Selective JAK1/TYK2 Inhibition: A Novel Way to Overcome Tofacitinib Resistance in RA?

Jun 12, 2023

Therapy with an investigative JAK1/TYK2 inhibitor led to remission in one-third of participants with difficult-to-treat rheumatoid arthritis (RA).

Not many treatment options are available for difficult-to-treat patients with RA, defined, per EULAR, as those who failed two or more targeted treatments, according to Xiaofeng Zeng, MD. Both cytokines signaling by Janus kinase 1 (JAK1) and those regulated by tyrosine kinase 2 (TYK2), including interleukin (IL)-17 and IL-23, are involved in RA pathogenesis. This was the rationale to find out whether TLL-018, an investigative, highly-selective dual JAK1/TYK2 inhibitor, can overcome resistance to JAK1 selective inhibitors. Dr. Zeng presented these findings at EULAR 2023, held May 31-June 2, in Italy.

The study conducted by Dr. Zeng and colleagues included participants with active RA and inadequate response or intolerance to methotrexate were randomized to receive tofacitinib 5 mg daily or TLL-018 in different dose regimens (10 mg, 20 mg, or 30 mg). The primary study endpoint was the percentage of participants who achieved American College of Rheumatology (ACR) response 50 at week 12. In addition, the percentage of participants who achieved ACR20, ACR70, and remission (disease activity score-28 <2.6) were assessed as secondary endpoints.

At week 12, 65.4% of participants treated with TLL-018 20 mg and 72% of those treated with TLL-018 30 mg achieved ACR50 compared with 41.7% of patients treated with tofacitinib (P<0.05 for both comparisons). In addition, the agent was also superior to placebo in secondary endpoints. “17% of patients treated with tofacitinib compared with >30% treated with the new compound achieved remission,” Dr. Zeng commented. TLL-018 in the two highest doses achieved an ACR50 response of more than 66%, independent of previous treatment (methotrexate only, prior biological drug, or prior TYK inhibitor).

The agent was also relatively well tolerated, with the most frequently reported adverse events being infections, in particular herpes zoster, elevations of gamma-glutamyltransferase, and hypertriglyceridemia. “Interestingly, the middle-dose group had more adverse events than the high-dose groups,” Dr. Zeng said. Lipid changes occurred in the first 4 weeks and then stabilized.

Dr. Zeng concluded that TLL-018 20 mg can overcome resistance to tofacitinib and may be a valuable treatment option for difficult-to-treat RA.