Abbvie Inc.'s late-stage oral JAK1 inhibitor, a candidate that could help fill a key gap in the drugmakers' revenue as Humira's (adalimumab) U.S. market exclusivity lapses, met all primary and secondary endpoints in a phase III rheumatoid arthritis (RA) study. Analysts said the trial results suggest that the candidate, upadacitinib (ABT-494), could hold key advantages over its competitors. The new results also further validate Abbvie's 2015 abandonment of an option to in-license the JAK1 inhibitor filgotinib from Galapagos NV. (See BioWorld Today, Sept. 28, 2015.)
Abbvie said it was the first phase III trial to show positive results for upadacitinib and a safety profile consistent with what it had observed in midstage trials.
Top-line results from Abbvie's Select-Next study reported Wednesday showed that, after 12 weeks of treatment with either a 15-mg or a 30-mg dose of upadacitinib, up to 66 percent of people with moderate to severe RA for whom ongoing treatment with conventional synthetic disease-modifying antirheumatic drugs such as methotrexate has fallen short achieved an ACR20 response – a standard measure used to assess treatment effects in RA trials that indicates a 20 percent overall improvement. Those who achieved it saw a 20 percent improvement in tender and swollen joint counts, self-assessed pain, global disease activity and physical function, as well as improvements in disease activity noted by their doctors, thus meeting the study's primary endpoint. By comparison, 36 percent of patients given a placebo during the trial achieved ACR20. Nearly half of the patients treated with upadacitinib during the study achieved low disease activity at both doses.
The candidate also hit secondary endpoints that included more stringent measures of efficacy, with 43 percent hitting ACR50 on the 30-mg dose vs. 15 percent on placebo, and 27 percent hitting ACR70 on the high dose vs. 6 percent on placebo. The 15-mg dose also separated from placebo, though by smaller margins.
Clinical remission was achieved by 31 percent and 28 percent of patients receiving 15 mg or 30 mg of upadacitinib, respectively, compared to 10 percent receiving placebo. All primary and key secondary endpoints achieved "p" values of <0.001 vs. placebo for both doses.
Analysts drew varied conclusions from the data. Leerink's Geoffrey Porges wrote that the placebo-adjusted ACR20 benefit rates for Abbvie's upadacitinib with methotrexate are, for the same patient populations, "numerically superior" to Incyte Corp. and Eli Lilly and Co.'s waylaid JAK1 and 2 inhibitor, baricitinib, which drew an FDA complete response letter in April. If superior results are repeated in the five other upadacitinib trials underway, he added, the candidate "could be first to market and best in class" in the important JAK inhibitor category.
Credit Suisse analyst Vamil Divan instead saw the results as indicating "efficacy generally comparable to what we have seen from other oral JAKs" and pointed to the need for deeper safety data, "especially in terms of hematological side effects, where we think filgotinib may have an advantage." However, looking beyond the data, he noted that Abbvie holds a distinct advantage in that it should be able to leverage its dominance in the RA space with Humira into commercial success for upadacitinib.
The other phase III trials of upadacitinib underway are all expected to read out in 2017 and 2018, setting up a potential FDA submission in the second half of 2018. If approved, upadacitinib would face immediate competition from the already-approved Kevzara (sarilumab), the interleukin-6 inhibitor co-developed by Regeneron Pharmaceuticals Inc. and Sanofi SA that gained approval in May and could potentially be opposed by sirukumab, another anti-IL-6 candidate being developed by Janssen Biotech Inc. and Glaxosmithkline plc. (See BioWorld Today, May 24, 2017.)
Despite the challengers, analysts forecast that sales of upadacitinib could surpass the billion-dollar mark by 2022, trending upward from there. With the U.S. composition-of-matter patent covering Humira having expired in December 2016 and biosimilar drugmakers such as Coherus Biosciences Inc. nipping at the heels of the stalwart, positive clinical data on its successor is no doubt welcome at Abbvie's North Chicago headquarters.