At the 2018 American College of Rheumatology and the Association of Rheumatology Health Professionals (ACR/ARHP) Annual Meeting, in an abstract session dedicated to JAK inhibitors in the treatment of RA, Dr Yoshiya Tanaka presented much-awaited details from Astellas’ RAJ 3 and RAJ4 trials—the basis of the company’s recent marketing approval submission to Japan’s PMDA.

Overall, peficitinib met all established primary efficacy endpoints and did not demonstrate any new or unexpected safety concerns. Based on these analyses, GlobalData believes it is highly likely that the drug will be approved and marketed in Japan within the next one to two years.

The RAJ3 study was conducted in patients with active rheumatoid arthritis (RA) and an inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) from Japan, Korea, and Taiwan. Patients were randomised to 52 weeks of treatment with placebo, peficitinib at 100mg or 150mg per day, or open-label etanercept at 50mg per week.

Patients that were already receiving stable doses of csDMARDs were allowed to continue them throughout the study. At Week 12, patients receiving peficitinib at either dose had significantly higher ACR20 response rates (57.7%/74.5%) in comparison to placebo (30.7%) and also showed significant improvements in a number of other secondary endpoints including ACR50, DAS28-CRP<2.6, ESR, and CRP.

Results of peficitinib studies

Notably, dosing with 150mg peficitinib consistently resulted in better efficacy compared to dosing with 100mg.  Although efficacy data were also presented for the etanercept arm, this group should not be directly compared to peficitinib treatment arms because of its open-label status and design as a safety comparator only.

RAJ4 enrolled Japanese patients with active RA who had shown inadequate responses to methotrexate (MTX). Patients were randomised to 52 weeks therapy with MTX or peficitinib at 100mg/150mg per day in combination with MTX (generally about 10mg weekly).

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Both peficitinib treatment arms met the primary efficacy endpoints of ACR20 response rate in comparison to placebo at Week 12 (58.6%/64.4% vs. 21.8%) and the mean change in mTSS from baseline at Week 28. While the peficitinib groups had mean changes in mTSS of 1.0 and 1.6, the placebo group showed a significantly faster rate of radiographic progression with a change in mTSS from baseline of 3.4.

In both Phase III studies, the occurrence of adverse events (AEs) and serious AEs was fairly similar across all study groups, including placebo. However, peficitinib did show many of the typical safety signals seen with other JAK inhibitors. Firstly, at the Week 12 time points, peficitinib-treated groups showed a low but increased risk of serious infection, herpes zoster-related disease, and malignancy.

Interestingly, the etanercept group in the RAJ3 trial showed similar outcomes for serious infections. In regards to haematology and laboratory parameters, peficitinib treatment resulted in an increase from baseline in serum creatinine, creatinine kinase, ALT, and HDL/LDL cholesterol, as well as a decrease in the platelet and absolute neutrophil counts.

Notably, etanercept-treated patients demonstrated a similar pattern of changes from baseline and in certain parameters showed even more drastic changes compared to peficitinib-treated patients. At the end of the full 52 week study period, the trends in laboratory parameters were similar to those seen at 12 weeks.

In both studies, Dr Tanaka noted that although there were clear dose-dependent effects in the efficacy of peficitinib, safety did not seem to be significantly worsened by increased dose. For this reason, he posited that the 150mg dose would likely be the dose of choice going forward.

Based on the newly presented Phase III data, GlobalData projects that peficitinib will be launched in Japan in the next one to two years and will likely occupy a similar niche as Pfizer’s Xeljanz (tofacitinib). The amount of market share peficitinib can obtain within the RA indication is currently unclear but will depend heavily on Astellas’ ability to promote the product in Japan and possibly expand development to other geographical markets.