Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial

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Abstract

Aim

To evaluate the effect of alirocumab on frequency of standard apheresis treatments [weekly or every 2 weeks (Q2W)] in heterozygous familial hypercholesterolaemia (HeFH).

Methods and results

ODYSSEY ESCAPE (NCT02326220) was a double-blind study in 62 HeFH patients undergoing regular weekly or Q2W lipoprotein apheresis. Patients were randomly assigned (2:1, respectively) to receive alirocumab 150 mg ( n = 41) or placebo ( n = 21) Q2W subcutaneously for 18 weeks. From day 1 to week 6, apheresis rate was fixed according to the patient’s established schedule; from weeks 7 to 18, apheresis rate was adjusted based on the patient’s low-density lipoprotein cholesterol (LDL-C) response in a blinded fashion. Apheresis was not performed when the LDL-C value was ≥30% lower than the baseline (pre-apheresis) value. The primary efficacy endpoint was the rate of apheresis treatments over 12 weeks (weeks 7–18), standardized to number of planned treatments. In the alirocumab group the least square (LS) mean ± SE (95% confidence interval [CI]) per cent change in pre-apheresis LDL-C from baseline at week 6 was −53.7 ± 2.3 (−58.2 to − 49.2) compared with 1.6 ± 3.1 (–4.7 to 7.9) in the placebo group. The primary efficacy endpoint showed statistically significant benefit in favour of alirocumab (Hodges–Lehmann median estimate of treatment difference: 0.75; 95% CI 0.67–0.83; P < 0.0001). Therefore, alirocumab-treated patients had a 0.75 (75%) additional reduction in the standardized rate of apheresis treatments vs. placebo-treated patients. During this period, 63.4% of patients on alirocumab avoided all and 92.7% avoided at least half of the apheresis treatments. Adverse event rates were similar (75.6% of patients on alirocumab vs. 76.2% on placebo).

Conclusions

Lipoprotein apheresis was discontinued in 63.4% of patients on alirocumab who were previously undergoing regular apheresis, and the rate was at least halved in 92.7% of patients. Alirocumab was generally safe and well tolerated.

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Most cited references 9

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2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults

Neil J Stone, Jennifer G Robinson, Alice H. Lichtenstein … (2014)

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ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia

John Kastelein, Henry N Ginsberg, Gisle Langslet … (2015)

Aims To assess long-term (78 weeks) alirocumab treatment in patients with heterozygous familial hypercholesterolaemia (HeFH) and inadequate LDL-C control on maximally tolerated lipid-lowering therapy (LLT). Methods and results In two randomized, double-blind studies (ODYSSEY FH I, n = 486; FH II, n = 249), patients were randomized 2 : 1 to alirocumab 75 mg or placebo every 2 weeks (Q2W). Alirocumab dose was increased at Week 12 to 150 mg Q2W if Week 8 LDL-C was ≥1.8 mmol/L (70 mg/dL). Primary endpoint (both studies) was percentage change in calculated LDL-C from baseline to Week 24. Mean LDL-C levels decreased from 3.7 mmol/L (144.7 mg/dL) at baseline to 1.8 mmol/L (71.3 mg/dL; −57.9% vs. placebo) at Week 24 in patients randomized to alirocumab in FH I and from 3.5 mmol/L (134.6 mg/dL) to 1.8 mmol/L (67.7 mg/dL; −51.4% vs. placebo) in FH II (P < 0.0001). These reductions were maintained through Week 78. LDL-C <1.8 mmol/L (regardless of cardiovascular risk) was achieved at Week 24 by 59.8 and 68.2% of alirocumab-treated patients in FH I and FH II, respectively. Adverse events resulted in discontinuation in 3.4% of alirocumab-treated patients in FH I (vs. 6.1% placebo) and 3.6% (vs. 1.2%) in FH II. Rate of injection site reactions in alirocumab-treated patients was 12.4% in FH I and 11.4% in FH II (vs. 11.0 and 7.4% with placebo). Conclusion In patients with HeFH and inadequate LDL-C control at baseline despite maximally tolerated statin ± other LLT, alirocumab treatment resulted in significant LDL-C lowering and greater achievement of LDL-C target levels and was well tolerated. Clinical trial registration Cinicaltrials.gov (identifiers: NCT01623115; NCT01709500).

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Effect of a monoclonal antibody to PCSK9, REGN727/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.

Evan A Stein, Dan Gipe, Jean Bergeron … (2012)

Inhibition of proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) resulted in large reductions of low-density lipoprotein cholesterol (LDL-C) in phase 1 trials. We assessed the efficacy and safety of various doses and dosing intervals of REGN727, a monoclonal antibody to PCSK9, added to statins, to further lower LDL-C in patients with heterozygous familial hypercholesterolaemia. This multicentre, randomised, placebo-controlled phase 2 trial was done at 16 lipid clinics in the USA and Canada. Between Jan 18, 2011, and Nov 7, 2011, we enrolled adults with heterozygous familial hypercholesterolaemia and LDL-C concentrations of 2·6 mmol/L or higher on stable diet and statin dose, with or without ezetimibe. Patients were randomly assigned to receive REGN727 150 mg, 200 mg, or 300 mg every 4 weeks, or 150 mg every 2 weeks, or placebo every 2 weeks (ratio 1:1:1:1:1). Randomisation was stratified by concomitant use of ezetimibe at baseline. Investigators, study staff, and patients were masked to treatment group. Blinding was maintained by administration of placebo alternating with REGN727 for the groups of 4 week dosing. The primary endpoint was mean percent reduction in LDL-C from baseline at week 12 and was analysed in the modified intention-to-treat population with an analysis of covariance (ANCOVA) model with treatment group. This trial is registered in ClinicalTrials.gov, number NCT 01266876. 77 patients were randomly assigned to study groups (15-16 patients per group) and all were analysed. Least-squares (LS) mean LDL-C reduction from baseline to week 12 was 28·9% (SE 5·08) for 150 mg every 4 weeks (p=0·0113), 31·54% (4·91) for 200 mg every 4 weeks (p=0·0035), 42·53% (5·09) for 300 mg every 4 weeks (p<0·0001), and 67·90% (4·85) for 150 mg every 2 weeks (p<0·0001), compared with 10·65% (5·04) with placebo. One serious adverse event was reported with placebo and none with REGN727. No increases of more than three times the upper limit of normal were reported for hepatic transaminases or creatinine kinase. The most common adverse event was injection-site reaction with one patient in the group of 300 mg REGN727 terminating treatment. REGN727 was well tolerated and achieved substantial further LDL-C reduction in patients with heterozygous familial hypercholesterolaemia and elevated LDL-C treated with high-dose statins, with or without ezetimibe. REGN727 has the potential to provide optimum control of LDL-C in patients with this disorder. Sanofi US and Regeneron Pharmaceuticals Incorporated. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Eur Heart J

Journal ID (iso-abbrev): Eur. Heart J

Journal ID (publisher-id): eurheartj

Journal ID (hwp): ehj

Title: European Heart Journal

Publisher: Oxford University Press

ISSN (Print): 0195-668X

ISSN (Electronic): 1522-9645

Publication date (Print): 21 December 2016

Publication date (Electronic): 29 August 2016

Publication date PMC-release: 29 August 2016

Volume: 37

Issue: 48 , Focus Issue on Prevention

Pages: 3588-3595

Affiliations

[1 ]Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA

[2 ]Medical Department II, Grosshadern, University Munich, Marchioninistraße 15, 81377 Munich, Germany

[3 ]Metabolic Leader, LLC, 71 US Route 1 Suite J, Scarborough, ME 04074-9375, USA

[4 ]Division of Endocrinology, Metabolism and Diabetes, Anschutz Health and Wellness Center‐Anschutz Medical Campus, Aurora, CO 80045, USA

[5 ]Knight Cardiovascular Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, L607, Portland, OR 97239, USA

[6 ]Department of Internal Medicine III, Extracorporeal Treatment and Lipoprotein Apheresis Center, University Hospital Carl Gustav Carus, Technische Universitaet Dresden, 01069 Dresden, Germany

[7 ]Apherese Zentrum Passau, Innstrasse 76, 94032 Passau, Germany

[8 ]Apheresis Centrum Rostock, Nobelstr. 53, 18059 Rostock, Germany

[9 ]Apheresis Centre, Nehrologisches Zentrum Göttingen GbR, An der Lutter 24, D-37075 Göttingen, Germany

[10 ]Mayo Clinic, Rochester, 200 First Street SW, Rochester, MN 55905, USA

[11 ]Charite—Universitätsmedizin Berlin–Campus Virchow–Klinikum, Augustenburger Platz 1, Ostring 3, Berlin 13353, Germany

[12 ]Cardiology, Hartford Hospital, 80 Seymour Street, JB722, Hartford, CT 06102, USA

[13 ]Medizinische Klinik und Poliklinik IV, LMU Klinikum der Universität München, 81377 Munich, Germany

[14 ]Medical Department, Sanofi–Aventis Deutschland GmbH, Potsdamer Straße 8, 10785 Berlin, Germany

[15 ]Regeneron Pharmaceuticals, Inc., 110 Allen Road, Basking Ridge, NJ 07920, USA

[16 ]Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA

Author notes

[* ]Corresponding author. Tel: +1 (913) 588-6057, Fax: +1 (913) 588-4074, Email: pmoriart@ 123456kumc.edu

^†The first two contributed equally to this study.

See page 3596 for the editorial comment on this article (doi: [Related article:]10.1093/eurheartj/ehw497)

Article

Publisher ID: ehw388

DOI: 10.1093/eurheartj/ehw388

PMC ID: 5233802

PubMed ID: 27572070

SO-VID: d6d72925-d0f8-4891-9b3f-19f42d38f9fe

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

History

Date received : 29 June 2016

Date revision received : 03 August 2016

Date accepted : 11 August 2016

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Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial

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Abstract

Aim

Methods and results

Conclusions

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Cardiovascular Innovations and Applications

Most cited references 9

2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults

ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia

Effect of a monoclonal antibody to PCSK9, REGN727/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.

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