Selective JAK1/TYK 2 inhibitor effective in patients with difficult-to-treat RA

In a Chinese trial, a novel JAK1/TYK2 inhibitor was able to achieve remission in >30% of participants with difficult-to-treat rheumatoid arthritis (RA). Its activity might be explained by blocking multiple pro-inflammatory cytokines that signal via JAK1 and TYK2.

According to the EULAR definition, patients with RA who failed ≥2 biological disease-modifying antirheumatic drugs (DMARDs)/targeted synthetic DMARDs (with different mechanisms of action) after failing conventional synthetic DMARD therapy (unless contraindicated) can be considered “difficult-to-treat” [1]. The definition also implies that these patients remain with active or symptomatic disease and that the management of signs or symptoms is perceived as problematic. According to this definition, 5-20% of RA patients fulfil these criteria [2].

As Prof. Xiaofeng Zeng (Peking Union Medical College Hospital, China) pointed out, not many treatment options are available for difficult-to-treat patients with RA. Both cytokines signalled by JAK1 and those regulated by TYK2, including IL-17 and IL-23, are involved in RA pathogenesis. This was the rationale for finding out whether TLL-018, an investigative, dual JAK1/TYK2 inhibitor, can overcome resistance to JAK1-selective inhibitors [3].

A total of 101 participants with moderate-to-severe active RA and inadequate response or intolerance to methotrexate were randomised 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 ACR50 at week 12. In addition, the percentages of participants who achieved ACR20, ACR70, and remission (disease activity score [DAS]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 participants treated with tofacitinib (P<0.05 for both comparisons). In addition, the agent was also superior to placebo in secondary endpoints.

Thus, “17% of participants treated with tofacitinib compared with >30% treated with the new compound achieved remission,” Prof. Zeng commented. TLL-018 in the 2 highest doses achieved an ACR50 response of >66%, independent of previous treatment (methotrexate only, prior biological drug, or prior TYK inhibitor).

The drug 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,” Prof. Zeng said. Lipid changes occurred in the first 4 weeks and then stabilised. Whilst we have previously seen studies in RA that use a biological DMARD as a reference arm, this use of tofacitinib as a JAK inhibitor comparator arm is noteworthy.

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

1. Nagy G, et Ann Rheum Dis. 2021;80:31-5.
2. Watanabe R, et Front Med (Lausanne). 2022:9:1049875.
3. Zeng X, et Head-to-Head Comparison of TLL-018 and Tofacitinib in Patients with Active Rheumatoid Arthritis: Interim Results from a Phase IIa Study. LB0001, EULAR 2023, 31 May–3 June, Milan, Italy.

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Posted on 30 July 20231 February 2024