Zimlovisertib and tofacitinib combo effective in treating rheumatoid arthritis: Study

A new study published in the journal of Arthritis and Rheumatology showed that the combination of zimlovisertib and tofacitinib shows promise in the treatment of rheumatoid arthritis.

Pain, stiffness, swelling, and eventually joint destruction are the main symptoms of rheumatoid arthritis (RA), a chronic inflammatory illness. However, it can also impact other organs, such as the heart, lungs, and eyes, in addition to joints. The synovium, or joint lining, is wrongly attacked by the immune system, which typically protects the body, since it perceives it as a threat.

As a complex autoimmune illness, rheumatoid arthritis is characterized by systemic characteristics and persistent joint inflammation that are driven by many routes. In moderate to severe instances, monotherapy is frequently insufficient, particularly when patients do not react to biologics or methotrexate. Combining Zimlovisertib with Tofacitinib to treat RA is a new and incredibly popular therapy option.

Thereby, to compare the safety and effectiveness of zimlovisertib (interleukin-1 receptor-associated kinase 4 inhibitor) with ritlecitinib (a Janus kinase [JAK] 3 and tyrosine kinase expressed in hepatocellular carcinoma [TEC] kinase family inhibitors) or tofacitinib (a JAK inhibitor) versus tofacitinib alone, Spencer Danto and team carried out this investigation.

The patients with moderate to severe active RA were randomly assigned to receive zimlovisertib 400 mg plus tofacitinib 11 mg, zimlovisertib 400 mg plus ritlecitinib 100 mg, ritlecitinib 100 mg, zimlovisertib 400 mg, or tofacitinib 11 mg (4:4:3:3:4) for a duration of 24 weeks in this phase 2 trial. Change from baseline (CFB) in Disease Activity Score in 28 joints and C-reactive protein (DAS28-CRP) at week 12 were the main endpoints. TEAEs (treatment-emergent adverse events) were tracked.

A total of 460 patients underwent randomization. At week 12, the mean CFB in DAS28-CRP was higher for zimlovisertib+tofacitinib than for tofacitinib and the mean CFB for zimlovisertib+ritlecitinib was comparable to that of tofacitinib.

The tofacitinib group had the greatest aggregate incidence of TEAEs (n = 60 [58.8%]), with 246 (53.5%) patients reporting TEAEs. The majority of TEAEs were mild, where 10 patients reported significant AEs, and 9 patients (2.0%) suffered severe TEAEs.

A serious COVID-19 infection claimed the life of one tofacitinib-treated patient. There was no indication of additive or synergistic problems, and safety profiles were comparable for all treatment groups. Overall, for the main endpoint, zimlovisertib+tofacitinib outperformed tofacitinib. However, zimlovisertib+ritlecitinib's effectiveness did not reach statistical significance when compared to tofacitinib. 

Reference:

Danto, S. I., Salganik, M., Banerjee, A., Hrycaj, P., Jashi, I., Shojaee, N., Singh, R. S. P., Gilbert, S. A., Page, K., Peeva, E., Vincent, M. S., & Beebe, J. S. (2025). Efficacy and safety of zimlovisertib, ritlecitinib and tofacitinib, alone and in combination, in patients with moderate to severe rheumatoid arthritis and an inadequate response to methotrexate. Arthritis & Rheumatology. https://doi.org/10.1002/art.43184