JAK Inhibitors and Biosimilars

The 19th Annual European League Against Rheumatism (EULAR) congress concluded its four-day event on June 16, 2018 in Amsterdam. The “Don’t Delay, Connect Today” campaign initiated by EULAR in 2017 is in its second year and has already sparked great interest and heated discussion among conference audiences, including not only medical practitioners but health professionals and patient organizations as well. A set of five-year EULAR strategic objectives, ranging from research and education to quality of care frameworks, advocacy, and governance, was laid out at the beginning of the congress. The extended area of the EULAR booth in the exhibition hall attracted all types of conference attendees who were enthusiastic about joining the EULAR community. With EULAR’s clear roadmap and firm commitment to promote awareness of rheumatic and musculoskeletal diseases (RMDs), one would not be surprised to see further improvement in timely diagnosis, facilitated access to treatment, and coordinated disease management for RMDs in Europe.

Analysts from Decision Resources Group attend the EULAR congress every year to keep abreast with the latest trends and topics in the European rheumatology field. Select conference highlights on JAK inhibitors and biosimilars, two main areas of discussion throughout the EULAR congress, are presented below:

JAK inhibitors, revolutionary or evolutionary? JAK inhibitors (JAKi) are by no means considered novel therapies in the rheumatoid arthritis (RA) field, as Pfizer’s Xeljanz has been on the U.S. market for nearly six years. But the first JAKi to launch in Europe, Eli Lilly’s Olumiant, has only been on the market for just over one year (or even less in countries where the drug’s launch was delayed by payer negotiations). As such, the European rheumatology community was eager to learn everything that key opinion leaders (KOLs) had to share at the conference about their experiences with the JAKis.

A number of KOLs at the EULAR considered JAKis a milestone in the management of RA, as they can effectively tune down the JAK pathway, a downstream essential signal transducer for many inflammatory stimuli, and at the same time, provide a more convenient treatment option for patients, especially those who are not used to or have difficulties with self-injection. Moreover, the JAKis’ strong efficacy as monotherapy even without methotrexate fulfills an important unmet need for methotrexate-intolerant RA patients.

According to U.S. rheumatologists interviewed by Decision Resources Group, Xeljanz is often used in the same RA population as non-TNF biologic DMARDs, i.e., TNF-refractory patients [1]. Perhaps owing to its strong efficacy as monotherapy and its oral administration, Xeljanz is taking the lion’s share of TNF-refractory patients, beating biologic DMARDs that launched earlier in this market. We expect that the European RA market will likely mirror how the U.S. market has evolved in terms of the impact of JAKis on non-TNF biologic DMARDs. However, important to note, in Europe, the first two JAKis, Olumiant and Xeljanz, were approved around the same time in 2017. Consequently, within the JAKi drug class specifically, the U.S. and European regions look drastically different. In the U.S., Olumiant’s market prospect suffers from its later-to-market entry (more than five years after Xeljanz was approved), its black box warning for thrombosis, and a lack of approval for the more-effective higher dose. As such, it is priced at a significant discount to Xeljanz in order to compete. Olumiant launched slightly earlier than Xeljanz in Europe, but the former has fewer patient-years considering Xeljanz’s longer market presence in the U.S. and is associated with the risk of thromboembolic events (although this was a safety concern some EULAR rheumatologists attributed to bad luck, not necessarily a safety concern inherent to the molecule). However, Olumiant’s better ACR response rates with the higher dose (which was approved in Europe) and its more convenient dosing schedule than Xeljanz’s (once daily versus twice daily for Xeljanz) were quickly noted by European physicians. Thus, it is a bit of a guessing game in Europe as to which JAKi will emerge as the class leader.

In addition to Xeljanz and Olumiant, there is a third JAKi in late-phase development for RA and expected to reach the market in the near term (i.e., AbbVie’s upadacitinib). Perhaps not surprisingly, the marketers of each were eager to discuss the JAKis’ positioning in the treatment algorithm, and a consistent theme that emerged across Eli Lilly’s, Pfizer’s, and AbbVie’s industry-sponsored symposium was the possible disruption the JAKis may have on current treatment paradigms. Although the JAKis have dominated—and are expected to continue to dominate—the TNF-refractory population, what remains uncertain is the impact JAKis will have on TNFis in the U.S. and Europe. The arrival of the second FDA-approved JAKi in the U.S. (Eli Lilly’s Olumiant) is expected to further increase awareness and thus the overall market presence of JAKis; as will the launch of AbbVie’s upadacitinib. As rheumatologists gain more experience with JAKis, and additional agents within the class become available, switching from TNFi to JAKi could become more frequent and more timely.

Biosimilars vs. Originators: While the year 2015 saw the launch of the first biosimilar, Celltrion’s Inflectra/Remsima (infliximab) in Europe, the prevalent use of biosimilars by European rheumatologists for RA was not taking shape until 2017, when two etanercept biosimilars, Samsung Bioepis’s Benepali and Novartis’s Erelzi, also reached the market. The slow initial uptake of biosimilars in Europe was due partly because physicians were waiting for more safety data from post-approval studies and partly because many payers had not implemented mandatory biosimilar switching or were slow to include biosimilars in their formularies. Also contributing to the slow uptake prior to 2017 is the fact that infliximab is not as frequently prescribed for RA as other more convenient and safer TNF inhibitors (i.e., etanercept and adalimumab). Not surprisingly, given the importance of post-approval studies to influencing physicians’ prescribing behavior of the biosimilars, several such studies confirming the efficacy and safety of etanercept biosimilars were presented at the EULAR congress this year.

A German study (N=283) showed that the retention rates for bionaive RA patients receiving either Benepali or originator were similar [2]. While the study claims that the overall distribution of adverse events was comparable, more patients in the biosimilar arm seem to discontinue treatment due to safety issues (32%) than in the originator arm (14%). In a larger study (N= 2,061) involving RA, PsA, and AxSpA patients conducted in Denmark, retention rates were compared between patients currently treated with–and remaining on—the brand and those who underwent a non-medical switch to an etanercept biosimilar. Interestingly, the one year adjusted retention rate was numerically lower in non-switchers, 77% (95% CI 72-82) than in switchers, 83% (95% CI 79-87) [3]. However, an increased risk of injection site reaction was also reported with the brand in the study, which may have contributed to the lower retention rates observed in non-switchers. The study author suggested that the manufacturing process and formulation of Enbrel in Europe could be the cause of the higher risk injection site reactions, which has since been addressed by the manufacturer according to the poster presenter.

In addition to the etanercept biosimilar data, the imminent European launch of adalimumab biosimilars, expected in October 2018, grabbed many EULAR attendees’ attention. Pfizer and Amgen presented clinical studies comparing their adalimumab biosimilars with the originator, paving the way for registration filing (for Pfizer) and commercial launch (for Amgen) [4-6]. Samsung Bioepis’s adalimumab biosimilar, boasting the earliest expected launch date, was featured in a pooled-analysis of the impact of anti-drug antibodies (ADAb) on efficacy [7]. The study found that the ACR20 response rate was lower in patients without the presence of ADAb. And according to the results presented, adalimumab biosimilar’s odds ratio (OR) for more ADAb leading to reduced efficacy was 3.17 (95%CI: 1.78-5.64) compared with Humira’s at 0.99 (95%CI: 0.55-1.80), meaning that SB5’s, but not Humira’s, efficacy can be significantly reduced by the development of ADAb. While this notable difference might not draw great attention from regulators, as SB5 has already been approved as a biosimilar to Humira, and its resulting clinical implications are still unknown, it is perhaps noteworthy that similar medicines (such as a biosimilar and its originator) can produce notably different results.

European rheumatologists are embracing the launch of biosimilars; a war between originators and biosimilars has broken out in the European TNF market. Biosimilar companies, including Celltrion, LG Chem, and several smaller-scale ones, set up their booths in the exhibition hall where Pfizer, Roche, and other major pharmaceutical companies used fancy technologies to showcase clinical trial data of their newly launched innovative therapies. Many European rheumatologists surveyed by Decision Resources Group have already started prescribing etanercept biosimilar as their first-line therapy after conventional DMARDs to their new RA patients [8]. This, together with the forthcoming launch of adalimumab biosimilars in late 2018, and the fact that physicians often cycle through no more than two TNF inhibitors before switching to medications with a different mechanism of action, suggests that biosimilars will likely start to dominate the TNF market in Europe in the near horizon.


  1. DRG’s Rheumatoid Arthritis | Disease Landscape and Forecast | G7 | July 2018
  2. A. Strangfeld, et al. Retention rates for etanercept: comparing the original with a biosimilar. EULAR 2018. Presentation number: THU0142
  3. B. Glintborg, et al. One-year treatment retention after a nationwide non-medical switch from originator to biosimilar etanercept in 2,061 patients with inflammatory arthritis followed in the danbio registry. EULAR 2018. Presentation number: THU0189
  4. P. Emery, et al. Impact of immunogenicity on clinical efficacy and administration related reaction in tnf inhibitors: a pooled-analysis from three biosimilar studies in patients with rheumatoid arthritis. EULAR 2018. Presentation number: THU0184
  5. R. Alten, et al. A comparative clinical study of pf-06410293, a candidate adalimumab biosimilar, and reference adalimumab for the treatment of active rheumatoid arthritis. EULAR 2018. Presentation number: THU0182
  6. E. Krishnan, et al. Immunogenicity associated with a transition from adalimumab reference product to abp 501 in patients with rheumatoid arthritis. EULAR 2018. Presentation number: THU0198
  7. P. Emery, et al. Impact of immunogenicity on clinical efficacy and administration related reaction in tnf inhibitors: a pooled-analysis from three biosimilar studies in patients with rheumatoid arthritis. EULAR 2018. Presentation number: THU0184
  8. DRG’s Rheumatoid Arthritis | Current Treatment | EU5 | August 2018 (planned)



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