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TOPLINE:

Zimlovisertib plus tofacitinib showed greater efficacy than tofacitinib alone in reducing Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) in patients with rheumatoid arthritis (RA), with a significant reduction observed at week 12.

METHODOLOGY:

• This randomized, phase 2 study, conducted across 77 centers in 10 countries, aimed to evaluate the efficacy, safety, and pharmacokinetic profiles of zimlovisertib in combination with tofacitinib or ritlecitinib compared with tofacitinib alone in 460 patients (age, 18-70 years) with moderate to severe RA.
• Participants were randomly assigned to five groups: 400 mg zimlovisertib modified release (MR) + 11 mg tofacitinib MR (n = 103), 400 mg zimlovisertib MR + 100 mg ritlecitinib (n = 101), 400 mg zimlovisertib MR (n = 77), 100 mg ritlecitinib (n = 77), or 11 mg tofacitinib MR (n = 102).
• A screening period of ≤ 28 days was followed by a 24-week treatment period and a 4-week follow-up period without treatment.
• The primary endpoint was the change from baseline in DAS28-CRP at week 12; the secondary endpoint included DAS28-CRP remission rates at week 24.
• Patients were required to discontinue methotrexate prior to randomization and were monitored for treatment-emergent adverse events (TEAEs) throughout the study.

TAKEAWAY:

• Overall, 88.7% of patients continued treatment at week 12, and 69.8% continued treatment at week 24; the main reason for discontinuation was failure to achieve the protocol-specific requirement of at least 20% improvement in American College of Rheumatology response criteria by week 12.
• Zimlovisertib plus tofacitinib resulted in a greater reduction in DAS28-CRP scores at week 12 than tofacitinib alone (mean change in scores from baseline, −2.65 vs −2.30; P = .032), but the reduction achieved with zimlovisertib plus ritlecitinib vs tofacitinib was not statistically significant.
• The combination of zimlovisertib and tofacitinib resulted in a higher proportion of patients achieving DAS28-CRP remission at week 24 than tofacitinib alone (40.8% vs 24.0%).
• TEAEs were reported in 53.5% of patients, with the highest incidence in the tofacitinib monotherapy group (58.8%) and similar rates across all treatment groups. Infections and infestations were the most common TEAEs, affecting 12.6% of patients in the zimlovisertib plus tofacitinib group.

IN PRACTICE:

“While improvements in clinical efficacy were seen with the combination groups vs monotherapies, there did not appear to be any increase in incidence, type, and severity of TEAEs,” the authors wrote.

SOURCE:

This study was led by Spencer I. Danto, MD, PhD, Pfizer Inc., Cambridge, Massachusetts. It was published online on April 14, 2025, in Arthritis & Rheumatology.

LIMITATIONS:

The relatively small sample size limited the generalizability of the findings. The lack of a placebo control group could have introduced bias and affected the interpretation of the results. Additionally, the study’s design included programmatic discontinuation of nonresponders, which may have influenced the observed outcomes.

DISCLOSURES:

This study was funded by Pfizer. About 10 of the 12 authors reported being employees and shareholders of Pfizer. One author reported receiving principal investigator’s grants and grants to support educational activities for physicians and employees from Pfizer.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.