Date: 2017-03-22
Type of information: Granting of a Market Authorisation in the EU
Product name: Xeljanz®
Compound: tofacitinib
Therapeutic area: Autoimmune diseases – Inflammatory diseases - Rheumatic diseases
Action mechanism:
- kinase inhibitor/Janus kinase inhibitor. Tofacitinib is an oral selective Janus kinase (JAK) inhibitor. Tofacitinib preferentially inhibits JAK1 and JAK3 leading to an attenuation of signalling of interleukins (IL-2, -4, -6, -7, -9, -15, -21) and type I and type II interferons, which will result in modulation of the immune and inflammatory response.
Company: Pfizer (USA - NY)
Disease:
- treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to, or who are intolerant of, methotrexate
Latest news:
- • On March 22, 2017, the European Commission has approved Xeljanz® (tofacitinib) for the treatment of rheumatoid arthritis.
- • On January 26, 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for Xeljanz®, intended for the treatment of rheumatoid arthritis. Xeljanz® will be available as 5-mg film-coated tablets. The benefits with Xeljanz are its ability to reduce the signs and symptoms of rheumatoid arthritis and to improve physical function. Xeljanz has the potential to slow the progression of joint damage in patients with rheumatoid arthritis. The most common side effects are headache, upper respiratory tract infections, nasopharyngitis, diarrhoea, nausea and hypertension. Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis.• On 25 July 2013, the Committee for Medicinal Products for Human Use (CHMP) has confirmed the negative opinion, recommending the refusal of the marketing authorisation for Xeljanz®, intended for the treatment of rheumatoid arthritis. Pfizer requested a re-examination of the opinion adopted on 25 April 2013 (See below). The CHMP had major concerns about the overall safety profile of Xeljanz®. There were significant and unresolved concerns about the risk and type of serious infections seen with tofacitinib, which are related to the immunosuppressant action of the medicine. These safety concerns also included a risk of other severe side effects including certain cancers, gastro-intestinal perforations (holes in the wall of the gut), liver damage and problems with increased lipid (fat) levels in the blood. It was not clear that these risks could be managed successfully in medical practice. At re-examination in July 2013 the company proposed to remove claims of an effect on structural damage from the indication. However, the lack of robust evidence on prevention of structural damage with Xeljanz® in the proposed dose and population still contributed to the Committee’s view that the benefits of treatment did not outweigh significant and unresolved concerns about safety. Therefore, in April 2013 the CHMP was of the opinion that the benefits of Xeljanz did not outweigh its risks and recommended that it be refused marketing authorisation. The CHMP refusal was confirmed after re-examination.
- • On July 15, 2013, Pfizer has announced that 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, the Swiss agency for therapeutic products, approved tofacitinib 5 and 10 mg twice-daily (BID) as monotherapy or in combination with a disease modifying non-biologic antirheumatic agent (DMARD), including methotrexate (MTX), in adult patients with moderate-to-severe active RA who have had an inadequate response or intolerance to MTX. Tofacitinib 5 mg BID has also been approved in Argentina, Kuwait and the United Arab Emirates, and tofacitinib 5 mg and 10 mg BID has been approved in Russia. The brand name for tofacitinib in the approved markets will be Xeljanz®, except for Russia, where the brand name will be Jaquinus®. Xeljanz® is also approved in the United States and Japan for the treatment of moderate-to-severe active RA. It was launched in the United States in November 2012, and Xeljanz® is expected to be commercially available in Japan this month following approval by the Japanese Ministry of Health, Labor and Welfare (MHLW) in March 2013. Xeljanz® will be co-promoted in Japan by Pfizer and Takeda Pharmaceutical Company Limited.
- • On 25 April 2013, the Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of the marketing authorisation for Xeljanz®, intended for the treatment of rheumatoid arthritis. The effects of Xeljanz® were first tested in experimental models before being studied in humans. Pfizer presented the results of five main studies of safety and effectiveness involving over 3,300 patients with rheumatoid arthritis. These studies compared Xeljanz® (in a dose of 5 or 10 mg twice daily) with placebo (a dummy treatment), either alone or as an addition to other background medicines (DMARDs). The main measures of effectiveness were changes in patient scores for signs and symptoms of disease, physical function of the patient, structural damage to joints and disease activity; these were measured after 3 or 6 months, depending on the study. The Committee considered that, taken together, the data from the five main studies showed that treatment with Xeljanz® resulted in an improvement in the signs and symptoms of rheumatoid arthritis and the physical function of patients. However, 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. The CHMP had major concerns about the overall safety profile of Xeljanz®. There were significant and unresolved concerns about the risk and type of serious infections seen with tofacitinib, which are related to the immunosuppressant action of the medicine.
- These safety concerns also included an increased risk of other severe side effects including certain cancers, gastro-intestinal perforations (holes in the wall of the gut), liver damage and problems with increased lipid (fat) levels in the blood. 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.
- • On November 6, 2012, the FDA has approved Xeljanz® (tofacitinib) to treat adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to, or who are intolerant of, methotrexate. Xeljanz® is being approved ahead of the product’s prescription drug user fee goal date of Nov. 21, 2012, the date the agency was scheduled to complete review of the drug application. The safety and effectiveness of Xeljanz® were evaluated in seven clinical trials in adult patients with moderately to severely active RA. In all of the trials, patients treated with Xeljanz® experienced improvement in clinical response and physical functioning compared to patients treated with placebo.
- The use of Xeljanz® was associated with an increased risk of serious infections, including opportunistic infections (infections that occur primarily when the immune system is suppressed), tuberculosis, cancers and lymphoma. Xeljanz® carries a Boxed Warning regarding these safety risks. Xeljanz® treatment is also associated with increases in cholesterol and liver enzyme tests and decreases in blood counts. The FDA approved Xeljanz® with a Risk Evaluation and Mitigation Strategy (REMS), which consists of a Medication Guide advising patients about important safety information and a communication plan to inform health care providers about the serious risks associated with Xeljanz. To study the long-term effects of Xeljanz® on heart disease, cancer, and serious infections, the FDA is requiring a postmarketing study that will evaluate two doses of Xeljanz® and include a group of patients on another approved treatment to serve as a comparison.
- The most common adverse reactions in clinical trials were upper respiratory tract infections, headache, diarrhea, and inflammation of the nasal passage and the upper part of the pharynx.
Patents:
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2012-11-06
UE authorization: 2017-03-22
Favourable opinion UE: 2017-01-26
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE:
OTC status:
Other news:
Is general: Yes
