Three cardiologists from the Division of Cardiovascular Medicine at the Brigham and Women’s Hospital Heart & Vascular Center presented a total of four late-breaking clinical trials at the American College of Cardiology’s (ACC’s) 71st Annual Scientific Session in April.
“Once again, the Brigham had a strong showing at the ACC in presenting some of the latest information relevant to the treatment of patients with cardiovascular disease,” says John F. Keaney, Jr., MD, chief of Cardiovascular Medicine and executive director of the Heart & Vascular Center.
Cholesterol-reducing drugs like statins can mitigate the risk of cardiovascular disease in patients with high levels of non-high-density lipoprotein cholesterol (non-HDL-C) in the blood. However, alternative cholesterol-lowering strategies are needed in patients whose cholesterol levels remain high after taking statins.
The TRANSLATE-TIMI 70 trial studied vupanorsen, an antisense oligonucleotide targeting the protein angiopoietin-like 3 (ANGPTL3) with the goal of lowering lipid levels to mitigate cardiovascular risk. Results showed that vupanorsen reduced non-HDL-C by a statistically significant amount at all doses studied among patients who were already taking a statin. The drug also lowered triglyceride levels by up to 57% and ANGPTL3 levels by up to 95% compared to placebo.
“Vupanorsen reduced the primary endpoint, non-HDL-C, but not to a degree that would likely translate into a clinically meaningful impact,” says Brian A. Bergmark, MD, associate physician in Interventional Cardiology, investigator at the TIMI Study Group at the Brigham, and the study’s lead author. “There were also some important safety signals, including elevations of hepatic fat content at the highest doses of vupanorsen and of liver enzymes. As a result, Pfizer, the trial sponsor, will not be moving forward with this compound. Nonetheless, this trial provides important information as new agents are studied targeting triglyceride-rich lipoproteins.”
The goal of this phase 2b trial was to assess the safety and efficacy of bentracimab, an investigational monoclonal antibody medication, in reversing the antiplatelet effects of ticagrelor in people ages 50 to 80 years old. Currently, no reversal agents are approved for this indication.
“What we showed with bentracimab infusion is an immediate and complete reversal of ticagrelor’s antiplatelet effect,” says Deepak L. Bhatt, MD, MPH, executive director of Interventional Cardiovascular Programs and a study author. “This potentially would be a drug of great interest to cardiologists and cardiac surgeons for patients who are currently being treated with ticagrelor but need emergent or urgent surgical procedures or have severe bleeding.”
Dr. Bhatt is part of the team studying bentracimab in patients with significant bleeding due to hemorrhage, urgent surgery, or invasive procedures in the ongoing phase 3 REVERSE-IT trial. The investigators hope to complete REVERSE-IT later this year and then submit data for FDA approval of bentracimab.
Dr. Bhatt led the SCORED and SOLOIST-WHF trials, both of which showed that the investigational agent sotagliflozin has salutary effects on cardiovascular outcomes among patients with type 2 diabetes mellitus (T2DM) and heart failure. He previously presented the studies, both of which were published in The New England Journal of Medicine, as late-breakers at the American Heart Association Scientific Sessions 2020.
At ACC 2022, Dr. Bhatt shared more about what SCORED—which enrolled patients with T2DM and chronic kidney disease (CKD)—has revealed. In addition to a reduction in heart failure, investigators found a significant decrease in myocardial infarction and stroke, including in patients with a history of cardiovascular disease as well as those without known cardiovascular disease. Dr. Bhatt speculated that this benefit may be due to sotagliflozin’s dual SGLT1/2 inhibition.
“We’re seeing a growing amount of data in support of sotagliflozin, and we hope to submit it for FDA approval later this year,” he says. “Regardless, these two trials have already made many important scientific contributions, some of which are generalizable to the whole class of SGLT2 inhibitors, such as a reduction in heart failure in patients with preserved ejection fraction, and other benefits that may or may not be generalizable to the class and may have to do specifically with this drug and its ability to inhibit not only SGLT2 but also SGLT1.”
CANTOS and ZEUS Trials
The groundbreaking CANTOS trial (published in The New England Journal of Medicine in 2017) proved that targeting inflammation by targeting the interleukin-1β pathway can reduce cardiovascular event rate independent of lowering cholesterol. This hypothesis was born in the research group of Paul M. Ridker, MD, MPH, director of the Brigham’s Center for Cardiovascular Disease Prevention, and his long-term Brigham collaborator, Peter Libby, MD.
In his new presentation of CANTOS data at ACC 2022, Dr. Ridker focused on residual inflammatory risk in patients with atherosclerosis and CKD. His main new findings were that once treated with a statin, the primary issue remaining for CKD patients is residual inflammatory risk, which was a strong predictor of recurrent heart attacks, cardiovascular death, and all-cause mortality.
The ACC CANTOS data strongly support targeting inflammation in CKD, exactly what Dr. Ridker is now testing in ZEUS, a new clinical trial. ZEUS will randomize 6,200 patients with atherosclerotic cardiovascular disease, stage 3 or 4 CKD, and residual inflammatory risk as detected by elevated levels of C-reactive protein. The novel drug being studied in ZEUS is ziltivekimab, a monoclonal antibody that targets interleukin-6, which Dr. Ridker and his colleagues believe is the next crucial target for inflammation inhibition.
“ZEUS picks up exactly where CANTOS left off,” Dr. Ridker says. “By moving one crucial step downstream for interleukin-1 to interleukin-6, we are now targeting the most important inflammatory cytokine with hopes of reducing cardiovascular events and improving renal function in the setting of CKD, a patient group with huge unmet need.”