Efficacy of Long-Term Treatment of Autosomal Recessive Hypercholesterolemia With Lomitapide: A Subanalysis of the Pan-European Lomitapide Study

Laura D’Erasmo; Antonina Giammanco; the Italian and European Working Group on Lomitapide in HoFH; Patrizia Suppressa; Chiara Pavanello; Gabriella Iannuzzo; Alessia Di Costanzo; Daniele Tramontano; Ilenia Minicocci; Simone Bini; Anja Vogt; Kim Stewards; Jeanine Roeters Van Lennep; Stefano Bertolini; Marcello Arca

doi:10.3389/fgene.2022.937750

Efficacy of Long-Term Treatment of Autosomal Recessive Hypercholesterolemia With Lomitapide: A Subanalysis of the Pan-European Lomitapide Study

Laura D’Erasmo^*
, Antonina Giammanco
, the Italian and European Working Group on Lomitapide in HoFH
, Patrizia Suppressa
, Chiara Pavanello
, Gabriella Iannuzzo
, Alessia Di Costanzo
, Daniele Tramontano
, Ilenia Minicocci
, Simone Bini
, Anja Vogt
, Kim Stewards
, Jeanine Roeters Van Lennep
, Stefano Bertolini
, Marcello Arca

^*Corresponding author for this work

Internal Medicine

University of Rome La Sapienza
University of Palermo
University Hospital Policlinico
University of Milan
University of Naples Federico II
Klinikum der Universität München
Erasmus University Rotterdam
University of Genoa

Research output: Contribution to journal › Article › Academic › peer-review

10 Citations (Scopus)

69 Downloads (Pure)

Abstract

Background and aim: Autosomal recessive hypercholesterolemia (ARH) is a rare autosomal recessive disorder of low-density lipoprotein (LDL) metabolism caused by pathogenic variants in the LDLRAP1 gene. Like homozygous familial hypercholesterolemia, ARH is resistant to conventional LDL-lowering medications and causes a high risk of atherosclerotic cardiovascular diseases (ASCVDs) and aortic valve stenosis. Lomitapide is emerging as an efficacious therapy in classical HoFH, but few data are available for ARH. Results: This is a subanalysis carried out on nine ARH patients included in the Pan-European Lomitapide Study. The age at starting lomitapide was 46 (interquartile range (IQR), 39.0–65.5) years, with a median treatment duration of 31.0 (IQR 14.0–40.5) months. At baseline, four (44.4%) patients had hypertension, one (11.1%) had diabetes mellitus, two (22.2%) were active smokers, and five (55.5%) reported ASCVD. The baseline LDL-C was 257.0 (IQR, 165.3–309.2) mg/dL. All patients were on statins plus ezetimibe, three were receiving Lipoprotein apheresis (LA), and one was also receiving proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i). The addition of lomitapide (mean dose, 10 mg) resulted in the achievement of a median on-treatment LDL-C of 101.7 mg/dL (IQR, 71.3–138.3; 60.4% reduction from baseline), with a best LDL-C value of 68.0 mg/dL (IQR, 43.7–86.7; 73.5% reduction from baseline). During follow-up, one patient stopped both PCSK9i and LA. Recurrence of ASCVD events was reported in one patient. The median on-treatment aspartate transaminase and alanine transaminase values were 31.1 (IQR, 22.6–48.3) U/L and 31.1 (IQR, 27.2–53.8) U/L, respectively. Among six ARH patients with available fibroscan examination, liver stiffness values recorded at the last visit were within the normal range (median, 4.7 KPa; IQR, 3.6–5.3 KPa). Conclusion: Lomitapide is effective and safe in ARH therapy as well as in classical HoFH.

Original language	English
Article number	937750
Journal	Frontiers in Genetics
Volume	13
DOIs	https://doi.org/10.3389/fgene.2022.937750
Publication status	Published - 22 Aug 2022

Bibliographical note

Funding Information:
LD'E has received personal fees for public speaking, consultancy or grant support from Amryt Pharmaceuticals, Akcea Therapeutics, Pfizer, Amgen, SOBI and Sanofi; ABC has served as a consultant for Amryt Pharmaceutical; and received lecturing fees from Amryt Pharmaceutical, MSD, Sanofi and AlfaSigma; MAV has served as a consultant for Amgen, Sanofi, Akcea, Novartin, Amgen; MA has received research grant support from Amryt Pharmaceutical, Amgen, IONIS, Akcea Therapeutics, Pfizer and Sanofi; has served as a consultant for Amgen, Aegerion, Akcea Therapeutics, Regeneron, Sanofi and Alfasigma and received lecturing fees from Amgen, Amryt Pharmaceuticals, Pfizer, Sanofi and AlfaSigma; GI has received personal fees for public speaking, consultancy or grant support from Amryt Pharmaceuticals, Akcea Therapeutics, Pfizer, Regeneron, Amgen and Sanofi; SD'A has received personal fees as advisor board from Akcea and IONIS; CP has received fees for public speaking and consultancy from SOBI, Akcea Therapeutics and Amryt Pharmaceuticals; LC has received personal fees for public speaking, consultancy or grant support from Abionyx Pharma, MedImmune, Alexion, Daichii-Sankyo, Pfizer, Akcea Therapeutics;JRVL has received grant support from Amryt Pharmaceuticals; CJ has received speaker, consultancy fees or research grants from Amgen, Sanofi, Amryt, Pfizer, Novartis, Akcea; EL reported non-financial support from HELLENIC ATHEROSCLEROSIS SOCIETY and personal fees from AMGEN, personal fees from NOVARTIS, MYLAN, SERVIER.

Funding Information:
This is a subanalysis of the Pan-European observational study that was supported by a grant in-aid from Amryt Pharmaceutical to LD'E and JRvL. In addition, LD'E received a grant in support of this project from Sapienza, University of Rome.

Publisher Copyright:
Copyright © 2022 D’Erasmo, Giammanco, Suppressa, Pavanello, Iannuzzo, Di Costanzo, Tramontano, Minicocci, Bini, Vogt, Stewards, Roeters Van Lennep, Bertolini, Arca and the Italian and European Working Group on Lomitapide in HoFH.

Funding Information:
This is a subanalysis of the Pan-European observational study that was supported by a grant in-aid from Amryt Pharmaceutical to LD'E and JRvL. In addition, LD'E received a grant in support of this project from Sapienza, University of Rome.

Funding Information:
This is a subanalysis of the Pan-European observational study that was supported by a grant in-aid from Amryt Pharmaceutical to LD'E and JRvL. In addition, LD'E received a grant in support of this project from Sapienza, University of Rome.

Publisher Copyright:
Copyright © 2022 D’Erasmo, Giammanco, Suppressa, Pavanello, Iannuzzo, Di Costanzo, Tramontano, Minicocci, Bini, Vogt, Stewards, Roeters Van Lennep, Bertolini, Arca and the Italian and European Working Group on Lomitapide in HoFH.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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Efficacy of Long-Term Treatment of Autosomal Recessive Hypercholesterolemia With LomitapideFinal published version, 975 KBLicence: CC BY

Cite this

D’Erasmo, L., Giammanco, A., the Italian and European Working Group on Lomitapide in HoFH, Suppressa, P., Pavanello, C., Iannuzzo, G., Di Costanzo, A., Tramontano, D., Minicocci, I., Bini, S., Vogt, A., Stewards, K., Roeters Van Lennep, J., Bertolini, S., & Arca, M. (2022). Efficacy of Long-Term Treatment of Autosomal Recessive Hypercholesterolemia With Lomitapide: A Subanalysis of the Pan-European Lomitapide Study. Frontiers in Genetics, 13, Article 937750. https://doi.org/10.3389/fgene.2022.937750

@article{ea53725a780946a3b5bac0d3b63bdd65,

title = "Efficacy of Long-Term Treatment of Autosomal Recessive Hypercholesterolemia With Lomitapide: A Subanalysis of the Pan-European Lomitapide Study",

abstract = "Background and aim: Autosomal recessive hypercholesterolemia (ARH) is a rare autosomal recessive disorder of low-density lipoprotein (LDL) metabolism caused by pathogenic variants in the LDLRAP1 gene. Like homozygous familial hypercholesterolemia, ARH is resistant to conventional LDL-lowering medications and causes a high risk of atherosclerotic cardiovascular diseases (ASCVDs) and aortic valve stenosis. Lomitapide is emerging as an efficacious therapy in classical HoFH, but few data are available for ARH. Results: This is a subanalysis carried out on nine ARH patients included in the Pan-European Lomitapide Study. The age at starting lomitapide was 46 (interquartile range (IQR), 39.0–65.5) years, with a median treatment duration of 31.0 (IQR 14.0–40.5) months. At baseline, four (44.4\%) patients had hypertension, one (11.1\%) had diabetes mellitus, two (22.2\%) were active smokers, and five (55.5\%) reported ASCVD. The baseline LDL-C was 257.0 (IQR, 165.3–309.2) mg/dL. All patients were on statins plus ezetimibe, three were receiving Lipoprotein apheresis (LA), and one was also receiving proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i). The addition of lomitapide (mean dose, 10 mg) resulted in the achievement of a median on-treatment LDL-C of 101.7 mg/dL (IQR, 71.3–138.3; 60.4\% reduction from baseline), with a best LDL-C value of 68.0 mg/dL (IQR, 43.7–86.7; 73.5\% reduction from baseline). During follow-up, one patient stopped both PCSK9i and LA. Recurrence of ASCVD events was reported in one patient. The median on-treatment aspartate transaminase and alanine transaminase values were 31.1 (IQR, 22.6–48.3) U/L and 31.1 (IQR, 27.2–53.8) U/L, respectively. Among six ARH patients with available fibroscan examination, liver stiffness values recorded at the last visit were within the normal range (median, 4.7 KPa; IQR, 3.6–5.3 KPa). Conclusion: Lomitapide is effective and safe in ARH therapy as well as in classical HoFH.",

author = "Laura D{\textquoteright}Erasmo and Antonina Giammanco and \{the Italian and European Working Group on Lomitapide in HoFH\} and Patrizia Suppressa and Chiara Pavanello and Gabriella Iannuzzo and \{Di Costanzo\}, Alessia and Daniele Tramontano and Ilenia Minicocci and Simone Bini and Anja Vogt and Kim Stewards and \{Roeters Van Lennep\}, Jeanine and Stefano Bertolini and Marcello Arca",

note = "Funding Information: LD'E has received personal fees for public speaking, consultancy or grant support from Amryt Pharmaceuticals, Akcea Therapeutics, Pfizer, Amgen, SOBI and Sanofi; ABC has served as a consultant for Amryt Pharmaceutical; and received lecturing fees from Amryt Pharmaceutical, MSD, Sanofi and AlfaSigma; MAV has served as a consultant for Amgen, Sanofi, Akcea, Novartin, Amgen; MA has received research grant support from Amryt Pharmaceutical, Amgen, IONIS, Akcea Therapeutics, Pfizer and Sanofi; has served as a consultant for Amgen, Aegerion, Akcea Therapeutics, Regeneron, Sanofi and Alfasigma and received lecturing fees from Amgen, Amryt Pharmaceuticals, Pfizer, Sanofi and AlfaSigma; GI has received personal fees for public speaking, consultancy or grant support from Amryt Pharmaceuticals, Akcea Therapeutics, Pfizer, Regeneron, Amgen and Sanofi; SD'A has received personal fees as advisor board from Akcea and IONIS; CP has received fees for public speaking and consultancy from SOBI, Akcea Therapeutics and Amryt Pharmaceuticals; LC has received personal fees for public speaking, consultancy or grant support from Abionyx Pharma, MedImmune, Alexion, Daichii-Sankyo, Pfizer, Akcea Therapeutics;JRVL has received grant support from Amryt Pharmaceuticals; CJ has received speaker, consultancy fees or research grants from Amgen, Sanofi, Amryt, Pfizer, Novartis, Akcea; EL reported non-financial support from HELLENIC ATHEROSCLEROSIS SOCIETY and personal fees from AMGEN, personal fees from NOVARTIS, MYLAN, SERVIER. Funding Information: This is a subanalysis of the Pan-European observational study that was supported by a grant in-aid from Amryt Pharmaceutical to LD'E and JRvL. In addition, LD'E received a grant in support of this project from Sapienza, University of Rome. Publisher Copyright: Copyright {\textcopyright} 2022 D{\textquoteright}Erasmo, Giammanco, Suppressa, Pavanello, Iannuzzo, Di Costanzo, Tramontano, Minicocci, Bini, Vogt, Stewards, Roeters Van Lennep, Bertolini, Arca and the Italian and European Working Group on Lomitapide in HoFH. Funding Information: This is a subanalysis of the Pan-European observational study that was supported by a grant in-aid from Amryt Pharmaceutical to LD'E and JRvL. In addition, LD'E received a grant in support of this project from Sapienza, University of Rome. Funding Information: This is a subanalysis of the Pan-European observational study that was supported by a grant in-aid from Amryt Pharmaceutical to LD'E and JRvL. In addition, LD'E received a grant in support of this project from Sapienza, University of Rome. Publisher Copyright: Copyright {\textcopyright} 2022 D{\textquoteright}Erasmo, Giammanco, Suppressa, Pavanello, Iannuzzo, Di Costanzo, Tramontano, Minicocci, Bini, Vogt, Stewards, Roeters Van Lennep, Bertolini, Arca and the Italian and European Working Group on Lomitapide in HoFH.",

year = "2022",

month = aug,

day = "22",

doi = "10.3389/fgene.2022.937750",

language = "English",

volume = "13",

journal = "Frontiers in Genetics",

issn = "1664-8021",

publisher = "Frontiers Media SA",

}

D’Erasmo, L, Giammanco, A, the Italian and European Working Group on Lomitapide in HoFH, Suppressa, P, Pavanello, C, Iannuzzo, G, Di Costanzo, A, Tramontano, D, Minicocci, I, Bini, S, Vogt, A, Stewards, K, Roeters Van Lennep, J, Bertolini, S & Arca, M 2022, 'Efficacy of Long-Term Treatment of Autosomal Recessive Hypercholesterolemia With Lomitapide: A Subanalysis of the Pan-European Lomitapide Study', Frontiers in Genetics, vol. 13, 937750. https://doi.org/10.3389/fgene.2022.937750

Efficacy of Long-Term Treatment of Autosomal Recessive Hypercholesterolemia With Lomitapide: A Subanalysis of the Pan-European Lomitapide Study. / D’Erasmo, Laura; Giammanco, Antonina; the Italian and European Working Group on Lomitapide in HoFH et al.
In: Frontiers in Genetics, Vol. 13, 937750, 22.08.2022.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Efficacy of Long-Term Treatment of Autosomal Recessive Hypercholesterolemia With Lomitapide

T2 - A Subanalysis of the Pan-European Lomitapide Study

AU - D’Erasmo, Laura

AU - Giammanco, Antonina

AU - the Italian and European Working Group on Lomitapide in HoFH

AU - Suppressa, Patrizia

AU - Pavanello, Chiara

AU - Iannuzzo, Gabriella

AU - Di Costanzo, Alessia

AU - Tramontano, Daniele

AU - Minicocci, Ilenia

AU - Bini, Simone

AU - Vogt, Anja

AU - Stewards, Kim

AU - Roeters Van Lennep, Jeanine

AU - Bertolini, Stefano

AU - Arca, Marcello

N1 - Funding Information: LD'E has received personal fees for public speaking, consultancy or grant support from Amryt Pharmaceuticals, Akcea Therapeutics, Pfizer, Amgen, SOBI and Sanofi; ABC has served as a consultant for Amryt Pharmaceutical; and received lecturing fees from Amryt Pharmaceutical, MSD, Sanofi and AlfaSigma; MAV has served as a consultant for Amgen, Sanofi, Akcea, Novartin, Amgen; MA has received research grant support from Amryt Pharmaceutical, Amgen, IONIS, Akcea Therapeutics, Pfizer and Sanofi; has served as a consultant for Amgen, Aegerion, Akcea Therapeutics, Regeneron, Sanofi and Alfasigma and received lecturing fees from Amgen, Amryt Pharmaceuticals, Pfizer, Sanofi and AlfaSigma; GI has received personal fees for public speaking, consultancy or grant support from Amryt Pharmaceuticals, Akcea Therapeutics, Pfizer, Regeneron, Amgen and Sanofi; SD'A has received personal fees as advisor board from Akcea and IONIS; CP has received fees for public speaking and consultancy from SOBI, Akcea Therapeutics and Amryt Pharmaceuticals; LC has received personal fees for public speaking, consultancy or grant support from Abionyx Pharma, MedImmune, Alexion, Daichii-Sankyo, Pfizer, Akcea Therapeutics;JRVL has received grant support from Amryt Pharmaceuticals; CJ has received speaker, consultancy fees or research grants from Amgen, Sanofi, Amryt, Pfizer, Novartis, Akcea; EL reported non-financial support from HELLENIC ATHEROSCLEROSIS SOCIETY and personal fees from AMGEN, personal fees from NOVARTIS, MYLAN, SERVIER. Funding Information: This is a subanalysis of the Pan-European observational study that was supported by a grant in-aid from Amryt Pharmaceutical to LD'E and JRvL. In addition, LD'E received a grant in support of this project from Sapienza, University of Rome. Publisher Copyright: Copyright © 2022 D’Erasmo, Giammanco, Suppressa, Pavanello, Iannuzzo, Di Costanzo, Tramontano, Minicocci, Bini, Vogt, Stewards, Roeters Van Lennep, Bertolini, Arca and the Italian and European Working Group on Lomitapide in HoFH. Funding Information: This is a subanalysis of the Pan-European observational study that was supported by a grant in-aid from Amryt Pharmaceutical to LD'E and JRvL. In addition, LD'E received a grant in support of this project from Sapienza, University of Rome. Funding Information: This is a subanalysis of the Pan-European observational study that was supported by a grant in-aid from Amryt Pharmaceutical to LD'E and JRvL. In addition, LD'E received a grant in support of this project from Sapienza, University of Rome. Publisher Copyright: Copyright © 2022 D’Erasmo, Giammanco, Suppressa, Pavanello, Iannuzzo, Di Costanzo, Tramontano, Minicocci, Bini, Vogt, Stewards, Roeters Van Lennep, Bertolini, Arca and the Italian and European Working Group on Lomitapide in HoFH.

PY - 2022/8/22

Y1 - 2022/8/22

N2 - Background and aim: Autosomal recessive hypercholesterolemia (ARH) is a rare autosomal recessive disorder of low-density lipoprotein (LDL) metabolism caused by pathogenic variants in the LDLRAP1 gene. Like homozygous familial hypercholesterolemia, ARH is resistant to conventional LDL-lowering medications and causes a high risk of atherosclerotic cardiovascular diseases (ASCVDs) and aortic valve stenosis. Lomitapide is emerging as an efficacious therapy in classical HoFH, but few data are available for ARH. Results: This is a subanalysis carried out on nine ARH patients included in the Pan-European Lomitapide Study. The age at starting lomitapide was 46 (interquartile range (IQR), 39.0–65.5) years, with a median treatment duration of 31.0 (IQR 14.0–40.5) months. At baseline, four (44.4%) patients had hypertension, one (11.1%) had diabetes mellitus, two (22.2%) were active smokers, and five (55.5%) reported ASCVD. The baseline LDL-C was 257.0 (IQR, 165.3–309.2) mg/dL. All patients were on statins plus ezetimibe, three were receiving Lipoprotein apheresis (LA), and one was also receiving proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i). The addition of lomitapide (mean dose, 10 mg) resulted in the achievement of a median on-treatment LDL-C of 101.7 mg/dL (IQR, 71.3–138.3; 60.4% reduction from baseline), with a best LDL-C value of 68.0 mg/dL (IQR, 43.7–86.7; 73.5% reduction from baseline). During follow-up, one patient stopped both PCSK9i and LA. Recurrence of ASCVD events was reported in one patient. The median on-treatment aspartate transaminase and alanine transaminase values were 31.1 (IQR, 22.6–48.3) U/L and 31.1 (IQR, 27.2–53.8) U/L, respectively. Among six ARH patients with available fibroscan examination, liver stiffness values recorded at the last visit were within the normal range (median, 4.7 KPa; IQR, 3.6–5.3 KPa). Conclusion: Lomitapide is effective and safe in ARH therapy as well as in classical HoFH.

AB - Background and aim: Autosomal recessive hypercholesterolemia (ARH) is a rare autosomal recessive disorder of low-density lipoprotein (LDL) metabolism caused by pathogenic variants in the LDLRAP1 gene. Like homozygous familial hypercholesterolemia, ARH is resistant to conventional LDL-lowering medications and causes a high risk of atherosclerotic cardiovascular diseases (ASCVDs) and aortic valve stenosis. Lomitapide is emerging as an efficacious therapy in classical HoFH, but few data are available for ARH. Results: This is a subanalysis carried out on nine ARH patients included in the Pan-European Lomitapide Study. The age at starting lomitapide was 46 (interquartile range (IQR), 39.0–65.5) years, with a median treatment duration of 31.0 (IQR 14.0–40.5) months. At baseline, four (44.4%) patients had hypertension, one (11.1%) had diabetes mellitus, two (22.2%) were active smokers, and five (55.5%) reported ASCVD. The baseline LDL-C was 257.0 (IQR, 165.3–309.2) mg/dL. All patients were on statins plus ezetimibe, three were receiving Lipoprotein apheresis (LA), and one was also receiving proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i). The addition of lomitapide (mean dose, 10 mg) resulted in the achievement of a median on-treatment LDL-C of 101.7 mg/dL (IQR, 71.3–138.3; 60.4% reduction from baseline), with a best LDL-C value of 68.0 mg/dL (IQR, 43.7–86.7; 73.5% reduction from baseline). During follow-up, one patient stopped both PCSK9i and LA. Recurrence of ASCVD events was reported in one patient. The median on-treatment aspartate transaminase and alanine transaminase values were 31.1 (IQR, 22.6–48.3) U/L and 31.1 (IQR, 27.2–53.8) U/L, respectively. Among six ARH patients with available fibroscan examination, liver stiffness values recorded at the last visit were within the normal range (median, 4.7 KPa; IQR, 3.6–5.3 KPa). Conclusion: Lomitapide is effective and safe in ARH therapy as well as in classical HoFH.

UR - https://www.scopus.com/pages/publications/85138108810

U2 - 10.3389/fgene.2022.937750

DO - 10.3389/fgene.2022.937750

M3 - Article

C2 - 36072671

AN - SCOPUS:85138108810

SN - 1664-8021

VL - 13

JO - Frontiers in Genetics

JF - Frontiers in Genetics

M1 - 937750

ER -

Efficacy of Long-Term Treatment of Autosomal Recessive Hypercholesterolemia With Lomitapide: A Subanalysis of the Pan-European Lomitapide Study

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