FDA staffers have expressed significant concerns about the side effects tied to Eli Lilly’s experimental rheumatoid arthritis drug baricitinib (Olumiant), which is once again up for review after the agency rejected it last year.
Next week, a panel of independent experts will convene to evaluate the merits of baricitinib. The FDA looks to these advisory panels in making regulatory decisions, though it doesn’t always agree with their insights.
Leading up to the meeting, FDA scientists on Thursday released briefing documents outlining their thinking on baricitinib. The agency cited the instance of deadly blood clots and questioned whether the higher of the two doses Lilly has tested will benefit patients—particularly since most of the safety problems were observed in patients on that dose. Assessing the risk of the drug versus its benefit at the higher 4 mg dose “is the main issue for discussion at the upcoming [advisory committee] meeting,” its staffers wrote. Lilly aims to sell the 4 mg dose, which bested blockbuster rheumatoid arthritis (RA) drug adalimumab (Humira) in a head to head study published in the New England Journal of Medicine last year.
Shares of Indianapolis-based Lilly (NYSE: LLY) dipped slightly to $79 Thursday morning following the release of the documents, then recovered to close at $79.75. Shares of Incyte (NASDAQ: INCY), the Wilmington, DE, company that licensed baricitinib to Lilly, ended the trading day at $69.05, down 1.46 percent from Wednesday’s closing price.
The FDA reviewers’ concerns are similar to those the agency raised a year ago when it rejected the drug and asked Lilly for more safety data. The agency was concerned about blood clots, and said it wasn’t clear the 4 mg dose was better than the 2 mg dose. Lilly resubmitted its application in December. The FDA scheduled an advisory panel for 8 a.m. Monday to debate the drug’s merits.
Baricitinib was tested in four Phase 3 studies. The 4 mg dose was tested in all four trials, but the lower dose was included in just two. In the studies that included both doses, the FDA said, it wasn’t clear whether the higher dose was better. Additionally, the study had a limited placebo control period and patients could cross over from the lower dose to the higher one, making it hard to assess how safe the drug was.
Lilly tried to address the FDA’s concerns by combining safety data from the various Phase 2 and 3 studies in its new approval application. It also added new data from another RA study and compared baricitinib to other RA medicines in terms of their propensity to cause blood clots. Those comparisons have limitations, the FDA review documents said, and combining safety data from various studies can’t overcome them or the other issues the agency has with Lilly’s program.
Lilly has proposed switching patients from the high to low dose if baricitinib is controlling their disease, or only giving the higher dose to patients who can’t take, or don’t respond to, more than one other RA treatment. But Lilly’s clinical trials weren’t designed to test those dosing strategies, FDA scientists countered.
Rheumatoid arthritis is an autoimmune disorder that causes swelling and pain in the tissues in the joints. The Lilly drug is a once-daily pill that blocks two Janus kinase (JAK) enzymes, proteins linked to inflammation. Lilly is trying to provide an alternative to injectable treatments like AbbVie’s (NYSE: ABBV) adalimumab. That drug, which suppresses the immune system, can also leave patients more vulnerable to potentially deadly infections.
There are other drugs that work by targeting JAK enzymes. The first such drug, tofacitinib (Xeljanz) from Pfizer (NYSE: PFE), received the FDA’s nod in 2012 for treating patients with moderate to severe RA who haven’t responded to or can’t take methotrexate, a chemotherapy that is also among the first-line treatments for arthritis. By comparison, Lilly is aiming to treat all adults with moderate to severe RA. Other experimental JAK inhibitors are trailing the Lilly drug. AbbVie’s upadacitinib and the Gilead Sciences (NASDAQ: GILD) drug filgotinib are in late-stage RA studies.
The most common side effect observed in patients treated with baricitinib was infection, such as respiratory and urinary tract infections. The FDA documents state that the Lilly drug was associated with an increase in platelet count, which was in contrast to other approved JAK inhibitors that are associated with decreases in platelet counts. The platelet increases were greater at the higher dose of baricitinib.
In the analysis of all patients treated with the Lilly drug, platelet counts in four of them were high enough to be characterized as thrombocytosis, a condition in which the body produces too many platelets. But the documents also say those high platelet levels could be due to a number of causes. One patient was reported to have a blood clot, though the documents add there was no clear relationship between the elevated platelet levels and the blood clot. Though FDA reviewers could not link JAK inhibition to elevated platelet levels, they noted that baricitinib didn’t have a safety advantage: its risks were consistent with drugs like adalimumab.
The comparison to adalimumab might be the wrong one. Lilly argued in its submission that its drug’s approach of targeting two specific JAK enzymes would offer a lower risks compared to other drugs that suppress the immune system. But one of the reviewers said that the opposite might be true. Elevated platelets and blood clot risks were observed in some of the patients treated with barictinib but not in studies testing Pfizer’s drug, the reviewer wrote. In a research note, Leerink analyst Geoffrey Porges said that that the FDA briefing documents suggest that the safety standard set by Pfizer’s JAK inhibitor is the mark that the Lilly drug and other second-generation JAK inhibitors must beat.
Barclays analyst Brian Abrahams pointed out in a research note that that the three FDA reviewers who wrote the briefing document had different views about the risks and benefits of baricitinib. Those views could lead the advisory panel to take a “middle ground” approach, recommending approval of the 2 mg dose. That outcome would be considerably less lucrative for Lilly because at that dose, the drug was not superior to AbbVie’s drug in head-to-head tests, Abrahams said.
The advisory panel will vote on seven questions regarding baricitinib, including whether the safety data submitted by Lilly are enough to support approval of the drug at either the 2 mg or 4 mg doses.