We can stop wondering where it will fit now: On May 27th, the FDA approved AbbVie/Biogen’s anti-CD25 monoclonal antibody Zinbryta (daclizumab high-yield process, a repurposing of Roche’s Zenapax, originally approved for kidney transplant rejection and later withdrawn) as a third- or later-line treatment for relapsing forms of multiple sclerosis (MS)—guidance that obviates any theorizing among U.S. neurologists (and analysts, as a May 26th draft of this blog would attest) as to where the drug will fit in MS treatment. Notably, the decision follows on the heels of a positive CHMP opinion delivered in April that retains flexibility for first-line use. The regional contrast in line of therapy guidance for Zinbryta mirrors that observed for Sanofi Genzyme’s Lemtrada in late 2014; taken together, the FDA stance appears to indicate a particular lack of comfort with medications that bring a risk of secondary autoimmunity. Zinbryta’s FDA-approved label contains black box warnings detailing the risk of hepatic injury and resultant monthly monitoring, as well as the risk of immune-mediated disorders. Furthermore, the drug will be available in the United States—beginning in Q3—only through a restricted distribution program that requires prescribers to be trained and registered, similar to Lemtrada and Biogen’s Tysabri before it.

Zinbryta is a solid performer, with risks: Zinbryta’s pivotal studies comprise a large, two-year active-comparator Phase III study (DECIDE) and a sizable, one-year placebo-controlled Phase IIb registrational study (SELECT), both of which assessed once-monthly subcutaneous Zinbryta as monotherapy for RR-MS using standard metrics. In DECIDE, treatment with Zinbryta (150 mg) resulted in a statistically significant 45% reduction in annualized relapse rate compared to treatment with Biogen’s Avonex; Zinbryta significantly reduced the risk of six-month SDP over Avonex (27%, P = 0.033), though three-month disability did not reach statistical significance. Adverse events in DECIDE were comparable across treatment arms, although Zinbryta-treated patients exhibited an increased incidence of serious infections (4% vs. 2% for Avonex), serious cutaneous reactions (2% vs. < 1% for Avonex), elevations in liver enzymes (5X the upper limit of normal) (6% vs. 3% for Avonex), and serious hepatic injuries (0.7% vs. 0.4% for Avonex). Immune-mediated disorders (e.g., skin reactions, lymphadenopathy) were observed in 32% (4% serious) of Zinbryta-treated patients and 12% (<1% serious) of Avonex-treated patients. Across all clinical studies, 0.3% of Zinbryta-treated patients developed autoimmune hepatitis.

But not a “mold-breaker”: Despite its novel immunomodulatory mechanism of action, Zinbryta’s clinical data position it more or less ordinarily along the benefit/risk matrix established by marketed DMTs. The drug will be the most convenient self-injected treatment available in an MS market transformed by oral options, in which positive differentiation is harder than ever to achieve. On balance, we expect Zinbryta to sit alongside Novartis’s Gilenya on the middle tier of relapse-prevention efficacy among MS DMTs, based on cross-trial comparison of data against a common active comparator; however, Zinbryta’s late-line FDA label and chronic monthly liver function monitoring put it at a significant disadvantage compared with the oral agent.

Its restrictive FDA label will prove a high hurdle: Zinbryta already faced an uphill battle as a modestly differentiated entrant into a crowded market, although the potential to gain traction across the MS treatment algorithm was there, assuming positive post-marketing experience. Now, the challenge for AbbVie/Biogen has been compounded by the late-line guidance and safety warnings in its FDA label. Like Lemtrada, the drug will have a more open label in Europe; however, interviewed European neurologists do not commonly report prescribing Lemtrada early in treatment and, with other, more-established drugs offering similar benefit, they may not be sufficiently motivated to do so with Zinbryta either—particularly at launch. However, the MS treatment algorithm—globally—is not at steady state, and Zinbryta may see room to grow if progressive multifocal leukoencephalopathy (PML) or lymphopenia-associated safety concerns intensify and cloud the water for Gilenya or Biogen’s own Tecfidera. Furthermore, because Zinbryta is designed to be immunomodulatory, it has the potential, from a safety perspective, to become the preferred post-Tysabri option in MS patients at risk of PML—pushing the more potent, but immunosuppressive, Lemtrada back in lines of treatment for those patients. All told, however, we expect Zinbryta’s role in MS treatment to be a small one

Moreover, a “mold breaker” is on the near-term horizon: Fierce competition for Zinbryta—and other MS DMTs—will arise beginning in early 2017 from Roche/Genentech’s Ocrevus (ocrelizumab). According to many interviewed MS experts, Ocrevus is a potentially transformative MS medication. Pivotal data, presented at the 2015 ECTRIMS conference in Barcelona, suggest the potential for Ocrevus to offer a standout benefit/risk balance in relapsing MS and, in a major clinical milestone, nonrelapsing PP-MS patients. Some thought leaders are cautiously optimistic that Ocrevus will be the tool that breaks the longstanding paradigm of escalation in MS treatment, but they are sobered by memories of similar expectations for Tysabri at the time of its launch. Ultimately, safety has set/will set, the ceiling for MS DMTs, potentially making Ocrevus a blockbuster many times over, while leaving Zinbryta struggling for a foothold.

For more, check out DRG’s upcoming, three-wave Emerging Therapies launch tracking series on Zinbryta and Ocrevus for RR-MS and, separately PP-MS to get a detailed look at these products’ early uptake.

 

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