Evolocumab lowers LDL in pediatric heterozygous familial hypercholesterolemia
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Children with heterozygous familial hypercholesterolemia who received monthly injections of evolocumab had greater reductions in LDL and other lipid variables at 24 weeks compared with placebo, according to results of the HAUSER-RCT trial.
The randomized, phase 3 trial assessed the effects of evolocumab (Repatha, Amgen), a PCSK9 inhibitor that is widely used in adults, in 157 pediatric patients (mean age, 14 years) with heterozygous familial hypercholesterolemia. Results of the randomized, placebo-controlled, phase 3 trial were presented at the European Society of Cardiology Congress and simultaneously published in The New England Journal of Medicine.
“HAUSER-RCT is the largest and first placebo-controlled clinical trial conducted with a PCSK9 inhibitor in the familial hypercholesterolemia non-adult population,” Daniel Gaudet, MD, PhD, professor of medicine at Université de Montréal and senior investigator of the HAUSER-RCT trial, told Healio. “We already know that in adults that PCSK9 inhibition works. For the pediatric population, now we know that for those needing further LDL cholesterol reduction despite the standard of care, there is an option.”
At the start of the study, all children followed a low-fat diet and were treated with stable lipid-lowering therapy for at least 4 weeks. Baseline LDL was 130 mg/dL or higher and triglycerides were 400 mg/dL or lower.
Patients were randomly assigned to receive monthly subcutaneous injections of evolocumab 420 mg (n = 104; 59% girls) or placebo (n = 53; 47% girls) over 6 months.
The primary efficacy endpoint of percent change in LDL from baseline to 24 weeks was 44.5% in patients assigned evolocumab compared with 6.2% in those assigned placebo (difference, 38.3 percentage points; 95% CI, 45.5 to 31.3; P < .001). Mean absolute change in LDL in the evolocumab group was 77.5 mg/dL vs. 9 mg/dL in the placebo group (difference, 68.6 mg/dL; 95% CI, 83.1 to 54; P < .001).
Results showed evolocumab treatment significantly improved other secondary lipid-related endpoints compared with placebo, including change in apolipoprotein B and non-HDL cholesterol.
Incidence of adverse events was similar in both groups over 24 weeks. At least one adverse event occurred in 62% of the evolocumab group vs. 64% of the placebo group.
While statins are the first-line treatment for this pediatric population, some patients may not attain LDL goals due to limited drug response, adverse effects or poor treatment adherence.
This trial also determined that the injectable delivery of evolocumab can be administered in the pediatric population.
“This was an important question: Would an injectable agent be usable in the non-adult population? The answer to that is yes,” Gaudet told Healio. He said the monthly injection was “well received, well perceived and well tolerated.”
Gaudet also emphasized a need for increased diagnosis of familial hypercholesterolemia.
“We estimate that approximately only 15% to 20% of familial hypercholesterolemia is diagnosed. This applies to adults and non-adults,” Gaudet said. “To start with, we have to adequately diagnose familial hypercholesterolemia. When diagnosed, it’s important to treat the patients. There is an increasing consensus that starting the pharmacological treatment early (8 years of age) is important to reducing the burden of familial hypercholesterolemia, but we lack definitive evidence for an absolute target for LDL cholesterol in affected children. More time and more individuals being treated are needed to fill the gaps.”
Reference:
Perspective
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Mary P. McGowan, MD
Familial hypercholesterolemia is a disorder that impacts 1 in 250 people worldwide and leads to markedly elevated LDL and premature atherosclerotic CVD. Untreated children begin to lay down plaque by around age 10 years. While most children with heterozygous familial hypercholesterolemia can significantly reduce their LDL with generic statins and generic ezetimibe, some children, including the children in this study, continue to have elevated LDL despite these agents and are in need of additional lipid-lowering therapies.
While it was expected that evolocumab would be safe and well tolerated in children as it is in adults, until this study was done, we did not know this for certain. This study was important to conduct in order to demonstrate both the safety and efficacy of evolocumab in children with heterozygous familial hypercholesterolemia.
This study demonstrates that, when added to statin therapy, evolocumab is capable of lowering LDL, on average, an additional 44.5% and is safe and well tolerated in children ages 10 to 17 years with documented heterozygous familial hypercholesterolemia.
If evolocumab is approved by the FDA for use in children with heterozygous familial hypercholesterolemia, this study will give practicing physicians the confidence that the addition of evolocumab can be a safe and effective option.
This study was 24 weeks long. It will be important to continue to follow children long term on evolocumab. Evolocumab has been on the market since 2015 and was the subject of a
very large CV outcome trial in adults (FOURIER; Sabatine MS, et al. N Engl J Med. 2017;doi: 10.1056/NEJMoa1615664.). Evolocumab has been very well tolerated in adults, and I expect the same to be true in children, but long-term follow-up will be important.
This study took pains to follow hormones, vitamin levels, glucose levels, evolocumab antibodies, cognitive and neurologic tests, as well as pubertal growth and development. No difference was found between the placebo and evolocumab. These are the kind of things that should be followed long term in children.
When treating children and adults with genetic dyslipidemias like heterozygous familial hypercholesterolemia, it is so important to have as many tools at our disposable as possible. If approved in children with heterozygous familial hypercholesterolemia, evolocumab will represent one more tool.
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Gaudet D, et al. Advances in Science. Presented at: European Society of Cardiology Congress; Aug. 29-Sept. 1, 2020 (virtual meeting).
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