On the Way to Becoming JAKs of All Trades

On July 13th, 2017 Pfizer announced that its application for approval in ulcerative colitis for its JAK inhibitor, Xeljanz (tofacitinib), had been accepted by the FDA. Pfizer could be on a roll:  Xeljanz recently (March 2017) gained approval for rheumatoid arthritis in the EU after its initial rejection 5 years ago, had a good showing at the FDA’s advisory meeting on its application for psoriatic arthritis, and was spared some competition in the U.S. when Eli Lilly’s baricitinib, a selective JAK inhibitor, failed to gain FDA approval for rheumatoid arthritis. That’s plenty of good news for Pfizer to enjoy before next March, when the FDA is expected to announce its decision on Xeljanz for ulcerative colitis.

 

 

Whether the FDA will grant approval in ulcerative colitis is yet to be seen. The safety concerns that bedevilled the drug during its initial approval in rheumatoid arthritis seem to be subsiding as long term data and experience builds from its use and continued testing in rheumatoid arthritis. Concern over the increased lipid levels seen in patients who take JAK inhibitors may also be easing as they have not been shown to result in a higher incidence of major cardiovascular events. While the efficacy data released from the OCTAVE Induction and OCTAVE Sustain trials were not quite as stellar as might have been hoped for based on Xeljanz’ phase II induction study, there was a clear improvement over placebo, with response and remission rates that compare favorably to those of the biologics currently on the market for ulcerative colitis. On balance, the easing of concerns over its safety profile and its positive efficacy compared with placebo would suggest that approval in ulcerative colitis is likely.

While Xeljanz has done well in ulcerative colitis trials, it has stumbled in Crohn’s disease, the other half of the IBD market. With disappointing results from a dose-ranging phase II study which had an unusually high placebo response, Pfizer has backed down from its efforts to develop Xeljanz for Crohn’s disease.  Crohn’s may be a smaller patient population than ulcerative colitis, but the standard first line agents in IBD (i.e., oral mesalamines) are generally ineffective in Crohn’s, meaning patients move much faster to more powerful immunosuppressants and biologics.  In this market, another JAK inhibitor, filgotinib, developed in partnership by Gilead and Galapagos, has stepped up. Filgotinib’s promising phase II data, which includes improved remission rates over placebo, are being followed up with two phase III trials in Crohn’s disease as well as two phase III trials in ulcerative colitis. Having approval for both conditions could be an advantage if it makes the drug more appealing to gastroenterologists, who may prefer to have one go-to drug for IBD.  Filgotinib’s trials in ulcerative colitis and Crohn’s report primary completion dates between 2019 and 2022, meaning Pfizer will, however, have a few years on the market before having to share the IBD space with another JAK inhibitor.

Physicians and payers alike appear to have high hopes for JAK inhibitors in both indications. According to a survey of 32 U.S. payers and 100 U.S. gastroenterologists conducted by Decision Resources Group and published in the 2017 Access and Reimbursement | CD/UC | US, a majority of payers selected Xeljanz in ulcerative colitis and filgotinib in Crohn’s disease as the emerging therapies with the most potential impact on treatment of the two IBD indications. Furthermore, two-thirds or more of surveyed physicians said they expect to prescribe the drugs within their first year of availability. It’s not too surprising that physicians and payers would be so eager for a new oral therapy as both ulcerative colitis and Crohn’s disease are still underserved markets. Mesalamines are rarely effective in Crohn’s and even in ulcerative colitis, many patients do not respond to them satisfactorily, while immunosuppressants and steroids come with long term risks and side-effects. The question will be whether physicians will use JAK inhibitors as an additional line of oral therapy before moving to IV or injected biologics, or whether they will reserve the novel therapies for those patients who have failed TNF-α inhibitors. Decision Resources Group’s survey of gastroenterologists suggests the latter is more likely, at least at first. Even among rheumatologists, who have used Xeljanz for rheumatoid arthritis for half a decade, use is generally reserved for TNF-α inhibitor refractory patients, according to survey data published in Decision Resources Group’s report Access and Reimbursement | Rheumatoid Arthritis and Systemic Lupus Erythematosus| US. JAKs will not be alone in this line of therapy in the IBD markets either, and will compete with Takeda’s Entyvio (vedolizumab) in both ulcerative colitis and Crohn’s disease as well as J&J’s Stelara (ustekinumab) in Crohn’s disease. Still, Decision Resources Group’s surveys suggest that JAK inhibitors will do well in Crohn’s disease and ulcerative colitis and that IBD is a logical choice for indication expansion as Pfizer, Gilead, and Galapagos develop their drugs into JAKs of all trades.

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