Rapid Improvement in Atopic Dermatitis With Dual JAK/TYK2 Inhibitor

ORLANDO — More than 80% of patients with moderate or severe atopic dermatitis (AD) had at least 75% improvement after 12 weeks of treatment with an investigational dual-target small-molecule inhibitor, according to a study from China.

The two highest doses of the JAK1/TYK2 inhibitor QY201 led to 75% skin clearance rates of 81-85%. In addition, 64-71% of patients met the secondary endpoint of clear/almost clear skin by investigator global assessment (IGA 0/1). As many as 40% of patients had complete skin clearance at 12 weeks by the Eczema Area and Severity Index (EASI 100).

“QY201 provided rapid and sustained pruritus relief, effective lesion clearance, and significant improvements in clinical symptoms, signs, and quality of life,” reported Jianhui Li, MD, PhD, of study sponsor E-nitiate Biopharmaceuticals in Hangzhou, China, at the American Academy of Dermatology meeting. “The overall safety profile was favorable, with the majority of adverse events being mild to moderate. The phase II results support advancing [the two highest doses] into phase III for long-term evaluation.”

The first-in-class QY201 simultaneously inhibits two molecules involved in JAK/STAT pathway signaling that drive inflammatory conditions such as AD. Li reported findings from a dose escalation clinical trial that compared effects of three doses of QY201 (5, 10, and 20 mg BID) against placebo in approximately 200 patients with moderate/severe AD, defined as IGA ≥3, EASI ≥16, body surface area ≥10%, and weekly pruritus score (PP-NRS) ≥4.

The primary endpoint was the proportion of patients achieving EASI 75 response at 12 weeks. All three doses significantly (P<0.001) outperformed placebo (18.5% response rate), with the lowest dose of QY201 achieving the lowest response rate of the three doses (72.9%). All three doses significantly reduced peak pruritus scores versus placebo, including patients with baseline PP-NRS ≥3 or ≥4.

The most common treatment-emergent adverse events (TEAEs) with QY201 were infections (34-48% vs 32.7% with placebo), upper respiratory tract infections (10-30% vs 14.3%), elevated total cholesterol (14-19% vs 8.2%), and elevated LDL cholesterol (10-12% vs 0%). Three patients total discontinued QY201 as a result of adverse events.

High Psoriasis Response With New TYK2 Inhibitor

Three-fourths of patients with moderate-to-severe plaque psoriasis had major responses at 52 weeks to the highly selective oral TYK2 inhibitor ESK-001.

Among patients treated with the higher of two doses of the drug, the proportion of patients achieving a 75% response by the Psoriasis Area and Severity Index (PASI 75) increased from 53.7% at 12 weeks to 82.7% at 28 weeks and remained at 77.5% at 52 weeks. The PASI 100 response rate increased from 11% at 12 weeks to 30.9% at 28 weeks to 38.8% at 52 weeks. TEAEs were mostly mild or moderate and self-limiting, reported Andrew Blauvelt, MD, of Blauvelt Consulting in Annapolis, Maryland.

The high response rates in the clinical study originated with optimization of the targets in laboratory studies. In the current study, the 40 mg BID dose of ESK-001 maintained a 90% inhibitory concentration against type 1 interferon over a 24-hour period.

“The key point with this drug is target optimization,” said Blauvelt. “We see a number of examples with the IL-23 inhibitors that have different efficacy, the IL-17 inhibitors have different efficacy. It’s because the ones with the best efficacy have been optimized to their target. I think that’s what’s happening with this drug. We’re seeing better results than previous drugs because of the work done in the laboratory.”

The phase II study involved 227 patients with moderate/severe plaque psoriasis, treated with placebo or one of five doses of ESK-001 (10 mg QD to 40 mg BID). The primary endpoint was PASI-75 response at 12 weeks. After a 4-week washout period, patients could continue in an open-label extension to 52 weeks with the two highest doses (40 mg QD or BID). Patients assigned to once-daily ESK-001 switched to BID dosing after the 28-week follow-up assessment.

A phase III development program is ongoing and has already enrolled more than 600 patients with plaque psoriasis, said Blauvelt.

New Drug Candidate for Alopecia Areata

Patients with severe alopecia areata had significant hair regrowth after 6 months of treatment with a novel bifunctional receptor antagonist, preliminary clinical data showed.

Baseline Severity of Alopecia Tool (SALT) scores of 50-100 declined by 16.3%, and 17.4% had at least 30% improvement. Following discontinuation of treatment with bempikibart at 24 weeks, hair regrowth continued during an additional 12 weeks of follow-up after stopping the drug, increasing to 18.2% at 26 weeks and 19.9% at 36 weeks. The proportion of patients with at least 30% improvement increased to 36.8%.

“Bempikibart has a proposed mechanism that suggests long-term durable responses,” said Brett King, MD, PhD, of Dermatology Physicians of Connecticut in Fairfield, Connecticut. “We see in a cohort of patients with severe alopecia areata some long-term durable responses post-dosing cessation, which is leading to continued investigation of patients with severe alopecia areata.”

Currently approved therapies for alopecia areata are all JAK inhibitors and carry boxed warning labels, King noted. Bempikibart simultaneously inhibits the IL-7 receptor, which “rebalances” T (effector/memory) and T (regulatory) function, and the thymic stromal lipoprotein (TSLP) receptor, which is a key regulator of dendritic cell differentiation and Th2 cytokine production. The monoclonal antibody targets the alpha-subunit of the IL-7 receptor, which is shared by IL-7 and TSLP.

King highlighted extensive literature documenting the role of IL-7 in modulating T-cell responses to inflammatory and autoimmune diseases. IL-7 blockade is hypothesized to induce a form of T-cell homeostasis.

The phase II study initially involved 40 patients, 33 randomized to bempikibart and seven to placebo. The per-protocol analysis included 23 patients treated with the monoclonal antibody and four from the placebo group. In both the intent-to-treat and per-protocol analyses, placebo-treated patients had less than 5% improvement in SALT score at 24 weeks.

The results also showed that patients with SALT scores of 95-100 (very severe) did not derive as much benefit as those with baseline scores of 50-94, confirming existing evidence that the 95-100 group has more resistant disease, said King.

Bempikibart was generally well tolerated, as grade 3/4 adverse events consisted of one acute myocardial infarction and one reaction related to peanut allergy, neither considered treatment related.

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