FROM ARTHRITIS & RHEUMATOLOGY
A 12-week course of daily oral peficitinib improved the severity of refractory rheumatoid arthritis in a manufacturer-sponsored phase II trial of the investigational drug, which inhibits all of the intracellular signaling molecules in the Janus kinase family.
The randomized, double-blind dose-finding study was performed at 41 sites in six countries and involved 289 adults with long-standing moderate to severe rheumatoid arthritis (RA) who had not responded to or who were intolerant of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). The participants were permitted to take nonsteroidal anti-inflammatory drugs, hydroxychloroquine, chloroquine, sulfasalazine, and/or oral corticosteroids (10 mg or less of prednisone or equivalent) as needed throughout the trial, but not methotrexate, gold, penicillamine, leflunomide, azathioprine, minocycline, and cyclophosphamide. The patients also were allowed to have previously taken a biologic and were not required to have had an inadequate response or intolerance to a previous biologic, said Mark C. Genovese, MD, of the division of immunology and rheumatology at Stanford University, Palo Alto, Calif., and his associates.
The study participants were randomly assigned to take 25 mg (59 patients), 50 mg (57 patients), 100 mg (58 patients), or 150 mg (64 patients) of peficitinib or a matching placebo (51 patients). The primary efficacy endpoint – the percentage of patients achieving an ACR20 level of improvement at week 12 – was significantly higher in patients taking the 100-mg dose (48.3%) and the 150-mg dose (56.3%) than in those taking placebo (29.4%). This treatment benefit was noted within 2 weeks of beginning the therapy and persisted throughout the study, the investigators reported ( Arthritis Rheumatol. 2017 Jan 24. doi: 10.1002/art.40054 ).
Patients receiving the two highest doses of peficitinib also showed a significant improvement in 28-joint Disease Activity Score, compared with those receiving placebo.
On safety outcomes, the investigators reported that peficitinib “demonstrated satisfactory tolerability” with an overall incidence of adverse events similar to that of the placebo group, and there were no new safety signals that differed from the other two previous phase II trials of peficitinib for RA. There were dose-dependent decreases in absolute neutrophil count, platelet count, and white blood cell count, as well as dose-dependent increases in creatine phosphokinase, high-density lipoprotein, and creatinine levels. Three cases of grade 3 or higher hypertriglyceridemia were considered to be drug related, and 10 patients discontinued peficitinib because of dyspepsia, nausea, vomiting, abdominal hernia, hidradenitis, skin lesions, MI, or limb abscess.
Peficitinib inhibits JAK1, JAK2, JAK3, and Tyk2 enzyme activities, with a moderate selectivity for JAK3. Two other phase II efficacy and safety studies of peficitinib have been conducted previously. One of these involved Japanese patients who were not required to fail one or more csDMARDs and received the same doses as in the current study. The 12-week study resulted in statistically significant improvements in ACR20 responses in patients who took 50-mg, 100-mg, and 150-mg doses of peficitinib monotherapy. The second 12-week phase II trial of peficitinib plus methotrexate in patients who had an inadequate response to methotrexate found that the combination was statistically significantly better than placebo plus methotrexate in ACR20 response rate only among those who took 50 mg.
Larger and longer-term phase III trials of the 100-mg and 150-mg doses of peficitinib are now underway, Dr. Genovese and his associates added. One trial is comparing peficitinib alone or in combination with DMARDs against placebo or an open-label active comparator, etanercept, for 52 weeks in patients who had an inadequate response to DMARDs. The other is a 52-week trial comparing peficitinib in combination with methotrexate versus placebo and methotrexate in patients who had an inadequate response to methotrexate.
The phase II trial was sponsored by Astellas Pharma. Dr. Genovese reported ties to Astellas, AbbVie, Johnson & Johnson, Pfizer, Eli Lilly, Vertex, Galapagos NV, and Gilead Sciences; his associates reported ties to numerous industry sources.