Serelaxin Rejection Shows “Breakthrough” Status Doesn’t De-Risk Programs
This article was originally published in Pharmaceutical Approvals Monthly
Executive Summary
FDA “complete response” appears to be the first for a product under the expedited pathway. But Novartis has a second trial that could support resubmission in 2016, and two other late-stage heart failure drugs in the pipeline.
FDA’s “complete response” letter for Novartis AG’s serelaxin should be an instructive lesson to sponsors and investors alike – just because a drug holds “breakthrough” designation doesn’t mean approval is a given.
Novartis sought approval, under the proposed trade name Reasanz, to improve the symptoms of acute heart failure through reduction of the rate of worsening of heart failure. It got the no-go from FDA May 16, brought down by a problematic Phase III trial design and a negative advisory committee review.
Serelaxin, a relaxin receptor agonist also known as RLX030, was among the first two dozen drugs to gain the expedited regulatory designation, and the Swiss pharma had been touting potential revenues of more than $1 billion (Also see "Recent Breakthrough Designations Break New Ground" - Pink Sheet, 22 Apr, 2014.). However, FDA’s “complete response” letter requesting further efficacy evidence will mean Novartis has to hold off seeking approval again until at least 2016 when results from a second Phase III trial are expected.
In March, the Cardiovascular and Renal Drugs Advisory Committee unanimously voted against approval based on data from serelaxin’s first Phase III trial – RELAX-AHF. Serelaxin met one of the two co-primary endpoints – measurement of the change in dyspnea from baseline over five days using the area under the curve of a visual analog scale – but did not show an improvement in dyspnea relative to the start of study drug at six, 12, and 24 hours as assessed using a seven-point Likert scale (Also see "Novartis Likely Stuck Waiting For Second Phase III For Serelaxin Approval" - Pink Sheet, 25 Mar, 2014.).
Dyspnea, or shortness of breath, is the most common symptom of acute heart failure.
The miss on the co-primary endpoint wasn’t the only problem, though; FDA’s outside experts questioned why Novartis chose the endpoints it did when the sponsor was trying to show that the drug kept patients from worsening heart failure (Also see "Stick To Basics: Attempt To Improve Heart Failure Symptomatic Endpoint Trips Up Novartis’ Serelaxin" - Pink Sheet, 7 Apr, 2014.). Despite voting against approval, the committee expressed confidence that serelaxin could have a benefit on more clinically meaningful endpoints (Also see "FDA Advisors Think Novartis’ Serelaxin Could Perform Better On More Difficult Endpoints" - Pink Sheet, 31 Mar, 2014.).
Novartis is conducting another Phase III trial – RELAX-AHF-2 – with a planned enrollment of more than 6,300 patients. The primary endpoint is cardiovascular mortality, and results are expected in 2016.
Should that trial yield better findings, Novartis stands positioned to reap significant benefits.
More than 5.8 million Americans and 23 million people globally are affected by heart failure, according to a recent report from Citeline. For a disease that puts a $32 billion drain on the health system, there are only 85 compounds in development, with 23 in late stages and 12 mid-stage trials.
Novartis can take credit for three late-stage compounds – serelaxin; a first-in-class angiotensin receptor neprilysin inhibitor dubbed LCZ696; and the renin inhibitor aliskiren, which is approved as Tekturna for hypertension. It currently has no compounds for heart failure in Phase II.
LCZ696 performed particularly well in a recent Phase III trial – PARADIGM-HF – prompting the study to be halted early due to efficacy (Also see "Data On Novartis’ Heart Failure Drug LCZ696 Fans Blockbuster Talk" - Pink Sheet, 31 Mar, 2014.).
“While Bayer leads all companies in total development compounds, Novartis may be in position to be a leader in this area if they can capitalize on two Phase III drugs as well as make any necessary modifications to the serelaxin program,” the May 2014 Citeline report noted. Bayer currently has six compounds in development for heart failure, with half of those in Phase II.