Pfizer Inc. announced top-line results from the ORAL Standard (A3921064) and ORAL Step (A3921032) phase 3 studies of tofacitinib (development code: CP-690,550), an investigational, novel, oral JAK inhibitor.

ORAL Standard is a completed twelve-month study in patients with moderate-to-severe active rheumatoid arthritis (RA) who had an inadequate response to methotrexate (MTX) and were randomized to receive tofacitinib 5 or 10 mg BID, adalimumab 40 mg subcutaneously every other week or placebo, each of which was added to stable background MTX.

The ORAL Standard study met all primary endpoints at the 5 and 10 mg BID doses of tofacitinib, showing statistically significant changes versus placebo in reducing signs and symptoms of RA, as measured by ACR20 response rates at six months; in improving physical function, as measured by mean change in HAQ DI at three months; and in reaching DAS28-4(ESR) <2.6 at six months.

ORAL Step is a completed six-month study in patients with moderate-to-severe active RA who had an inadequate response to a TNF inhibitor and were randomized to receive tofacitinib 5 or 10 mg BID or placebo, which were added to stable background MTX.

The ORAL Step study met all primary endpoints at the 5 and 10 mg BID doses, showing statistically significant changes versus placebo in reducing signs and symptoms of RA, as measured by ACR20 response rates; in improving physical function, as measured by mean change in HAQ DI; and in reaching DAS28-4(ESR) <2.6, all assessed at three months.

No new safety signals emerged in the ORAL Standard and ORAL Step studies. The efficacy and safety profile of tofacitinib in these studies remains consistent with that seen previously in the clinical programme.

A detailed analysis of the ORAL Standard and ORAL Step efficacy and safety data, including secondary endpoints which are not reported here, will be submitted to a future scientific meeting.

ORAL Standard is a twelve-month study that enrolled 717 patients with moderate-to-severe active RA who had an inadequate response to MTX to receive tofacitinib 5 or 10 mg BID or adalimumab 40 mg subcutaneously every other week or placebo, each of which was added to stable background MTX. Patients who had previously received adalimumab or had an inadequate response to a TNF inhibitor were excluded from participation. Patients were randomized such that at the month-three visit, nonresponding placebo-assigned patients were advanced in a blinded fashion to a predetermined treatment of tofacitinib, 5 or 10 mg BID, for the remainder of the study; at the end of six months, all placebo-assigned patients were advanced to their predetermined tofacitinib treatment assignment in a blinded fashion for the remainder of the study. Those patients assigned to 5 or 10 mg BID tofacitinib or adalimumab 40 mg every other week at the start of study remained on those dose regimens throughout the 12 months of the study.

ORAL Step is a six-month study that enrolled 399 patients with moderate-to-severe active RA who had an inadequate response to at least one TNF inhibitor to receive tofacitinib 5 or 10 mg BID or placebo added to stable background MTX. Those patients were randomized such that at the month-three visit, placebo-assigned patients were advanced in a blinded fashion to a predetermined treatment of tofacitinib, 5 or 10 mg BID, for the remainder of the study. Those patients assigned to 5 or 10 mg BID tofacitinib at the start of study remained on those dose regimens throughout the six months of the study.

Tofacitinib is a novel, oral Janus kinase (JAK) inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for RA. More than 4,000 RA patients have been treated with tofacitinib in clinical trials to date. Unlike more recent therapies for RA, which are directed at extracellular targets such as pro-inflammatory cytokines, tofacitinib takes a novel approach, targeting the intracellular signaling pathways that operate as hubs in the inflammatory cytokine network.

Pfizer is studying tofacitinib for RA in the phase 3 ORAL (Oral Rheumatoid Arthritis phase 3 TriaLs) programme, which consists of five pivotal trials and a sixth long-term treatment study at more than 350 locations in 35 countries worldwide. ORAL Standard and ORAL Step are the final two pivotal trials in the programme.
 
Pfizer is also studying orally administered tofacitinib in psoriasis, inflammatory bowel disease (Crohn’s disease and ulcerative colitis) and renal transplant, and topical tofacitinib in both psoriasis and dry eye disease.

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