Xeljanz® (tofacitinib) and the Negative Opinion for Marketing Authorization in Europe

Some colleagues are already telling patients that we only have a short while to bridge until Xeljanz® (tofacitinib) will be available in Europe. Now the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a negative opinion for Xeljanz® (tofacitinib) [treatment of adult patients with moderate to severe active rheumatoid arthritis]. The point hasn’t been an improvement in the signs and symptoms of rheumatoid arthritis, but the insufficient demonstration of a consistent reduction in disease activity and structural damage to joints. The CHMP has also been concerned about serious infections, gastrointestinal perforations, and malignancies as observed in studies.
Pfizer will appeal this opinion and seek a re-evaluation of the opinion by the Committee for Medicinal Products for Human Use (CHMP). “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,” said Dr. Yvonne Greenstreet, senior vice president and the head of the Medicines Development Group for Pfizer Specialty Care.
I don’t think that we have to say goodbye to Xeljanz, but it will take more time until we will have access to a new class of drug treating rheumatoid arthritis.

My statement on tofacitinib after EULAR 2012: http://rheumatologe.blogspot.de/2012/07/tofacitinib-oral-jak-inhibitor-at-eular.html  

I’ve already told people about the black box warning, which came with the FDA approval: http://rheumatologe.blogspot.de/2013/01/neue-therapien-bei-rheumatoider.html  (German text)

There’s a short passage on tofacitinib and the ACR 2012 here: http://rheumatologe.blogspot.de/2012/11/2012-acr-meeting-in-washington-answers.html  

See Pfizer’s statement here:
http://pfizer.newshq.businesswire.com/press-release/pfizer-receives-chmp-negative-opinion-regarding-marketing-authorization-europe-rheumat

The official statement of Pfizer by Yvonne Greenstreet is here:
http://www.europeanpharmaceuticalreview.com/18652/news/industry-news/pfizer-receives-chmp-negative-opinion-regarding-marketing-authorization-in-europe-for-rheumatoid-arthritis-treatment-xeljanz-tofacitinib-citrate/

02.05.2013:
I've just received a PeerVoice update on novel Ooral Jak inhibitors. Prof. Ronald F. van Vollenhoven talked about tofacitinib in: "Recent Efficacy Data on JAK Inhibitors: How Well Will They Work for Your Patients?"

Here's an extract from his slides:

Left side is after 6 months and right side after 12 months. If I would be on the CHMP I'd be convinced of a radiographic benefit.

This part of his slide also tells about a radiographic benefit. Let me add that it's p<0 .01="" for="" the="">

No other new information.

I hope that CHMP / EMA may be satisfied with a new appraoch to existing data as we have the patients waiting for a novel drug.

No newer information. 06.05.2013

27.07.2013
The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has voted again not to recommend marketing authorization for tofacitinib for the treatment of moderately to severely active rheumatoid arthritis. “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.”

The Committee had major concerns about the risk and type of serious infections seen with tofacitinib, which are due to the immunosuppressant action of the drug. Further safety concerns also included certain cancers, gastro-intestinal perforations, liver damage and problems with increased lipid levels in the blood. When the FDA approved Xeljanz, the drug had to carry a boxed warning regarding safety risks such as serious infections, including opportunistic infections, tuberculosis, lymphoma, and other cancers.

This is a setback not only for tofacitinib but for all protein kinase inhibitors. Pfizer was confident to launch Xeljanz in Europe early next year. How long will it take now? Will the FDA reconsider its’ approval? How about baricitinib, fostamatinib, GLPG0634, etc.? The next ACR meeting will be most interesting as some drug companies might consider to abandon or postpone their research programs on protein kinase inhibitors.

I hope that Pfizer produces the needed studies to change Committee for Medicinal Products for Human Use (CHMP) opinion. Otherwise this novel principle to treat rheumatoid arthritis is at stake.

Links:
EU Declines to Approve Tofacitinib (Xeljanz) for RA / Medscape: http://www.medscape.com/viewarticle/808497?src=smo_tw_rheu  
More on small molecules - Protein kinase inhibitors - hype or hope? http://rheumatologe.blogspot.de/2013/06/protein-kinase-inhibitors-hype-or-hope.html  
EMA: Refusal of the marketing authorisation for Xeljanz (tofacitinib)
Outcome of re-examination
http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002542/WC500146629.pdf