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Evinacumab Offers ‘Remarkable’ Lipid Lowering in Severe HoFH

Evinacumab (Regeneron) appears to have a dramatic effect on low-density lipoprotein (LDL) cholesterol levels in patients with homozygous familial hypercholesterolemia (HoFH) with little or no LDL receptor activity, suggests a post hoc analysis of phase 3 trial data.

The results, which one expert described as a “game changer” for these patients, were presented at the European Atherosclerosis Society 2020 Virtual Congress on October 5, held online this year because of the COVID-19 pandemic.

The phase 3 ELIPSE trial showed that evinacumab, a human monoclonal antibody inhibitor of angiopoietin-like 3 (ANGPTL3), given intravenously every 4 weeks reduced LDL cholesterol levels in HoFH patients by an average of 47%.

As reported by | Medscape Cardiology, the treatment, which was generally well tolerated, was also effective in the approximately one third of patients with minimal residual LDL receptor activity.

Now, Frederick Raal, MD, PhD, the University of the Witwatersrand, Johannesburg, South Africa, presented a post hoc analysis of 10 patients with less than 2% functional LDL receptor activity. These patients experienced an even greater reduction of 72% over placebo.

Raal said that, taken together, the results are “remarkable in these very, very difficult to treat patients,” who have “a very unmet need.” He noted that the drug is “generally well tolerated.”

“Evinacumab may provide an effective treatment option for patients with HoFH who are unable to reach target LDL cholesterol levels despite multiple lipid lowering therapies, with or without apheresis,” Raal concluded.

Anne C. Goldberg, MD, a lipidologist and professor of medicine at Washington University in St. Louis, St. Louis, Missouri, told | Medscape Cardiology that HoFH patients with little or no LDL receptor activity, who number in the hundreds around the world, are a “very difficult group to treat because things don’t work.”

She pointed out that over 90% of patients in the trial were aged in their 30s and that the majority of them already had heart disease.

“So if you have something where you could start treating them relatively young and safely, theoretically, you could try to prevent some of these terrible cardiovascular outcomes in this group,” she said.

Goldberg highlighted that a drug such as evinacumab that can lower LDL levels in patients, often “for the first time ever, is quite a game changer.” She said that this was also seen with anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) therapies among patients with HoFH.

She also noted that the safety profile of evinacumab is encouraging.

“There are always going to be people with problems with anything, but there are not a lot of side effects,” she said, underlining that this is not seen “that often.”

Summarizing, Goldberg said that evinacumab “just seems to work, I think pretty nicely,” although she added that it “would be nice if we had a better idea about the mechanism of action, because it’s still a bit unclear how it works.”

Raal explained that HoFH is rare genetic disorder primarily due to mutations in the LDL receptor that result in highly elevated

Intensive Blood Pressure Lowering Potentially Harmful in ICH

Intensive lowering of systolic blood pressure (SBP) for patients with intracerebral hemorrhage (ICH) whose initial SBP is excessively high does not improve outcomes and is linked to safety concerns, new research shows.

Investigators found that ICH patients whose initial SBP was 220 mmHg and who underwent intensive BP lowering had twice the relative risk for neurologic deterioration at 24 hours without any reduction in hematoma expansion or 3-month risk for death and disability compared to their counterparts who underwent standard SBP lowering.

“The significantly higher rate of neurological deterioration associated with intensive treatment in patients with initial systolic blood pressure of 220 mm Hg or more warrants caution against broad recommendations for intensive systolic blood pressure reduction in patients with intracerebral hemorrhage,” the investigators, led by Iryna Lobanova, MD, Zeenat Qureshi Stroke Institute, University of Missouri, in Columbia, write.

The study was published online September 8 in JAMA Neurology.

Efficacy Unknown

American Heart Association and American Stroke Association guidelines recommend lowering SBP to 140 mmHg for ICH patients whose SBP is between 150 mmHg and 220 mmHg. However, guideline authors note that the safety and efficacy of intensive SBP lowering for patients with SBP >220 mmHg “appears to be unknown.”

To evaluate the safety and efficacy of intensive SBP reduction for ICH patients with excessively high initial SBP, the investigators analyzed data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage–II (ATACH-II) trial, which compared intensive and standard SBP reduction for patients with spontaneous supratentorial ICH.

Eligible participants had SBP >180 mmHg on two measurements. The first measurement that was recorded in the emergency department was considered the initial SBP.

Consistent with practice guidelines, treatment to lower SBP before randomization was permitted. The SBP measurement recorded immediately before randomization was the prerandomization SBP.

The treatment goal was to reduce SBP to a target range of 140 mmHg to 179 mmHg in the standard reduction group and 110 mmHg to 139 mmHg in the intensive reduction group over 24 hours.

The primary outcome was the proportion of patients who died or experienced severe disability at 90 days, defined as a Modified Rankin Scale score of 4 to 6.

Secondary outcomes included neurologic deterioration, as determined by the Glasgow Coma Scale or the NIH Stroke Scale, as well as hematoma expansion and hypotension.

Neurologic Deterioration

The study included 999 participants. Of these, 228 had an initial SBP of ≥220 mmHg. The mean age was significantly less in the excessively high SBP group than in the lower SBP group, at 59.0 and 62.8 years, respectively.

The mean minimum SBP at 6 to 7 hours and at 23 to 24 hours after randomization was significantly higher among the high SBP group than the lower SBP group.

Of the 228 patients whose initial SBP was ≥220 mmHg, 110 were randomly assigned to intensive SBP reduction, and 118 were assigned to standard SBP reduction. These two treatment groups did not differ significantly with respect to age or sex distribution.

Results showed that among participants with excessively high