- An Advisory Committee has recommended the Food and Drug Administration approve a lower dose of Eli Lilly & Co.'s baricitinib, though the drug may still face an uphill battle to market due to looming concerns about its data package.
- The committee voted 10 to 5 in favor of approving the 2 mg dose of Lilly's treatment for adults with moderate-to-severe rheumatoid arthritis (RA) who don't adequately respond or are intolerant to methotrexate. It then turned around and voted 10 to 5 against approving a 4 mg dose for the same indication.
- Blood clots were key to the rebuff of the 4 mg dose. Across four pivotal late-stage studies, there was a rate of seven thrombotic events per 100 patient years of exposure, whereas the placebo and 2 mg groups had rates of one and two events, respectively. Committee members did point out, however, that the data pool was smaller for the 2 mg dose, which Lilly investigated in just two Phase 3 studies.
Lilly entered the Food and Drug Administration advisory committee meeting on Monday with a fuzzy outlook for its potentially billion-dollar arthritis drug. It left in much the same fashion.
The committee's split votes for both baricitinib doses underscored a general confusion regarding the safety data included in the drug's approval application. Indeed, regulators rejected the application last April for not having enough information on dosing regimens and safety imbalances — particularly with regard to blood clots — between the placebo and treatment groups of pivotal late-stage studies. While Lilly's resubmission included new data analyses, they frequently raised more questions than answers for panelists during the committee meeting.
For example, pooling data from the four late-stage trials proved tricky because of their protocols. Two of the trials, JADX and JADW, were essentially identical, evaluating both doses of the drug against placebo. Another, JADV, tested just the 4 mg dose against placebo and an active comparator, AbbVie Inc.'s Humira (adalimumab). The last one, JADZ, had three arms: the 4 mg dose, the 4 mg dose plus methotrexate, and methotrexate alone.
Additionally, each study had a crossover period at which point patients switched from whatever treatment they were on to 4 mg baricitinib (or 4 mg baricitinib plus methotrexate, in the case of JADZ). This design element was especially burdensome when it came to assessing dose-dependent responses and safety signals.
And design was just one issue. In their own presentation, FDA officials argued that the number of patients who took the 2 mg dose — 403 between JADX and JADW — was too small to compare to the findings from the 4 mg population.
"The laboratory findings alone raises concern about higher safety risk with baricitinib 4 mg compared to baricitinib 2 mg, and given no convincing efficacy benefit of the 4 mg dose over the 2 mg dose, would tip the benefit-risk assessment in favor of the 2 mg dose over the 4 mg dose," the agency said in briefing documents.
This may be problematic. While the FDA normally follows suit with advisory committee votes, the unresolved data issues surrounding baricitinib could spur an unusual departure, or at the very least a restricted label.
A 'very uncomfortable yes'
The less-than-perfect data package complicated things for the committee. Several times, Acting Chairperson Jose Scher, also an assistant professor in medicine and rheumatology at the New York University School of Medicine, had to reorient the discussion back to the central questions at hand: whether the data submitted showed adequate efficacy and safety.
On efficacy, the consensus was a resounding yes. But on safety, there was much less confidence.
"I voted yes. I could have definitely voted no. It was a coin flip basically," said Erica Brittain, a committee member and deputy branch chief in the division of clinical research at the National Institute of Allergy and Infectious Diseases.
|Question No.||What did it ask?||Yes||No|
|2||Do the data provide substantial evidence of the efficacy of baricitinib 2 mg for the proposed indication?||14||1|
|3||Do the data provide substantial evidence of the efficacy of baricitinib 4 mg for the proposed indication?||15||0|
|5||Are the safety data adequate to support approval of baricitinib 2 mg for the proposed indication?||9||6|
|6||Are the safety data adequate to support approval of baricitinib 4 mg for the proposed indication?||4||11|
|7||Is the benefit-risk profile adequate to support approval of baricitinib 2 mg for the proposed indication?||10||5|
|8||Is the benefit-risk profile adequate to support approval of baricitinib 4 mg for the proposed indication?||5||10|
Like others on the committee, Britain noted that the 2 mg dose, at least from a straight numbers perspective, proved safer than 4 mg dose on multiple categories of adverse events. Even so, she said it was a "very uncomfortable yes," and several of her peers acknowledged a need for more data on the 2 mg dose post-market.
Jon Russell, a medical director at the Arthritis and Osteoporosis Center of South Texas and fellow committee member, was particularly wary of baricitinib's data package, likening the strong efficacy yet murky safety to Merck & Co.'s anti-inflammatory drug Vioxx (rofecoxib), which was pulled from market in 2004 because of cardiovascular risks.
"Any panel discussion that includes comparisons to Vioxx is never going to end well for the sponsor, and given the liabilities and reservations disclosed in the discussion, unfortunately baricitinib is likely going to come out of the gate mostly exciting future plaintiff’s attorneys," Leerink analyst Geoffrey Porges wrote in an April 24 note.
Though upbeat on the 2 mg approval recommendation, Terrence Rooney, medical director for rheumatoid arthritis at Lilly Bio-Medicines, noted that clearing "both doses gives doctors the flexibility to match treatment to patients' individual characteristics."
On that front, President of Lilly Bio-Medicines Christi Shaw said during a first quarter earnings call Tuesday that the company is looking at the possibility of a carve out label for the 4 mg dose aimed at the most at-risk RA patients, and then a broader label for the 2 mg dose.
Such efforts may be well worth it for baricitinib, which analysts at one point forecasted as a potential blockbuster. In its most recent annual filing, Lilly identified the drug as one of its key growth drivers in the years to come.
Shares of the Indianapolis-based drugmaker opened at $81.17 apiece Tuesday, up a little more than 1% from the prior day's close. Incyte Corp., which is co-developing baricitinib, fared worse, with shares down 3.6% to $65.66 apiece.