SAN DIEGO – A novel molecule that inhibits two major inflammatory pathways acquitted itself well in its first safety and efficacy clinical trial in patients with moderate to severe atopic dermatitis.
After 29 days, 100% of those taking the highest dose of the molecule, ASN002, achieved a 50% improvement in skin involvement.
“This is an interesting molecule,” Robert Bissonnette, MD, said at the annual meeting of the American Academy of Dermatology. “By targeting the entire JAK family, it inhibits cytokine signaling through IL-4 [interleukin-4], IL-13, IL-23, and thymic stromal lymphopoietin,” which plays a role in maturing T cells. The SYK inhibition targets IL-17, increases the terminal differentiation of keratinocytes, and inhibits B-cell signaling.
, president of presented the results in a late-breaking session at the meeting. Innovaderm designs, conducts, and analyzes dermatology clinical trials, and ran the study for Asana BioSciences.
In an Asanaabout the study results, CEO Sandeep Gupta, PhD, said that ASN002 “is the only oral compound in clinical development targeting JAK [including Tyk2] and SYK signaling, two clinically validated mechanisms.” He added that inhibition of JAK and SYK pathways “diminishes cytokine production and signaling including those mediated by Th2 and Th22 cytokines. Dysregulation of Th2 and Th22 cytokine pathways is implicated in the pathogenesis of atopic dermatitis.”
Safety was the primary endpoint in the phase 1b dose-ranging, but there were also several efficacy endpoints, Dr. Bissonnette said at the meeting. The study comprised 36 patients separated into three 12-patient groups. In each group, nine received the active drug every day, and three received a placebo. The first group received 20 mg ASN002 or placebo for 28 days, followed by the 14-day safety period. The next group received 40 mg ASN002 or placebo for 28 days, followed by the safety analysis. The third group followed the same treatment pattern, but received 80 mg of the drug.
All patients were aged 29-42 years. The Eczema Area and Severity Index (EASI) was imbalanced among the groups, ranging from 21 in the placebo group and 40-mg group, to 29 in the 20-mg and 80-mg groups. The Body Surface Area (BSA) index also differed between groups: 25% among the placebo patients, 45% in the 20-mg group, 32% in the 40-mg group, and 29% in the 80-mg group. The average Investigator Global Assessment (IGA) score was 3.
A pharmacokinetic analysis showed rapid uptake of the drug with a half-life of 10-14 hours depending on dose.
There were no concerning safety signals, Dr. Bissonnette said and no thromboembolic events, serious infections, or opportunistic infections. The most common adverse event was headache, which occurred at equal rates among the groups. The single serious adverse event was anxiety, which occurred in one patient taking 80 mg ASN002, 4 days after the medication was stopped, and was judged unrelated to ASN002.
There were no significant changes in any lab parameters, no changes in lipid profiles, and no hematologic abnormalities. One patient experienced an increase in creatinine phosphokinase, something that has been seen in other studies of JAK inhibitors, Dr. Bissonnette said.
The molecule performed well on secondary efficacy endpoints. By day 15, 63% of the 40-mg group and 75% of the 80-mg group had achieved EASI-50, and by day 29, these rates were 88% and 100%, respectively. These doses also performed well on the EASI-75 endpoint. By day 29, 63% of the 40-mg group and 50% of the 80-mg group had achieved a 75% improvement in EASI score.
The 40- and 80-mg groups also did well with regards to BSA improvement. By day 29, the 80-mg group had achieved a mean BSA reduction of 58%, and the 40-mg group a mean reduction of 64%. IGA tracked that improvement, with 25% of the 80-mg group and 38% of the 40-mg group achieving an IGA score of 1 or 0.
Itching responded well to ASN002, but here, the 20-mg dose threw investigators a bit of a curve ball. Pruritus decreased most in the 80-mg group (about 70% by the end of the study). But at 3 weeks, patients taking 20 mg and 40 mg were experiencing the same 30% decrease in itch. By 4 weeks, however, the scores had separated, with the 40-mg group landing at about a 40% reduction, and the 20-mg group rebounding to about a 20% reduction.
“I would say that this first trial of ASN002 showed clear efficacy in patients with moderate to severe atopic dermatitis, with rapid improvement itch and a large proportion of patients reaching EASI-50 as early as 2 weeks,” Dr. Bissonnette said.
Asana will soon initiate a phase 2b study of ASN002 in moderate to severe atopic dermatitis patients. Clinical studies in other dermatologic and autoimmune indications are under consideration, according to the company website.
Dr. Bissonnette is the president of Innovaderm Research, which was paid to run the ASN002 study.