Phase 2 dose-finding study with PCSK9i in children and adolescents with HeFH

PCSK9 inhibition with alirocumab in pediatric patients with heterozygous familial hypercholesterolemia: The ODYSSEY KIDS study

Literature - Daniels S, Caprio S, Chaudhari U et al., - J Clin Lipidol. 2020. doi: 10.1016/j.jacl.2020.03.001.

Introduction and methods

Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder that is characterized by elevated LDL-c levels and increased risk of CV events [1-3]. It has been shown that early initiation of lipid lowering therapy is effective in reducing surrogate markers of CVD in youth [4]. The PCSK9 inhibitor alirocumab lowers LDL-c in adults, but is not approved in pediatric patients [5-7]. This open-label study evaluated the efficacy, safety and optimal dosing of alirocumab in a phase 2 trial (ODYSSEY KIDS) children and adolescents (8 to 17 years) with HeFH.

A total of 42 HeFH patients enrolled. Participants were 8 to 17 years old (mean age 12.4 years), had a body weight (BW) ≥25 kg, and LDL-c ≥130 mg/dL despite being on optimal statin or other lipid-modifying therapies (95% of patients were on a statin). Patients were enrolled into 4 cohorts with different dosing regimens: Cohort 1 (n=10): 30 mg (BW<50 kg) or 50 mg (BW ≥50 kg) alirocumab Q2W; cohort 2 (n=10): 40 mg (BW <50 kg) or 75 mg (BW ≥50 kg) Q2W; cohort 3 (n=11): 75 mg (BW <50 kg) or 150 mg (BW ≥50 kg) Q4W; cohort 4 (n=11): 150 mg (BW <50kg) or 300 mg (BW ≥50kg) Q4W.

After a screening period of up to 6 weeks, patients received treatment with alirocumab for 8 weeks (12 weeks in cohort 4), followed by a follow-up period of 6-8 weeks in cohorts 1-3. Cohort 4 had no follow-up period. Patients who successfully completed the main phase (open-label dose-finding period [OLDFI]), could enter the open-label extension (OLE) phase. After completion of the first 3 cohorts, the dosing regimen of cohort 2 was selected for the planned phase 3 study. Patients from cohorts 1 to 3 received the regimen of cohort 2 during the OLE period. Patients in cohort 4 remained on their initial regiment during the OLE period. Efficacy and Pharmacokinetics were analysed from baseline to week 8 (OLDFI period). Safety of the treatment was analyzed in combined OLDFI and OLE periods.

The primary endpoint was percentual change in LDL-c from baseline to week 8. Safety analysis was based on treatment emergent adverse events (TEAEs).

Main results

  • Greatest reductions in calculated LDL-c levels were found in the higher dose cohorts (cohort 2 and 4). Mean percentual changes in LDL-c from baseline to week 8 were -21.2% (95%CI -37.4 to -5.1) in cohort 1, -46.1% (95%CI -62.8 to -29.4) in cohort 2, -7.8% (95%CI -23.2 to 7.7) in cohort 3, and -44.5% (95%CI -60.0 to -29.1) in cohort 4.
  • Mean absolute changes in calculated LDL-c from baseline to week 8 in cohort 1, 2, 3 and 4 were -50.0 mg/dL (95%CI -75.1 to -25.0), -75.2 mg/dL (95%CI -101.4 to -48.9), -17.6 mg/dL (95%CI -41.5 to -6.3), -77.9 mg/dL (95%CI -101.7 to -54.0), respectively.
  • Proportion of patients who achieved LDL-c levels<130 mg/dL at week 8 were highest in cohorts 2 and 4 (60.0% in cohort 1, 88.8% in cohort 2, 27.3% in cohort 3, 72.7% in cohort 4). The proportions of patients who achieved LDL-c levels <110 mg/dL at week 8 in cohorts 1, 2, 3 and 4 were 0.0%, 76.8%, 18.2%, 72.7%, respectively.
  • Non-HDL-c and Apo B levels decreased from baseline to week 8 in all cohorts, with greatest reductions in cohorts 2 and 4 (mean % change in non-HDL-c: -20.1% in cohort 1, -42.2% in cohort 2, -6.4% in cohort 3, -42.0% in cohort 4; mean % change in Apo B: -21.2% in cohort 1, -38.6% in cohort 2, -7.3% in cohort 3, -38.2% in cohort 4). Lp(a) levels also decreased across cohorts, with greatest reductions in cohorts 1 and 2 (mean % change in Lp(a): -14.4% in cohort 1, -14.5% in cohort 2, -2.3% in cohort 3, -3.5% in cohort 4).
  • Reductions in free PCSK9 and LDL-c were dose-dependent. Lowest mean levels of free PCSK9 were observed in cohorts 2 and 4 (mean levels of free PCSK9 at week 8: 91.8 ng/mL in cohort 1, 42.2 ng/mL in cohort 2, 104.4 ng/mL in cohort 3, 8.6 ng/mL in cohort 4).
  • TEAEs were reported in 9 patients (90%) in cohort 1, 5 patients (50%) in cohort 2, 10 patients (91%) in cohort 3 and 7 patients (64%) in cohort 4. There were no deaths or serious adverse events. Two patients discontinued treatment due to TEAEs of fatigue and neutropenia; neither event was considered to be related to the studied treatment. Most common TEAEs were nasopharyngitis (14%), upper respiratory tract infection (12%), viral gastroenteritis (12%), and diarrhea (12%).


This phase 2 dose-finding study showed that PCSK9 inhibitor alirocumab decreased LDL-c levels and was generally well tolerated in pediatric HeFH patients. However, further investigation is required. The doses/dosing regimens used in cohorts 2 (40 mg [BW<50 kg] or 75 mg [BW ≥50 kg] Q2W) and 4 (150 mg [BW <50kg] or 300 mg [BW ≥50kg] Q4W) were selected for further evaluation in a subsequent phase 3 trial in children and adolescents with HeFH.


1. Masana L, Zamora A, Plana N, et al. Incidence of cardiovascular disease in patients with familial hypercholesterolemia phenotype: analysis of 5 years follow-up of real-world data from more than 1.5 million patients. J Clin Med. 2019;8:1080.

2. Rodriguez-Borjabad C, Ibarretxe D, Girona J, et al. Lipoprotein profile assessed by 2D-1H-NMR and subclinical atherosclerosis in children with familial hypercholesterolaemia. Atherosclerosis. 2018;270:117–122.

3. Ershova AI, Meshkov AN, Rozhkova TA, et al. Carotid and aortic stiffness in patients with heterozygous familial hypercholesterolemia. PLoS One. 2016;11:e0158964.

4. Luirink IK, Wiegman A, Kusters DM, et al. 20-year follow-up of statins in children with familial hypercholesterolemia. N Engl J Med. 2019;381:1547–1556.

5. 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.

6. 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.

7. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097–2107.

Find this article online at J Clin Lipidol.

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