Pfizer can request a re-examination of the opinion with the next 15 days, EMA (European Medicines Agency) informed.
Xelianz is intended as treatment for moderate to severe active rheumatoid arthritis, a disease of the immune system which damages and inflames the joints. It is designed to be used in patients who did not respond to or could not tolerate at least two other DMARDs (disease-modifying antirheumatic drugs), including biological DMARDs.
Biological DMARDs target specific immune system proteins. They are produced using recombinant DNA technology and are made by cells that have been genetically altered to produce the medicine.
How does Xelianz work?Tofacitinib, the active ingredient of Xeljanz, is an immunosuppressant that blocks the action of Janus kinases, enzymes that play a crucial role in the process of inflammation and damage of the joints. Tofacitinib, by blocking the enzymes, reduces the inflammation and other symptoms of rheumatoid arthritis.
What did Pfizer present to support its application for approval?Xeljanz' effects were initially tested on animals before being studied in humans.
Pfizer supplied CHMP with the results of five human studies which focused on the drug's safety and efficacy. 3,300 patients with rheumatoid arthritis took part.
The studies compared 5mg or 10mg of Xeljanz twice daily with placebo, either alone or in combination with other DMARDs. Effectiveness was measured according to patient scores for signs and symptoms of rheumatoid arthritis, including their physical function, disease activity and structural damage to joints. Studies ranged from three to six months.
Why did CHMP advise turning down the application?Although the Committee found that Xeljanz improved patients' signs and symptoms as well as physical function "(the studies) were not sufficient to show a consistent reduction in disease activity and structural damage to joints, particularly at the lower 5-mg dose of Xeljanz and in the target population of patients in whom treatment with at least two other DMARDs has been unsuccessful."
There were also serious concerns about Xeljanz' overall safety. The Committee said there were considerable and unresolved concerns regarding the risk and type of serious infections associated with tofacitinib, which are not related to the medication's immunosuppressant action.
The Committee was also concerned about the raised risk of other serious side effects, such as liver damage, problems with increased lipid blood levels, certain cancers, and gastro-intestinal perforations.
The Committee added "It was not clear that these risks could be managed successfully in medical practice. Therefore, at that point in time, the CHMP was of the opinion that the benefits of Xeljanz did not outweigh its risks and recommended that it be refused marketing authorisation."
What was Pfizer's response?Dr. Yvonne Greenstreet, senior vice president and the head of the Medicines Development Group for Pfizer Specialty Care, said:
"We have confidence in XELJANZ and believe our application to the EMA demonstrates that XELJANZ has a favorable risk:benefit profile.
XELJANZ's safety profile is well-characterized, and the issues raised by the EMA, including serious infections, gastrointestinal perforations and malignancies, are familiar to rheumatologists who are experienced working with treatments for patients to manage this difficult disease.
Each regulatory authority will review and interpret applications individually and different assessments are not uncommon.
The re-examination process will enable us to seek to address the CHMP's questions, and we will continue to work closely with the EMA with the goal of making this medicine available to appropriate patients in Europe."
US FDA approved Xeljanz in 2012In November 2012, the US Food and Drug Administration approved Xeljanz (tofacitinib) for patients with rheumatoid arthritis who have an insufficient or allergic response to methotrexate, as treatment for fiercely active rheumatoid arthritis.
On announcing its approval, Badrul Chowdhury, M.D., Ph.D., director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA's Center for Drug Evaluation and Research, said "Xeljanz provides a new treatment option for adults suffering from the debilitating disease of RA who have had a poor response to methotrexate."
The FDA requires that Pfizer carries out a post-marketing study of Xeljanz to determine what the drug's long-term outcomes on cancer, serious infections and heart disease are. The Agency recommended a comparison with a group of patients on another approved medication to determine what differences there are.
Xeljanz treatment costs approximately US$24,000 per year. Experts had expected sales to eventually reach between $2.5 billion and $3 billion annually. However, this forecast included sales in the European Union market.