April 19th, 2018
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 documentsoutlining 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.
Frank Vinluan is editor of Xconomy
Raleigh-Durham, based in Research Triangle Park. You can reach him at fvinluan
[at] xconomy.com
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