On January 23, 2014, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a negative opinion on Novartis's novel acute heart failure (AHF) treatment serelaxin (Reasanz). The CHMP expressed concerns about the benefits of the drug, stating that further studies would be needed to confirm the effectiveness of serelaxin in the treatment of AHF. Novartis subsequently announced that it would submit a revised filing package, including new data analyses, for re-examination for conditional approval and that, in accordance with CHMP process, a revised opinion could be granted in Q2 2014.

Meanwhile, on the other side of the Atlantic: this coming Thursday, February 13, will see Novartis presenting efficacy and safety data at the FDA's Cardiovascular and Renal Drugs Advisory Committee meeting to discuss a potential U.S. approval for serelaxin in AHF. The drug received fast-track status from the FDA for AHF in 2009. Then in June 2013, the FDA granted serelaxin breakthrough therapy designation based on the drug's potential to address a serious unmet medical need in AHF; and a positive opinion on Thursday could lead to it becoming the first branded treatment to launch for AHF since Scios/Johnson & Johnson's nesiritide (Natrecor) in 2001 (nesiritide is not approved in the EU or Japan).

Serelaxin is a recombinant form of the human hormone relaxin-2 that plays a role in the hemodynamic and renovascular adaptive changes that occur during pregnancy. Serelaxin's regulatory filing was based on the results of the RELAX-AHF Phase III trial, which showed that treatment with serelaxin met one of the co-primary end points evaluating dyspnea improvement, therefore satisfying the prespecified criterion for efficacy. Significant improvements were also observed with serelaxin treatment in the signs and symptoms of heart failure and mean length of hospital stay. Most interestingly, results showed that serelaxin was associated with a 37 percent reduction in all-cause and cardiovascular mortality at six months. However, no significant effects were observed on the secondary end points, hospitalization for heart failure or renal failure and days alive out of the hospital up to day 60.

Given that serelaxin met only one of its primary dyspnea end points and did not achieve statistical significance on its two secondary end points, thought leaders interviewed by Decision Resources were cautious in interpreting the mortality benefit. This caution was prompted by the lessons learned with nesiritide, where efficacy benefits, demonstrated in a relatively small clinical trial, were later called into question in a much larger trial.

Novartis have since initiated RELAX-AHF-2 (NCT01870778), which will investigate serelaxin in over 6,000 AHF patients and seeks to replicate the key findings of RELAX-AHF; it will also assess cardiovascular mortality as the primary end point. Another 1,500 patient trial (NCT02007720), expected to begin in March 2014, will assess the percentage of patients with a clinical composite end point of treatment success, treatment failure, or no change. Both studies are expected to complete in 2016.

Despite the negative decision by the CHMP, we predict a promising outlook for serelaxin in the treatment of AHF, where favorable clinical trial results, including a six-month mortality benefit, will provide a strategic advantage over current AHF therapies, which lack data showing efficacy on this important end point. Indeed, according to survey results reported in Decision Resources Acute Heart Failure DecisionBase report (June 2013), U.S. cardiologists would prescribe a drug matching the profile of serelaxin to a median 24 percent of their drug-treated AHF patients, reflecting the great unmet need for therapies that can reduce mortality in AHF. However, due to the question marks raised over the Phase III data, and due to the highly genericized nature of the AHF therapy market, we forecast a lower patient share for serelaxin; nevertheless, we still predict it to be the sales leading heart failure brand in 2021.

Coming Soon:
DecisionBase: Chronic Heart Failure (April 2014)
Pharmacor: Heart Failure [AHF & CHF] 2014 (September 2014)

Conor Walsh, M.Sc., Ph.D., is a senior director on the Cardiovascular, Metabolic and Renal Disorders team at Decision Resources Group.

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