Lilly's Baricitinib: US FDA Panel To Weigh Thrombosis Risk, Dose Selection

Agency remains skeptical of JAK inhibitor's risk/benefit profile in rheumatoid arthritis even after Lilly submitted Sentinel network data showing baricinitib does not present an increased risk of thromboembolic events among RA patients; review documents suggest need to show an efficacy or safety benefit relative to other RA treatments, particularly Pfizer's Xeljanz.

Eli Lilly & Co.'s new drug application (NDA) resubmission for the rheumatoid arthritis treatment Olumiant (baracitinib) appears to have done little to assuage the US FDA's first-cycle concerns about the oral JAK inhibitor's thrombosis risk, and the adequacy of the sponsor's dose selection, ahead of an Arthritis Advisory Committee review April 23.

In a briefing document released April 19, FDA said the additional data provided in Lilly's NDA resubmission, which followed an April 2017 complete response letter, "did not substantially alter the efficacy and safety data in the original submission. Thus, questions remain regarding the benefit/risk of assessment of baricitinib for RA patients."

Lilly is seeking approved for treatment of adult patients with moderately to severely active RA who have had an inadequate response or intolerance to methotrexate. However, review documents suggest that given the unique thrombosis risk seen in baricitinib clinical trials, Lilly would need to demonstrate an efficacy or safety benefit relative to other RA treatments, particularly Pfizer Inc.'s Xeljanz (tofacitinib), the only JAK inhibitor approved for RA, to justify acceptance of this risk.

Although FDA concluded that both the 2 mg and 4 mg doses of baricitinib demonstrated efficacy compared to placebo in RA patients, the agency questions whether the 4 mg dose provides any additional benefit over the 2 mg dose in light of safety issues identified with compound.

However, the adequacy of the safety database to support approval of the 2 mg dose is in question because most of the pivotal safety data are with the 4 mg dose. In addition, FDA suggests Lilly failed to adequately explore lower doses.

As for safety issues, FDA was unpersuaded by Lilly's submission of epidemiological data, including data from the Sentinel surveillance system, purporting to show that the rates of venous thromboembolic events (VTEs), deep vein thromboses (DVTs) and pulmonary embolisms (PE) among baricitinib-treated patients were lower than, or within the lower range of, rates observed in the RA population treated with disease-modifying anti-rheumatic drugs (DMARDs).

FDA is asking the advisory committee to vote separately on the adequacy of the efficacy and safety evidence, and the overall risk/benefit profile, for both the 2 mg and 4 mg doses, according to draft questions for the meeting.

First-Cycle Complete Response Letter

Baricitinib was first approved in the European Union in February 2017 and has since been approved for the treatment of RA in more than 40 countries. In all countries where it has launched, both the 2 mg and 4 mg doses are approved, with the recommended dose being 4 mg once daily, Lilly's briefing document states.

However, Lilly and partner Incyte Corp. have found the road to the US market far more challenging than in other countries.

Lilly submitted the original NDA in January 2016, seeking approval as monotherapy or in combination with non-biologic DMARDs for the treatment of adult patients with moderately to severely active rheumatoid arthritis.

After extending the user fee goal date by three months, FDA issued a complete response letter in April 2017 that outlined several deficiencies, including:

• An imbalance in thrombotic events in the baricitinib RA program, with potential thrombotic risk with use of baricitinib in RA;

• Inadequate safety exposure for 2 mg dose;

• Lack of consistent findings to conclude greater efficacy with the 4 mg dose over 2 mg;

• Lower doses should be considered for use in RA as there was evidence that lower doses may be effective for treatment of RA; and

• Cases consistent with drug-induced liver injury were observed with baricitinib use and need to be described.

How Does Baricitinib Stack Up Against Other Treatments?

Review documents show that the complete response followed differences of opinion among agency staff on the adequacy of the data to support approval.

While the Division of Pulmonary, Allergy and Rheumatology Products cross-discipline team leader recommended approval of both the 2 mg and 4 mg doses, the division director initially recommended approval of only the 2 mg dose but subsequently questioned the adequacy of the data to support that dose.

Office of Drug Evaluation II Deputy Director Mary Thanh Hai, the signatory on the application, favored a complete response, noting that the thrombosis risk seen with baricitinib appears to compare unfavorably relative to other RA therapies, including tofacitinib.

"Review of this NDA has identified a serious safety risk of thrombosis not observed in other marketing applications for available RA therapies, especially tofacitinib," she said in an April 12, 2017 first-cycle decisional memo. "Absent an advantage of baricitinib over available therapies, the applicant will need to explore whether a lower dose can provide efficacy without this safety concern."

"Although the number of thrombotic events was low (16 VTE in Phase III trials, two VTEs in Phase II trials, three arterial thrombotic events in Phase II/III trials, and one pulmonary embolus in a non-RA trial), the absolute number and imbalance to controls during the first 16 weeks of pivotal studies distinguishes baricitinib from other approved RA therapies, particularly tofacitinib," she said.

 

Although a benefit over an existing therapy is not required for approval if a safe and effective dose of baricitinib can be identified, "such a benefit might justify tolerating a unique risk of baricitinib if that risk continues to be observed with additional studies." – FDA's Thanh Hai

 

Thanh Hai rejected the notion that a subpopulation of RA patients could be identified for whom the benefit/risk profile for baricitinib 4 mg or 2 mg would be favorable.

"If it were the first-in-class oral JAK-inhibitor, there may be a justifiable basis for carving out a niche population for baricitinib 2 and 4 mg," she said. "However, the evidence with tofacitinib in its premarketing application and subsequent Phase IV trials since its approval in 2012 has established its efficacy in RA patients across a spectrum of disease severity, its efficacy relative to adalimumab and [methotrexate], and its ability to reduce radiographic progression. These are the same populations and endpoints for which baricitinib is seeking approval; however, without the concerning thrombotic risk that appears unique to baricitinib."

Baricitinib Phase II dose-ranging studies suggested that lower doses, such as 1 mg, may have been effective and possibly safer, Than Hai said. Only the 4 mg dose was evaluated in all four of the pivotal trials, while the 2 mg dose was evaluated in only two of them. "The 2 mg dose might have been a viable safe and effective dose, had it been evaluated as extensively as the 4 mg dose in the Phase III program," she said.

Thanh Hai noted that although a benefit over an existing therapy is not required for approval if a safe and effective dose of baricitinib can be identified, "such a benefit might justify tolerating a unique risk of baricitinib if that risk continues to be observed with additional studies."

New Dosing Recommendation

Lilly resubmitted the NDA on Dec. 4 with data from another RA study of the 4 mg dose that was ongoing at the time of the original submission, a safety update, and epidemiological data on the incidence of venous thrombosis in the RA population.

In the resubmission, Lilly proposed a different dosing strategy than in the original NDA. (See table.)

Lilly's Proposed Dosing For Baricitinib

NDA Version	Baricitinib 2 mg	Baricitinb 4 mg
Original Submission	For some patients, a dose of 2 mg once daily may be acceptable	Recommended dose
Resubmission	Recommended dose; dose tapering to 2 mg once daily may be considered for patients who have achieved sustained control of disease activity with 4 mg once daily	For patients with an inadequate response or intolerance to more than one DMARD, a dose of 4 mg once daily is recommended

In line with the proposed dosing recommendations, Lilly's briefing document highlight's the 4 mg dose's efficacy in patients who have failed multiple prior DMARDs.

In patients with an inadequate response to biologic DMARDs, "baricitinib 4 mg showed significant benefit across domains of efficacy, even for those most refractory patients failing multiple bDMARDs of differing mechanisms," Lilly said. "For these difficult-to-manage patients with limited treatment options, the magnitude of its enhanced benefit over the 2 mg dose was large, often adding more than 50% relative to 2 mg versus placebo effects on RA disease activity. The benefits of the 4 mg dose for patients with multi-DMARD refractory disease were also consistently demonstrated in a corroborative analysis from the corresponding Phase III" population of patients with inadequate response to conventional DMARDs.

However, FDA raises concerns about the adequacy of the evidence to support the new dosing strategy, which it says is "more complicated and deviates from labeling for other non-biologic DMARD RA products."

"This is also problematic, given that the clinical development program was not designed to support the proposed dosing strategy," FDA said. "While Lilly submitted a rationale for the dosing recommendations, it is primarily based on post hoc analyses which do not provide convincing evidence that the relative benefit of the two doses differs according to degree of prior DMARD use, or that the 4 mg dose provides meaningful added benefit over 2 mg in the proposed subpopulation of patients with an inadequate response or intolerance to two or more DMARDs."

"To avoid being distracted with nuances of the proposed dosage and administration of baricitinib, we ask the AC panel to consider the benefit/risk assessment of each proposed dose of baricitinib for the treatment of adult patients with RA who have had an inadequate response or intolerance to methotrexate (MTX)."

FDA Rejects Epidemiological Data Comparisons

In its analysis of the resubmission, FDA said there was not a large, consistent difference in the rate of serious adverse events between the two doses of baricitinib, although there was a numerically higher incidence rate of various infections with the higher dose.

The incidence rate of major adverse cardiovascular events in the RA program was 0.6 per 100 patient years for the 4 mg dose and 0.2 per 100 patient years for the 2 mg dose. The VTE incidence rates were 0.6 and 0.4 per 100 patient years in the 4 mg and 2 mg dose groups, respectively.

In the resubmission, Lilly compared the VTE incidence rate for all patients exposed to baricitinib in the Phase II/III clinical trials to population-based VTE rates in RA patients drawn from FDA's Sentinel data network and the Truven Marketscan Commercial Claims and Encounters Database. Lilly used the Reagan-Udall Foundation's Innovation in Medical Evidence Development and Surveillance (IMEDS) program to tap the Sentinel network.
(Also see "Lilly's Olumiant Resubmission Includes Safety Data From US FDA's Sentinel Network" - Pink Sheet, 22 Feb, 2018.)

Although the incidence rates of VTEs, DVTs and PEs in the baricitinib clinical trials were lower than those seen in the Sentinel and Truven databases, FDA put little stock in this analysis.

"The VTE rates from the baricitinib clinical trials should not be compared to those of DMARD users in the IMEDS/Truven data to conclude that baricitinib is less safe, as safe as, or safer than DMARDs. The study designs and populations are fundamentally different and aim to address different objectives," FDA said. For example, the agency noted that data collection methods for medical history, RA information and baseline drug exposure differed between the clinical trial and observational studies, as did inclusion and exclusion criteria.

FDA concludes that analyses in the resubmission suggest that while there may be slightly greater efficacy with the 4 mg dose over 2 mg, any true differences are likely to be small and should be interpreted in the context of the potential toxicity associated with the two doses.