FDA Panel Gives Partial Nod to Rheumatoid Arthritis Drug Baricitinib

Kerry Dooley Young

April 24, 2018

A US Food and Drug Administration (FDA) advisory panel on Monday lent cautious and limited support to Eli Lilly's bid to win US approval of baricitinib (Olumiant) to treat rheumatoid arthritis (RA), while also highlighting a potential thrombosis risk for the drug.

The Arthritis Advisory Committee voted 10 to 5 to tell the FDA that the benefit-risk profile for baricitinib given as 2 mg once daily was adequate to merit approval as a treatment in adults whose moderately to severely active rheumatoid arthritis has not responded well to methotrexate or who cannot tolerate that drug. The panel then voted 5 to 10 to say that the benefit-risk profile for the drug given at 4 mg once daily was not adequate for approval.

FDA officials will consider the recommendations of Monday's advisory panel but is not obliged to act on them.

"We know we didn't make your lives any easier," Jose U Scher, MD, the acting chairperson of the panel, said to FDA staff as he moved to conclude the day-long meeting.

Scher, a rheumatologist and assistant professor at the New York University School of Medicine, had been among the more skeptical members of the panel regarding baricitinib. He was among the naysayers in earlier votes specifically on the safety of baricitinib.

The panel split 9 to 6 in Lilly's favor on a question focused solely on whether the safety data were adequate to support approval of baricitinib at 2-mg dose. It then flipped to vote 5 to 10 against Lilly's favor on the same safety question when applied to the 4-mg dose. One panelist said publicly that he miscast this vote, meaning the tally should have been 4 to 11.

Diane Aronson of Naples, Florida, who served as the patient representative on the panel, echoed the views of many of her fellow panelists in explaining her reason for voting no on the safety questions.

"There was a serious signal for patients in this population for thrombotic events," she said."

Second Go-round for Drug

Lilly is making a second try for US approval of baricitinib. The FDA rebuffed the initial application that Lilly submitted in 2016. In April 2017, the FDA then gave the Indianapolis-based drugmaker a complete response letter that spelled out its safety concerns with the medicine, which is similar to those for an already approved drug, Pfizer's tofacitinib (Xeljanz) tablet.

On Monday, FDA staff remained clearly concerned about the drug. In the briefing document for the meeting, the FDA staff said Lilly's resubmission with additional data "did not substantially alter the efficacy and safety data in the original submission." The briefing documents for the Monday meeting also included the FDA's 2017 write-up on the baricitinib application, in which agency staff argued against approving what amounts to a follow-on drug.

Baricitinib and Pfizer's tofacitinib tablet were developed with the same target in mind, the enzyme Janus kinase (JAK). The medicines are meant to disrupt the intracellular signaling that contributes to rheumatoid arthritis' harmful and intense inflammatory response.

"Given that tofacitinib has established efficacy in the same RA populations baricitinib is seeking but lacks the potential risk for serious thrombotic events, one cannot make an argument that baricitinib might address an unmet need without first providing a better assessment of a lower dose," the FDA staff wrote.

FDA staff and panelists both noted that many questions remain about the risk for harmful and potentially deadly blood clots with baricitinib. Testing of medicines to win FDA approval often involves too few patients, the FDA claims, to allow definitive conclusions about these kinds of harmful side effects.

Still, the FDA staff highlighted data that could be an early clue about baricitinib and thrombosis. One case was seen among 1070 people given placebo, but 2 occurred among 479 people who took 2-mg doses of baricitinib. There were 7 cases among the 997 people who took baricitinib at the 4-mg dose, the FDA said in its presentation Monday.

Theories for Thrombotic Events

The FDA even presented theories as to why baricitinib might have thrombotic effects, citing its intent to more precisely target members of the JAK family of tyrosine kinases.

Baricitinib is intended to be selective for JAK1, JAK2, and TYK2 relative to JAK3, with an aim of limiting the immune suppressive effects associated with broad inhibition of this family, the FDA said in its briefing. The FDA theorized that this could result in a cascade that may lead to an increase in platelet production. Agency staff noted that these ideas about baricitinib are far from certainties. "Disruption of biologic processes associated with platelet removal cannot be ruled out" as a possible trigger for a potential thrombotic risk, Matthew Whittaker, PhD, on the FDA staff, said during his Monday presentation.

The targeted approach used in creating baricitinib reminded one of the FDA panelists of a Merck drug, the Vioxx painkiller, which that company pulled from the market in 2004 because of concerns about heart risk. Before that setback, Merck had been proud of having designed Vioxx with an aim of specifically fitting into a receptor for a kind of cyclooxygenase enzyme linked to pain.

 "It did that beautifully, but then it turned on its maker and caused some other problems because it was so effective at binding to a receptor," said I Jon Russell, MD, PhD, a rheumatology expert from San Antonio, Texas. "It looks to me like the submitted drug binds very effectively to JAK2."

Several patients and doctors had appealed to the FDA panel to support Lilly's application during the public session of the meeting. Russell said greater awareness of the risks of baricitinib is needed.

"The patients who have advocated for approval of this medication would not be doing so if a family member had had pulmonary embolism from a medication that had a quirk," Russell said. "We need to be cognizant of that as we evaluate and make decisions."

Despite introducing the example of Vioxx into the discussion, though, Russell supported approval of baricitinib. He was one of the five panelists to vote "yes" on the question of whether the benefit-risk profile supported approval of baricitinib at the 4-mg dose.

Lilly also got more clear support from the panel regarding questions on the drug's effectiveness. The panel voted 14 to 1 to say that there's "substantial evidence" that a 2-mg once-daily dose of baricitinib can aid people with rheumatoid arthritis whose disease has not been fully helped by methotrexate or who are intolerant of it. The panel then voted 15 to 0 to say that there was evidence of this claim for the 4-mg once-daily dose.        

In making a new bid for approval, Lilly offered several steps intended to address the FDA's concerns with the initial application. These included changing proposed dosing. It originally sought to have a 4-mg recommended dose, with the 2-mg once-daily dose as an option for some patients. In the resubmission, Lilly switched to have a recommended dose of 2 mg once daily. For patients with an inadequate response or intolerance to more than one other rheumatoid arthritis drug, a dose of 4-mg once daily is recommended, Lilly said.

Lilly also noted that the European Union cleared the drug in 2017. It's now approved in more than 40 countries, including Japan and Australia. In all countries where baricitinib has been launched, both the 2-mg and the 4-mg doses are approved, with the recommended dose being 4 mg once daily, Lilly said in its briefing document. The medicine can be used as a monotherapy or in combination with methotrexate. 

Lilly "Hopeful"

After the meeting, Lilly said it remains "hopeful" of securing US clearance of baricitinib in the months ahead.

"We are confident that baricitinib, if approved, can help people in the U.S. manage the challenges of living with RA," said Christi Shaw, president of Lilly Bio-Medicines, in a statement. "While we are disappointed with the Advisory Committee's assessment of the data for the 4-mg dose, we are confident in the positive benefit-risk profile of both the 2-mg and the 4-mg doses."

A key trial of the drug, called RA-BEACON, showed the medicine working for patients by a measure of rheumatoid arthritis known as ACR20, which represents at least a 20% improvement across selected measures of disease activity. Lilly has said that 55% of patients given baricitinib at the 4-mg dose achieved this result, as did 49% of a group given baricitinib at the 2-mg dose. Only 27% of those in the placebo had this result.

Rheumatoid arthritis affects approximately 1% of the adult population in North America and northern Europe, according to the FDA. The body's attack on its own tissues can deform joints and leave people disabled, while also spurring damage elsewhere in the body. People with this disease often find that treatments fail over time, which may leave them willing to consider risks in alternative medicines, several FDA panelists noted.

"Rheumatoid arthritis is a devastating disease. Organs are being destroyed, joints and organs," Russell said in explaining his support for a 4-mg dose regimen of baricitinib. "It's war and we need to make the patients aware that it's war and then fight it like it is."

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