REPORTING FROM AAD 2018
SAN DIEGO (FRONTLINE MEDICAL NEWS) – Upadacitinib, a selective inhibitor of the Janus kinase 1 enzyme, affected up to 90% skin clearance in a phase 2 study in patients with moderate to severe atopic dermatitis (AD).
The molecule significantly outperformed placebo with all three of the doses tested, with patients experiencing improvement in itch and skin are involved in the first week of use. During the 16-week trial, there were none of the thromboembolic events that have proven a concern with other inhibitors of the Janus kinase family of enzymes, Emma Guttman, MD, PhD, said at the annual meeting of the American Academy of Dermatology.
The findings of the phase 2b dose-ranging study support taking upadacitinib forward into phase 3 for this indication, said Dr. Guttman , director of the laboratory of inflammatory skin diseases and associate professor of dermatology at the Icahn School of Medicine at Mount Sinai, New York. The results also reinforce the potential importance of upadacitinib as a first-in-class systemic therapy for AD. In January, the FDA granted upadacitinib breakthrough designation for the indication.
The study enrolled adults (mean age, 40 years) with moderate to severe atopic dermatitis of about 30 years’ duration. Their mean Eczema Area and Severity Index (EASI) score at baseline was about 30, and mean Body Surface Area score ranged from 42-50. The mean pruritus numerical rating scale score was about 6.5.
After a month-long washout period that excluded all medications except a topical emollient, patients were randomized to placebo (40 patients) or to daily upadacitinib at 7.5-mg, 15-mg, or 30-mg doses, taken orally (42 in each group). The 16-week placebo-controlled period is being followed by a 72-week blinded extension study in which the placebo patients will be switched to upadacitinib 30 mg, and half of each upadacitinib group will be switched to placebo. Dr. Guttman reported only the 16-week results.
The study’s primary endpoint was the mean percent EASI improvement from baseline. Dr. Guttman reported several of the key secondary endpoints as well.
On the primary endpoint, all three doses of upadacitinib separated from placebo quickly and dramatically. Patients began to see some skin clearance after 1 week; by 2 weeks, the 7.5-mg group had achieved a 39% improvement and the 15- and 30-mg groups, 56% and 59% improvement, respectively.
Efficacy in the 7.5-mg group peaked at a 50% improvement by week 4, and then trailed off somewhat, with a mean 39% improvement by week 16.
Efficacy in the two higher dose groups also peaked around 4 weeks, with a 66% improvement in the 15-mg group and a 78% improvement in the 30-mg group. There was some tailing off of effect in each of these groups as well. By 16 weeks, the mean EASI improvement was 61.7% in the 15-mg group and 74.4% in the 30-mg group.
A good number of patients in each dosing group even achieved 90% skin clearance, Dr. Guttman noted.
“We generally say that we like to see an EASI 50, but now we are talking about EASI 75 and even 90. More than 60% on the highest dose achieved an EASI 75 and 60% an EASI 90. Even the 15-mg group achieved a nice EASI 90 response, at around 26%.”
Itching also responded well to upadacitinib, Dr. Guttman said. Within 1 week, all three active groups had separated significantly from the placebo group. By 2 weeks, the 7.5-mg group had a mean 29% improvement on the pruritus numerical rating scale. The improvement was 46% in the 15-mg group and 57.6% in the 30-mg group. By 16 weeks, the improvements were 39.6%, 48%, and 68.9%, respectively, compared with 9.7% among those on placebo.
The most common treatment-emergent adverse event was upper respiratory infection, which Dr. Guttman noted has been seen with JAK inhibitors. This occurred in 10% of those taking placebo and in 16.7% of the 7.5-mg group and 11.9% of both the 15-mg and 30-mg groups. A few patients experienced exacerbation of their AD on the medication (16.7%, 7% and 11.9% of the active groups, compared with 7.5% of those on placebo). New acne developed in 2.5% of placebo patients and in 9.5%, 4.8%, and 14.3% of those taking upadacitinib. The acne was on the body, considered mild, and resolved, Dr. Guttman said.
Two patients taking 7.5 mg and one taking 15 mg developed a serious infection, although she did not elaborate on the illnesses. Two taking 15 mg developed a liver disorder. There were four cases of neutropenia and one lymphopenia, all among the active groups. Creatine phosphokinase elevations occurred in one taking placebo and seven taking the study drug.
There were no pulmonary or deep vein thromboses; no opportunistic infections or malignancies; and no cases of herpes zoster, tuberculosis, or renal dysfunction. There were no deaths during the trial.
Phase 3 studies of upadacitinib in patients with rheumatoid arthritis, psoriatic arthritis, and Crohn’s disease are underway, according to AbbVie.
AbbVie sponsored the AD study. Dr. Guttman is a consultant for the company.
SOURCE: Guttman E et al. AAD late-breaking clinical trials, Abstract 6533