Eli Lilly and Company and Incyte jointly announced on Mar. 3, 2021 that baricitinib, an oral JAK inhibitor, met its primary endpoint in Phase 3 clinical trial for the treatment of adult patients with severe alopecia areata (AA). After 36 weeks of treatment, the drug significantly improved hair regrowth compared to the placebo group.

AA is an autoimmune disease that mainly causes patchy hair loss on the scalp, face and other areas of the body. The average age of onset of AA is between 25 and 35 years old, however, it can also affect children and teenagers and occur in both sexes and all races. More than half of AA patients experience health-related deterioration in the quality of life, and AA can also lead to serious psychological disorders such as depression and anxiety.

Baricitinib is an oral JAK3 inhibitor. JAK belongs to a family of cytoplasmic tyrosine kinases with four subtypes: JAK1, JAK2, JAK3, and TYK2, and subtypes are overlapping in the bound objects. JAK kinases are considered to play an important role in inflammation because they are involved in the signaling of more than 50 cytokines and growth factors, many of which are involved in driving immune-mediated reactions. The inhibitors of this family of kinases have shown efficacy in the treatment of certain inflammatory and autoimmune diseases.

Baricitinib has been approved in more than 70 countries as a treatment for moderate to severe active rheumatoid arthritis, with the trade name being Olumiant, and it has received Breakthrough Therapy designation from the FDA for the treatment of AA.

This BRAVE-AA2 study included 546 patients who had ≥50% scalp hair loss (SALT score ≥ 50) and severe AA lasting at least six months but no more than eight years. The study included a diverse patient population from China, South Korea, Japan, Brazil, Australia, Argentina, the U.S., etc. In Phase 2, according to the 36-week treatment results, no new severe adverse events were discovered in the baricitinib group compared to the placebo group, and treatment-related adverse events were mild to moderate, mainly including upper respiratory tract infections, nasopharyngitis, and acne. Phase 3 mainly assessed the differences in efficacy and safety between 2-mg and 4-mg baricitinib and the placebo.

The trial results showed that both doses of baricitinib met the primary efficacy endpoint at week 36, with safety outcomes consistent with its established safety profile in patients with rheumatoid arthritis and atopic dermatitis. Detailed results will be presented at an upcoming medical conference and published in a peer-reviewed journal later this year.

Besides baricitinib, there has been a boom in the development of blockbuster JAK inhibitors in recent years, which are effective in many diseases.

Market layout

1. Pfizer: PF-06651600

PF-06651600 is a JAK3 inhibitor that has received Breakthrough Therapy designation from the FDA for the treatment of AA. Based on a Phase 2a, randomized, double-blind, multicenter trial, PF-06651600 met the primary efficacy endpoint of promoting hair regrowth in the treatment of moderate to severe AA: relative to baseline at week 24, the SALT (Severity of Alopecia Tool) score improved to 33.6 points and 49.5 points (out of a maximum of 100), respectively.

Pfizer is currently conducting two Phase 2b/3 international multicenter clinical trials in China in AA subjects. Globally, the product will also continue to be tested for the treatment of rheumatoid arthritis, Crohn’s disease and ulcerative colitis.

2. Innovent/Incyte: itacitinib

Itacitinib is a novel, potent, small-molecule selective inhibitor of the JAK1 signaling pathway. Innovent has entered into an exclusive license agreement with Incyte to advance the clinical development and commercialization of three new oncology drugs, including itacitinib, as monotherapies or combination therapies in Greater China. These two companies received a clinical trial implied permission in Nov. 2019 for itacitinib in China, with the proposed indication of graft-versus-host disease.

3. Hengrui Medicine/Reistone Biopharma: SHR0302

SHR0302 is a highly selective small-molecule JAK1 kinase inhibitor. Its selectivity for JAK1 is more than 10 times that for JAK2, 77 times that for JAK3, and 420 times that for TYK2. The high selectivity of SHR0302 may lead to better safety and efficacy compared to general JAK inhibitors, and SHR0302 may produce better efficacy through the JAK1-STAT3 pathway. The drug is currently in a Phase III trial for moderate to severe active rheumatoid arthritis and also in clinical trials for indications such as ulcerative colitis, Crohn’s disease, atopic dermatitis, and vitiligo. Its Phase 2 clinical trial for AA completed the first patient dosing in China at the end of July 2020.

4. Chipscreen: CS12192 capsules

CS12192 capsules are a JAK3 kinase inhibitor developed by Chipscreen, which also partially inhibit JAK1 and TBK1 kinases. According to studies, CS12192 could not only effectively inhibit inflammation mediated by excessive activation of immune cells, but also reduce tissue invasion by immune cells through inhibition of TBK1, to offer better efficacy and safety. It is expected to provide a new and differentiated treatment choice for the clinical treatment of autoimmune-related diseases. In June 2020, the product received two clinical trial implied permissions in China for the proposed indication of rheumatoid arthritis.

5. Zelgen Biopharmaceuticals: jaktinib

Jaktinib is a small-molecule inhibitor of JAK kinase developed independently by Zelgen Biopharmaceuticals through the drug stabilization technology in its precision small molecule new drug R&D and industrialization platform. It is a Class 1 new drug and is available in dosage forms including tablet and cream. Zelgen Biopharmaceuticals is currently conducting a Phase 2 clinical trial of jaktinib tablets for the treatment of active ankylosing spondylitis, severe AA and intermediate-high-risk myelofibrosis, as well as two Phase 1 trials for graft-versus-host disease and idiopathic pulmonary fibrosis.

JAK is one of the most popular targets in the development of numerous targeted therapies at present. The R&D of JAK inhibitors is still in full swing in China and abroad, especially the new-generation JAK inhibitors that have more extensive indications and have great potential and market. They are particularly promising in treating AA. As a result, many companies have expanded the development of indications.

References:

1. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O'Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov. 2017 Dec 28;17(1):78. 

2. Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects. Drugs. 2017 Apr;77(5):521-546.