Standards are high for JAK inhibitors in psoriasis

Dermatology Times, Dermatology Times, April 2019 (Vol. 40, No. 4), Volume 40, Issue 4

While this new class of medications still has a role in treating psoriasis, this physician says the standard for both their efficacy and safety is very high because of the existing, already very effective systemic therapies available today.

In psoriasis, Janus kinase (JAK) inhibitors must meet the high standard set by existing biologics and systemic agents if they are to gain usage by the dermatology community.

"Janus kinases are involved in the Th17 signaling pathway, which is important in the pathogenesis of psoriasis,” said April W. Armstrong, M.D., M.P.H., professor of dermatology and associate dean of clinical research at the University of Southern California, in a presentation made at the American Academy of Dermatology 77th Annual Meeting in Washington, D.C. “They help mediate the downstream effects of interleukin (IL)-23. As a result, the Janus kinase pathway is highly relevant to treating psoriasis."

IL-23 and IL-12 signal through JAK2 and tyrosine kinase 2 (Tyk2), she noted. Oral JAK inhibitors that have been explored for psoriasis include tofacitinib, baricitinib, BMS-986165 and abrocitinib.

"They all are variably effective in decreasing psoriasis activity,” Dr. Armstrong said, “What's different in psoriasis compared to other diseases is that we have many systemic agents, including the biologic medications, that are highly effective. Therefore, for a JAK inhibitor to be competitive, being an oral medication alone is not sufficient. It has to have good efficacy and an acceptable safety profile."

Tofacitinib underwent extensive studies in psoriasis, but did not complete the approval process, she noted. In separate phase three trials, tofacitinib demonstrated good efficacy and was the first oral medicine shown to be non-inferior to a biologic (etanercept). Tofacitinib-treated patients experienced a 0.8 percent rate of herpes infections (versus none in placebo-treated patients) and slight abnormalities in creatinine phosphokinase (CPK) and low-density lipoprotein (LDL).
Tyk2 inhibitors represent a novel target and mechanism of action for psoriasis, Dr. Armstrong said. "That is a promising target because early studies have shown good efficacy as well as acceptable safety."

BMS-986165 is functionally more selective than other Tyk inhibitors because it inhibits the regulatory domain rather than the adenosine triphosphate (ATP) binding active domain, said Dr. Armstrong. This difference makes it potentially less likely to cause systemic problems in areas such as the hematopoietic pathway.

Topical delivery of JAK inhibitors could limit systemic absorption and systemic side effects. The topical JAK inhibitor that has garnered the most attention is tofacitinib.

"Topical JAK inhibition has promise because these drugs are not steroids," she concluded, "But data are limited. Future development of JAK inhibitors for psoriasis will need a higher bar because we have so many biologics that work extremely well and have good safety profiles. It's a different story than, say, atopic dermatitis.”

April Armstrong MD, MPH. "Janus Kinase Inhibitors in Psoriasis," S016, American Academy of Dermatology. March 1, 2019.

Disclosures:Dr. Armstrong is a clinical researcher and/or consultant for AbbVie, Janssen, Eli Lilly (maker of baricitinib), Pfizer (maker of tofacitinib), Bristol-Myers Squibb (maker of BMS-986165), Novartis, Ortho Dermatologics and Sanofi-Regeneron.