Dermatology’s Embrace of JAK inhibitors

Janus kinases (JAKs) are a group of inflammatory proteins associated with the pathogenesis of several inflammatory and autoimmune disorders, including skin conditions such as atopic dermatitis, vitiligo, alopecia areata and others. The JAK group includes JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2).

These proteins are involved in the JAK-signal transducer and activator of transcription (JAK-STAT) pathway, which is central to the pathophysiology of many inflammatory and autoimmune diseases. Activation of the STAT protein induces the expression of several inflammatory cytokines. JAK inhibitors suppress the production of inflammatory cytokines by interrupting this pathway.

Over the past three years, JAK inhibitors have swept into the dermatology field, starting with the approval of Opzelura (ruxolitinib) cream in 2021. The FDA has approved six JAK inhibitors, and several more are in the wings.

Deuruxolitinib

In March 2023, Sun Pharmaceutical Industries Ltd., based in Mumbai, India, and Princeton, New Jersey, acquired Concert Pharmaceuticals Inc. to access the company’s investigational JAK inhibitor, deuruxolitinib. Deuruxolitinib is a selective JAK1 and JAK2 inhibitor under development for the potential treatment of moderate to severe alopecia areata in adults.

Alopecia areata is a chronic autoimmune disease that affects up to 2.5% of people in the United States and worldwide. With alopecia areata, the immune system attacks hair follicles, resulting in complete or partial hair loss on the scalp or any other hair-bearing part of the body. Rarely, the nails and part of the retina are also affected.Often, people living with alopecia areata develop serious mental health conditions, such as depression and anxiety.

Deuruxolitinib has received breakthrough therapy and fast track designation from the FDA for treating alopecia areata. In October 2023, Sun Pharma filed for approval of the JAK inhibitor for the treatment of alopecia areata in adults.

The FDA accepted the application based on results from two pivotal phase 3 trials (THRIVE-AA1 and THRIVE-AA2), which included 1,223 adult patients with moderate to severe alopecia across the U.S., Canada and Europe. Participants had at least 50% scalp hair loss with an average baseline Severity of Alopecia Tool (SALT) score of 85.9 for the THRIVE-AA1 trial and 87.9 for the THRIVE-AA2 trial. SALT scores range from 0 to 100, with 0 indicating no scalp hair loss and 100 representing total scalp hair loss.

The investigators randomly assigned participants to receive 8 milligrams (mg) or 12 mg of deuruxolitinib twice daily, or placebo for 24 weeks. The study’s primary end point was the percentage of patients who achieved a SALT score of 20 or less at week 24. A total of 33% of patients in the 8-mg group and 38% in the 12-mg group achieved this end point. Only 1% of patients who received placebo reached this goal.

Additionally, 21% of patients who received 8 mg of the study drug and 35% of those who received 12 mg achieved a SALT score of 10 or less. No one in the placebo group achieved this score. In an extension trial, 49% of patients taking the 8-mg dose reached the primary end point at 68 weeks, an increase of 16 percentage points. Of those taking the 12-mg dose, the percentage increased by 23 points to 61%.

These results were presented in March 2024 at the American Academy of Dermatology (AAD) annual meeting in San Diego, California.

Gusacitinib

Gusacitinib is an oral dual JAK and spleen tyrosine kinase (SYK) inhibitor under development to treat chronic hand eczema. The investigational drug, licensed to Libertas Bio from Asana BioSciences (both companies are based in New Jersey), performed well in a phase 2 trial evaluating its efficacy in treating moderate to severe chronic hand eczema. The inflammatory skin condition is a type of atopic dermatitis that typically affects the hands, fingers and wrists with symptoms that range from itching and dryness to more severe fissures and thickening of the affected skin.

The study’s investigators randomly assigned 97 adults with moderate to severe chronic hand eczema who had failed corticosteroid therapy to receive 40 mg or 80 mg of gusacitinib or placebo for 16 weeks. The primary endpoint was the percentage change from baseline in modified total lesion symptom score (mTLSS), a measure of hand eczema severity.

At 16 weeks, participants receiving 80 mg and 40 mg of gusacitinib showed a 70% and 49% improvement in mTLSS, respectively. In comparison, the group that received placebo saw a 34% improvement in mTLSS. Adverse events were typically mild and included headache, nausea and upper respiratory tract infection.

Libertas Bio plans to advance the experimental drug to phase 3 trials. If successful, gusacitinib could become the first oral treatment approved to treat chronic hand eczema.

Opzelura and povorcitinib

Incyte Corporation, headquartered in Wilmington, Delaware, has a couple of JAK inhibitors in the dermatology pipeline. The company developed and markets Opzelura cream, a selective JAK1/JAK2 inhibitor approved in September 2021 to treat mild to moderate atopic dermatitis in patients 12 years and older. In July 2022, the FDA approved an indication to treat vitiligo in the same age group. The company is now seeking an expanded indication of mild to moderate atopic dermatitis in children 2 to 11 years of age.

In the ongoing TRuE-AD3 phase 3 study, children ages 2 to 11 years are randomly assigned to receive Opzelura 0.75% or 1.5% cream or inactive vehicle twice daily for 8 weeks, then as needed in a 44-week extension study. A significantly higher percentage of participants using the 0.75% or 1.5% cream (37% and 57%, respectively) achieved the primary endpoint of symptom improvement by week 8 than those who received the vehicle (11%).

Incyte is also developing povorcitinib, an oral selective JAK1 inhibitor, for the potential treatment of several inflammatory diseases, including prurigo nodularis. This rare skin condition is a chronic inflammatory disorder characterized by thick, itchy and sometimes painful nodules on the skin. Scratching begets new nodules, perpetuating the scratch-itch cycle.

Povorcitinib met all endpoints in a phase 2 trial evaluating the agent’s safety and efficacy in adults with prurigo nodularis. A total of 146 participants were randomly assigned to receive 15 mg, 45 mg or 75 mg of povorcitinib or placebo once per day for 16 weeks. The primary endpoint was a four-point improvement in the itch Numeric Rating Scale (NRS4) score. At 16 weeks, 36%, 44% and 54% of patients receiving 15 mg, 45 mg and 75 mg of povorcitinib, respectively, achieved a reduction of at least four points in the NRS4 score compared with 8% of those taking placebo. The time to achieve this endpoint ranged from 17 days for participants who received the highest 75-mg dose to 58 days for
those receiving the 15-mg dose.

Data from the TRuE-AD3 and prurigo nodularis studies were presented at the 2024 AAD annual meeting.

Incyte is planning a phase 3 trial for povorcitinib in the treatment of prurigo nodularis. The investigational drug is also in phase 3 trials for other uses in dermatology, including vitiligo and hidradenitis suppurativa, a chronic condition that causes painful nodules under the skin.