Jak inhibitors continue to be the most active area of drug development for RA. At the 2016 EULAR Congress held June 8-11 in London, many presentations focused on important aspects of RA management including the optimization of methotrexate dosing, value of ultrasound-assisted treatment strategies, and tapering of biologics dosages. However, data on novel therapies highlighting new opportunities in RA were rather sparse. While the early-stage pipeline remains active in the $14 billion G7 RA market1, drugs in late-stage development are those in existing drug classes such as the Jak and the IL-6 inhibitors. In particular, several Jak inhibitors—baricitinib, filgotinib, ABT-494, peficitinib—are in late-stage development in RA and likely to reach the market by the end of the decade.

How is Xeljanz, the first Jak inhibitor, faring in RA? The FDA approval of Xeljanz in 2012 was initially met with great expectations and excitement as the first oral agent with efficacy in the range of biologics. However, uptake in the U.S. has been slower than expected, as physician perception of the safety and the high price of Xeljanz have largely relegated its use in RA patients failing multiple biologics. Xeljanz has also been unable to achieve regulatory approval for RA by the EMA. In 2015, Pfizer reported U.S. sales of $470 million for Xeljanz and global sales of $609 million, far below analysts’ sales estimates of $1.6B by 2016.2

Xeljanz’s potential to reach blockbuster status was further dampened by the FDA’s rejection of Xeljanz for psoriasis in October 2015, suggesting that analysts’ consensus peak sales of $2-3 billion may be a far reach based on the agent’s performance and regulatory history to date.  However, Pfizer continues to seek development in other indications including ulcerative colitis (see DRG blog post on emerging therapies in UC), Crohn’s disease, and psoriatic arthritis. And Xeljanz sales will continue to grow in RA, as uptake in earlier lines of therapy will increase as physicians gain more confidence in the agent’s long-term safety. At the 2016 EULAR Congress, Pfizer presented several posters highlighting the long-term safety of Xeljanz. In one poster presenting pooled safety data for up to 8 years, in more than 4800 patients and almost 15,000 patient-years of Xeljanz exposure, the incidence rate (IR) of serious infections was 2.8 per 100 patient-years3, which is comparable to the range of incidence rates observed with all RA biologics in a meta-analyses study.4 Other safety signals were consistent with those observed at earlier timepoints, including the risk of herpes zoster infections (IR: 4.0/100 patient-years).

The second Jak inhibitor, baricitinib, on the horizon for RA. Eli Lilly/Incyte’s Jak inhibitor baricitinib was filed for regulatory approval in the U.S., Europe, and Japan for RA in early 2016. Remarkably, in the Phase III RA-BEAM trial, baricitinib demonstrated statistical superiority to Humira on various efficacy end points including the ACR response rates5, supporting the use of baricitinib as a first-line agent in methotrexate-refractory RA patients. (In contrast, Xeljanz’s head-to-head trial against Humira was not powered to detect statistical significance.) At the 2016 EULAR Congress, new one-year results from RA-BEYOND demonstrated that treatment with 4 mg, once-daily baricitinib statistically significantly reduced radiographic inhibition in conventional DMARD-refractory patients6, further supporting its robust efficacy in RA.

The integrated safety data from baricitinib’s clinical program with more than 3400 patients and 4200 patient-years of exposure to baricitinib were presented for the first time at EULAR.7 No new safety signals emerged and only those known to be associated with Jak inhibition such as serious infections, increases in LDL/HDL and creatinine levels were observed. The incidence rate of serious infections was 3.2/100 patient-years, and like Xeljanz, baricitinib is also associated with a greater risk of herpes zoster reactivation (IR= 3.4/100 patient-years), suggesting a class-specific safety signal.

Competitive dynamics of Jak inhibitors in the EU5. When baricitinib launches in the U.S., Xeljanz will still hold the upper hand on a few aspects such as long-term safety and physician familiarity. In addition, the once-daily formulation is not going to be an advantage for baricitinib as Pfizer launched the once-daily Xeljanz XR. In Europe, the dynamics of the in-class competition of the Jak inhibitors may be different. While Xeljanz has been gaining several years of postmarketing experience in the U.S., in the EU5 countries, Xeljanz and baricitinib are likely to launch around the same time. The long-awaited resubmission of Xeljanz’s European application was confirmed by Pfizer in March 2016. But assuming Xeljanz is approved by the EMA this time around, it faces a much different and considerably more challenging market landscape than it would have faced if it was approved three years ago.

Initially, Xeljanz may benefit from its long-term safety data and post-marketing experience from more than 45 countries worldwide. However, the RA-BEAM trial demonstrating baricitinib’s superiority to Humira will likely be a key point of marketing and differentiation for baricitinib compared to Xeljanz. This data will be significant in the EU5 countries, where head-to-head trials against standard of care comparators are crucial for favorable Health Technology Assessments and pricing and reimbursement decisions. Other factors in baricitinib’s favor include lingering negative perceptions about Xeljanz’s safety and efficacy based on its initial rejection and its once-daily dosing (until Xeljanz’s once-daily dose becomes available in Europe).

Carving out a place in the RA treatment algorithm. A preview of the updated RA treatment guidelines8 presented at the 2016 EULAR Congress set the stage for Jak inhibitors as early-line treatment options. The most notable change in the updated guidelines is the inclusion of targeting synthetic DMARDs (tsDMARDs), such as Jak inhibitors, at the same line of therapy as TNF and non-TNF biologics in methotrexate-refractory patients, based on the growing evidence with Xeljanz and baricitinib. The prior EULAR guidelines placed Jak inhibitors after biologics in the treatment algorithm. Jak inhibitors will fill an unmet need for an effective oral DMARD in the EU5, but price will be key for achieving broad uptake in the cost-constrained European healthcare systems, especially with the availability of cost-effective biosimilars (which will be available for most RA biologics by the end of the decade). Despite Xeljanz’s slow start, if Xeljanz and baricitinib can gain use in early-lines of therapy, they are anticipated to reach blockbuster status and be the primary drivers for the continued growth of the RA market.

For further detailed analyses on the RA market based on primary research with key opinion leaders please see: DRG’s RA Disease Landscape and Forecast.

 

References

  1. Decision Resources Group. Rheumatoid Arthritis Disease Landscape and Forecast (2015)
  2. http://www.bloomberg.com/news/articles/2013-06-13/pfizer-s-two-new-top-pills-selling-slower-than-expected
  3. Wollenhaupt J, et al., Tofacitinib, an oral Jak inhibitor, in the treatment of rheumatoid arthritis: Safety and clinical and radiographic efficacy in open-label, long-term extension studies over 7 years. 2016 EULAR Congress; London. Abstract THU0185.
  4. Strand V, et al., Systematic review and meta-analysis of serious infections with tofacitinib and biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials. Arthritis Res Ther. 2015; 17:362.
  5. http://lilly.mediaroom.com/index.php?s=9042&item=137496
  6. Van der Heijde D, et al., Baricitinib Inhibits Radiographic Progression of Structural Joint Damage at 1 Year in Patients with Rheumatoid Arthritis (RA) and An Adequate Response to csDMARDs. 2016 EULAR Congress; London. Abstract THU0168.
  7. Smolen J, et al., Safety Profile of Baricitinib in Patients with Active RA: An Integrated Analysis. 2016 EULAR Congress; London. Abstract THU0166.
  8. http://eular.org/myUploadData/files/EULAR%20RA%20Management%20recommendations%202016%20update%20June%202016-c_2.pdf

 

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