Uncertainties Loom as Jak inhibitor Baricitinib Encounters Regulatory Roadblock in the United States

Contributors: Ronnie Yoo, Principal Business Insights Analyst
Published on: 19 May, 2017

CRL issued for Eli Lilly’s RA candidate baricitinib. In a surprising turn of events, Eli Lilly announced that the FDA issued a complete response letter (CRL) for Jak inhibitor baricitinib on Friday, April 14th. Even when the PDUFA date (initially scheduled for January 14th, 2017) was pushed back three months because the FDA needed more time to review additional data, many still assumed Lilly had baricitinib’s U.S. approval in the bag, especially after the EU approval of the agent in February. According to Lilly and Incyte’s press release, the CRL stated the need for additional clinical data for determination of the correct dose and further characterization of the safety concerns.


Surprising decision… or maybe not? The FDA decision is particularly surprising given the European approval of baricitinib (marketed as Olumiant) just a few months ago. While the FDA granted approval for Pfizer’s Xeljanz, the first Jak inhibitor in RA in late 2012, the EMA opted to take a more cautious route for this agent, rejecting Xeljanz’s European marketing authorization based on safety concerns and inconsistent demonstration of radiographic inhibition in 2013. Xeljanz was finally approved in the European Union in March 2017. This time the FDA and EMA have swapped positions and Lilly is faced with overcoming the FDA regulatory hurdle after a successful bid in Europe. On the other hand, perhaps the FDA’s decision on baricitinib is not that surprising given Xeljanz’s regulatory review history with the two doses tested in the Phase III trials. Ultimately, both the U.S. and European regulatory agencies concluded that the risk-benefit profile of the 10 mg dose of Xeljanz is not favorable and only approved the 5 mg dose, despite the 10 mg showing greater efficacy, especially in inhibiting the progression of radiographic damage progression.


Of the four Phase III baricitinib trials submitted for regulatory review, two (RA-BUILD and RA-BEACON) included both the 2 mg and 4mg doses, while the other two trials (RA-BEGIN and RA-BEAM) only tested the 4 mg dose. In RA-BUILD (cDMARD-refractory patients), the 2 mg and 4 mg doses demonstrated comparable efficacy across the various measures (ACR response rates, DAS28-CRP and SDAI remission), with the exception in the radiographic progression measure (DmTSS), which showed greater efficacy with the 4 mg baricitinib dose (Table 1). The RA-BUILD data suggest that there is no obvious benefit of treatment with the higher dose for reducing signs and symptoms of the disease (except for the inhibition of radiographic progression), but the safety data through 24 weeks also show that the risk of serious adverse events and serious infections is similar among the placebo, 2 mg and 4 mg baricitinib arms. In contrast, the RA-BEACON (TNF-refractory patients) results suggest that while treatment with the 4 mg dose may be more effective in reducing signs and symptoms of disease than the 2 mg dose (the radiographic end point was not assessed in this study), the higher dose also trends to show a greater risk of serious adverse events, including herpes zoster and malignancies. Nevertheless, the FDA concluded that neither dose could be approved in the application’s current form.


Table 1. Summary of Phase III RA-BUILD and RA-BEACON trials.

  RA-BUILD a,b (Placebo/2mg/4mg) RA-BEACON a, c (Placebo/2mg/4mg)
Patient Population cDMARD-refractory (n=684) TNF-refractory (n=527)
ACR 20 at 12 weeks 39% / 66% / 62% 27% / 49% / 55%
ACR 50 at 12 weeks 13% / 33% / 34% 8% / 20% / 28%
ACR 70 at 12 weeks 3% / 18% / 18% 2% / 13% / 11%
DAS28-CRP ≤ 2.6 at 12 weeks 9% / 26% / 26% 4% / 11% / 16%
SDAI ≤ 3.3 at 12 weeks 1% / 9% / 9% 2% / 2% / 5%
DmTSS at 24 weeks 0.70 / 0.33 / 0.15 N/A
Safety (0-24 weeks)    
Adverse events 71% / 67% / 71% 64% / 71% / 77%
Serious adverse events 5% / 3% / 5% 7% / 4% / 10%
Infections 35% / 31% / 42% 31% / 44% / 40%
Serious infections 2% / <1% / 2% 3% / 2% / 3%
Herpes zoster 0% / 2% / 1% 1% / 1% / 4%
Malignancies 0% / 0% / <1% 0% / 0%/ 1%


Impact of CRL on RA market landscape. Pfizer is likely to reap the biggest benefit from the delay of baricitinib’s U.S. approval especially as physician perceptions of early-line use of Jak inhibitors evolve. A U.S. rheumatologist interviewed by DRG said, “If I exclude the insurance reasons, I could see using a Jak inhibitor ahead of an anti-TNF. If you asked me four years ago, I would have said, no, I’d use anti-TNF first. But there has been more experience with the Jak inhibitors and some reassurance regarding cancer rates and infection rates.” Xeljanz use will continue to grow in the United States, now unhindered by a challenger that was anticipated to exert strong in-class competition.


The question remaining is how long Xeljanz can enjoy its status as the only Jak inhibitor in the U.S. RA market. During Lilly’s Q1 2017 earning’s call Q&A on April 25, 2017, no indication was given about the timeline for baricitinib’s resubmission, but the company noted that an update on the development will be provided following a meeting with the FDA, which they anticipate will occur within the next 60 days. The company reiterated their confidence in the risk-benefit profile of both the 2 mg and 4 mg doses of baricitinib. Because the 4 mg dose was the only dose tested in the head-to-head trial against Humira, Lilly is going to need the 4 mg dose approved to include this superiority data—a key differentiator from Xeljanz—on their label (in the absence of additional clinical trials). While some KOLs interviewed by DRG were restrained in their enthusiasm about the clinical relevance of the baricitinib’s superiority data against Humira and cautious about making any comparisons to Xeljanz in the absence of any head-to-head data between the two agents, most agree that baricitinib’s efficacy is impressive and the agent is a welcome addition to the RA armamentarium. To date, baricitinib is the only RA agent that has shown superiority to the combination of Humira and methotrexate (Actemra and sarilumab demonstrated superiority to Humira monotherapy). Top-line results from ORAL-Strategy, a Phase 3/4 trial assessing the efficacy of Xeljanz (5 mg) as a monotherapy and in combination with methotrexate and Humira (in combination with methotrexate), showed that the Xeljanz and methotrexate combination was non-inferior to Humira and methotrexate (and Xeljanz monotherapy did not meet the non-inferiority goal versus Humira)d.


To prevent further delay of baricitinib’s launch, Lilly will need to convince the FDA that additional clinical trials are not necessary for addressing the CRL. On the earnings call, Lilly noted that there were additional analyses from the extension studies that haven’t been submitted to the FDA, which could potentially address the safety concerns, but it remains unclear how the dosing issue will be resolved. However, even if additional clinical trial are not required, the launch of baricitinib will likely be delayed at least a year. If additional trials are necessary, or if the FDA wants to wait until the primary completion of the long-term extension study in 2020, baricitinib could even lose its position as the second-to-market Jak inhibitor to AbbVie’s upadacitinib (ABT-494) or Gilead/Galapagos’ filgotinib, both of which are expected to launch for RA by 2020—a situation Lilly will want to avoid as competition in the Jak inhibitors class heats up.


DRG will continue to follow the development of baricitinib closely, interview KOLs to gain insights on this FDA decision, and update our RA market forecast as the landscape evolves.



  1. EMA Olumiant: EPAR – Product information. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004085/WC500223723.pdf
  2. Dougados M., et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis. 2017; 76: 88-95.
  3. Genovese MC., et al. Baricitinib in Patients with Refractory Rheumatoid Arthritis. N Engl J Med. 2016; 374: 1243-52.