On, October 21st, new detailed data on AbbVie’s selective JAK 1 inhibitor candidate upadacitinib (UPA) were presented at the 2018 ACR/ARHP Annual Meeting. These data from the remaining three of Abbvie’s Phase III SELECT trials demonstrated, once again, that UPA has exceptional efficacy across multiple patient populations.
UPA’s unique JAK1 selective mechanism of action, apparent versatility in treating multiple targeted patient populations, and lack of new and concerning safety signals make it a promising new candidate in the rheumatoid arthritis (RA) space. UPA’s future may be especially promising in the US where it will likely be launched before Abbvie’s rheumatology power-house drug, Humira (Adalimumab), loses exclusivity.
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The fact that Humira is a best-seller in the US and will likely remain so for the next five years may give UPA an advantage when it comes to securing health insurance coverage. In particular, Abbvie’s long-standing patient-volume contracting agreements with insurance providers could be instrumental in helping UPA quickly obtain formulary access.
JAK inhibitor treatment in rheumatoid arthritis
The three studies covered in Sunday’s abstract session dedicated to JAK inhibitor treatment in RA included SELECT-MONOTHERAPY, SELECT-COMPARE, AND SELECT-EARLY. SELECT-MONOTHERAPY and SELECT-EARLY both assessed UPA monotherapy versus methotrexate (MTX) but targeted different patient populations: patients with an inadequate response to MTX and patients who were naïve to MTX, respectively. SELECT-COMPARE assessed UPA in combination with MTX versus placebo or adalimumab in patients who have had an inadequate response to MTX. Across the three studies, all primary efficacy endpoints were met and no new safety concerns for UPA emerged.
In SELECT-MONOTHERAPY, the longitudinal increase in ACR20/50/70 for both 15mg and 30mg doses of UPA over the course of the 14 weeks was impressive, reaching similar response rates as seen in published data for the SELECT-NEXT trial, which evaluated UPA in combination with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) in patients with an inadequate response to csDMARDs. This suggests that UPA can be an effective treatment both as a monotherapy as well as in combination with csDMARDs.
The SELECT-EARLY trial targeted MTX-naïve patients who, based on the presence of poor prognostic factors, were deemed at a high risk for rapid disease progression. MTX-naive patients treated with UPA monotherapy showed significantly improved disease activity and a higher prevalence of low disease activity and remission compared to patients treated with MTX alone. Even in very early disease, patients treated with UPA showed significantly slowed radiographic progression in comparison to patients treated with MTX.
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By GlobalDataFinally, in SELECT-COMPARE, patients administered 15mg UPA plus MTX achieved a significantly higher rate of low disease activity and remission compared to patients treated with adalimumab and MTX. For example, after 26 weeks of treatment, the UPA group had remission rates between 8%-10% higher than for the adalimumab group (based on CDAI, SDAI, and Boolean criteria).
Across all aforementioned Phase III studies, when compared to placebo, UPA continued to show a safety profile similar to other JAK inhibitors. When compared to adalimumab in SELECT-COMPARE, UPA showed slightly higher rates of infection, hepatic disorder, gastrointestinal perforation, lymphopenia and neutropenia, while adalimumab showed higher rates of AEs leading to study discontinuation. Overall however, the safety profiles of the two drugs were similar.
Competition in the pipeline
The improved clinical activity of UPA in comparison to adalimumab in SELECT-COMPARE suggests its efficacy may eclipse that of Xeljanz (tofacitinib), which in the ORAL Standard study was not found to be superior to adalimumab. UPA may instead be more similar in efficacy to Olumiant (baricitinib), which was found in the RA-BEAM study to also be superior to adalimumab. However, the RA-BEAM study was only conducted using the 4mg dose of baricitinib, which is not currently available in the US. Therefore, when considering JAK inhibitor efficacy in the US, the 2mg dose of baricitinib may not be equally efficacious as UPA.
In regards to UPA’s potential competition in the pipeline, Astellas’ peficitinib is unlikely to launch in the US in the near term, but Galapagos/Gilead’s filgotinib may prove a worthy rival. However, according to a payer interviewed by GlobalData, the widespread usage of AbbVie’s Humira improves the company’s chances of forming favourable contracting agreements with US insurance providers and pharmacy benefits managers, meaning that UPA may receive greater than expected patient access.
To add to its potential for success, in addition to RA, Abbvie is also developing UPA for a long list of other immunological indications. It is currently in Phase III trials for ulcerative colitis, Crohn’s disease, ankylosing spondylitis, psoriatic arthritis, and atopic dermatitis. Filgotinib is a bit behind in comparison, with Phase III development ongoing only for Crohn’s Disease and ulcerative colitis. The potential for use across multiple indications increases the likelihood that Abbvie will be able to receive patient volume-based contracting agreements that will optimise patient access to UPA.
Based on the extensive clinical data from Abbvie, UPA appears to be a highly versatile and effective JAK inhibitor—improving disease activity and slowing disease progression in both patients at the very beginning of their treatment journey and those who have failed several therapy options. GlobalData believes that because of Abbvie’s entrenchment in many immunology indications, UPA may have a particular advantage when it comes to obtaining formulary access in the US.
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