FDA panel rejects serelaxin approval for heart failure, but urges future study

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 11 to 0 that serelaxin should not be approved for the treatment of acute heart failure, but agreed that the data on the drug were promising and that it should be studied further, at a meeting on March 27.

Members of the FDA’s Cardiovascular and Renal Drugs Advisory Committee agreed there was evidence that serelaxin, a recombinant form of human relaxin-2 hormone that is administered in an intravenous infusion over 48 hours, had a positive effect on worsening heart failure in the phase III RELAX-AHF study. But this was not a primary endpoint of the study, and panelists agreed that the study results were hypothesis-generating and were not sufficient to recommend approval. And because only one of the study’s two primary endpoints was positive, the study did not meet the level required for approval of a drug based on a single trial, several panelists pointed out.

"It’s clear that the drug does have an effect on worsening heart failure, but ... given the limitations on how that was not rigorously defined ... we don’t know how much of the effect was on minor heart failure changes, versus major [changes]," said the panel chair, Dr. A. Michael Lincoff, vice chairman for research in the department of cardiovascular medicine at the Cleveland Clinic. "We need better data on understanding the magnitude of benefit in a rigorous fashion, and the data we have here don’t stand alone as a single trial," he added.

Relaxin, which is present in men and women and increases during the first trimester of pregnancy, "primarily stimulates both the rapid and sustained nitric oxide (NO)-mediated vasodilation pathways," and results in vasodilation within minutes of administration, according to the manufacturer, Novartis Pharmaceuticals. The company’s proposed indication for serelaxin is for improving the symptoms of acute heart failure "through reduction of the rate of worsening of heart failure," based on the results of the phase III RELAX-AHF study, an international randomized, placebo-controlled, double-blind study of 1,161 patients with acute heart failure.

The study compared serelaxin started within 16 hours of hospitalization (at a dose of 30 mcg/kg per day for 48 hours) vs. placebo, plus standard therapy, on two primary endpoints that evaluated the drug’s effect on dyspnea: the Visual Analogue Scale (VAS) dyspnea scale and the Likert dyspnea scale. The area under the curve (AUC), representing the change in patient-reported dyspnea from baseline through day 5, significantly increased among those on serelaxin, compared with those on placebo. But the proportion of patients with moderate to marked improvements in dyspnea, based on the 7-point Likert scale at 6, 12, and 24 hours, however, was not significantly different between the two groups (27% among those on serelaxin vs. 26% among those on placebo).

Novartis also presented data to support serelaxin’s effects on worsening heart failure events through day 5, during which time 6.4% of those on serelaxin had a first episode of worsening heart failure or death within 5 days, vs. almost 12% of those on placebo; and less than 1% of those on serelaxin had recurrent worsening heart failure or death with prior event, vs. 2.6% of those on placebo.

In briefing documents provided before the meeting, the FDA stated that it does not recommend approval of serelaxin, citing various reasons, including the claim in the proposed indication that was "somewhat different" from what was evaluated in the study, as well as the "vague" definition of worsening heart failure in the study.

At the meeting, Dr. Melanie Blank, the FDA’s clinical reviewer, pointed out that the study protocol did not include prespecified criteria, such as signs, symptoms, and lab results, for defining worsening heart failure, and it was left to the investigator to determine whether a patient had worsening heart failure. Cases of worsening heart failure ranged from those that required mechanical ventilation to cases that required only a single 20-mg dose of furosemide, she added. Hypotension was the main safety issue in the study, but most cases were managed by reducing the dose and would not preclude approval, according to the FDA.

Because the study was designed to evaluate the effect of treatment on dyspnea, panelist Dr. Stuart Rich, professor of medicine at the University of Chicago, said "this was more a failure of trial design than it was of the drug itself." He added that that like other panelists, he was enthusiastic about the drug’s potential, and "hopefully, this will be a learning study where the hypotheses will be better thought out, tested, and then proven in a subsequent trial."

In a statement issued after the meeting, Tim Wright, global head of development at Novartis, said that the discussion during the meeting "provided important information that we will address with the FDA as it completes its review," and that the company will "continue to drive our robust clinical trial program and build upon the already established body of evidence." In 2013, Novartis started enrolling patients in RELAX-AHF-2, an international, phase III outcomes study of serelaxin in more than 6,300 patients with acute heart failure; results are expected in 2016.

Serelaxin has not been approved elsewhere. The FDA granted serelaxin fast track status in 2009, and in 2013 it was granted breakthrough therapy designation for reduction of cardiovascular mortality. Breakthrough therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.

In January, the Committee for Medicinal Products for Human Use recommended against approving serelaxin for acute heart failure in Europe, citing issues that included no apparent benefit for short-term relief of dyspnea.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 11 to 0 that serelaxin should not be approved for the treatment of acute heart failure, but agreed that the data on the drug were promising and that it should be studied further, at a meeting on March 27.

Members of the FDA’s Cardiovascular and Renal Drugs Advisory Committee agreed there was evidence that serelaxin, a recombinant form of human relaxin-2 hormone that is administered in an intravenous infusion over 48 hours, had a positive effect on worsening heart failure in the phase III RELAX-AHF study. But this was not a primary endpoint of the study, and panelists agreed that the study results were hypothesis-generating and were not sufficient to recommend approval. And because only one of the study’s two primary endpoints was positive, the study did not meet the level required for approval of a drug based on a single trial, several panelists pointed out.

"It’s clear that the drug does have an effect on worsening heart failure, but ... given the limitations on how that was not rigorously defined ... we don’t know how much of the effect was on minor heart failure changes, versus major [changes]," said the panel chair, Dr. A. Michael Lincoff, vice chairman for research in the department of cardiovascular medicine at the Cleveland Clinic. "We need better data on understanding the magnitude of benefit in a rigorous fashion, and the data we have here don’t stand alone as a single trial," he added.

Relaxin, which is present in men and women and increases during the first trimester of pregnancy, "primarily stimulates both the rapid and sustained nitric oxide (NO)-mediated vasodilation pathways," and results in vasodilation within minutes of administration, according to the manufacturer, Novartis Pharmaceuticals. The company’s proposed indication for serelaxin is for improving the symptoms of acute heart failure "through reduction of the rate of worsening of heart failure," based on the results of the phase III RELAX-AHF study, an international randomized, placebo-controlled, double-blind study of 1,161 patients with acute heart failure.

The study compared serelaxin started within 16 hours of hospitalization (at a dose of 30 mcg/kg per day for 48 hours) vs. placebo, plus standard therapy, on two primary endpoints that evaluated the drug’s effect on dyspnea: the Visual Analogue Scale (VAS) dyspnea scale and the Likert dyspnea scale. The area under the curve (AUC), representing the change in patient-reported dyspnea from baseline through day 5, significantly increased among those on serelaxin, compared with those on placebo. But the proportion of patients with moderate to marked improvements in dyspnea, based on the 7-point Likert scale at 6, 12, and 24 hours, however, was not significantly different between the two groups (27% among those on serelaxin vs. 26% among those on placebo).

Novartis also presented data to support serelaxin’s effects on worsening heart failure events through day 5, during which time 6.4% of those on serelaxin had a first episode of worsening heart failure or death within 5 days, vs. almost 12% of those on placebo; and less than 1% of those on serelaxin had recurrent worsening heart failure or death with prior event, vs. 2.6% of those on placebo.

In briefing documents provided before the meeting, the FDA stated that it does not recommend approval of serelaxin, citing various reasons, including the claim in the proposed indication that was "somewhat different" from what was evaluated in the study, as well as the "vague" definition of worsening heart failure in the study.

At the meeting, Dr. Melanie Blank, the FDA’s clinical reviewer, pointed out that the study protocol did not include prespecified criteria, such as signs, symptoms, and lab results, for defining worsening heart failure, and it was left to the investigator to determine whether a patient had worsening heart failure. Cases of worsening heart failure ranged from those that required mechanical ventilation to cases that required only a single 20-mg dose of furosemide, she added. Hypotension was the main safety issue in the study, but most cases were managed by reducing the dose and would not preclude approval, according to the FDA.

Because the study was designed to evaluate the effect of treatment on dyspnea, panelist Dr. Stuart Rich, professor of medicine at the University of Chicago, said "this was more a failure of trial design than it was of the drug itself." He added that that like other panelists, he was enthusiastic about the drug’s potential, and "hopefully, this will be a learning study where the hypotheses will be better thought out, tested, and then proven in a subsequent trial."

In a statement issued after the meeting, Tim Wright, global head of development at Novartis, said that the discussion during the meeting "provided important information that we will address with the FDA as it completes its review," and that the company will "continue to drive our robust clinical trial program and build upon the already established body of evidence." In 2013, Novartis started enrolling patients in RELAX-AHF-2, an international, phase III outcomes study of serelaxin in more than 6,300 patients with acute heart failure; results are expected in 2016.

Serelaxin has not been approved elsewhere. The FDA granted serelaxin fast track status in 2009, and in 2013 it was granted breakthrough therapy designation for reduction of cardiovascular mortality. Breakthrough therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.

In January, the Committee for Medicinal Products for Human Use recommended against approving serelaxin for acute heart failure in Europe, citing issues that included no apparent benefit for short-term relief of dyspnea.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 11 to 0 that serelaxin should not be approved for the treatment of acute heart failure, but agreed that the data on the drug were promising and that it should be studied further, at a meeting on March 27.

Members of the FDA’s Cardiovascular and Renal Drugs Advisory Committee agreed there was evidence that serelaxin, a recombinant form of human relaxin-2 hormone that is administered in an intravenous infusion over 48 hours, had a positive effect on worsening heart failure in the phase III RELAX-AHF study. But this was not a primary endpoint of the study, and panelists agreed that the study results were hypothesis-generating and were not sufficient to recommend approval. And because only one of the study’s two primary endpoints was positive, the study did not meet the level required for approval of a drug based on a single trial, several panelists pointed out.

"It’s clear that the drug does have an effect on worsening heart failure, but ... given the limitations on how that was not rigorously defined ... we don’t know how much of the effect was on minor heart failure changes, versus major [changes]," said the panel chair, Dr. A. Michael Lincoff, vice chairman for research in the department of cardiovascular medicine at the Cleveland Clinic. "We need better data on understanding the magnitude of benefit in a rigorous fashion, and the data we have here don’t stand alone as a single trial," he added.

Relaxin, which is present in men and women and increases during the first trimester of pregnancy, "primarily stimulates both the rapid and sustained nitric oxide (NO)-mediated vasodilation pathways," and results in vasodilation within minutes of administration, according to the manufacturer, Novartis Pharmaceuticals. The company’s proposed indication for serelaxin is for improving the symptoms of acute heart failure "through reduction of the rate of worsening of heart failure," based on the results of the phase III RELAX-AHF study, an international randomized, placebo-controlled, double-blind study of 1,161 patients with acute heart failure.

The study compared serelaxin started within 16 hours of hospitalization (at a dose of 30 mcg/kg per day for 48 hours) vs. placebo, plus standard therapy, on two primary endpoints that evaluated the drug’s effect on dyspnea: the Visual Analogue Scale (VAS) dyspnea scale and the Likert dyspnea scale. The area under the curve (AUC), representing the change in patient-reported dyspnea from baseline through day 5, significantly increased among those on serelaxin, compared with those on placebo. But the proportion of patients with moderate to marked improvements in dyspnea, based on the 7-point Likert scale at 6, 12, and 24 hours, however, was not significantly different between the two groups (27% among those on serelaxin vs. 26% among those on placebo).

Novartis also presented data to support serelaxin’s effects on worsening heart failure events through day 5, during which time 6.4% of those on serelaxin had a first episode of worsening heart failure or death within 5 days, vs. almost 12% of those on placebo; and less than 1% of those on serelaxin had recurrent worsening heart failure or death with prior event, vs. 2.6% of those on placebo.

In briefing documents provided before the meeting, the FDA stated that it does not recommend approval of serelaxin, citing various reasons, including the claim in the proposed indication that was "somewhat different" from what was evaluated in the study, as well as the "vague" definition of worsening heart failure in the study.

At the meeting, Dr. Melanie Blank, the FDA’s clinical reviewer, pointed out that the study protocol did not include prespecified criteria, such as signs, symptoms, and lab results, for defining worsening heart failure, and it was left to the investigator to determine whether a patient had worsening heart failure. Cases of worsening heart failure ranged from those that required mechanical ventilation to cases that required only a single 20-mg dose of furosemide, she added. Hypotension was the main safety issue in the study, but most cases were managed by reducing the dose and would not preclude approval, according to the FDA.

Because the study was designed to evaluate the effect of treatment on dyspnea, panelist Dr. Stuart Rich, professor of medicine at the University of Chicago, said "this was more a failure of trial design than it was of the drug itself." He added that that like other panelists, he was enthusiastic about the drug’s potential, and "hopefully, this will be a learning study where the hypotheses will be better thought out, tested, and then proven in a subsequent trial."

In a statement issued after the meeting, Tim Wright, global head of development at Novartis, said that the discussion during the meeting "provided important information that we will address with the FDA as it completes its review," and that the company will "continue to drive our robust clinical trial program and build upon the already established body of evidence." In 2013, Novartis started enrolling patients in RELAX-AHF-2, an international, phase III outcomes study of serelaxin in more than 6,300 patients with acute heart failure; results are expected in 2016.

Serelaxin has not been approved elsewhere. The FDA granted serelaxin fast track status in 2009, and in 2013 it was granted breakthrough therapy designation for reduction of cardiovascular mortality. Breakthrough therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.

In January, the Committee for Medicinal Products for Human Use recommended against approving serelaxin for acute heart failure in Europe, citing issues that included no apparent benefit for short-term relief of dyspnea.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

[email protected]