Stephen Daniels1, Sonia Caprio2, Umesh Chaudhari3, Garen Manvelian3, Marie T Baccara-Dinet4, Aurelie Brunet4, Michel Scemama5, Virginie Loizeau5, Eric Bruckert6. 1. University of Colorado School of Medicine, Aurora, CO, USA. Electronic address: Stephen.Daniels@childrenscolorado.org. 2. Yale Pediatric Endocrinology, New Haven, CT, USA. 3. Regeneron Pharmaceuticals Inc, Tarrytown, NY, USA. 4. Sanofi, Montpellier, France. 5. Sanofi, Chilly-Mazarin, France. 6. Hôpital Pitié Salpêtrière, Paris, France; Institute of Cardiometabolism and Nutrition, Paris, France.
Abstract
BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C). OBJECTIVE: This phase 2 dose-finding study (NCT02890992) evaluated the efficacy, safety, and dose selection of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab in pediatric HeFH patients. METHODS: HeFH patients (n = 42) who were aged 8-17 years, had body weight (BW) ≥25 kg, and had LDL-C ≥130 mg/dL despite optimal statin/other lipid-modifying therapies were enrolled in 4 cohorts according to BW: cohort #1: 30 mg (<50 kg) or 50 mg (≥50 kg) every 2 weeks (Q2W), #2: 40 mg (<50 kg) or 75 mg (≥50 kg) Q2W, #3: 75 mg (<50 kg) or 150 mg (≥50 kg) every 4 weeks (Q4W), #4: 150 mg (<50 kg) or 300 mg (≥50 kg) Q4W. Primary endpoint was LDL-C % change from baseline to week 8. RESULTS: Mean age was 12.4 years and 95% of patients were on a statin. Baseline LDL-C levels were 160.0-188.9 mg/dL and free PCSK9 was 186.4-201.7 ng/mL across the cohorts. At week 8, the higher dose cohorts (2 and 4) demonstrated the greatest reductions in LDL-C (-46% and -45%, respectively). Free PCSK9 levels were lowest at week 8 in cohorts 2 and 4 (42.2 ng/mL and 8.6 ng/mL, respectively). Adverse events were reported in 50-90% of patients across the cohorts, and 2 patients discontinued due to adverse events. CONCLUSIONS: In pediatric HeFH patients, LDL-C reductions were greatest in the higher dose cohorts. Alirocumab was generally well tolerated at all doses.
BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C). OBJECTIVE: This phase 2 dose-finding study (NCT02890992) evaluated the efficacy, safety, and dose selection of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab in pediatric HeFH patients. METHODS: HeFH patients (n = 42) who were aged 8-17 years, had body weight (BW) ≥25 kg, and had LDL-C ≥130 mg/dL despite optimal statin/other lipid-modifying therapies were enrolled in 4 cohorts according to BW: cohort #1: 30 mg (<50 kg) or 50 mg (≥50 kg) every 2 weeks (Q2W), #2: 40 mg (<50 kg) or 75 mg (≥50 kg) Q2W, #3: 75 mg (<50 kg) or 150 mg (≥50 kg) every 4 weeks (Q4W), #4: 150 mg (<50 kg) or 300 mg (≥50 kg) Q4W. Primary endpoint was LDL-C % change from baseline to week 8. RESULTS: Mean age was 12.4 years and 95% of patients were on a statin. Baseline LDL-C levels were 160.0-188.9 mg/dL and free PCSK9 was 186.4-201.7 ng/mL across the cohorts. At week 8, the higher dose cohorts (2 and 4) demonstrated the greatest reductions in LDL-C (-46% and -45%, respectively). Free PCSK9 levels were lowest at week 8 in cohorts 2 and 4 (42.2 ng/mL and 8.6 ng/mL, respectively). Adverse events were reported in 50-90% of patients across the cohorts, and 2 patients discontinued due to adverse events. CONCLUSIONS: In pediatric HeFH patients, LDL-C reductions were greatest in the higher dose cohorts. Alirocumab was generally well tolerated at all doses.
Authors: Maciej Banach; Paweł Burchardt; Krzysztof Chlebus; Piotr Dobrowolski; Dariusz Dudek; Krzysztof Dyrbuś; Mariusz Gąsior; Piotr Jankowski; Jacek Jóźwiak; Longina Kłosiewicz-Latoszek; Irina Kowalska; Maciej Małecki; Aleksander Prejbisz; Michał Rakowski; Jacek Rysz; Bogdan Solnica; Dariusz Sitkiewicz; Grażyna Sygitowicz; Grażyna Sypniewska; Tomasz Tomasik; Adam Windak; Dorota Zozulińska-Ziółkiewicz; Barbara Cybulska Journal: Arch Med Sci Date: 2021-11-08 Impact factor: 3.318
Authors: Ari E Horton; Andrew C Martin; Shubha Srinivasan; Robert N Justo; Nicola K Poplawski; David Sullivan; Tom Brett; Clara K Chow; Stephen J Nicholls; Jing Pang; Gerald F Watts Journal: J Paediatr Child Health Date: 2022-07-15 Impact factor: 1.929