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Cytokinetics recently (Dec.
13) announced that its heart failure drug omecamtiv mecarbil (aka, AMG
423, hereinafter referred to as OM) in the FDA's Cardiovascular and Renal Drug Advisory Committee (CRDAC) meeting by a vote of 8 to 3 concluded that the benefits of OM in patients with heart failure did not outweigh the risks
it posed.
The FDA expects to make a final decision
on OM in the coming months.
PDUFA's target action date is February 28
, 2023.
on OM in the coming months.
PDUFA's target action date is February 28, 2023
OM is an investigational selective small molecule myomyosin activator that directly targets the contractile mechanism of the heart, binding and increasing the number of
cardiac myosin head regions that interact with actin during contraction.
If approved by the FDA, omecamtiv
mecarbil will be the first therapy
for HFrEF to directly target the contractile mechanism (or its pumping function).
The debate revolves around whether OM is too effective and whether the OM delivery strategy is safe
.
for HFrEF to directly target the contractile mechanism (or its pumping function).
From the point of view of efficacy, the end point is indeed achieved
From the point of view of efficacy, the end point is indeed achievedOM's listing was first based on a global multicenter clinical trial, GALACTIC-HF, which enrolled more than 8,200 patients
at 945 SITES IN 35 COUNTRIES AROUND WORLDWIDE.
OM successfully reduced cardiovascular death or heart failure events by 8% (p-0.
025) in more than 8200 heart failure (HFrEF) patients with reduced epiejection fraction, meeting the primary endpoint, particularly in its subgroup analysis showing higher efficacy
in patients with more severe disease.
In patients with a left ventricular ejection fraction of no more than 28% (a classic marker of worsening of heart failure), OM reduced the likelihood of cardiovascular death or the occurrence of a heart failure event by 16%, with a p-value of 0.
003
.
In addition, OM showed a higher therapeutic effect
in patients with more severe disease.
For example, the drug reduced the composite endpoint risk by 17% in hospitalized patients in the past three months and by 23%
in patients with elevated levels of N-terminal brain natriuretic peptide precursors.
However, the FDA concluded that 8% met the primary efficacy index, but the overall treatment effect was small, and none of the secondary endpoints were met
.
In its released document, the FDA said that "small therapeutic effects, while p-values are not very convincing for a single trial, nor do they have a definitive effect on any secondary efficacy endpoints, raise questions about whether the statutory requirement
for substantial evidence of effectiveness is met.
"
Dosing is toxic and the dosing strategy needs to be adjusted
Dosing is toxic and the dosing strategy needs to be adjustedTHE FDA HAS QUESTIONED THE SAFETY OF THE TREATMENT, AND RESULTS FROM THE GALACTIC-HF TRIAL AND PHASE 2 TRIALS HAVE SHOWN THAT INCREASED OM CONCENTRATIONS ARE ASSOCIATED WITH INCREASED TROPONIN I AND/OR NT-PROBNP VALUES AND CARDIAC ADVERSE EVENTS SUCH AS MYOCARDIAL ISCHEMIA AND HF
.
Given OM's cardiotoxicological profile, the FDA is concerned that the company's proposed dosing strategy may increase the potential risk
of OM-related cardiotoxicity.
Overall, the FDA believes that if plasma OM concentrations are not measured for dose adjustment, patients may suffer higher levels of drug exposure, which "may increase the potential risk of OM-related cardiotoxicity.
"
Cytokinetics then agreed to a PK-guided dosing strategy
.
.
Summary
SummaryOverall, the FDA's concern about whether the benefits outweigh the risks is the main reason for this rejection, and it is believed that Cytokinetics can pass
smoothly if it changes its dosing strategy.
It is worth mentioning that Mistar Pharmaceutical currently owns omecamtiv
Mecarbil's commercial interests in Greater China, in addition, OM's marketing application has also been accepted by the State Food and Drug Administration, hoping that the domestic application can solve this problem and successfully benefit patients
.
Reference source:
Reference source:
