Meeting News

Alirocumab lowers LDL cholesterol in hypercholesterolemia

CHICAGO – Alirocumab decreases LDL cholesterol in a “clinically meaningful way” among patients with autosomal dominant hypercholesterolemia caused by apolipoprotein B loss-of-function mutations and PCSK9 gain-of-function mutations, according to findings presented at American Heart Association Scientific Sessions.

“Causes of autosomal dominant hypercholesterolemia include apolipoprotein B loss-of-function mutations and PCSK9 gain-of-function mutations,” the researchers wrote, adding that PCSK9 mutations are quite rare. “Alirocumab [Praluent, Sanofi and Regeneron] pharmacodynamics have been examined in patients with PCSK9 gain-of-function mutations or apolipoprotein B loss-of-function mutations in a phase 2, double-blind study.”

In an open-label extension of the study, Michel Krempf, MD, PhD, head of the department of endocrinology, metabolic diseases and nutrition at the University Hospital of Nantes in France, and colleagues analyzed the long-term safety and efficacy of alirocumab in patients with PCSK9 gain-of-function mutations or apolipoprotein B loss-of-function mutations. The 14-week double-blind period and 8-week follow-up period included 23 patients with an LDL cholesterol level of greater than or equal to 70 mg/dL despite treatment with other lipid-lowering agents. Almost all patients (n = 21) chose to participate in the open-label extension, including 15 patients with PCSK9 gain-of-function mutations and 6 patients with apolipoprotein B loss-of-function mutations.

Mean age of patients with PCSK9 gain-of-function mutations was 44.7 years (standard deviation, 12.7 years); mean age of patients with apolipoprotein B loss-of-function mutations was 45.5 years (standard deviation, 4.2 years). Mean BMI was 29 kg/m2 (standard deviation, 6.3 kg/m2) among patients with PCSK9 gain-of-function mutations and 30.1 kg/m2 (standard deviation, 5.3 kg/m2) among patients with apolipoprotein B loss-of-function mutations. There were more men in the group of patients with apolipoprotein B loss-of-function mutations than in the group of patients with PCSK9 gain-of-function mutations (67% vs. 20%, respectively).

At baseline in the open-label extension, mean measured LDL cholesterol concentrations was 154.5 mg/dL (standard deviation, 86.8 mg/dL) in patients with PCSK9 gain-of-function mutations and 129.8 mg/dL (standard deviation, 31.1 mg/dL) in patients with apolipoprotein B loss-of-function mutations.

Patients were treated with alirocumab 150 mg every 2 weeks for about 3 years or until the agent became commercially available, depending on which outcome occurred first, according to the researchers. The open-label extension began at week 32 and continued for up to 3 years. Mean exposure to the study drug was 129 weeks.

Alirocumab decreased mean measured LDL cholesterol by 72.4% in patients (n = 17) with PCSK9 gain-of-function mutations and 55.1% in patients (n = 6) with apolipoprotein B loss-of-function mutations after 8 weeks of double-blind treatment in the initial phase 2 study. The decline in LDL cholesterol was maintained through 3 years in patients with PCSK9 gain-of-function mutations and 84 weeks in patients with PCSK9 gain-of-function mutations.

However, due to the small sample sizes across groups, the researchers note that the data on LDL cholesterol over time “should be interpreted cautiously.” The timing of treatment cessation, whether it was because alirocumab became commercially available or because treatment reached the 3-year mark, decreased the number of patients enrolled in the study between weeks 116 and 200.

Treatment-emergent adverse events occurred in 90.5% of patients (n = 19) during the open-label extension of the study, although no patients stopped treatment because of these events.

“Alirocumab resulted in clinically meaningful LDL cholesterol reductions ... and was generally well tolerated,” the researchers wrote. - by Julia Ernst, MS

Reference:

Krempf M, et al. Abstract Su1233/1233. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Disclosures: Krempf reports consultant/advisory board roles with Modest and Sanofi. Please see the abstract for all other authors’ relevant financial disclosures.

CHICAGO – Alirocumab decreases LDL cholesterol in a “clinically meaningful way” among patients with autosomal dominant hypercholesterolemia caused by apolipoprotein B loss-of-function mutations and PCSK9 gain-of-function mutations, according to findings presented at American Heart Association Scientific Sessions.

“Causes of autosomal dominant hypercholesterolemia include apolipoprotein B loss-of-function mutations and PCSK9 gain-of-function mutations,” the researchers wrote, adding that PCSK9 mutations are quite rare. “Alirocumab [Praluent, Sanofi and Regeneron] pharmacodynamics have been examined in patients with PCSK9 gain-of-function mutations or apolipoprotein B loss-of-function mutations in a phase 2, double-blind study.”

In an open-label extension of the study, Michel Krempf, MD, PhD, head of the department of endocrinology, metabolic diseases and nutrition at the University Hospital of Nantes in France, and colleagues analyzed the long-term safety and efficacy of alirocumab in patients with PCSK9 gain-of-function mutations or apolipoprotein B loss-of-function mutations. The 14-week double-blind period and 8-week follow-up period included 23 patients with an LDL cholesterol level of greater than or equal to 70 mg/dL despite treatment with other lipid-lowering agents. Almost all patients (n = 21) chose to participate in the open-label extension, including 15 patients with PCSK9 gain-of-function mutations and 6 patients with apolipoprotein B loss-of-function mutations.

Mean age of patients with PCSK9 gain-of-function mutations was 44.7 years (standard deviation, 12.7 years); mean age of patients with apolipoprotein B loss-of-function mutations was 45.5 years (standard deviation, 4.2 years). Mean BMI was 29 kg/m2 (standard deviation, 6.3 kg/m2) among patients with PCSK9 gain-of-function mutations and 30.1 kg/m2 (standard deviation, 5.3 kg/m2) among patients with apolipoprotein B loss-of-function mutations. There were more men in the group of patients with apolipoprotein B loss-of-function mutations than in the group of patients with PCSK9 gain-of-function mutations (67% vs. 20%, respectively).

At baseline in the open-label extension, mean measured LDL cholesterol concentrations was 154.5 mg/dL (standard deviation, 86.8 mg/dL) in patients with PCSK9 gain-of-function mutations and 129.8 mg/dL (standard deviation, 31.1 mg/dL) in patients with apolipoprotein B loss-of-function mutations.

Patients were treated with alirocumab 150 mg every 2 weeks for about 3 years or until the agent became commercially available, depending on which outcome occurred first, according to the researchers. The open-label extension began at week 32 and continued for up to 3 years. Mean exposure to the study drug was 129 weeks.

Alirocumab decreased mean measured LDL cholesterol by 72.4% in patients (n = 17) with PCSK9 gain-of-function mutations and 55.1% in patients (n = 6) with apolipoprotein B loss-of-function mutations after 8 weeks of double-blind treatment in the initial phase 2 study. The decline in LDL cholesterol was maintained through 3 years in patients with PCSK9 gain-of-function mutations and 84 weeks in patients with PCSK9 gain-of-function mutations.

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However, due to the small sample sizes across groups, the researchers note that the data on LDL cholesterol over time “should be interpreted cautiously.” The timing of treatment cessation, whether it was because alirocumab became commercially available or because treatment reached the 3-year mark, decreased the number of patients enrolled in the study between weeks 116 and 200.

Treatment-emergent adverse events occurred in 90.5% of patients (n = 19) during the open-label extension of the study, although no patients stopped treatment because of these events.

“Alirocumab resulted in clinically meaningful LDL cholesterol reductions ... and was generally well tolerated,” the researchers wrote. - by Julia Ernst, MS

Reference:

Krempf M, et al. Abstract Su1233/1233. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Disclosures: Krempf reports consultant/advisory board roles with Modest and Sanofi. Please see the abstract for all other authors’ relevant financial disclosures.

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