The rheumatoid arthritis (RA) market has come a long way since Enbrel (etanercept, Amgen Inc.) was first approved to treat the disease in 1998. Nearly two decades later, there are now a handful of additional TNF-alpha inhibitors, including some long-acting varieties, and multiple other drugs working through different mechanisms of action that have been approved by the FDA to treat RA. In addition to the multitude of biologics, there's even an oral disease-modifying antirheumatic drug (DMARD), Xeljanz (tofacitinib, Pfizer Inc.) that works by inhibiting Janus kinase (JAK). (See BioWorld Today, Nov. 8, 2012.)

Last month, Regeneron Pharmaceuticals Inc. and Sanofi SA stoked the competition fire with the approval of Kevzara (sarilumab), an IL-6 inhibitor, after manufacturing issues at Sanofi's Fill-Finish facility in Le Trait, France resulted in a complete response letter (CRL) for the biologics license application (BLA) last year. In Europe, Kevzara is set to gain approval after the EMA's Committee for Medicinal Products for Human Use adopted a positive opinion for the marketing authorization of the drug in April. (See BioWorld Today, Oct. 31, 2016 and May 24, 2017.)

Crowded market

Kevzara is approved for adult patients with moderately to severely active RA who have had an inadequate response or intolerance to a DMARD such as methotrexate. Like many RA drugs, Kevzara is approved as either a monotherapy or in combination with long-genericized methotrexate. The approval was based on two phase III trials, MOBILITY and TARGET, which compared Kevzara to methotrexate. A third head-to-head study, the MONARCH trial, testing Kevzra to Humira comparator, wasn't included in the label.

While the label technically places Kevzara in direct competition with drugs that have been on the market for many years, Leerink analyst Geoffrey Porges said Kevzara will take a back seat initially. "We forecast adoption of Kevzara, and other IL-6 antibodies, primarily in patients who have failed first line biologicals, mainly TNFs," Porges wrote in a note to clients.

J.P. Morgan analyst Cory Kasimov concurred. "We do think there is a place in the market for Kevzara with potential positioning for patients who don't do well on a TNF (i.e., convince them to try another agent instead of another TNF)," he wrote, noting that he thinks "the dynamics of the space may necessitate a slow grind higher" toward his peak sales estimate of $1.1 billion.

In a statement to BioWorld, Regeneron and Sanofi hinted that patients switching may be their main target, "In clinical practice, switching between TNF inhibitors, such as Humira and Enbrel, is a common treatment strategy to manage both efficacy and tolerability issues in RA patients. However, there is evidence that patients may respond better when switching to a biologic with an alternative mechanism of action rather than continuing to cycle between TNF inhibitors."

If Actemra (tocilizumab, Roche Group), the other marketed IL-6 inhibitor, ends up being Kevzara's biggest competition, Regeneron and Sanofi will have a distinct advantages to trumpet since Kevzara is injected every other week compared to Actemra which is injected weekly. Actemra also has a monthly formulation, but that requires intravenous delivery.

Unfortunately it isn't just Actemra that Kevzara has to compete with. Porges noted there are quite a few other classes of drugs that are likely to be used after TNF inhibitors, "In this setting, IL-6 antibodies compete with other targets and classes of biologicals, including CD-20 antibodies, CTLA-4 biologicals, JAK kinase inhibitors and second-generation anti-TNFs such as golimumab. This field is likely to become even more crowded later this year when Johnson & Johnson adds sirukumab to its lineup of biologicals, and in 2018 and 2019 when additional JAK inhibitors come into the market."

One JAK inhibitor, baricitinib (Incyte Corp. and Eli Lilly and Co.), received a CRL in April with an FDA request for more clinical data on the best dose for the drug as well as additional safety data. JAK inhibitors upadacitinib (Abbvie Inc.), filgotinib (Galapagos NV and Gilead Sciences Inc.), and peficitinib (Astellas Pharma Inc.) are all in late-stage testing for rheumatoid arthritis. (See BioWorld Today, April 17, 2017.)

Jefferies analyst Biren Amin pointed to the efficacy data on the drugs label as a potential way for Kevzara to compete with the multitude of drugs that came before it. "In addition to traditional [American College of Rheumatology] (ACR) endpoints, radiographic response in Kevzara treated patients is included which could help to support the clinical efficacy of Kevzara," Amin wrote in a note to clients.

Competing on a price

Kevzara is being launched at a wholesale acquisition cost (WAC) of $39,000 per year, an approximately 30 percent discount to the leading TNF-alpha inhibitors – Enbrel and Humira (adalimumab, Abbvie Inc.) – and a 16 percent discount to Actemra, the other FDA-approved IL-6 inhibitor. The 150 mg and 200 mg doses will be priced the same.

"While Regeneron/Sanofi are in somewhat uncharted territory with this aggressive approach, and the market is indeed crowded, we note that Kevzara comes with what we see as attractive label and now a price that's bound to make some waves," noted Raymond James analyst Christopher Raymond.

Of course WAC is only the published price and most payers will get a discount off that price, making it hard for analysts to know how much price will play in the overall competition.

"Entering a very crowded market, we will be monitoring to see how much additional discounting will be necessary," J.P. Morgan analyst Cory Kasimov noted.

Raymond concurred about the expectation for rebating, "Given the nature of this category, we anticipate significant rebating and discounting and continue to model a net price of $25,000."

While the list price for Kevzara is lower than other drugs, Leerink's Porges cited a recent study by the Institute for Clinical and Economic Review on the cost effectiveness of RA drugs that suggests an even lower price is needed, "Kevzara did not reach a typical $100,000 per quality-adjusted life year cost effectiveness threshold at this level, but neither did any of the other widely prescribed biologicals for this disease, including Enbrel, Humira, Cimzia, Orencia, Actemra and Xeljanz."