AbbVie Soothes Safety Fears With More Upadacitinib RA Data
Executive Summary
Following the fifth positive pivotal trial for AbbVie's JAK1 inhibitor in rheumatoid arthritis, it is looking increasingly likely that upadacitinib is going to be approved next year, although the company is hoping robust safety data mean that it will not get a black box warning similar to the one issued by the FDA for Lilly's recently approved same-class rival Olumiant.
With filings imminent for upadacitinib, AbbVie Inc. has announced positive results from a fifth late-stage trial assessing the investigational JAK1 inhibitor in rheumatoid arthritis (RA) which could help allay safety concerns regulators may have about the closely watched drug.
The US firm has presented top-line results which show that the SELECT-EARLY Phase III trial met the co-primary endpoints of patients achieving ACR50 (50% improvement in signs and symptoms of RA) at week 12 and clinical remission at week 24 with both doses of upadacitinib monotherapy (15 mg and 30 mg) compared with methotrexate (MTX). Specifically, 56% of patients in the once-daily 30 mg upadacitinib cohort achieved ACR50 compared with 28% for MTX. 66% of those on the 30 mg dose achieved clinical remission compared to 33% for MTX. (Also see "AbbVie's Upadacitinib Safety Appears Improved In Largest, Longest RA Study" - Scrip, 9 Apr, 2018.)
While the results confirm the efficacy of the JAK class and its superiority over MTX, AbbVie stressed the safety profile of upadacitinib, notably in terms of venous thromboembolic events (VTEs). There were two cases of VTE in the study, one pulmonary embolism in the MTX group and one deep vein thrombosis in the 30 mg upadacitinib cohort – there was none in the 15 mg group.
In an investor note, Leerink analyst Geoffrey Porges wrote that this is the first study for upadacitinib in MTX-naïve patients and this data, plus positive results from four other Phase III RA trials of around 2,800 patients treated with the drug, mean "we view the approval of upadacitinib as near certain." He highlighted the importance of only one VTE occurring in 631 upadacitinib patients over 24 weeks, which brings the total Phase III VTEs across the five trials to date in the SELECT rheumatoid arthritis program to six and "based on the length of the trials, we calculate the overall VTE event rate for upadacitinib to be 0.6 per 100 patient years."
The SELECT-EARLY data come days after the FDA approved a 2 mg daily dose of Eli Lilly & Co.'s oral JAK1/2 inhibitor Olumiant (baricitinib) to treat adults with moderate to severe RA who have had an inadequate response to at least one tumor necrosis factor (TNF) inhibitor. However, the 4 mg dose was not approved, in line with the recommendation of an FDA advisory committee, which had concerns about the safety of the higher dose, including thrombosis – one of multiple risks flagged in a boxed warning on Olumiant's label.
Porges said that "the critical question for investors will be whether upadacitinib can avoid a similar black box [but] given the data disclosed by AbbVie, we don’t see a reason why the FDA would restrict the approval to just the lower 15 mg dose."
BMO Capital Markets analyst Alex Arfaei issued a note saying the data indicate that there is no major VTE imbalance and if the FDA's review produces a similar conclusion (AbbVie is planning global regulatory submissions in the second half of 2018), upadacitinib should be approved. However, citing the agency's review of Olumiant, "the FDA seems to be taking a cautious stance with the JAK1s," he wrote.
Arfaei added that "with all the caveats of cross-trial comparison in mind, the efficacy results of upadacitinib in MTX-naïve patients look better than Pfizer's Xeljanz (tofacitinib)," the US behemoth's JAK inhibitor which the FDA approved for RA six years ago. However, he claimed that it would be "difficult to displace well-entrenched Xeljanz", noting that about half of the latter's volume is from TNF-naive patients "who would likely be treated with the cheaper TNF biosimilars unless the prices for the JAKs are lowered, as Lilly did with baricitinib."
Olumiant's US list price of $25,000 per year is 60% lower than the $60,000 cost – before rebates and discounts – for AbbVie's own market-leading anti-TNF therapy Humira (adalimumab) and half the $50,000 list price for Xeljanz.
Leerink's Porges said that while MTX was the universally accepted – and low priced – standard of care treatment for this indication and setting, the SELECT-EARLY data "suggest that for some patients at least, its days might be numbered. However, payers are likely to implement tactics that restrict access to even the most effective medicine in this indication, given the patient numbers involved."
He concluded by claiming that failure to secure a differentiated label over Olumiant would decrease expectations for the drug and open a significant opportunity for Gilead Sciences Inc. and Galapagos NV's investigational JAK inhibitor filgotinib, "while avoiding some of the class labeling would strengthen investor confidence in AbbVie’s ability to deliver on their ambitious $3bn 2025 guidance for upadacitinib in RA." (Also see "Filgotinib Shaping Up To Be Success Story For Gilead and Galapagos " - Scrip, 31 May, 2018.)
AbbVie has forecast sales of $6.5bn in 2025 across multiple indications for upadacitinib, a drug that is key to softening the blow of patent expiries on Humira. In addition to RA, Phase III trials are ongoing in psoriatic arthritis and Crohn's disease and it is also being investigated for ulcerative colitis, ankylosing spondylitis and atopic dermatitis.