Alirocumab lowers LDL in patients with heterozygous familial hypercholesterolemia

LONDON — Patients with heterozygous familial hypercholesterolemia assigned the PCSK9 inhibitor alirocumab had significant lowering of LDL at 78 weeks, according to results from four 18-month placebo-controlled studies.

The drug was well tolerated among patients with heterozygous familial hypercholesterolemia (HeFH) and poor LDL control despite maximally tolerated statin therapy with or without other lipid-lowering therapies, researchers reported at the European Society of Cardiology Congress. Two of the studies, ODYSSEY FH I and ODYSSEY FH II, were simultaneously published in the European Heart Journal.

John J.P. Kastelein

“These findings really hold potential for reducing LDL levels in these individuals,” John J.P. Kastelein, MD, MPH, said during a presentation here. “Basically, this therapy in conjunction with statins and/or ezetimibe (Zetia, Merck) cures this genetic disease because LDL levels in these individuals are now lower than in the general population, which is of course something that we’ve never seen before.”

Kastelein and colleagues conducted two randomized, double blind studies (ODYSSEY FH I, n = 486; ODYSSEY FH II, n = 249) in which patients received an injection of alirocumab (Praluent, Sanofi/Regeneron) 75 mg or placebo every 2 weeks. Those in the alirocumab group who had LDL of 70 mg/dL or greater at 12 weeks had their dose increased to 150 mg every 2 weeks. At the ESC Congress, researchers presented those results along with those from the ODYSSEY HIGH FH study (n = 107) of patients with HeFH and LDL 160 mg/dL or greater and the HeFH subgroup from the ODYSSEY LONG TERM study (n = 415), both of which assigned patients to alirocumab 150 mg or placebo every 2 weeks.

The primary endpoint for all studies was percentage change in LDL at 24 weeks. Kastelein, from the department of vascular medicine at Academic Medical Center, University of Amsterdam, Netherlands, and colleagues followed the patients through 78 weeks.

In ODYSSEY FH I, mean LDL level dropped from 144.7 mg/dL at baseline to 71.3 mg/dL at 24 weeks (–57.9% compared with placebo), while in ODYSSEY FH II, mean LDL level dropped from 134.6 mg/dL at baseline to 67.7 mg/dL at 24 weeks (–51.4% compared with placebo; P < .0001 for both studies), according to the researchers. Among those studied from ODYSSEY LONG TERM and ODYSSEY HIGH FH, the alirocumab group at 24 weeks had an LDL decline of –2.32 mmol/L vs. –0.11 mmol/L for the placebo group (least squared mean percentage change, –55%; P < .0001).

At week 78, the LDL reductions were still maintained, they found.

LDL 70 mg/dL or less was reached by 59.8% of the alirocumab group in ODYSSEY FH I, 68.2% of the alirocumab group in ODYSSEY FH II and 56.3% of the alirocumab groups in ODYSSEY LONG TERM and ODYSSEY HIGH FH at week 24, Kastelein and colleagues reported.

In all studies, the alirocumab group had a greater reduction in lipoprotein(a), apolipoprotein B and non-HDL levels than the placebo group at 24 weeks (P < .0001 for all), Kastelein said during a presentation.

The rate of adverse events that contributed to discontinuation was 3.4% for alirocumab and 6.1% for placebo in ODYSSEY FH I and 3.6% for alirocumab and 1.2% for placebo in ODYSSEY FH II, they found. A pool of safety data for all four studies indicated similar adverse event rates between the alirocumab and placebo groups, Kastelein said.

Injection-site reactions occurred in 12.4% of the alirocumab group and 11% of the placebo group in ODYSSEY FH I and in 11.4% of the alirocumab group and 7.4% of the placebo group in ODYSSEY FH II, according to the researchers.

“From this experience in 1,257 HeFH patients, we can conclude that in this phase 3 clinical study program, in patients who received the maximally available treatment, alirocumab reduced mean LDL levels to less than 2.2 mmol/L (85 mg/dL) at weeks 24 to 78, levels that were until now unobtainable with maximum dose of statin and any other lipid-lowering therapy,” Kastelein said. – by Erik Swain

References:

Kastelein JJ, et al. Clinical Trial Update III: Pharmacology & Therapy. Presented at: European Society of Cardiology Congress; Aug. 29-Sept. 2, 2015; London.

Kastelein JJ, et al. Eur Heart J. 2015;doi:10.1093/eurheartj/ehv370.

Disclosures: The studies were funded by Sanofi and Regeneron. Kastelein reports receiving consulting fees and/or honoraria from Aegerion, Amgen, AstraZeneca, AtheroNova, Boehringer Ingelheim, Catabasis, Cerenis, CSL Behring, Dezima, Eli Lilly, Esperion, Genzyme, Isis Pharmaceuticals, Kowa, Merck, Novartis, Omthera, Pfizer, Pronova, Regeneron, Sanofi, The Medicines Company, UniQure and Vascular Biogenics.