MADRID – (AD) on the strength of its knockout performance in the pivotal phase 3 JADE MONO-1 trial, presented at the annual congress of the European Academy of Dermatology and Venereology.
“The IGA [Investigator Global Assessment] and EASI [Eczema Area and Severity Index]-75 responses for both doses of abrocitinib were significantly greater than placebo as early as week 2 and continued to increase until week 12 with no plateau. This study stopped at week 12. I would have liked to see what happened at 16 weeks or further. I don’t know where this is going to end up maxing out,” commented principal investigator, professor of dermatology at Oregon Health & Science University, Portland.
(JAK1 Atopic Dermatitis Efficacy and Safety Monotherapy–1) was a 12-week, double-blind, multicenter study which included 387 adolescents and adults with moderate or severe AD randomized 2:2:1 to abrocitinib at 200 mg or 100 mg once daily, or to placebo. Overall, this was a fairly severely affected population, with a mean baseline EASI (Eczema Area and Severity Index) score of about 30, a peak pruritus numeric rating scale score of 7 out of 10, and a mean Dermatology Quality Life Index score greater than 14. Nonetheless, this was a rigorous abrocitinib monotherapy trial, as participants were not allowed to take even a single dose of topical corticosteroids.
The coprimary endpoints in JADE MONO-1 were achievement of an IGA score of 0 or 1 – that is, clear or almost clear – at week 12 plus at least a 2-point improvement, compared with baseline on the 0-4 scale, and an EASI-75 response as defined by a 75% or greater improvement from baseline.
A clear-cut dose response was evident: the IGA response rate was 43.8% in the group on abrocitinib at 200 mg/day, 23.7% with 100 mg, and 7.9% with placebo. The EASI-75 response rates were 62.7%, 39.7%, and 11.8%, respectively, with a statistically significant separation from placebo by week 2.
Key secondary endpoints included the rigorous EASI-90 response rate: 38.6% with the higher dose of abrocitinib, 18.6% at 100 mg per day, and 5.3% with placebo. And again, that’s without resort to topical steroids, Dr. Simpson noted.
Another important secondary endpoint was the proportion of patients who achieved at least a 4-point improvement in itch on the pruritus self-rating scale by week 12: 57.2%, 37.7%, and 15.3%. The rapidity of the improvement was notable: By week 2, this endpoint was achieved in 45.6% of patients on abrocitinib on the 200-mg dose, 20.4% on the 100-mg dose, and 2.7% of placebo-treated controls.
“By day 2, 1 day after taking the first pill, you can see really nice reductions in itch at both doses, compared with placebo,” the dermatologist said.
Study dropout rates were low despite the inability to utilize topical steroids: 11% in the higher-dose abrocitinib group and 13.5% with abrocitinib at 100 mg/day, both of which were lower than in controls.
Turning to safety results, Dr. Simpson noted that the 9.1% rate of discontinuations because of adverse events in the placebo group was significantly higher than the 5.8% rates in each of the active treatment arms. The serious adverse event rate was 3.2% in each of the abrocitinib groups and 1.9% with placebo. Among the serious adverse events in abrocitinib-treated patients Dr. Simpson considered worthy of special mention were a single case of inflammatory bowel disease, which resolved after halting treatment; one case of peritonsillitis; and a case of pancreatitis in an alcoholic patient. No deaths, major adverse cardiovascular events, or malignancies occurred in this brief 12-week trial. Nor were there any cases of deep vein thrombosis or pulmonary embolism, which has been an issue with some other JAK inhibitors.
“We need long-term safety data, of course,” he said.
Laboratory findings were generally unremarkable, with no clinically significant changes. Platelet counts dropped to a nadir at about 4 weeks while staying within normal range, then came back up. Mean LDL cholesterol levels rose by about 10%, an unwelcome event that was counterbalanced by a favorable 20% rise in HDL cholesterol.
Asked about the efficacy rates in the 20%-plus adolescent study participants, compared with the adults, Dr. Simpson replied that a detailed analysis is planned, adding: “I can say that things are looking pretty similar.”
Abrocitinib is selective for inhibition of JAK1, with resultant modulation of interleukins-4, -13, and -31, as well as interferon-gamma, all of which are cytokines involved in the pathophysiology of AD.
Of note, Pfizer, the drug’s developer, has announced positive results from the sister pivotal phase 3 trial, JADE MONO-2, with full details forthcoming in early 2020. Results of a phase 2b study of abrocitinib were also recently published ().
Dr. Simpson reported receiving research grants from and serving as a consultant to Pfizer, the study sponsor. He has similar financial relationships with close to a dozen other pharmaceutical companies.