Peficitinib shows promise for RA patients with insufficient response to DMARDs, methotrexate

The novel oral pan-Janus kinase (JAK) inhibitor peficitinib showed superior efficacy and safety over placebo in patients with rheumatoid arthritis (RA) who have insufficient response to prior disease-modifying antirheumatic drugs (DMARDs) and methotrexate, the phase III RAJ3 and 4 trials show.

 

RAJ3: insufficient response to DMARDs

A total of 507 RA patients (mean age 55.3 years, 72.2 percent female) with insufficient response to prior DMARDs were randomized 1:1:1:2 to receive once-daily peficitinib 100 or 150 mg, placebo, or subcutaneous open-label etanercept* for 52 weeks. Placebo recipients were switched to peficitinib 100 or 150 mg at week 12. [Ann Rheum Dis 2019;78:1320-1332]

At week 12, ACR20** response rates were significantly higher with peficitinib 100 and 150 mg vs placebo (57.7 percent vs 30.7 percent; odds ratio [OR], 3.13 [100 mg] and 74.5 percent vs 30.7 percent; OR, 6.59 [150 mg]; p<0.001 for both).

“[ACR20 responses were rapid] through the first 4–8 weeks … which were either maintained or improved … up to week 52. Even in the placebo group, improvements were observed after switching to peficitinib 100 or 150 mg and then maintained during the study,” said the researchers.

Changes in DAS28-CRP*** and ACR core parameters^# at week 12 were significantly greater for both peficitinib doses vs placebo (p<0.001), with greater changes in the peficitinib 150- vs 100-mg arm across all outcomes.

Adverse event rates were similar across treatment arms, ranging from 54–59 percent. Both peficitinib doses generated higher incidences of serious infections (88.2 and 92.1 patient-years [PY] for 100 and 150 mg, respectively, vs 22.6 PY) and herpes zoster (HZ)-related diseases (86.8 and 90.9 PY, respectively, vs 22.6 PY) than placebo but without clear dose-dependent increase.

Previous evidence had demonstrated the risk of developing HZ among Asians receiving JAK inhibitors. [Arthritis Rheumatol 2014;66:2675-684] In the current study, the incidence of HZ-related disease was roughly doubled with peficitinib vs etanercept, but this remained within the range observed with other JAK inhibitors in other Asian cohorts. [Ann Rheum Dis 2017;76:1253-1262; Mod Rheumatol 2018;28:20-29] “As historical data of vaccination for HZ or varicella in each patient were not captured in this study, the relationship between the observed incidence and vaccination rate is unknown … further investigation would be required to elucidate this,” said the researchers.

Although the study allowed for long-term evaluation, the short treatment duration in the placebo arm could be a limiting factor. There is also a lack of global diversity as the population was confined to individuals from Japan, Korea, and Taiwan, added the researchers.

“[Nonetheless, our findings suggest that] peficitinib may be a viable treatment option for patients who fail to respond to previous lines of therapy with other biological and nonbiological DMARDs,” they said.

Despite the apparently greater improvements with the higher peficitinib dose, the researchers called for further trials to ascertain the ability of a higher dose to generate greater clinical benefits without additional safety issues.

In an animal study, tyrosine kinase 2 (TYK2)-deficient mice were resistant to collagen antibody-induced arthritis, suggesting the role of TYK2 in the development of inflammatory arthritis. [Int Immunol 2011;23:575-582] “TYK2 inhibition may contribute to the clinical efficacy of peficitinib in RA patients … [A]dditional investigation is necessary to elucidate the involvement of TYK2 in the pathogenesis of RA,” said the researchers.

 

RAJ4: insufficient response to methotrexate

Peficitinib remained superior to placebo in a separate Japanese study on RA patients (n=519; mean age 56.7 years, 70.3 percent female) with inadequate response to methotrexate. As in RAJ3, ACR20 response rates were significantly higher with peficitinib vs placebo (58.6 percent [100 mg] and 64.4 percent [150 mg] vs 21.8 percent; p<0.001 for both). [Ann Rheum Dis 2019;78:1305-1319]

Radiographic changes were also evident as reflected by the significant reduction in the van der Heijde-modified total Sharp score from baseline with peficitinib 100 and 150 mg vs placebo (mean, 1.62 and 1.03, respectively, vs 3.37; p<0.001), suggesting the structural efficacy of peficitinib.

Safety outcomes mirrored those in RAJ3, with both peficitinib doses leading to increased incidences of serious infections (159.5 and 160.8 PY for 100 and 150 mg, respectively, vs 62.9 PY) and HZ-related disease (156.2 and 159.8 PY, respectively, vs 62.6 PY) vs placebo.

“[Our findings demonstrated] the significant superiority [of peficitinib over] placebo in reducing RA symptoms and suppressing joint destruction … [among] Japanese patients with RA and inadequate response to methotrexate,” said the RAJ4 investigators. An extension study is underway to confirm the persistence of treatment response with peficitinib and to ascertain its long-term safety.

 

The new kid on the block?

Despite the multitude of treatment modalities currently available for RA, these have restricted efficacy. [J Autoimmun 2015;65:1-18] “Patients either fail to respond to biological treatment or only a fraction achieve complete remission … [Therefore,] new treatment options with mechanisms of action distinct from those of conventional synthetic DMARDs are needed,” said the RAJ4 investigators.

Researchers of both trials concur that peficitinib has the potential to be a valuable addition to the RA treatment armamentarium, particularly for RA patients with more restricted treatment options.