Pfizer Novel RA Drug Passes Mid-Stage Test

 

• The combination of tofacitinib plus zimlovisertib improved outcomes over tofacitinib alone in patients with rheumatoid arthritis.
• Ritlecitinib failed to show additive efficacy in rheumatoid arthritis when combined with tofacitinib.
• Rheumatologists have been more wary of using multiple targeted therapies for fear of excessive immune suppression.

Combining the Janus kinase (JAK) inhibitor tofacitinib (Xeljanz) with an investigational oral drug targeting a different type of kinase enzyme was more effective against rheumatoid arthritis (RA) than tofacitinib alone in a phase II study, researchers reported.

Patients receiving the combination of tofacitinib and zimlovisertib -- an inhibitor of the interleukin-1 receptor-associated kinase 4 (IRAK4) -- for 12 weeks showed significantly greater improvement in 28-joint Disease Activity Score (DAS28) values than did a group assigned to tofacitinib alone, according to Spencer Danto, MD, PhD, of Pfizer's lab in Cambridge, Massachusetts, and colleagues writing in Arthritis & Rheumatologyopens in a new tab or window.

Disappointingly, a third drug also tested in the study failed to show additive efficacy in RA when combined with tofacitinib -- ritlecitinib (Litfulo), approved in 2023 for alopecia areataopens in a new tab or window, which inhibits both JAK3 and so-called TEC enzymesopens in a new tab or window (tyrosine kinases expressed in hepatocellular carcinoma). Pfizer has sought to broaden its indications to a variety of other autoimmune conditions, and while it missed its endpoints in the current study, Danto and colleagues pointed to "encouraging trends" that could support another study with more prolonged treatment.

While drug combinations are commonplace in RA treatment, those typically involve a targeted drug plus a broader and milder old-line immunosuppressant such as methotrexate. Rheumatologists have been more wary of using multiple targeted therapies for fear of excessive immune suppression. As it is, single drugs such as JAK inhibitorsopens in a new tab or window and tumor necrosis factor blockersopens in a new tab or window come with boxed warnings about increased infection risk.

Danto's group believed, however, that combining zimlovisertib or ritlecitinib with tofacitinib would not have a worse safety profile than the latter alone, while efficacy could be increased. That proved to be the case, at least for zimlovisertib plus tofacitinib.

The researchers enrolled 460 RA patients who had not responded adequately to methotrexate, randomizing them to five groups: each of the three drugs alone and combinations of tofacitinib with each of the other two. Methotrexate was discontinued. Treatment lasted 24 weeks, but the primary endpoint -- change from baseline in DAS28 as modified by C-reactive protein (CRP) level -- was taken at week 12. A key secondary endpoint was the responder rate at week 24, i.e., the fraction of patients with DAS28-CRP values less than 2.6, indicating clinical remission.

Patients were in their early 50s on average, and some 80% were women. Nearly all were white (most participants were from Eastern Europe and Chile). Mean disease duration was about 8 years. DAS28-CRP scores averaged 6.1 to 6.4 in the five treatment groups at baseline. Roughly 15% had tried a tumor necrosis factor inhibitor.

About 100 patients each were randomized to tofacitinib monotherapy and the two combination groups; 77 each received zimlovisertib or ritlecitinib monotherapy, according to the investigators' 4:4:4:3:3 randomization scheme.

Change from baseline in DAS28-CRP values for the five groups at week 12 were as follows:

• Tofacitinib monotherapy: -2.30 (90% CI -2.49 to -2.11)
• Ritlecitinib monotherapy: -2.21 (90% CI -2.44 to -1.99)
• Zimlovisertib monotherapy: -1.82 (90% CI -2.04 to -1.61)
• Zimlovisertib plus tofacitinib: -2.65 (90% CI -2.83 to -2.46)
• Ritlecitinib plus tofacitinib: -2.35 (90% CI -2.54 to -2.15)

As can be seen, the only group to show a significant advantage over tofacitinib alone was the one receiving it in combination with zimlovisertib. At week 24, the zimlovisertib combination group still showed significantly greater improvement in DAS28-CRP scores than the tofacitinib monotherapy arm (difference -0.39, 90% CI -0.69 to -0.09). Meanwhile, zimlovisertib monotherapy had a significant disadvantage compared with tofacitinib alone at week 24 (difference 0.41, 90% CI 0.08-0.74).

No significant differences in responder rates were seen at week 12, though the zimlovisertib combination enjoyed a numerical advantage (19.2% vs 16.8%). By week 24, responder rates for the zimlovisertib combination reached 40.1%, versus 24% for tofacitinib monotherapy (difference 16.8%, 90% CI 3.8-27.4). The ritlecitinib combination, with a responder rate of 31.3% at week 24, showed a nonsignificant numerical advantage.

A more important finding, perhaps, was that the combination therapies didn't appear any more risky than tofacitinib alone. Rates of treatment-emergent adverse events were very similar across all five groups (49.4% to 58.8%), with the highest rate seen with tofacitinib alone. Serious (10 total) and severe adverse events (nine total) were rare and weren't noticeably more common with the combinations than tofacitinib monotherapy. There was maybe a hint of more infection risk with the combinations (11.9% and 12.6% of patients in those groups vs 10.8% with tofacitinib alone). Also, a few patients receiving zimlovisertib, either alone or with tofacitinib, showed moderate elevations in liver enzymes.

All in all, Danto and colleagues concluded, "both combination treatments were well tolerated, with acceptable safety profiles." They noted that the study was conducted during the pandemic and some of the adverse events were related to COVID-19. The lack of a placebo group, though, was a significant limitation, both for efficacy and for safety analyses.

Pfizer's plans for zimlovisertib remain uncertain. No ongoing or planned trials are listed on Clinicaltrials.gov for this agent, and the company has made no announcements about it.

Disclosures

The study was funded by Pfizer.

Danto and most other authors were Pfizer employees.

Primary Source

Arthritis & Rheumatology

Source Reference: opens in a new tab or windowDanto SI, et al "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 Rheumatol 2025; DOI: 10.1002/art.43184.

https://www.medpagetoday.com/rheumatology/arthritis/115171