Lilly’s revelation that clotting events scuppered US FDA approval of the rheumatoid arthritis pill Olumiant was the first major disclosure of what looks to be an emerging risk with Jak inhibitors.
This is echoed by pharmacovigilance data from the first drug in this class, Pfizer's Xeljanz: US FDA adverse events monitoring has revealed 18 primary cases of pulmonary embolism in patients taking this Jak inhibitor. With Olumiant under the microscope, it cannot be taken as good news for Abbvie and Gilead Sciences as these groups await phase III data on their similar agents.
Lilly announced yesterday that the thromboembolic events – five cases of deep vein thrombosis or pulmonary embolism among patients taking Olumiant in controlled phase II or III trials – could require an additional clinical trial that will delay launch by at least 18 months. The response to this statement showed a mismatch between the expectations of sellside analysts and investors: analysts had largely written off US sales, but shares fell 3% in heavy trading yesterday.
FAERS thee well
The regulator’s concern might have been heightened by the thrombotic events in Xeljanz patients that have been reported to the FDA Adverse Events Reporting System (FAERS).
FAERS data compiled by Advera Health detail 18 primary suspect cases of pulmonary thrombosis. This yielded a reporting odds ratio – the rate of pulmonary thrombosis among Xeljanz patients compared with the adverse events rate among all other drugs in its database – of 2.46, above Advera’s 2.0 threshold and warranting extra attention.
This is not cited on the Xeljanz label, which already has extensive warnings about risk of infections, gastrointestinal perforations and certain types of cancer. Pfizer says the incidence rate of venous thromboembolism is similar to the rate observed in people taking biologic drugs for rheumatoid arthritis.
Yesterday, Lilly executives said they disagree with the FDA’s assessment and added that the occurrence of thrombotic events was no greater in Olumiant patients than in rheumatoid arthritis patients not taking the drug. Nevertheless, the agency is intent on ruling out added risk, which is why it issued a complete response letter in April (Olumiant setback opens the door to rivals, April 18, 2017).
A safety extension trial of nearly 3,000 patients is under way, and it is conceivable that Lilly could persuade the regulator to accept analyses from that to determine risk.
Demonstrating that the clotting risk was under the radar, data from pooled phase III trials and long-term safety extensions submitted to the Eular conference last month made no mention of it.
Xeljanz’s performance has not discouraged other companies from exploring Jak inhibition, which suppresses inflammatory cytokines. Abbvie recently announced positive data from the first pivotal trial of ABT-494 (Abbvie vaults first pivotal hurdle with oral RA candidate, June 8, 2017).
|Jak inhibitors in rheumatoid arthritis|
|Xeljanz||Pfizer||Marketed||Infections, certain cancer, stomach and intestinal perforation|
|Olumiant (baricitinib)||Lilly/Incyte||Delayed in US/marketed in EU and Japan||Thromboembolic events|
|ABT-494 (upadacitinib)||Abbvie||One phase III readout, five remaining||AE rates of 3-4% in phase III|
|Filgotinib||Gilead Sciences/Galapagos||Four phase III trials||Infections (phase II)|
|ASP015K Oral (peficitinib)||Astellas Pharma||Three phase III trials||Neutropenia, infections (phase II)|
The Illinois-based group disclosed detailed efficacy data, but only topline adverse events rates: 4% and 3% in the 15mg and 30mg dose arms respectively, compared with 2% with placebo. Full data are being held for journal publication and a medical meeting, likely the American College of Rheumatology conference in November.
ABT-494 is in six phase III trials covering a total of 4,000 rheumatoid arthritis patients, which should provide further clarity on whether thromboembolism is a class effect as they read out. Olumiant’s new drug application contained trial data from 3,100 patients.
Two of ABT-494’s trials, Select Compare in patients not controlled with methotrexate and Select Early in patients who have never taken methotrexate, have completion dates in July and August 2017, so data should be available soon. Filgotinib’s first phase III data will probably not be seen until next year, and Astellas Pharma’s ASP015K Oral could yield data at the end of 2017 or in early 2018.
These three agents have an opportunity to capitalise on the stumbles of Xeljanz and Olumiant. To do so, their makers need to hope that phase III trials reveal no risk of thromboses – or that the FDA becomes more comfortable with them in the overall risk/benefit profile of Jak inhibitors.