American College of Cardiology

American College of Cardiology

March 30, 2020
6 min read

Alirocumab, evinacumab confer LDL benefit in homozygous familial hypercholesterolemia

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Frederick J. Raal

Two studies presented at the virtual American College of Cardiology Scientific Session highlight new options for LDL cholesterol reduction in patients with homozygous familial hypercholesterolemia.

In the ODYSSEY HoFH study, the PCSK9 inhibitor alirocumab (Praluent, Sanofi/Regeneron) reduced LDL cholesterol by 35.6% compared with placebo in adults with homozygous familial hypercholesterolemia (HoFH). In a second study, the investigational therapy evinacumab (Regeneron), a monoclonal antibody that binds to ANGPTL3, reduced cholesterol to near-normal levels in this population.

“There have been remarkable advances in the last 30 years for the treatment of homozygous familial hypercholesterolemia,” Frederick J. Raal, MBBCh, FRCP, FRCPC, FCP(SA), Cert Endo, MMED, PhD, told Healio. “We have converted homozygous familial hypercholesterolemia from a lethal disease in childhood to a manageable lipid disorder — something I never dreamed possible.”


ODYSSEY HoFH included 69 patients with HoFH who were assigned 150 mg alirocumab (n = 45; mean age, 42 years; 47% men; mean baseline LDL, 295 mg/dL) every 2 weeks or placebo (n = 24; mean age, 45 years; 54% men; mean baseline LDL, 260 mg/dL). Background lipid-lowering treatment at baseline included a high-intensity statin regimen with atorvastatin 40 mg to 80 mg daily or rosuvastatin 20 mg to 40 mg daily. (86%), statin (97%), lomitapide (14.5%; Juxtapid, Aegerion), ezetimibe (72%) and apheresis (14.5%).

Based on genotyping, 40% of patients assigned alirocumab and 41.7% assigned placebo were true homozygotes with identical mutations on both LDL receptor alleles. Compound heterozygous mutations were observed in 24.4% in the alirocumab group and 29.2% in the placebo group.

The primary endpoint was LDL reduction compared with placebo at 12 weeks. From baseline to 12 weeks, alirocumab reduced LDL by 26.9% while LDL increased by 8.6% in patients assigned placebo, resulting in an average relative reduction of 35.6% among patients assigned alirocumab, and thus meeting the trial’s primary endpoint (P < .0001). The average absolute reduction in LDL was 62.8 mg/dL in the alirocumab group.

“The LDL-C response was more variable in patients with HoFH than in other forms of

Dirk Blom

Hypercholesterolemia,” Dirk Blom, MD, PhD, head of the division of lipidology and associate professor at the University of Cape Town and head of the lipid clinic at Groote Schuur Hospital in Cape Town, said during the presentation.

Researchers also assessed the percentage of patients who achieved LDL reductions greater than 30% and greater than 50% at 12 weeks. Overall, 57.1% of patients assigned alirocumab achieved at least a 30% reduction in LDL compared with 4.2% of patients assigned placebo (P = .001) and 26.7% assigned alirocumab achieved at least a 50% reduction compared with none in the placebo group (P = .0017).


The researchers also examined placebo-adjusted changes in other atherogenic lipids. At 12 weeks, levels of triglycerides improved by 26.5%, apolipoprotein B by 29.8% non-HDL by 32.9% and lipoprotein(a) by 28.4% (P < .0001 for all).

Treatment-emergent adverse events occurred in 44.4% of patients assigned alirocumab vs. 50% of those assigned placebo.  No serious adverse events, deaths or treatment discontinuations occurred during the trial.

“Alirocumab is a useful addition in patients with [homozygous familial hypercholesterolemia] and works as expected,” Blom told Healio. “The results are similar to those seen with evolocumab (Repatha, Amgen).”

Raul D. Santos

During a discussion of the trial, 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, said, “ODYSSEY HoFH is a very important trial because it expands our knowledge about the importance of PCSK9 inhibitors in reducing LDL cholesterol in these patients. This is a state-of-the-art trial in a very high-risk population.”

Evinacumab in patients with HoFH

In a second HoFH-focused Late-Breaking Clinical Trial at this year’s virtual meeting, Raal presented data from patients with HoFH who were assigned 15 mg/kg evinacumab (n = 43; mean age, 44 years; 56% women; mean baseline LDL, 260 mg/dL) or placebo (n = 22; mean age, 37 years; 50% women; mean baseline LDL, 247 mg/dL) via IV infusion every 4 weeks for 24 weeks. All patients were on stable lipid-lowering therapy with or without lipoprotein apheresis and had an LDL greater than 70 mg/dL.

The primary endpoint was LDL reduction from baseline to 24 weeks. At 24 weeks, the mean LDL reduction was 47.1% with evinacumab compared with an increase of 1.9% with placebo, resulting in an average relative reduction of 49% among those receiving evinacumab, and thus meeting the trial’s primary endpoint (P < .0001). For patients assigned evinacumab, LDL reductions were similar for those with null/null (n = 15) and non-null/null mutations (n = 28).

The absolute change in LDL at 24 weeks was 134.7 mg/dL in the evinacumab group vs. 2.6 mg/dL in the placebo group (difference = 132.1 mg/dL; P < .0001).

“For the first time, with the addition of evinacumab, we have been able to achieve desirable LDL cholesterol levels in the majority of HoFH patients,” Raal told Healio.

In terms of safety, adverse events occurred in 65.9% of patients assigned evinacumab vs. 81% assigned placebo. Serious adverse events occurred in 4.5% of patients assigned evinacumab and in no patients assigned placebo. Events that occurred in the evinacumab group were unrelated to the study drug, according to the researchers.

Eileen Handberg

Eileen Handberg, PhD, ARNP, FACC, research professor of medicine and director of the clinical trials program at University of Florida College of Medicine, discussed the findings during a press conference.

“This is truly groundbreaking in terms of this population. The fact that they were able to go for a different mechanism and in patients that have not been able to be responsive to a PCSK9 inhibitor, the reductions in LDL were quite impressive. The fact that [the reductions] occurred so rapidly and remained over the course of therapy is extremely important,” Handberg said. – by Darlene Dobkowski


Blom DJ, et al.

Raal FJ, et al. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials. Both presented at: American College of Cardiology Scientific Session; March 28-30, 2020 (virtual meeting).

Disclosures: The ODYSSEY HoFH trial was funded by Regeneron Pharmaceuticals and Sanofi. The study assessing evinacumab was funded by Regeneron Pharmaceuticals. Blom reports he received honoraria from Aegerion, Amgen, AstraZeneca and Sanofi and consultant/advisory board fees from Akcea, Amgen, Gemphire and Sanofi. Raal reports he received grants from Regeneron and personal fees from Amgen, The Medicines Company, Regeneron and Sanofi Aventis. Yancopoulos is co-founder of Regeneron. 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. Healio could not confirm relevant financial disclosures for Handberg at the time of publication.

Editor's Note: This article was modified on April 14, 2020 to reflect an update to the data.