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CaMKII Inhibitor Disappoints in Post-MI Cardioprotection

— First agent of its kind to test the waters in heart disease

MedpageToday
A computer rendering of the human heart showing a lack of blood flow

The first calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor to be tested for prevention of post-MI heart failure stumbled in a small phase II trial.

Among patients who had residual left ventricular (LV) dysfunction after successful percutaneous coronary intervention (PCI) for an anterior ST-segment elevation MI (STEMI), cardiac MRI revealed that LV remodeling was no more improved after 3 months of treatment with the CaMKII delta inhibitor NP202 compared with placebo (median change in LV end-systolic volume index [LVESVi] -3.53 vs -0.60 mL/m2, P=0.78).

Changes in LV end-diastolic volume index, LV ejection fraction (LVEF), infarct size, and diastolic function were also similar between NP202 and placebo recipients in the study, according to researchers led by Andrew Boyle, MBBS, PhD, of John Hunter Hospital at the University of Newcastle, Australia, reporting online in .

NP202 showed acceptable safety, as major adverse cardiac and cerebrovascular event rates were similar between groups (7.6% vs 9.9%, P=0.32). Two deaths occurred in each group over follow-up.

"Although preclinical studies targeting CaMKII have yielded mixed results, the strong mechanistic link between CaMKII and cardiac hypertrophy and failure warrants further exploration," the authors wrote.

Expressed in cardiomyocytes, CaMKII is activated by ischemia-reperfusion injury and contributes to myocyte death and dysfunction. It had been thought that a CaMKII delta inhibitor such as NP202 could halt the progression of adverse LV remodeling that may follow STEMI and result in subsequent heart failure.

Boyle and colleagues noted that their trial suffered from a higher-than-expected withdrawal rate of 23% and wound up underpowered to detect a meaningful difference in LVESVi. Patients also stayed on guideline-directed medical therapy after PCI, which could have made NP202 redundant.

"In my opinion, the major positive aspect of the study by Boyle et al is its groundbreaking intention to test a CaMKII inhibitor in patients with heart disease," wrote Mark Anderson, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, in an .

"However, my guess is that NP202 did not substantially inhibit CaMKII in heart or brain. At this point, we do not have more than a guess because a biomarker substantiating efficacy is lacking," he added.

The was conducted at 32 sites across the U.S., Australia, and New Zealand in 2015-2018. Included were 147 patients (mean age 58 years, 88% men, 88% white) receiving primary PCI for anterior STEMI.

This was a group deemed to be high risk for adverse LV remodeling, as LVEFs had remained <45% more than 48 hours after revascularization. The protocol selected for moderate-sized baseline infarcts.

Study participants were randomized to oral NP202 (1,000 mg daily) or placebo for 3 months.

Notably, the NP202 group had entered the trial with greater LVESVi (48.2 vs 41.3 mL/m2, P=0.03) and weight (mean 97 vs 89 kg, P=0.03) at baseline. This could have biased the trial against the treatment group, investigators cautioned.

"By the completion of the trial, the differences in LV size were no longer significant between the groups. One may therefore ask, could the observation that the NP202 group had greater improvement in LV remodeling after myocardial infarction be an indication that CaMKII inhibition was successful? I do not think so," Anderson wrote.

"The biggest issue in this trial is that NP202 is not a potent CaMKII inhibitor, and we have no evidence that CaMKII activity, in heart or anywhere else, was actually inhibited in patients randomized to NP202," he explained.

Anderson noted that CaMKII has a role in learning and memory, but Boyle's group did not report the neurocognitive evaluations expected for a CaMKII inhibitor trial in humans.

"We simply do not know if more of the NP202-treated patients performed worse in tests of learning and memory, were more likely to lose their car keys or forget passwords, or struggled more frequently to conjure the names of their friends and family," he observed.

Boyle's group also acknowledged that area at risk and the myocardial salvage index were not calculated, and the study was not continued beyond 3 months.

"My hope is that this trial is only the first to test the exciting potential of CaMKII inhibitor therapies for cardiovascular diseases. Future studies may benefit by using high-potency CaMKII inhibitor drugs or genetic inhibitor strategies, using validating biomarkers, and performing neurocognitive testing," Anderson concluded.

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    Nicole Lou is a reporter for 鶹ý, where she covers cardiology news and other developments in medicine.

Disclosures

The study was sponsored by Armaron Bio and performed by Medpace Clinical Research Organisation.

Boyle reported receiving grants from Armaron Bio.

Anderson disclosed having a patent issued to Allosteros Therapeutics and now owned by Johns Hopkins University, and NIH funding.

Primary Source

JAMA Cardiology

Boyle AJ, et al "Calcium/calmodulin-dependent protein kinase II delta inhibition and ventricular remodeling after myocardial infarction: a randomized clinical trial" JAMA Cardiol 2021; DOI: 10.1001/jamacardio.2021.0676.

Secondary Source

JAMA Cardiology

Anderson ME "To be or not to be a CaMKII inhibitor?" JAMA Cardiol 2021; DOI: 10.1001/jamacardio.2021.0701.