EVOLOCUMAB (REPATHA)

Brenda Kohn MD, Dania Al-Hamad MD, Ambika P. Ashraf MD

On September 24, 2021, Amgen announced that the FDA approved evolocumab (Repatha) as an adjunct treatment to diet and other LDL cholesterol (LDL-C)-lowering medications for patients aged 10 years and older with heterozygous Familial Hypercholesterolemia (HeFH). The approval followed results of the HAUSER-RCT Phase 3b study evaluating the safety and efficacy of evolocumab in pediatric patients 10 – 17 years of age with HeFH(1).

 

Background

HeFH is one of the most common monogenic disorders, with an estimated frequency of 1:250. This genetic disorder places the individual at increased risk of premature atherosclerotic cardiovascular disease (ASCVD) due to a lifelong burden of elevated circulating LDL-C that begins at birth. The homozygous form of FH (HoFH), occurring in 1:100,000-1:300,000, with LDL-C levels as high as 400-500 mg/dL (~10.3-13 mmol/L), is associated with severely accelerated ASCVD resulting in myocardial infarction and overt cardiovascular disease as early as 5 years of age. HeFH is silent in childhood, but greatly increases the risk of premature ASCVD as early as 30-45 years of age. Youth with HeFH have LDL-C levels of ≥160 mg/dL (4.1 mmol/L) or non-HDL-C levels of ≥190 mg/dL (4.9 mmol/l L)(2-4).

Mechanism of action

Evolocumab is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that targets LDL receptors for degradation. By preventing PCSK-9-mediated LDL-receptor degradation, PCSK9 inhibitors such as evolocumab function to increase LDL-receptor expression on the surface of hepatocytes, thereby enhancing the degradation of LDL-C and reducing levels of LDL-C in the circulation(5, 6). Patients with an LDL-receptor null mutation will not be responsive to the PCSK9 inhibitors (PCSK9-i). Variability of response may relate to the degree of residual LDL-receptor activity(2).

Pediatric clinical trials

Results of clinical trials in pediatric patients with FH(1, 7) confirm that LDL-C lowering with PCSK9 inhibitors is effective in lowering the surrogate markers of atherosclerosis and lend support that lowering LDL-C levels with PCSK9 inhibitors is an effective measure in lowering the risk  of lifelong cardiovascular disease(8).

 

The HAUSER-RCT study(1, 9), a 24-week, double-blind, randomized placebo-controlled trial, was conducted to evaluate the efficacy and safety of evolocumab treatment in pediatric patients with HeFH. The study included 157 patients with HeFH ages 10-17 years with LDL-C of 130 mg/dL (3.4 mmol/L or greater on stable doses of lipid-lowering medication. Patients were randomized in a 2:1 ratio to receive evolocumab (420 mg subcutaneous monthly injections) vs. placebo. Results indicated a relative 38 % reduction in LDL-C levels in the evolocumab-treated patients compared to placebo.

 

The TAUSSIG study(7, 10), an open-label, single-arm, multicenter study, was conducted to evaluate the efficacy and safety of evolocumab in the long-term treatment of adults and adolescents with HoFH or severe HeFH ≥12 years of age. The study included 14 patients with HoFH <18 years of age at enrollment.  Results of evolocumab treatment (420 mg subcutaneously monthly or biweekly if on lipoprotein apheresis) with a median duration of treatment of 4.1 years were reported. Evolocumab, added to conventional treatment (with or without apheresis), resulted in further lowering of LDL-C levels at 12 weeks by 21.2% (159.8 mg/dL) in patients with HoFH and LDL-C lowering by 54.9% (104.4 mg/dL) in those patients with severe HeFH. This effect was sustained throughout the treatment period.

 

There are few published reports of patients < 10 years of age with HoFH or severe HeFH treated with evolocumab or other PCSK-9 inhibitors. Preliminary results indicate that PCSK9 inhibitors are effective and well-tolerated in the few children < 10 years of age reported in the literature(11). Clinical trials with other PCSK9 inhibitors (e.g., alirocumab) lend support to the efficacy and safety of other PCSK9 inhibitors in the treatment of HoFH and HeFH(12, 13).

 

Indications and Dosaging

Evolocumab (420 mg by subcutaneous injection once-monthly) is approved for HeFH patients 10 years of age and older as an adjunctive therapy for LDL-C lowering. Maximally tolerated high-intensity statins and ezetimibe are first- and second-line treatment. Evolocumab may be initiated when additional LDL-C lowering is warranted (goal <135 mg/dlL; <3.5 mmol/L).

Safety

Potential side effects include: nasopharyngitis, headache, sore throat, rare hypersensitivity reaction (e.g., angioedema, rash, urticaria)(1, 7, 14). The single-use on-body infusor with pre-filled cartridge should be used for those with potential latex allergy(15).

Conclusion:  

Evolocumab offers an additional option to lower LDL-C for those patients with FH who require further LDL-C reduction to attain the pediatric therapeutic goal of LDL-C <135 mg/dL (<3.5 mmol/L) when maximally tolerated doses of statins in conjunction with ezetimibe are insufficient(16) (17). Further, the potential for a clinically beneficial effect of PCSK9 inhibitors in lowering high Lipoprotein A [Lp(a)] levels(18) and other actions of PCSK9 inhibitors beyond its action on the LDL receptor need to be explored.

 

References

  1. Santos RD, Ruzza A, Hovingh GK, Wiegman A, Mach F, Kurtz CE, et al. Evolocumab in Pediatric Heterozygous Familial Hypercholesterolemia. N Engl J Med. 2020;383(14):1317-27.
  2. Wiegman A, Gidding SS, Watts GF, Chapman MJ, Ginsberg HN, Cuchel M, et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015;36(36):2425-37.
  3. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1046-e81.
  4. Uma Ramaswami MF, Martin P Bogsrud, Kirsten B Holven, Jeanine Roeters van Lennep, Albert Wiegman, Olivier S Descamps, Michal Vrablik, Tomas Freiberger, Hans Dieplinger, Susanne Greber-Platzer, Gabriele Hanauer-Mader, Mafalda Bourbon, Euridiki Drogari, Steve E Humphries. Comparison of the characteristics at diagnosis and treatment of children with heterozygous familial hypercholesterolaemia (FH) from eight European countries. Atherosclerosis. 2020.
  5. Ma W, Guo X, Ma Y, Hu Z. Meta-analysis of randomized clinical trials comparing PCSK9 monoclonal antibody versus ezetimibe/placebo in patients at high cardiovascular risk. Atherosclerosis. 2021;326:25-34.
  6. Pasta A, Cremonini AL, Pisciotta L, Buscaglia A, Porto I, Barra F, et al. PCSK9 inhibitors for treating hypercholesterolemia. Expert opinion on pharmacotherapy. Expert Opin Pharmacother. 2020;21(3):353-63.
  7. Frederick J Raal GKH, Dirk Blom, Raul D Santos, Mariko Harada-Shiba, Eric Bruckert, Patrick Couture, Handrean Soran, Gerald F Watts, Christopher Kurtz, Narimon Honarpour, Lihua Tang, Sree Kasichayanula, Scott M Wasserman, Evan A Stein. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes Endocrinol

2017.

  1. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-22.
  2. Gaudet D, Langslet G, Gidding SS, Luirink IK, Ruzza A, Kurtz C, et al. Efficacy, safety, and tolerability of evolocumab in pediatric patients with heterozygous familial hypercholesterolemia: Rationale and design of the HAUSER-RCT study. J Clin Lipidol. 2018;12(5):1199-207.
  3. Santos RD, Stein EA, Hovingh GK, Blom DJ, Soran H, Watts GF, et al. Long-Term Evolocumab in Patients With Familial Hypercholesterolemia. J Am Coll Cardiol. 2020;75(6):565-74.
  4. Buonuomo PS, Mastrogiorgio G, Leone G, Rana I, Gonfiantini MV, Macchiaiolo M, et al. Evolocumab in the management of children <10 years of age affected by homozygous familial hypercholesterolemia. Atherosclerosis. 2021;324:148-50.
  5. Blom DJ, Harada-Shiba M, Rubba P, Gaudet D, Kastelein JJP, Charng MJ, et al. Efficacy and Safety of Alirocumab in Adults With Homozygous Familial Hypercholesterolemia: The ODYSSEY HoFH Trial. J Am Coll Cardiol. 2020;76(2):131-42.
  6. Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R, 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(43):2996-3003.
  7. Giugliano RP, Pedersen TR, Park JG, De Ferrari GM, Gaciong ZA, Ceska R, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet (London, England). 2017;390(10106):1962-71.
  8. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125522s014lbl.pdf.
  9. de Ferranti SD. Evolocumab in Children with Heterozygous Familial Hypercholesterolemia. N Engl J Med. 2020;383(14):1385-6.
  10. Murphy SA, Pedersen TR, Gaciong ZA, Ceska R, Ezhov MV, Connolly DL, et al. Effect of the PCSK9 Inhibitor Evolocumab on Total Cardiovascular Events in Patients With Cardiovascular Disease: A Prespecified Analysis From the FOURIER Trial. JAMA Cardiol. 2019;4(7):613-9.
  11. Schwartz GG, Steg PG, Szarek M, Bittner VA, Diaz R, Goodman SG, et al. Peripheral Artery Disease and Venous Thromboembolic Events After Acute Coronary Syndrome: Role of Lipoprotein(a) and Modification by Alirocumab: Prespecified Analysis of the ODYSSEY OUTCOMES Randomized Clinical Trial. Circulation. 2020;141(20):1608-17.
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Evolocumab

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