. Dr. Lebwohl declared having no financial conflicts of interest, because all funds went directly to the medical center in which he practices.