NEW YORK – Among new medications under development for rheumatoid arthritis, oral Janus kinase inhibitors appear to be close to coming to market and have strong supportive clinical data, according to Dr. Martin Jan Bergman at a course sponsored by New York University.
Unlike most drugs for RA that affect extracellular cytokines, oral JAK inhibitors are small molecules that act to disrupt one of the intracellular signal pathways used by some cytokines to regulate immune and regulatory responses. Of this family of drugs, Pfizer’s tofacitinib primarily targets JAK3 (the JAK protein kinase that is most associated with inflammation), although it also overlaps to JAK1 and JAK2.
On Dec. 20, Pfizer announced that the Food and Drug Administration has accepted a New Drug Application for tofacitinib, formerly known as tasocitinib. About 1 month earlier, the European Medicines Agency had taken similar action, according to Pfizer.
According to Pfizer, nearly 5,000 patients with RA have undergone treatment in clinical trials of tofacitinib held at more than 350 sites in 35 countries worldwide. The data come primarily from the ORAL (Oral Rheumatoid Arthritis Phase III) trials, comprising five studies for which the data necessary for registration are complete, and one ongoing phase III trial. Two long-term, open-label extension studies are also ongoing.
During his presentation, Dr. Bergman reviewed data presented in 2001 at the annual European Congress of Rheumatology by Dr. Joel M. Kremer, head of the division of rheumatology at Albany (N.Y.) Medical College. Those data concerned the effects of tofacitinib in patients whose active RA had not responded to therapy with DMARDs (disease-modifying antirheumatic drugs). Patients received tofacitinib in doses of either 5 mg or 10 mg, in combination with background DMARDs. In this double-blind, placebo-controlled, randomized study of 792 patients, any patient in the placebo group who had not met the target efficacy response by 3 months was switched to tofacitinib 5 mg or 10 mg. All remaining placebo-treated patients were switched to tofacitinib by 6 months. At 6 months, 52.7% in those treated with tofacitinib 5 mg achieved ACR 20 (defined as 20% improvement on an American College of Rheumatology evaluation scale), as did 58.3% in those treated at the 10-mg dose, a response significantly greater than the placebo group. "Now we are starting to see levels that we see with [tumor necrosis factor] inhibitors," said Dr. Bergman of Drexel University in Philadelphia.
Dr. Kremer also found significant improvement on the DAS28-4 (ESR) – that is, the Disease Activity Score including a 28-joint count and the erythrocyte sedimentation rate – less than 2.6 for both doses of tofacitinib, as well as on the HAQ-DI (Health Assessment Questionnaire–Disability Index). "The minimally clinically important (MCI) difference for the HAQ-DI is 0.21 or 0.23; patients on tofacitinib had double the MCI improvement," noted Dr. Bergman, referring to the change of –0.46 for the 5-mg dose and –0.56 for the 10-mg dose (P less than .001, compared with placebo, for both differences). "What we see is very reassuring."
Dr. Bergman then highlighted some of data included in nine abstracts presented on tofacitinib at the 2011 annual meeting of the American College of Rheumatology. Dr. Roy M. Fleischmann of the University of Texas Southwestern Medical Center, Dallas, addressed the question of whether tofacitinib’s efficacy and safety hold up against the standard of care, such as a tumor necrosis factor (TNF) inhibitor (Arthritis Rheum. 2011;63[suppl.]:S153; abstract 408). In this 12-month trial, 717 patients were randomized to tofacitinib (5 mg or 10 mg twice daily), adalimumab (40-mg subcutaneous injections every 2 weeks), or placebo. "This was not a head-to-head trial, but rather comparability vs. placebo," commented Dr. Bergman. The results showed that tofacitinib 5 mg and 10 mg, as well as adalimumab, were statistically superior to placebo for all primary efficacy end points, and efficacy results for tofacitinib and adalimumab were numerically similar. "The ACR 20 responses (tofacitinib 5 mg, 51.5%; tofacitinib 10 mg, 52.6%; adalimumab, 47.2%) are very robust and comparable to the responses we see [with anti-TNFs] all the time," he added.
Tofacitinib also holds promise as a rescue therapy for RA patients with inadequate response to TNF inhibitors, as suggested by the results of a study by Dr. Gerd-Rüdiger Burmester of Charité Medical University Berlin (Arthritis Rheum. 2011;63[suppl.]:S279; abstract 718). In this 6-month study of 399 patients who were randomized to 5 mg or 10 mg of tofacitinib or placebo (or who were first treated with placebo and then given tofacitinib), rapid, significant and clinically meaningful improvements were noted in the signs and symptoms of RA (according to ACR 20/50/70 scores), physical functioning (per HAQ-DI scores) and disease activity (per DAS28-4 [ESR] scores less than 2.6). After looking at the ACR responses of the group that was initially given placebo and then 5-mg tofacitinib, Dr. Bergman commented that the 6-month ACR 20/50/70 responses (45.5, 28.79, and 10.6, respectively) were "identical to what we see with all of the rescue therapies currently available."