FDA review slams Novartis's case for beleaguered heart drug serelaxin

One of Novartis's top late-stage drug prospects is in deep trouble. In advance of an upcoming advisory committee meeting, the FDA in-house review says point blank that the application for the heart drug serelaxin should be rejected as the pharma giant has yet to provide the decisive data on efficacy needed to green-light the therapy.

The review wastes no time in cutting to the chase. Novartis ($NVS) failed to back up the proposed indication on acute heart failure, didn't conduct a second trial--or design the single study to provide the equivalent data load of two studies--to confirm the drug's effect on dyspnea, and didn't actually engineer the pivotal trial to back up its double-edged claims on easing symptoms and changing the rate of heart failure in any case.

"We recommend that serelaxin not be approved at this time because there is insufficient evidence to support the proposed indication: to "improve the symptoms of acute heart failure through reduction of the rate of worsening of heart failure,"' noted the review by Melanie Blank and Tzu-Yun McDowell. "We did not identify any significant safety concerns precluding approval. In particular, the favorable 180-day mortality data for serelaxin is reassuring."

In late 2012 the pharma giant cited serelaxin as Exhibit A in making the case to investors that it has the late-stage drugs needed to arrest a slide in sales revenue. The drug--a synthetic version of the hormone relaxin that aids pregnant women--helped improve shortness of breath among patients over 5 days, the company asserted. But the drug missed other endpoints, raising fears among analysts that an approval this year could simply set up a more critical review process among payers.

That showdown with payers may have to wait, though.

Novartis is now 0 for 2 on the regulatory front. Back in January the European Medicines Agency's Committee for Medicinal Products for Human Use rejected Novartis' application for serelaxin, calling out the development team for failing to demonstrate quick relief for heart disease in the first 24 hours, failing to demonstrate the significance of the benefit over 5 days and calling into question the data that were presented. Novartis immediately shifted tactics, though, saying it would shoot for a conditional approval. That option, though, is increasingly looking like a long shot, at best.

Ironically, the FDA blessed serelaxin with its breakthrough drug designation last summer. The BTD title was bestowed during the first big wave in the months after the agency launched the effort to speed up the development of the industry's most promising therapies. Novartis is now gathering mortality data on the drug, but a spokesperson told Bloomberg that the data wouldn't be available until 2016.

The FDA review makes for an interesting critique of the development team which designed and executed the study for this drug, finding fault with what the reviewer determined was a badly flawed trial.

The FDA wrote: "The results of RELAX-AHF were driven by worsening heart failure that could be easily medically managed with small increases in doses of IV diuretics. In fact, the mean difference in IV furosemide doses between treatment groups over the 5-day assessment period was 60 mg and the median difference was 20 mg (higher in the placebo group). The small difference in diuretic use provides some evidence of drug activity but it is a small treatment effect seen in one trial."

"Even if one were to accept the results of RELAX-AHF at face value with the prespecified worsening heart failure imputation method, the clinical meaningfulness of the difference in VAS dyspnea scores is questionable. A 447.7 mm-hr mean difference in VAS-AUC change from baseline between treatment groups translates into a an average difference between treatment groups of ~ 4 mm on the 100 mm VAS scale."

The FDA advisory committee meets on Thursday.

- here's the review