Evolocumab lowers LDL in familial hypercholesterolemia
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Evolocumab effectively lowered plasma LDL in patients with homozygous or severe heterozygous familial hypercholesterolemia, according to long-term data from the TAUSSIG trial published in the Journal of the American College of Cardiology.
“We’ve shown for the first time that PCSK9 inhibition with evolocumab (Repatha, Amgen) is efficacious and safe in the long term in a very special population with a high unmet need to reduce LDL-C; that is, familial hypercholesterolemia (FH),” Raul D. Santos, MD, MSc, PhD, associate professor and director of the Lipid Clinic Heart Institute at the University of São Paulo Medical School Hospital and researcher at the Hospital Israelita Albert Einstein in São Paulo, told Healio. “Our study shows that the treatment sustained its effects, no neutralizing antibodies affected treatment in the long term and no new adverse events showed up with time.”
Study design
In this open-label, single-arm, multicenter study, researchers analyzed data from 300 patients with homozygous (n = 106; mean age, 34 years; 49% men) or severe heterozygous FH (n = 194; mean age, 55 years; 60% men) aged 12 years and older who were on stable lipid-lowering therapy for at least 4 weeks.
Patients were given either 420 mg of evolocumab per month if they were not on lipoprotein apheresis and 420 mg of evolocumab every 2 weeks if they were undergoing the treatment. Those not on apheresis could be uptitrated after 12 weeks to 420 mg every 2 weeks if needed. Follow-up was conducted every 12 weeks to assess adverse events, fasting lipids and anti-evolocumab antibodies.
Patients were treated for a median of 4.1 years. During that time, treatment-emergent adverse events occurred in 89.3% of patients, most of which were influenza (12.7%), nasopharyngitis (17.7%), headache (11.3%) and upper respiratory tract infection (11.7%).
For patients with homozygous FH, the mean change in LDL was –21.2% at week 12 and –24% at week 216. The mean change for patients with severe heterozygous FH was –54.9% at week 12 and –47.2% at week 216. In patients who were uptitrated (n = 48), the mean change improved from –19.6% at 12 weeks to –29.7% after being treated with 420 mg every 2 weeks for 12 weeks.
“FH patients seldom attain proposed LDL-C goals with statins and ezetimibe and persist at elevated residual risk of cardiovascular disease,” Santos said in an interview. “PCSK9 inhibitors add further 50% to 55% additional LDL-C reduction, and 60% to 70% of heterozygous FH patients can now attain LDL-C [less than] 70 mg/dL, something that we thought we never would achieve. ... For the homozygotes, it’s more complicated. On average, evolocumab reduced LDL-C by 20%. We got benefit in some patients where we doubled the dosage, but residual LDL-C was still very high. For these patients, LDL apheresis is still the optimal treatment and maybe further drugs like evinacumab (Regeneron) that is under development may add benefit in further LDL-C lowering.”
The annualized CV event rate was 2.7% per year: 2.8% in the homozygous group and 2.6% in the severe heterozygous group.
Of the patients who were undergoing apheresis at baseline (n = 61), discontinuation occurred in 9% of patients with homozygous FH and in 48% of those with severe heterozygous FH.
“For the heterozygotes we hopefully will have inclisiran (The Medicines Company), a small interference RNA drug that inhibits PCSK9 production and will facilitate patient’s life with two or three shots a year, but we still need more data specially on long-term safety,” Santos told Healio. “For the homozygotes, it’s still a challenge to normalize LDL-C, and newer medications like evinacumab (anti-ANGPTL3) are being tested. We’ll have results soon at the upcoming American College of Cardiology Scientific Session in March.”
Treating patients
In a related editorial, P. Barton Duell, MD, professor of medicine in the division of cardiovascular medicine at Oregon Health and Science University in Portland, and Sergio Fazio, MD, PhD, director of the Center for Preventive Cardiology at Knight Cardiovascular Institute at Oregon Health and Science University, wrote “New experimental therapies are under development that may enhance our capacity to achieve excellent LDL-C lowering in these high-risk patients, but in the meantime, specialty providers need to use all available LDL-C lowering medications, possibly in combination with ... lipoprotein apheresis, in the quest to adequately lower the LDL-C concentration in patients with FH for whom this is the most extreme and often single risk exposure.” – by Darlene Dobkowski
For more information:
Raul D. Santos, MD, MSc, PhD, can be reached at raul.santos@incor.usp.br; Twitter: @rauldsf_santos.
Disclosures: The study was funded by Amgen. Santos reports he received honoraria for consulting, speaking activities or research from Akcea, Amgen, AstraZeneca, Biolab, Esperion, Kowa, Merck, Merck Sharp & Dohme, Novo Nordisk and Sanofi/Regeneron. Duell reports he consulted for Akcea, AstraZeneca, Esperion, Regeneron, RegenxBio and Retrophin and received institutional grants from Regeneron, RegenxBio and Retrophin. Fazio reports he consulted for Amarin, Amgen, AstraZeneca and Novo Nordisk. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Joshua W. Knowles, MD, PhD, FAHA, FACC
This is a very impressive study, including 106 patients with homozygous FH, making this one of the largest studies of its kind. For those patients in particular, any treatments this effective are certainly welcome. That’s the main takeaway from this study, the dramatic effect of this agent on patients with homozygous FH.
These medications are going to become standard of care for patients with homozygous FH. Homozygous FH individuals often have untreated LDL levels over 500 mg/dL. In this study, they had baseline LDLs of 329 mg/dL, which is more than three times than normal, and they often have heart disease in their teenage years. The fact that they were able to achieve a 20% reduction in LDL and about a quarter of them were able to get off apheresis was very impressive.
For homozygous FH, there are several other drugs that are currently in the pipeline. The key here is that the typical drugs to lower cholesterol often don’t work well in homozygous FH, so part of the conundrum has been how do we lower LDL with unique or novel mechanisms. There’s a lot of work in that regard right now. There are other antibody therapies that work in other pathways. There are now companies that have formed that are trying to do gene editing to correct the molecular defect in the cells of the liver. These approaches hold promise for these patients with homozygous FH.
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