Espicom View: These approvals are a further step in Xeljanz's worldwide commercialisation, but are another example of the different opinions held by the various regulatory bodies overseeing drug approvals. Pfizer will have to satisfy concerns over Xeljanz's benefit-risk profile, plus the need for additional data on the 10mg twice daily dose, if it is to tap into the drug's full potential, especially in the lucrative European market. Meanwhile, Xeljanz has additional revenue-generating possibilities in the autoimmune area, being in Phase III development for ulcerative colitis and psoriasis (oral), and Phase II for psoriatic arthritis, ankylosing spondylitis, psoriasis (topical) and Crohn's disease.
Pfizer's Xeljanz (tofacitinib) has been approved for the treatment of rheumatoid arthritis (RA) in patients who had an inadequate response to existing therapies, in several additional countries around the world, including Switzerland, which is the first European country to receive approval. Swissmedic approved Xeljanz 5 and 10mg twice daily (bid) as monotherapy or in combination with a disease-modifying non-biologic antirheumatic agent, including methotrexate (MTX), in adult patients with moderate-to-severe active RA who have had an inadequate response or intolerance to MTX. Xeljanz 5mg bid has also been approved in Argentina, Kuwait and the United Arab Emirates (UAE), and Xeljanz 5 and 10mg bid has been approved in Russia. The brandname in the approved markets will be Xeljanz, except for Russia, where it will be Jaquinus.
Xeljanz is a novel, oral JAK inhibitor for the treatment of RA. Unlike recent therapies for RA, which are directed at extracellular targets such as pro-inflammatory cytokines, Xeljanz takes a novel approach targeting the intracellular pathways that operate as hubs in the inflammatory cytokine network.
Xeljanz 5mg bid is also approved in the US and Japan for the treatment of moderate-to-severe active RA. Xeljanz was launched in the US in November 2012, and is expected to be commercially available in Japan in July 2013, following approval by the Japanese Ministry of Health, Labour and Welfare in March. Xeljanz will be co-promoted in Japan by Pfizer and Takeda. Initially, Xeljanz will be made available in Japan to medical institutions participating in an all-patient surveillance programme, designed by Pfizer in collaboration with Japan's Pharmaceuticals and Medical Devices Agency and the Japan College of Rheumatology.
The recent marketing authorisations were based on data from the comprehensive, global, multi-study clinical development programme for Xeljanz, which included approximately 5,000 patients in more than 40 countries, resulting in 7,000 patient-years of experience at the time of regulatory submission.
Notable safety findings observed in the Xeljanz RA programme include serious and other important infections, including tuberculosis and Herpes zoster; malignancies, including lymphoma; gastrointestinal perforations; decreased neutrophil and lymphocyte counts; and lipid elevations. The most common serious adverse events (AEs) were serious infections. The most commonly reported AEs were upper respiratory tract infections, headache, nasopharyngitis and diarrhoea.
Regulatory applications for Xeljanz for the treatment of moderate-to-severe active RA remain under review in more than 30 additional countries. In Europe, Pfizer is seeking a re-examination of the CHMP negative opinion that was announced in April, and the company is currently working with the CHMP on the next steps in the process.
The CHMP was of the opinion that Xeljanz did not demonstrate a favourable risk-benefit profile at that time and recommended against marketing authorisation. The Committee considered that treatment with Xeljanz resulted in an improvement in the signs and symptoms of RA and the physical function of patients, but did not believe that a consistent reduction in disease activity and structural damage to joints had been sufficiently demonstrated. The CHMP also raised questions about the serious infections, gastrointestinal perforations and malignancies observed in Xeljanz trials.
In the US, the FDA approved the 5mg bid dose in the second-line setting and indicated that further data were required to assess the benefit-risk profile of the 10mg bid dose. In addition, the Agency approved Xeljanz with a Risk Evaluation and Mitigation Strategy. Pfizer agreed to conduct post-marketing clinical trials to evaluate the long-term safety of the drug and to assess it in the paediatric population with polyarticular juvenile idiopathic arthritis. In June 2013, it was reported that the FDA had accepted for review an sNDA for the Xeljanz RA indication seeking expansion of the label to include inhibition of progression of structural damage. The Agency is expected to provide a decision by February 2014, based on the anticipated PDUFA action date for the application.