Janus kinases (JAKs) are a group of inflammatory proteins implicated in the development of various inflammatory and autoimmune skin disorders, including atopic dermatitis, vitiligo, and alopecia areata. The JAK family comprises JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2).
These proteins play a crucial role in the JAK-signal transducer and activator of transcription (JAK-STAT) pathway, which is central to the pathophysiology of numerous inflammatory and autoimmune diseases. Activation of the STAT protein leads to the expression of several inflammatory cytokines. JAK inhibitors inhibit the production of inflammatory cytokines by disrupting this pathway.
Over the past few years, JAK inhibitors have gained traction in dermatology, beginning with the approval of Opzelura (ruxolitinib) cream in 2021. The FDA has approved six JAK inhibitors, with several more in development.
Deuruxolitinib
In March 2023, Sun Pharmaceutical Industries Ltd., headquartered in Mumbai, India, and Princeton, New Jersey, acquired Concert Pharmaceuticals Inc. to gain access to deuruxolitinib, an investigational selective JAK1 and JAK2 inhibitor intended for the treatment of moderate to severe alopecia areata in adults.
Alopecia areata is a chronic autoimmune disease affecting up to 2.5% of individuals in the United States and globally. It involves the immune system attacking hair follicles, resulting in complete or partial hair loss on the scalp or other hair-bearing areas of the body, with potential effects on nails and parts of the retina. Individuals with alopecia areata often experience serious mental health challenges such as depression and anxiety.
Deuruxolitinib has received breakthrough therapy and fast track designation from the FDA for the treatment of alopecia areata. In October 2023, Sun Pharma filed for FDA approval of deuruxolitinib for this indication.
The FDA’s acceptance of the application was based on data from two pivotal phase 3 trials (THRIVE-AA1 and THRIVE-AA2), which enrolled 1,223 adults with moderate to severe alopecia across the U.S., Canada, and Europe. Participants had at least 50% scalp hair loss, with average baseline Severity of Alopecia Tool (SALT) scores of 85.9 and 87.9 for THRIVE-AA1 and THRIVE-AA2, respectively. SALT scores range from 0 (no scalp hair loss) to 100 (total scalp hair loss).
Participants were randomly assigned to receive 8 mg or 12 mg of deuruxolitinib twice daily or placebo for 24 weeks. The primary endpoint was the percentage of patients achieving a SALT score of 20 or less at week 24. Results showed 33% and 38% of patients in the 8-mg and 12-mg groups, respectively, achieved this endpoint, compared to 1% in the placebo group.
Moreover, 21% of patients in the 8-mg group and 35% in the 12-mg group achieved a SALT score of 10 or less, compared to none in the placebo group. An extension trial demonstrated that 49% and 61% of patients in the 8-mg and 12-mg groups, respectively, reached the primary endpoint at 68 weeks.
These findings were presented at the American Academy of Dermatology (AAD) annual meeting in March 2024.
Gusacitinib
Gusacitinib, an oral dual JAK and spleen tyrosine kinase (SYK) inhibitor, is being developed to treat chronic hand eczema. The investigational drug, licensed to Libertas Bio from Asana BioSciences (both New Jersey-based companies), demonstrated promising results in a phase 2 trial for moderate to severe chronic hand eczema.
Ninety-seven adults who had failed corticosteroid therapy were randomly assigned 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, compared to a 34% improvement in the placebo group. Adverse events were typically mild, including headache, nausea, and upper respiratory tract infection.
Libertas Bio intends to advance gusacitinib to phase 3 trials. If successful, gusacitinib could be the first oral treatment approved for chronic hand eczema.
Opzelura and Povorcitinib
Incyte Corporation, based in Wilmington, Delaware, is progressing with Opzelura cream, a selective JAK1/JAK2 inhibitor initially approved in September 2021 for mild to moderate atopic dermatitis in patients aged 12 and older. The FDA extended approval to treat vitiligo in July 2022 and is currently considering an expanded indication for children aged 2 to 11 with mild to moderate atopic dermatitis.
In the ongoing TRuE-AD3 phase 3 study, children aged 2 to 11 years are being randomly assigned to receive Opzelura 0.75% or 1.5% cream or placebo twice daily for 8 weeks, followed by a 44-week extension study. A significantly higher proportion of participants using Opzelura achieved symptom improvement by week 8 compared to those receiving placebo.
Incyte is also developing povorcitinib, an oral selective JAK1 inhibitor, for the potential treatment of various inflammatory diseases, including prurigo nodularis. Povorcitinib met all endpoints in a phase 2 trial evaluating safety and efficacy in adults with prurigo nodularis.
These developments were presented at the 2024 AAD annual meeting. Incyte plans to initiate phase 3 trials for povorcitinib in prurigo nodularis and continues to explore other dermatologic applications, including vitiligo and hidradenitis suppurativa.
