Baricitinib Complete Response May Put Lilly/Incyte Behind IL-6 Blockers In RA

FDA complete response letter seeks additional data on dosing and other safety concerns, delaying potential approval for an NDA that already had been pushed back three months. Interleukin-6 inhibitors sarilumab and sirukumab, now under review at FDA, both could obtain approval before baricitinib.

Eli Lilly & Co. and Incyte Corp.'s hopes to bring their oral selective JAK1/2 inhibitor baricitinib to market soon in rheumatoid arthritis were dashed by an FDA complete response letter announced April 14, potentially putting a pair of interleukin-6 inhibitors now under review by the US regulator ahead in the race to get new RA therapies approved.

Filed for approval in January 2016, baricitinib initially had a January 2017 user fee deadline, but that was pushed back three months by FDA to allow for additional data analysis. With the complete response letter, the drug Lilly and Incyte have partnered on since 2009 looks likely to reach market after GlaxoSmithKline PLC/Janssen Pharmaceuticals Inc.'s sirukumab and Sanofi/Regeneron Pharmaceuticals Inc.'s sarilumab, both IL-6 inhibitors.

FDA's CRL calls for additional data to determine the most appropriate dose of baricitinib and further address other safety concerns from clinical trials, which could take a while to collect.

Lilly revealed that it had received the CRL on April 14, saying that it and Incyte "disagree with the Agency's conclusions." Lilly declined to comment due to the ongoing nature of discussions with FDA – in a release the Indianapolis pharma said timing of a resubmission depends on the outcome of those discussions.

Sanofi and Regeneron received a CRL for their Biologics License Application (BLA) for sarilumab last October, citing manufacturing concerns following a routine on-site FDA inspection of a "fill-and-finish" site in France. The sarilumab BLA at the time had an action date of Oct. 30. (Also see "Sanofi CEO Upbeat Despite Medivation M&A Miss, Sarilumab Diss" - Scrip, 31 Oct, 2016.)

Sanofi reported during a March 28 investor call that the two companies recently had re-filed the sarilumab BLA. (Also see "Sanofi/Regeneron Choose Access Over Price With Dupixent Launch" - Scrip, 28 Mar, 2017.) They hope for a two-month review of the resubmission for sarilumab, which gained its first approval Feb. 1 in Canada under the brand name Kevzara. (Also see "Canada First To OK Sanofi/Regeneron’s Sarilumab, But Struggle To Differentiate Looms" - Scrip, 1 Feb, 2017.)

"This follows the FDA's classification of Sanofi's Le Trait [France] manufacturing site as acceptable after recent inspection of the facility," Sanofi CEO Olivier Brandicourt told the call. "We continue to anticipate an FDA action date for Kevzara in the second quarter of 2017, which is, of course, subject to FDA's acceptance of the resubmission and determination of a new action date."

GSK/J&J's sirukumab BLA currently is under review by FDA with a Sept. 22 action date. If Sanofi and Regeneron get the speedy review they seek for their re-submitted application, sarilumab could reach the US market first, with sirukumab now also likely ahead of baricitinib in the timeline.

Baricitinib's Likelihood Of Approval Decreases

Biomedtracker downgraded baricitinib's likelihood of approval by 28 percentage points to 70% based on the news of the CRL April 14, which is still 11 points above average for a Phase III candidate for RA. However, the service gives sarilumab a 96% chance of approval and sirukumab a 94% likelihood.

Baricitinib's new drug application (NDA) was based on a five-study Phase III program, including the RA-BEAM study in which it demonstrated superiority against AbbVie Inc.'s widely used tumor-necrosis factor (TNF) inhibitor Humira (adalimumab) on signs and symptoms of the disease as well as on patient-reported outcomes, and the RA-BEGIN study, where it demonstrated superiority to methotrexate. (Also see "With Baricitinib, Lilly Hopes To Succeed Where Pfizer Has Struggled" - Pink Sheet, 30 May, 2016.)

Lilly/Incyte's JAK inhibitor has earned approval in Europe under the brand name Olumiant, following a December 2016 endorsement by the Committee for Medicinal Products for Human Use (CHMP). (Also see "Lilly's Olumiant To Be EU's First RA JAK Inhibitor, But Pricing Is Key" - Scrip, 16 Dec, 2016.) It is indicated for the treatment of moderate-to-severe RA in adults with inadequate response or who are intolerant to one or more disease-modifying anti-rheumatic drugs, either as monotherapy or in tandem with methotrexate.

In an April 7 note, Jefferies analyst Brian Abrahams pointed out that Olumiant's list price has been set in Germany at approximately $1,560 for a four-week supply of the once-daily tablet or $5,316 for a 14-week supply. This pricing suggests that Lilly and Incyte intend to compete with Humira and Amgen Inc.'s anti-TNF Enbrel (etanercept) on price in Europe.

Baricitinib also will need to be positioned price-wise to compete with biosimilars of the anti-TNF drugs – biosimilar etanercept and adalimumab already are on some European markets and are expected soon in the US. "Anti-TNFs, either the reference brands or their biosimilars, are likely to be the preferred first-line agents based on formulary placement. Payers may enforce step therapy requiring treatment with an anti-TNF before baricitinib can be used," Datamonitor Healthcare analyst Christina Vasiliou previously told Scrip.

Abrahams sees the pricing as indication that, even with superior efficacy over market-leading Humira, Lilly is willing to set a modest discount to the TNFs. "We believe this suggests they are committed to making the drug highly competitive versus well-entrenched, already-discounted/contracted incumbents, which could help long-term adoption," he wrote.

In Germany, drug sponsors typically set pricing for new products in the first year on market, which is negotiated downward thereafter. Abrahams said the German pricing comes in about 15% below the already discounted cost for the anti-TNF drugs, which is lower than Jefferies anticipated. It also may suggest a similar pricing strategy will be adopted in the US, the analyst said.

Competing In JAK Inhibitor Class With Xeljanz

In both Europe and the US, baricitinib will compete not only with the anti-TNF class and potentially two new IL-6 inhibitors, but also Pfizer Inc.'s selective JAK1/3 inhibitor Xeljanz (tofacitinib), a sales underachiever since its US approval in 2012. The drug only obtained EU approval as an RA therapy this past January, after two previous rejections in 2013 due to safety concerns. (Also see "Pfizer's Xeljanz Set To Lag Lilly's Olumiant In Europe Following Past Rebuffs" - Scrip, 27 Jan, 2017.)

There has been no direct head-to-head comparison of Xeljanz and baricitinib in RA, but market analysts generally expect the newer drug to offer better efficacy. That, combined with the fact that the Pfizer drug in it is original formulation is dosed twice-daily, should give Lilly and Incyte's product some differentiation in the JAK inhibitor class. (Editor's note: While this story initially said Xeljanz is taken twice a day, a once-daily, 11 mg Xeljanz XR version of the drug was approved by FDA in February 2016.) Datamonitor analyst Vasiliou projected peak sales of $1.9bn for baricitinib in 2025, outpacing Xeljanz, which brought in $927m during 2016 and has yet to post a blockbuster sales year.

In the larger RA competition, Regeneron recently indicated it was not inclined to try to compete on price, at least in the US. Senior Director for Health Economic and Outcomes Research Andreas Kuznik told the Institute for Clinical and Economic Review March 24 that a low price for sarilumab would be unlikely to result in high volume for the product. (Also see "Market Failure? Lower Drug Prices Don't Improve Access In Rheumatoid Arthritis" - Pink Sheet, 7 Apr, 2017.)

"Rebates are massive in this class. And those rebates create a disincentive to compete on price," the exec said. "Regeneron and Sanofi are launching a new drug but there is very little incentive for us to price it low and compete on price because price doesn't matter. We are not going to get better access in the marketplace."