Dr Strand Reviews the Use of JAK Inhibitors for IMIDs

Vibeke Strand, MD, MACR, FACP, adjunct clinical professor in the division of immunology and rheumatology at Stanford University in Palo Alto, California, presented the latest data regarding the efficacy and safety of Janus kinase (JAK) inhibitors at the virtual Interdisciplinary Autoimmune Summit 2020.

While JAK inhibitors display different in vitro profiles and modulate distinct cytokine pathways to different degrees, they behave similarly. Dr Strand noted that JAKs do not potently or continuously inhibit any individual cytokine signaling pathway for 24 hours and it is unclear which cell types and signaling pathways are affected at any given time.

Dr Strand reviewed the efficacy of JAKs for various autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, and spondyloarthropathy. Filogotinib, a JAK1 inhibitor, showed superior efficacy to placebo in the treatment of psoriatic arthritis in the EQUATOR trial; it also showed statistical significance for improved outcomes for patients with ankylosing spondylitis (AS). Similarly, upadacitinib showed positive statistically and clinically meaningful improvements in the UPA AXIS-1 trial for patients with AS.

Several JAKs are in development for dermatologic conditions. Abrocitinib just finished all phase 3 trials for atopic dermatitis and had positive results and may be rapidly reviewed by the FDA when submitted, noted Dr Strand. Tofacitinib also showed dramatic, early, and significant improvements in patients with alopecia areata. Upadacitinib showed early response on Eczema Area and Severity Index scores in a small phase 2 study.

While tofacitinib was effective at the 10-mg dose for psoriasis, it was rejected by the FDA because of safety concerns at the higher dose, noted Dr Strand. A phase 2 study assessing the efficacy of 2-mg, 4-mg, 8-mg, and 10-mg doses of baricitinib among patients with psoriasis showed 8 mg and 10 mg were more effective than the lower doses. Topical ruxolitinib showed clinical improvement in skin biomarkers for psoriasis. BMS-986165, a tyrosine-protein kinase 2 inhibitor, demonstrated improvements in Psoriasis Area and Severity Index scores and rapid onset, with response seen as early as 15 days. The safety of this therapy is good, but there is a higher incidence of acne, noted Dr Strand.

In inflammatory bowel disease (IBD), tofacitinib is approved for ulcerative colitis but not Crohn disease. Dr Strand stressed that the 10-mg dose can only be used in patients with refractory disease due to safety concerns. In the FITZROY study, filgotinib met primary endpoints and showed improvements at 10 weeks in patients with IBD, as well as improvements in quality of life.

Dr Strand also reviewed the literature for several other autoimmune diseases. In systemic lupus erythematosus, phase 1 trials showed positive results with a 4-mg dose of tofacitinib. Tofacitinib and filogotinib is also being investigated for primary Sjogren syndrome.

In addition, Dr Strand reviewed the combination JAK inhibitors currently being developed: ABBV-59, lanraplenib, and tirabrutinib. Two JAK inhibitors, baricitinib and tofacitinib, are being investigated for treating SARS-CoV-2 and cytokine storm syndrome, respectively.

JAK inhibitors are generally safe, said Dr Strand. There is an increased risk for herpes zoster reactivation, but malignancies are similar and risk for serious infections are less than tumor necrosis factor inhibitors. Hematologic and other laboratory parameters do require monitoring, but Dr Strand noted it is rare to see clinically meaningful changes.

However, there is a concern for thromboembolic events and deep vein thrombosis (DVT). An FDA safety study that included patients with rheumatoid arthritis and 1 or more comorbidities associated with cardiovascular disease risk showed an increased risk for thromboembolic events. “However, the study is still under way and we do not know all the details,” said Dr Strand. She noted that an abstract study showed disease activity was associated with an increased risk for DVT. In addition, data from Truven and MEDICARE databases showed a numerically higher risk for these events, but this was not statistically significant, Dr Strand noted. Another study that used the World Health Organization safety database showed disproportionate DVTs in Europe among patients treated with tofacitinib and baricitinib. “We are not sure whether this is associated with JAK inhibitors or the disease itself,” she added.

Overall, JAK inhibitors are safe and effective among patients with various autoimmune diseases, she concluded.

For more coverage of IAS 2020 virtual, visit the newsroom.

–Melissa Weiss

Reference

Strand V. Expanding Role of JAK inhibitors across IMIDs. Presented virtually at: Interdisciplinary Autoimmune Summit 2020; July 10, 2020.