A PCSK9 inhibitor lowers LDL-c in patients with gene mutations that are causative for FH

Alirocumab efficacy in patients with double heterozygous, compound heterozygous, or homozygous familial hypercholesterolemia

Literature - Hartgers ML, Defesche JC, Langslet G, et al. - J Clin Lipidol 2018;12:390–396

Introduction and methods

Heterozygous and homozygous familial hypercholesterolemia (FH) are caused by mutations in the genes for the LDL receptor (LDLR), apolipoprotein B (APOB), and PCSK9. Both conditions are characterized by high levels of LDL-c and increased risk of CVD [1]. Residual LDLR pathway activity correlates with disease severity and response to some lipid-lowering agents, and LDL-c levels are the main determinants of CVD risk and not the genetic defect per se [2].

In this study, the treatment effect of alirocumab was evaluated in patients with FH and >1 mutation who were double heterozygotes, compound heterozygotes, or homozygotes. For this purpose, DNA samples from patients with a diagnosis of FH who were enrolled in 6 clinical trials were sequenced for mutations in genes causative for FH (LDLR, APOB, PCSK9, LDLRAP1, and signal-transducing adaptor protein 1). The trials included 1 phase 2 trial and 5 phase 3 clinical trials from the ODYSSEY program [3-7].

Clinical diagnosis was based on the Simon Broome criteria for definite FH or the World Health Organization/Dutch Lipid Network criteria [8,9]. The primary efficacy endpoint in the phase 3 trials was the percentage reduction in LDL-c from baseline to week 24.

Main results

  • Of 1191 patients sequenced, 20 patients had >1 mutation of interest (double heterozygotes: n=7; compound heterozygotes: n=10; homozygotes: n=3 with 1 who had LDLR defective mutations).
  • An LDL-c reduction of ≥15% at week 12 or 24 was observed in patients who had received alirocumab 75/150 or 150 mg Q2W (n=11).
  • At week 12, an LDL-c reduction of 21.7% to 63.9% with alirocumab treatment was observed in all but 1 patient, however, this patient had an LDL-c reduction of 34.3% at week 24. This was 8.8% to 65.1% in other patients at week 24.
  • Alirocumab treatment reduced LDL-c levels by 39.3% to 55.7% and 55.1% to 62.0% in patients with double heterozygous mutations (APOB defective/LDLR negative and APOB defective/LDLR defective, n=3) at weeks 12 and 24, respectively.
  • LDL-c reductions in patients with compound heterozygous mutations (LDLR defective/LDLR negative and LDLR defective/LDLR defective, n=4) were 21.7% to 63.9% and 8.8% to 65.1% at weeks 12 and 24, respectively.
  • In patients with homozygous mutations (LDLR defective, LDLRAP1 negative, n=2), LDL-c levels were reduced by 22.9% or increased by 7.1% at week 12, and reduced by 11.9% to 34.3% at week 24.
  • Reductions with alirocumab treatment at weeks 12 and 24 were also observed across the mutation backgrounds in levels of ApoB, Lp(a), non-HDL-c, and triglycerides.
  • The rates of treatment-emergent adverse events in the overall sequenced cohort were comparable for alirocumab (82.9%) vs comparator (83.3%; comparator included placebo as well as ezetimibe).


A clinically meaningful LDL-c–lowering activity was observed in patients receiving alirocumab who are double or compound heterozygous, or homozygous for genes that are causative for FH, such as LDLR, APOB, PCSK9, and LDLRAP1. LDL-c–lowering activity of alirocumab in patients with these mutations is likely to be attributable to the presence of at least 1 partially functional allele. In the future, the impact of rare mutation types may be better assessed in specifically designed trials using a placebo-phase approach, whereby each patient acts as their own control.


1. Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment. Atherosclerosis. 2012;223:262–268.

2. Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest. 2003;111:1795–1803.

3. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, EGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet. 2012;380:29–36.

4. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489–1499.

5. Ginsberg HN, Rader DJ, Raal FJ, et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia and LDL-C of 160 mg/dl or higher. Cardiovasc Drugs Ther. 2016;30:473–483.

6. Kastelein JJ, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36:2996–3003.

7. Moriarty PM, Thompson PD, Cannon CP, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9:758–769.

8. Scientific Steering Committee on behalf of the Simon Broome Register Group. Risk of fatal coronary heart disease in familial hypercholesterolaemia. BMJ. 1991;303:893–896.

9. World Health Organization. Familial Hypercholesterolaemia (FH): Report of a second WHO consultation. Available at: whqlibdoc.who.int/hq/1999/WHO_HGN_FH_CONS_99.2.pdf. Accessed January 15, 2018.

Find this article online at J Clin Lipidol 2018

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