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

Open AccessPublished:March 28, 2020DOI:https://doi.org/10.1016/j.jacl.2020.03.001

      Highlights

      • Heterozygous familial hypercholesterolemia is underdiagnosed in children, placing them at risk of cardiovascular events.
      • Target low-density lipoprotein cholesterol levels are often not reached despite optimal lipid-modifying therapies.
      • We assessed the effects, safety, and doses of alirocumab in pediatric patients with heterozygous familial hypercholesterolemia.
      • Reductions in low-density lipoprotein cholesterol were observed across all assessed doses.
      • Overall, treatment with alirocumab was generally well tolerated.

      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.

      Graphical abstract

      Keywords

      Introduction

      Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder, typified by elevated levels of low-density lipoprotein cholesterol (LDL-C), early-onset atherosclerosis, and increased risk of cardiovascular events.
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      Early treatment with lipid-lowering medications has been shown to be effective in reducing surrogate markers of cardiovascular disease in youth.
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      20-year follow-up of statins in children with familial hypercholesterolemia.
      Alirocumab, a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), is not approved in pediatric patients but has demonstrated remarkable ability to lower LDL-C in adults.
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      ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia.
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      Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.
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      Alirocumab and cardiovascular outcomes after acute coronary syndrome.
      This study will evaluate the optimal dosing, efficacy, and adverse effects in a phase 2 trial of alirocumab (ODYSSEY KIDS, NCT02890992) in pediatric patients with HeFH.

      Methods

      This was an open-label study designed to evaluate the efficacy, safety, and pharmacokinetics of alirocumab in children and adolescents with HeFH and to support appropriate dose selection of alirocumab for the phase 3 pediatric program. Main inclusion criteria for the study are shown in Table 1. Full eligibility criteria are shown in the Supplemental Materials.
      Table 1Main inclusion and exclusion criteria
      Inclusion criteria:
      • Children and adolescent male and female participants aged 8 to 17 y at the time of signed informed consent. For Russia only: Male and female participants aged ≥12 and ≤17 y at the time of signed informed consent.
      • Participants with diagnosis of HeFH through genotyping or clinical criteria.
      • Participants treated with optimal dose of statin ± other LMT(s) or nonstatin LMT(s) if statin intolerant at stable dose for at least 4 wk before screening lipid sampling.
      • Participants with calculated LDL-C ≥130 mg/dL (≥3.37 mmol/L) at the screening visit.
      • Participants with body weight ≥25 kg.
      • Participants aged of 8 to 9 y to be at Tanner stage 1 and participants aged of 10 to 17 y to be at least at Tanner stage 2 in their development.
      • A signed informed consent indicating parental permission with or without participant assent.
      Exclusion criteria:
      • Participant with secondary hyperlipidemia.
      • Diagnosis of homozygous familial hypercholesterolemia.
      • Participant who had received lipid apheresis treatment within 2 mo before the screening period or has plans to receive it during the study.
      • Known history of type 1 or type 2 diabetes mellitus.
      • Known history of thyroid disease.
      • Known history of hypertension.
      • Fasting triglycerides >350 mg/dL (3.95 mmol/L).
      • Severe renal impairment (ie, estimated glomerular filtration rate <30 mL/min/1.73 m2).
      • Alanine aminotransferase or aspartate aminotransferase >2× upper limit of normal.
      • CPK >3× ULN.
      CPK, creatinine phosphokinase; HeFH, heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; LMT, lipid-modifying therapy.
      The study protocol was approved by independent ethics committees and/or institutional review boards. The study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki, consistent with Good Clinical Practice and applicable regulatory requirements. Informed consent from the patient and his/her parent(s) were obtained before the conduct of any study-related procedures. In addition, in patients electing to undergo genotyping, the patient and his/her parents were asked to provide consent for genetic testing for HeFH.
      Patients were initially enrolled in 3 cohorts using dosing regimens of either alirocumab every 2 weeks (Q2W; cohorts 1 and 2) or every 4 weeks (Q4W; cohort 3). However, following results observed at the completion of these cohorts, an additional cohort was added to further evaluate Q4W dosing regimens (cohort 4). Each cohort assessed 2 dose categories according to body weight (</≥ 50 kg): cohort 1: 30 mg or 50 mg Q2W, cohort 2: 40 mg or 75 mg Q2W, cohort 3: 75 or 150 mg Q4W, cohort 4: 150 or 300 mg Q4W (Table 2).
      Table 2Cohort dosing regimens based on body weight
      Cohort<50 kg≥50 kg
      Cohort 130 mg Q2W50 mg Q2W
      Cohort 240 mg Q2W75 mg Q2W
      Cohort 375 mg Q4W150 mg Q4W
      Cohort 4150 mg Q4W300 mg Q4W
      The study design is shown in Figure 1. Following a screening period of up to 6 weeks to establish eligibility, patients received treatment for 8 weeks (12 weeks in cohort 4). After treatment, there was a follow-up period for 6–8 weeks (except for cohort 4, which had no follow-up period). All patients enrolled in each cohort who successfully completed the main phase (open-label dose-finding period [OLDFI]) were offered entry into an open-label extension (OLE) phase.
      Figure thumbnail gr1
      Figure 1Study design of (A) cohorts 1–3 and (B) cohort 4. (A) ∗The inclusion or entry into the open-label dose-finding treatment period is always week 0 of the corresponding cohort. n represents the number of patients to be included in each study cohort. Week 8 is the end of the open-label dose-finding treatment period visit for the corresponding cohort. Week 14 or 16 is the final follow-up visit and the end of the main phase of the study. Dose escalation will occur sequentially from cohort 1 to both cohorts 2 and 3, whereby the dose escalation to cohorts 2 and 3 will commence after cohort 1 completes 8 weeks of the open-label dose-finding treatment period and the Data Monitoring Committee review the ongoing safety data and renders a recommendation on dose escalation. Cohort 2 will initially begin enrollment. Once enrollment is completed for cohort 2, then this will immediately be followed by enrollment into cohort 3 (ie, sequential enrollment). (B) ∗The inclusion or entry into the open-label dose-finding treatment period for cohort 4. The main phase for cohort 4 will include 3 alirocumab injections (at weeks 0, 4, and 8). For cohort 4, the study duration includes an extended 12-week treatment period, including a week 10 visit, but will not have a follow-up period, in contrast to the study design for cohorts 1, 2, and 3. §Week 12 is the end of the open-label dose-finding treatment period and possible entry point into the extension for cohort 4. aThe primary efficacy endpoint was analyzed in the modified intent-to-treat population and used a mixed-effect model with repeated measures approach with fixed categorical effects of alirocumab doses/dose regimen, planned postbaseline time point up to week 8, and dose-by-time point interaction. bInclusion into the open-label dose-finding treatment period (week 0). cWeek 8 was the end of the open-label dose-finding treatment period visit for the corresponding cohort. dThe primary endpoint was LDL-C percentage change from the baseline to week 8. eWeek 14 or 16 was the final follow-up visit and the end of the main phase of the study. Subjects did not receive treatment during the follow-up period in cohorts 1, 2, and 3. fThe main phase for cohort 4 included three alirocumab injections (at weeks 0, 4, and 8). gFor cohort 4, the study duration included an extended 12-week treatment period, with a week 10 visit, but did not have a follow-up period. Cohort 4 was added after completion of cohort 3 to further evaluate Q4W dosing regimens. hWeek 12 was the end of the open-label dose-finding treatment period and possible entry point into the extension for cohort 4. BW, body weight; LDL-C, low-density lipoprotein cholesterol; Q2W, every 2 weeks; Q4W, every 4 weeks; W, week.
      The initial dose of alirocumab that was administered Q2W or Q4W during the OLE period was to be a continuation of the same doses/dose regimen administered during the OLDFI treatment period of the main phase. However, after completion of the first 3 cohorts, the doses/dosing regimen (Q2W) evaluated in cohort 2 were selected for the planned phase 3 study in HeFH pediatric patients. Thus, these doses were administered to all patients from cohorts 1 to 3 until the end of their participation in the OLE period, consistent with the patient's body weight at the time of that switch. For cohort 4 (which further evaluated the Q4W dosing regimen), patients remained on their initial regimen due to the delay in initiating this cohort and consequently the limited duration of their participation in the OLE period.
      The primary endpoint was LDL-C % change from baseline to week 8. Key secondary endpoints included the absolute change in calculated LDL-C from baseline to week 8 and week 12 (for cohort 4), proportion of patients achieving LDL-C <130 and <110 mg/dL at week 8, percent change in LDL-C from baseline to week 12 for cohort 4, and the percent and absolute changes from baseline to week 8 in apolipoprotein (Apo) B, high-density lipoprotein cholesterol (HDL-C), total cholesterol, non-HDL-C, lipoprotein(a) [Lp(a)], triglycerides, and Apo A-1.
      Safety was assessed on treatment emergent adverse events (TEAEs); vital signs, including heart rate and blood pressure; body weight; height; Tanner stages; and the proportion of patients with 2 consecutive LDL-C levels <50 mg/dL and <25 mg/dL, respectively, that were monitored throughout the study. Potentially clinically significant abnormalities (PCSAs) in red blood cells and platelets during the TEAE period were also assessed. PCSA criteria included neutrophil, lymphocyte, eosinophil, and leukocyte counts. Safety data are reported for the combined OLDFI and OLE phases, including the period up to and following the switch to phase 3 doses during the OLE.
      Alirocumab and free PCSK9 concentrations were determined using validated enzyme-linked immunosorbent assays.
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      • Farnier M.
      • Kastelein J.J.P.
      • et al.
      Relationship between alirocumab, PCSK9, and LDL-C levels in four phase 3 ODYSSEY trials using 75 and 150 mg doses.
      Anti-drug antibody (ADA) samples were analyzed using a validated, nonquantitative, tier-based bridging immunoassay.
      • Roth E.M.
      • Goldberg A.C.
      • Catapano A.L.
      • et al.
      Antidrug antibodies in patients treated with alirocumab.
      Samples which were positive in the ADA assay were assessed for neutralizing antibodies using a validated, nonquantitative, competitive ligand-binding assay.
      • Roth E.M.
      • Goldberg A.C.
      • Catapano A.L.
      • et al.
      Antidrug antibodies in patients treated with alirocumab.

       Statistical analyses

      The duration of treatment exposure was calculated as follows: (last injection date + 14 days - first injection date)/7 for cohorts 1 and 2, or (last injection date + 28 days - first injection date)/7 for cohorts 3 and 4, regardless of intermittent discontinuations.
      No power sample size calculations were performed for the main phase. A sample size of 10 patients per cohort was empirical and based on the sample size of the phase 1 adult studies. At least 4 patients with a body weight of <50 kg and 4 patients with a body weight of ≥50 kg were enrolled in the cohorts. The percent change from baseline in calculated LDL-C at week 8 was analyzed in the modified intent-to-treat (mITT) population using a mixed-effect model with repeated measures approach with fixed categorical effects of alirocumab doses/dose regimen, planned post-baseline time point up to week 8, and dose-by-time point interaction. The mITT population consisted of all patients who received at least one dose or partial dose of the investigational injection and who had an evaluable primary endpoint during the OLDFI efficacy treatment period. The primary endpoint was considered evaluable when both of the following conditions were met: (1) availability of baseline calculated LDL-C value and (2) availability of at least 1 calculated LDL-C value during the OLDFI efficacy treatment period and within one of the analysis windows up to week 8.
      Continuous secondary endpoints anticipated to have a normal distribution (lipids other than Lp[a] and triglycerides) were assessed using the same model as for the primary endpoint. Continuous secondary endpoints anticipated to have a non-normal distribution were analyzed in the mITT population using multiple imputation approach to handle missing values followed by a robust regression model. Binary secondary efficacy endpoints were analyzed using multiple imputation approach for handling of missing values, as described for non-normally distributed endpoints, but without log-transformation.
      Safety was analyzed descriptively on the safety population, according to the dose of alirocumab received in the OLDFI period. The TEAE period was defined as the time from the first injection of the study drug up to 70 days after the last injection. Other safety parameters were reported during the combined OLDFI/OLE treatment period from the time of the first dose of OLDFI injection up to the day of the last OLE injection plus 21 days (cohorts 1 and 2) and 35 days (cohorts 3 and 4).

      Results

      A total of 63 patients were screened, and 42 patients were enrolled: 10 patients into cohorts 1 and 2, and 11 patients into cohorts 3 and 4 (Fig. 2). All enrolled patients completed the OLDFI period, with all entering the OLE period except for one patient in cohort 1. Three patients in cohort 1 and 2 patients in cohort 4 discontinued OLE treatment due to adverse events, patient decision, or misregistration (Fig. 2). Patient baseline characteristics are shown in Table 3. The mean patient age was 12.4 years, 45% were female, and most (95%) were on a statin. Baseline mean LDL-C levels were 160.0–188.9 mg/dL and mean free PCSK9 was 186.4–201.7 ng/mL across the cohorts (Table 3).
      Figure thumbnail gr2
      Figure 2Patient flow through the study. ∗Mainly due to LDL-C criteria. LDL-C, low-density lipoprotein cholesterol; OLDFI, open-label dose finding; OLE, open-label extension.
      Table 3Patient baseline characteristics
      CharacteristicCohort 1 30 mg (<50 kg) or 50 mg (≥50 kg) Q2W (N = 10)Cohort 2 40 mg (<50 kg) or 75 mg (≥50 kg) Q2W (N = 10)Cohort 3 75 mg (<50 kg) or 150 mg (≥50 kg) Q2W (N = 11)Cohort 4 150 mg (<50 kg) or 300 mg (≥50 kg) Q2W (N = 11)
      Age, y, mean (SD)12.7 (2.8)13.1 (2.6)11.6 (2.7)12.4 (2.3)
       Min; Max8; 179; 178; 168; 17
      Females, n (%)6 (60)4 (40)6 (55)3 (27)
      Race, n (%)
       Black or African American0002 (18)
       Black or African American/white001 (9)0
       White10 (100)10 (100)10 (91)9 (82)
      BMI, kg/m2, mean (SD)20.1 (3.7)22.0 (6.6)20.3 (3.3)20.2 (3.8)
      Clinical diagnosis of HeFH (Simon Broome Criteria), n (%)
       Definite2 (67)9 (100)7 (100)7 (78)
       Possible1 (33)002 (22)
      Genetic diagnosis of HeFH, n (%)
      A patient can be counted in several categories.
       Yes10 (100)10 (100)9 (82)9 (82)
       No002 (18)2 (18)
      Presence of cardiovascular history and risk factors, n (%)10 (100)10 (100)11 (100)11 (100)
      Family history of myocardial infarction
      Includes family history of myocardial infarction below 50 y of age in second-degree relative or below 60 y of age in first-degree relative.
      , n (%)
      4 (40)1 (10)7 (64)6 (55)
      Family history of raised cholesterol, n (%)10 (100)10 (100)11 (100)9 (82)
      Family history of tendon xanthoma (in first- or second-degree relative), n (%)3 (30)1 (10)5 (46)2 (18)
      Familial defective Apo B-100, n (%)1 (10)2 (20)01 (9)
      DNA-based evidence of an LDLR mutation (of the subject), n (%)8 (80)6 (60)7 (64)3 (27)
      Tendon xanthoma (of the subject), n (%)1 (10)000
      Subject history of raised total cholesterol, n (%)8 (80)9 (90)11 (100)9 (82)
      Subject history of raised LDL-C, n (%)10 (100)10 (100)10 (91)10 (91)
      Type 1 diabetes, n (%)1 (10)000
      Statin use, n (%)7 (70)10 (100)11 (100)11 (100)
      Ezetimibe use, n (%)
      In combination with statin or not.
      4 (40)000
      LDL-C (calculated) mean (SD), mg/dL180.3 (13.2)160.0 (12)172.8 (13.4)188.9 (11.9)
      Non-HDL-C, mean (SD), mg/dL198.4 (42.7)181.4 (39.7)190.4 (47.1)209.2 (39.4)
      Apo B, mean (SD), mg/dL119.7 (24.4)112.0 (24.3)112.0 (24.1)128.6 (22.8)
      HDL-C, mean (SD), mg/dL50.7 (10.0)45.1 (10.7)48.8 (8.4)54.8 (10.2)
      Triglycerides, mean (SD), mg/dL93.4 (31: 136)92.9 (35: 244)78.8 (32:151)101.8 (50:170)
      Lipoprotein (a)6.1 (2: 12)16.1 (2: 50)19.7 (6:51)54.3 (2:175)
      Free PCSK9, mean (SD), ng/mL192.7 (108.2)171.5 (59.1)201.7 (76.6)186.4 (80.2)
      Apo, apolipoprotein; BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; HeFH, heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; PCSK9, proprotein convertase subtilisin/kexin type; SD, standard deviation.
      A patient can be counted in several categories.
      Includes family history of myocardial infarction below 50 y of age in second-degree relative or below 60 y of age in first-degree relative.
      In combination with statin or not.

       Efficacy analysis (OLDFI period)

      All patients (100%) had ≥80% compliance for injections during the OLDFI period. Mean percent reductions from baseline to week 8 in LDL-C (primary endpoint) for each cohort are shown in Table 4. The higher dose cohorts (2 and 4) demonstrated the greatest reductions in LDL-C (–46% and –45%, respectively). Absolute changes in LDL-C to week 8 are also in Table 4. In cohort 4, the least squares mean (standard error) percent and absolute changes in LDL-C to week 12 were –39% (5.1) and –67.8 mg/dL (8.3), respectively. The proportion of patients who reached the prespecified LDL-C targets at week 8 was higher in cohorts 2 and 4. At week 8, 89% (cohort 2) and 73% (cohort 4) of patients reached a calculated LDL-C level of <130 mg/dL. At week 8, 77% (cohort 2) and 73% (cohort 4) of patients reached a calculated LDL-C level of <110 mg/dL (Table 4).
      Table 4Primary and secondary endpoints
      Cohort 1 30 mg (<50 kg) or 50 mg (≥50 kg) Q2W (N = 10)Cohort 2 40 mg (<50 kg) or 75 mg (≥50 kg) Q2W (N = 10)Cohort 3 75 mg (<50 kg) or 150 mg (≥50 kg) Q2W (N = 11)Cohort 4 150 mg (<50 kg) or 300 mg (≥50 kg) Q2W (N = 11)
      Week 8 LS mean (SE) % change from baseline in calculated LDL-C–21.2 (7.9)–46.1 (8.3)–7.8 (7.6)–44.5 (7.6)
       95% CI–37.4 to –5.1–62.8 to –29.4–23.2 to 7.7–60.0 to –29.1
      Week 8 LS mean (SE) absolute change from baseline in calculated LDL-C, mg/dL–50.0 (12.3)–75.2 (13.0)–17.6 (11.7)–77.9 (11.7)
       95% CI–75.1 to –25.0–101.4 to –48.9–41.5 to –6.3–101.7 to –54.0
      Proportion of patients achieving LDL-C <130 mg/dL at week 8, %60.088.827.372.7
      Proportion of patients achieving LDL-C <110 mg/dL at week 8, %0.076.818.272.7
      Week 8 LS mean (SE) % changes from baseline in other lipids
       Non-HDL-C–20.1 (7.5)–42.2 (7.8)–6.4 (7.2)–42.0 (7.2)
      95% CI–35.4 to –4.8–58.0 to –26.4–21.0 to 8.2–56.6 to –27.4
       Apolipoprotein B–21.2 (7.5)–38.6 (7.9)–7.3 (6.7)–38.2 (6.7)
      95% CI–36.5 to –5.9–54.7 to –22.5–21.0 to 6.4–51.9 to –24.5
       Lipoprotein(a)
      Combined estimate for adjusted mean (SE).
      –14.4 (10.9)–14.5 (10.7)–2.3 (7.5)–3.5 (7.5)
      95% CI–35.7 to 7.0–35.5 to 6.5–17.0 to 12.5–18.2 to 11.2
       Triglycerides
      Combined estimate for adjusted mean (SE).
      –2.5 (12.4)5.7 (16.4)9.1 (11.8)–20.7 (11.8)
      95% CI–26.9 to 21.8–26.4 to 37.8–14.0 to 32.3–43.8 to 2.4
       HDL-C13.8 (4.5)12.3 (4.8)9.1 (4.3)3.7 (4.3)
      95% CI4.7 to 23.02.5 to 22.00.4 to 17.9–5.0 to 12.4
      CI, confidence interval; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LS, least squares; SE, standard error.
      Combined estimate for adjusted mean (SE).
      Changes in other lipid parameters are shown in Table 4. In all cohorts, decreases were observed from baseline to week 8 (on-treatment analysis) for Apo B and non-HDL-C, with the greatest reductions in cohorts 2 and 4. Overall, a decrease from baseline to week 8 was observed for Lp(a) across the cohorts (with a decrease of 15% and 4% in cohorts 2 and 4, respectively) and in triglycerides (21%) in cohort 4.

       Pharmacokinetic analysis (OLDFI period)

      Mean concentrations of total alirocumab increased with dose for both Q2W and Q4W dosing regimens (Fig. 3A). Dose-dependent decreases in free PCSK9 and LDL-C were observed (Fig. 3B). At week 8, free PCSK9 had been reduced to the lowest mean levels in cohorts 2 and 4 (to 42.2 and 8.6 ng/mL, respectively; reductions of ∼75% and ∼95% from baseline). In comparison, at week 8 in cohorts 1 and 3, free PCSK9 levels were reduced to 91.8 and 104.4 ng/mL, respectively (reductions of ∼52% and ∼48% from baseline).
      Figure thumbnail gr3
      Figure 3(A) Alirocumab concentrations and (B) free PCSK9 concentrations over time. ALI, alirocumab; Q2W, every 2 wk; Q4W, every 4 wk; PCSK9, proprotein convertase subtilisin/kexin type 9; SE, standard error; W, week. Ctrough for Q2W regimen: alirocumab concentration sample taken between 8 and 21 d after previous injection of alirocumab (may be just before the next injection); Ctrough for Q4W regimen: alirocumab concentration sample taken between 22 and 35 d after previous injection of alirocumab (may be just before the next injection); Cfollow-up for Q2W regimen: alirocumab concentration sample taken more than 21 d after last injection of alirocumab and no more than 14 wk after last injection of alirocumab; Cfollow-up for Q4W regimen: alirocumab concentration sample taken more than 35 d after last injection of alirocumab and no more than 14 weeks after last injection of alirocumab.

       Safety analysis (combined OLDFI/OLE periods)

      The total median duration of treatment exposure in the combined OLDFI/OLE period regardless of the dose switch was 105 weeks in cohort 1, 88 weeks in cohorts 2 and 3, and 24 weeks in cohort 4. TEAEs are summarized in Table 5. There were no deaths or serious adverse events. Two patients discontinued treatment, one in the OLDFI period and one in the OLE period, due to TEAEs of fatigue and neutropenia, respectively; neither event was considered related to study treatment. The most common TEAEs by preferred term were nasopharyngitis (6/42 patients, 14%), upper respiratory tract infection, viral gastroenteritis, and diarrhea (each reported in 5/42 patients, 12%; Supplemental Table 1). Most other TEAEs reported occurred in only 1–2 patients and there was no pattern by dosing cohort. Injection-site reactions occurred in 2 patients (one in cohort 3 and one in cohort 4) and were both mild in intensity.
      Table 5Safety analysis (OLDFI/OLE periods combined, regardless of switch to phase 3 doses in OLE)
      n (%)Cohort 1 30 mg (<50 kg) or 50 mg (≥50 kg) Q2W (N = 10)Cohort 2 40 mg (<50 kg) or 75 mg (≥50 kg) Q2W (N = 10)Cohort 3 75 mg (<50 kg) or 150 mg (≥50 kg) Q2W (N = 11)Cohort 4 150 mg (<50 kg) or 300 mg (≥50 kg) Q2W (N = 11)
      Patients with any TEAE, n (%)9 (90)5 (50)10 (91)7 (64)
      Patients with any treatment-emergent SAE, n (%)0000
      Patients with any TEAE leading to death, n (%)0000
      Patients with any TEAE leading to permanent treatment discontinuation, n (%)1 (10)001 (9)
      OLDFI, open-label dose finding; OLE, open-label extension; SAE, serious adverse event; TEAE, treatment-emergent adverse event.
      No patients had 2 or more consecutive LDL-C values <25 mg/dL. One patient had 2 consecutive LDL-C measurements <50 mg/dL (in cohort 2); however, no TEAEs after the first of the LDL-C <50 mg/dL measurement were reported.
      One patient (in cohort 1) had hyperglycemic events during the on-treatment period. The patient had a history of intermittent hyperglycemia for 4 years but did not have signs or symptoms consistent with a diagnosis of diabetes during the study. The patient was found to be positive for anti-glutamic acid decarboxylase (GAD) antibodies; however, the patient was found to be negative for anti-tyrosine phosphatase IA2 and anti-insulin antibodies. Coincidentally, a second patient (in cohort 4) with a history of autoimmune thyroiditis and no change in glucose homeostasis during the study had a diagnosis of type 1 diabetes assessed to be of autoimmune origin (high positive titer of GAD) in the post-treatment period after the end of their participation in the study. Both events were judged not related to study treatment. Narrative descriptions of the diabetes cases are shown in the Supplemental Materials.
      No clinically important changes were observed in the safety hematology and serum chemistry parameters. There were few individual changes in vital signs, hematology, metabolic, electrolyte, renal, or liver function parameters that met the PCSA criteria. These changes were transient. No relevant changes were observed in cortisol or vitamins A, D, and K. As observed in the adult population, a decrease in vitamin E parallel to the decrease in LDL-C levels and a positive correlation between calculated LDL-C and vitamin E were observed in all cohorts from baseline to week 8. No patients had vitamin E values lower than the normal range. No significant changes over time were observed in gonadal and pituitary hormones in boys or girls. A progression to a more advanced Tanner stage was noted in a few patients. Positive ADAs were detected in 4 patients (10%) during the treatment period; however, no safety concerns related to positive ADAs were raised.

      Discussion

      Across the cohorts, patients had elevated LDL-C levels at baseline that ranged from 160.0 to 188.9 mg/dL, despite the majority being treated with a statin. Alirocumab demonstrated the highest reductions in LDL-C of –46% and –45% in the highest dose cohorts (2; 40/75 mg Q2W and 4; 150/300 mg Q4W), respectively, at week 8, vs placebo. Overall, treatment with alirocumab was generally well tolerated, including during the OLE period.
      In the present study, reductions from baseline in LDL-C in the higher dose cohorts were similar to those observed in the adult HeFH populations: –46% (with alirocumab 40 [body weight <50 kg] or 75 mg [body weight ≥50 kg] Q2W), and –45% (with alirocumab 150 [body weight <50 kg] or 300 mg [body weight ≥50 kg] Q4W).
      Overall, the safety profile in the present study was consistent with that seen in studies conducted in adults.
      • Kastelein J.J.
      • Ginsberg H.N.
      • Langslet G.
      • et al.
      ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia.
      ,
      • Schwartz G.G.
      • Steg P.G.
      • Szarek M.
      • et al.
      Alirocumab and cardiovascular outcomes after acute coronary syndrome.
      ,
      • Jones P.H.
      • Bays H.E.
      • Chaudhari U.
      • et al.
      Safety of alirocumab (a PCSK9 monoclonal antibody) from 14 randomized trials.
      Notably, previous studies found no effect of alirocumab on the incidence of diabetes or glycemic parameters.
      • Ray K.K.
      • Colhoun H.M.
      • Szarek M.
      • et al.
      Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial.
      • Leiter L.A.
      • Tinahones F.J.
      • Karalis D.G.
      • et al.
      Alirocumab safety in people with and without diabetes mellitus: pooled data from 14 ODYSSEY trials.
      • Colhoun H.M.
      • Ginsberg H.N.
      • Robinson J.G.
      • et al.
      No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies.
      However, 2 hyperglycemic events (one consistent with a diagnosis of type 1 diabetes) were detected in the present study. Although the study was conducted in a relatively small number of pediatric patients, these events were judged not related to the study treatment. Four patients (10%) were found to be positive for ADAs, although no safety signals were associated with these patients. A low level of immunogenicity was observed in previous alirocumab studies conducted in adults.
      • Roth E.M.
      • Goldberg A.C.
      • Catapano A.L.
      • et al.
      Antidrug antibodies in patients treated with alirocumab.
      Dose-dependent decreases in free PCSK9 and LDL-C were observed, consistent with the known mode of action of alirocumab in adults.
      • Robinson J.G.
      • Farnier M.
      • Kastelein J.J.P.
      • et al.
      Relationship between alirocumab, PCSK9, and LDL-C levels in four phase 3 ODYSSEY trials using 75 and 150 mg doses.
      ,
      • Chaudhary R.
      • Garg J.
      • Shah N.
      • Sumner A.
      PCSK9 inhibitors: a new era of lipid lowering therapy.
      The greatest reductions in free PCSK9 were observed in the higher dose cohorts (2 and 4), which also had the greatest reductions in LDL-C. The reductions in free PCSK9 in the higher dose cohorts were of a similar magnitude to those seen in the FH I study conducted in adults with HeFH.
      • Robinson J.G.
      • Farnier M.
      • Kastelein J.J.P.
      • et al.
      Relationship between alirocumab, PCSK9, and LDL-C levels in four phase 3 ODYSSEY trials using 75 and 150 mg doses.
      Limitations of this study include the small number of participants, short duration, lack of a control group, and lack of blinding to study treatment. The study was designed to identify suitable doses for use in subsequent trials, and no formal statistical testing was planned. Randomized, controlled trials with a longer treatment duration are required to establish efficacy and safety of alirocumab in this population.
      In conclusion, in this pediatric population, alirocumab showed a decrease in LDL-C similar to the adult population in cohorts 2 and 4 and was generally well tolerated at all doses assessed in the 4 cohorts. Alirocumab may offer an additional therapeutic option for lowering LDL-C in pediatric patients with HeFH; however, this requires further investigation. Following the results from the present study, doses used in cohorts 2 (40/75 mg Q2W) and 4 (150/300 mg Q4W) were selected for further investigation in a subsequent phase 3 trial in pediatric patients with HeFH.

      Acknowledgments

      The authors would like to thank the patients, their families, and all investigators involved in this study. Medical writing assistance and editorial support, under the direction of the authors, was provided by Michele Damo, PharmD, and Rob Campbell, PhD, both of Prime (Knutsford, UK), funded by Sanofi and Regeneron Pharmaceuticals, Inc according to Good Publication Practice guidelines (https://annals.org/aim/fullarticle/2424869/good-publication-practice-communicating-company-sponsored-medical-research-gpp3). The sponsors were involved in the study design and collection, analysis, and interpretation of data, as well as data checking of information provided in the manuscript. The authors had unrestricted access to study data, were responsible for all content and editorial decisions, and received no honoraria related to the development of this publication.

      Disclosures

      Stephen Daniels is a consultant/steering committee member of Sanofi and the DMC chair for Novo Nordisk. Eric Bruckert reports honoraria from Aegerion, Genfit, MSD, Sanofi, Regeneron Pharmaceuticals, Inc, AstraZeneca, Unilever, Akcea, Merck, and Servier. Sonia Caprio has nothing to disclose. Umesh Chaudhari is an employee of and stockholder in Regeneron and was previously employed by Sanofi. Garen Manvelian is an employee of and stockholder in Regeneron. Marie T. Baccara-Dinet, Aurelie Brunet, Michel Scemama, and Virginie Loizeau are employees of and stockholders in Sanofi.

      Appendix

      Supplemental Table 1TEAEs for OLDFI/OLE periods combined, regardless of switch to phase 3 doses in OLE
      n (%)Cohort 1 (n = 10)Cohort 2 (n = 10)Cohort 3 (n = 11)Cohort 4 (n = 11)
      Patients with any TEAE9 (90.0)5 (50.0)10 (90.9)7 (63.6)
      Patients with any treatment-emergent SAE0000
      Patients with any TEAE leading to death0000
      Patients with any TEAE leading to permanent treatment discontinuation1 (10.0)001 (9.1)
      TEAEs
      Infections and infestations5 (50.0)3 (30.0)9 (81.8)3 (27.3)
       Sinusitis0001 (9.1)
       Tonsillitis01 (10.0)01 (9.1)
       Upper respiratory tract infection01 (10.0)3 (27.3)1 (9.1)
       Abscess limb001 (9.1)0
       Cystitis bacterial1 (10.0)000
       Cytomegalovirus hepatitis1 (10.0)000
       Ear infection2 (20.0)1 (10.0)1 (9.1)0
       Gastroenteritis viral2 (20.0)03 (27.3)0
       Infectious mononucleosis1 (10.0)000
       Nasopharyngitis3 (30.0)1 (10.0)2 (18.2)0
       Otitis externa001 (9.1)0
       Otitis media01 (10.0)1 (9.1)0
       Pharyngitis01 (10.0)00
       Pharyngitis streptococcal01 (10.0)00
       Postprocedural infection1 (10.0)000
       Pyelonephritis1 (10.0)000
       Urinary tract infection001 (9.1)0
       Varicella001 (9.1)0
       Viral upper respiratory tract infection001 (9.1)0
       Vulvovaginal mycotic infection001 (9.1)0
      Neoplasms benign, malignant, and unspecified (Incl. cysts and polyps)001 (9.1)0
       Pyogenic granuloma001 (9.1)0
      Blood and lymphatic system disorders001 (9.1)2 (18.2)
       Lymphadenopathy0001 (9.1)
       Neutropenia001 (9.1)1 (9.1)
      Immune system disorders1 (10.0)000
       Food allergy1 (10.0)000
      Metabolism and nutrition disorders2 (20.0)1 (10.0)01 (9.1)
       Vitamin D deficiency1 (10.0)1 (10.0)01 (9.1)
       Type 1 diabetes mellitus1 (10.0)000
      Psychiatric disorders1 (10.0)01 (9.1)0
       Alcohol abuse1 (10.0)000
       Anxiety disorder1 (10.0)000
       Depressed mood001 (9.1)0
      Nervous system disorders4 (40.0)01 (9.1)0
       Headache2 (20.0)000
       Hypoesthesia1 (10.0)000
       Presyncope001 (9.1)0
       Syncope1 (10.0)000
       Thoracic outlet syndrome1 (10.0)000
      Eye disorders0001 (9.1)
       Excessive eye blinking0001 (9.1)
      Vascular disorders1 (10.0)000
       Pallor1 (10.0)000
      Respiratory, thoracic, and mediastinal disorders2 (20.0)01 (9.1)3 (27.3)
       Epistaxis2 (20.0)001 (9.1)
       Oropharyngeal pain0001 (9.1)
       Sinus congestion0001 (9.1)
       Asthma001 (9.1)0
      Gastrointestinal disorders5 (50.0)03 (27.3)4 (36.4)
       Diarrhea2 (20.0)01 (9.1)2 (18.2)
       Abdominal discomfort0001 (9.1)
       Toothache0001 (9.1)
       Abdominal pain1 (10.0)01 (9.1)0
       Constipation1 (10.0)000
       Nausea001 (9.1)0
       Vomiting1 (10.0)01 (9.1)0
      Skin and subcutaneous tissue disorders0001 (9.1)
       Acne0001 (9.1)
      Musculoskeletal and connective tissue disorders2 (20.0)02 (18.2)0
       Arthritis1 (10.0)000
       Flank pain1 (10.0)000
       Muscle spasms001 (9.1)0
       Myalgia1 (10.0)000
       Tendon pain001 (9.1)0
      Reproductive system and breast disorders1 (10.0)000
       Premenstrual pain1 (10.0)000
      General disorders and administration-site conditions2 (20.0)01 (9.1)2 (18.2)
       Influenza-like illness2 (20.0)001 (9.1)
       Injection-site reaction001 (9.1)1 (9.1)
       Fatigue1 (10.0)000
      Investigations01 (10.0)00
       Blood follicle stimulating hormone decreased01 (10.0)00
       Blood luteinizing hormone decreased01 (10.0)00
       Low-density lipoprotein decreased01 (10.0)00
      Injury, poisoning, and procedural complications3 (30.0)2 (20.0)3 (27.3)0
       Animal scratch01 (10.0)00
       Arthropod bite01 (10.0)00
       Concussion1 (10.0)000
       Fall2 (20.0)01 (9.1)0
       Hand fracture001 (9.1)0
       Ligament sprain1 (10.0)2 (20.0)1 (9.1)0
       Post-traumatic pain1 (10.0)000
       Radius fracture001 (9.1)0
       Road traffic accident1 (10.0)000
       Traumatic hematoma1 (10.0)000
      SAE, serious adverse event; TEAE, treatment-emergent adverse event.

      Inclusion and exclusion criteria

       Inclusion criteria

      • 1.
        Children and adolescent male and female patients aged 8
        Patients between 8 and <10 years of age had to have other available interventions to lower calculated LDL-C, but these were insufficient.
        to 17 years at the time of signed informed consent.
        • (a)
          For Russia only: Male and female patients aged ≥12 and ≤17 years at the time of signed informed consent.
        Patients between 8 and <10 years of age had to have other available interventions to lower calculated LDL-C, but these were insufficient.
      • 2.
        Patients with diagnosis of heterozygous familial hypercholesterolemia (HeFH) through genotyping or clinical criteria
        Diagnosis of HeFH had to be made by previous genotyping, current genotyping, or by clinical criteria according to Simon Broome criteria. Previous genotyping referred to documented results that were available from prior genotyping testing supporting a diagnosis of HeFH. Current centralized genotyping referred to patients consenting to undergo mandatory genotyping during the screening period with results supporting a diagnosis of HeFH. The clinical diagnosis had to be based on the Simon Broome criteria for possible or definite familial hypercholesterolemia. Once eligibility was confirmed based on prior genetic testing or Simon Broome criteria, results of elective genetic testing did not impact the patient's eligibility.
        Diagnosis of HeFH had to be made by previous genotyping, current genotyping, or by clinical criteria according to Simon Broome criteria. Previous genotyping referred to documented results that were available from prior genotyping testing supporting a diagnosis of HeFH. Current centralized genotyping referred to patients consenting to undergo mandatory genotyping during the screening period with results supporting a diagnosis of HeFH. The clinical diagnosis had to be based on the Simon Broome criteria for possible or definite familial hypercholesterolemia. Once eligibility was confirmed based on prior genetic testing or Simon Broome criteria, results of elective genetic testing did not impact the patient's eligibility.
      • 3.
        Patients treated with optimal dose of statin
        The optimal dose of statin was defined as the stable daily dose prescribed based on regional practice or local guidelines or was the stable daily dose that was maximally tolerated due to adverse events on higher doses. For patients not receiving the maximally tolerated dose of statin, statin intensification was to be carefully considered before inclusion in this study to ensure that the addition of a nonstatin LDL-C-lowering therapy (ie, alirocumab) would be the next appropriate step in the management of the patient's hypercholesterolemia. The highest dose of statin had not to exceed the maximum labeled dose of statin for pediatric patients as per the local prescribing information.
         ± other lipid-modifying therapies (LMTs) or nonstatin LMT(s) if statin intolerant
        A statin-intolerant patient was defined someone with the inability to tolerate at least 2 statins: 1 statin at the lowest daily starting dose, and another statin at any dose, due to skeletal muscle-related symptoms, other than those due to strain or trauma, such as pain, aches, weakness, or cramping that began or increased during statin therapy and stopped when statin therapy was discontinued. Patients not receiving a daily regimen of a statin (eg, 1–3 times weekly) were also considered as not able to tolerate a daily dose.
        at stable dose for at least 4 weeks.
        The optimal dose of statin was defined as the stable daily dose prescribed based on regional practice or local guidelines or was the stable daily dose that was maximally tolerated due to adverse events on higher doses. For patients not receiving the maximally tolerated dose of statin, statin intensification was to be carefully considered before inclusion in this study to ensure that the addition of a nonstatin LDL-C-lowering therapy (ie, alirocumab) would be the next appropriate step in the management of the patient's hypercholesterolemia. The highest dose of statin had not to exceed the maximum labeled dose of statin for pediatric patients as per the local prescribing information.
        §A statin-intolerant patient was defined someone with the inability to tolerate at least 2 statins: 1 statin at the lowest daily starting dose, and another statin at any dose, due to skeletal muscle-related symptoms, other than those due to strain or trauma, such as pain, aches, weakness, or cramping that began or increased during statin therapy and stopped when statin therapy was discontinued. Patients not receiving a daily regimen of a statin (eg, 1–3 times weekly) were also considered as not able to tolerate a daily dose.
      • 4.
        Patients with calculated low-density lipoprotein cholesterol (LDL-C) greater than or equal to 130 mg/dL (≥3.37 mmol/L) obtained during the screening period after the patient has been on stable LMT (ie, stable optimal dose of statin ± other stable LMTs or stable nonstatin LMTs in statin-intolerant patients) treatment for at least 4 weeks.
      • 5.
        Patients with body weight ≥25 kg.
      • 6.
        Patients aged 8–9 years to be at Tanner stage 1, and patients aged 10–17 years to be at least at Tanner stage 2 in their development.
      • 7.
        A signed informed consent indicating parental permission with or without patient assent, depending on capacity for understanding based on developmental maturity. In cases involving emancipated or mature minors with adequate decision-making capacity, or when otherwise permitted by law, a signed informed consent directly from patients.

       Exclusion criteria related to study methodology

      • 1.
        Age of less than 8 or >17 years at the time of signed informed consent.
      • 2.
        Calculated LDL-C <130 mg/dL (3.37 mmol/L) during the screening period, after patient has been on stable LMT for at least 4 weeks.
      • 3.
        Patient without a diagnosis of HeFH by genotyping or clinical criteria.
      • 4.
        Patients aged of 8 to <10 years in whom other available interventions to lower LDL-C have been sufficient.
      • 5.
        Patients not on a stable dose of LMT (including statin, as applicable) for at least 4 weeks before the screening visit and from screening visit to day 1.
      • 6.
        Daily dose of statin that is above the maximum recommended dose for pediatric patients as per the local prescribing label.
      • 7.
        Use of nutraceutical products or over-the-counter therapies that may affect lipids, which have not been at a stable dose for at least 4 weeks before the screening visit.
      • 8.
        Patients not previously instructed on a cholesterol-lowering diet before the screening visit.
      • 9.
        Body weight <25 kg.
      • 10.
        Patients aged 8–9 years not being at Tanner stage 1, and patients aged 10–17 years not being at least at Tanner stage 2 in their development.
      • 11.
        Patients with secondary hyperlipidemia.
      • 12.
        Patients with diagnosis of homozygous familial hypercholesterolemia.
      • 13.
        Patient who has received lipid apheresis treatment within 2 months before the screening period or had plans to receive it during the study.
      • 14.
        Known history of type 1 or type 2 diabetes mellitus.
      • 15.
        Known history of thyroid disease.
      • 16.
        Known history of hypertension.
      • 17.
        Fasting triglycerides >350 mg/dL (3.95 mmol/L) at the screening visit.
      • 18.
        Severe renal impairment (ie, estimated glomerular filtration rate <30 mL/min/1.73 m2 at the screening visit).
      • 19.
        Alanine aminotransferase or aspartate aminotransferase >2 x the upper limit of normal (ULN; 1 repeat laboratory was allowed).
      • 20.
        Creatine phosphokinase >3 x ULN (1 repeat laboratory was allowed).
      • 21.
        Patient/parents who withdrew consent during the screening period (patient who was not willing to continue or failed to return).
      • 22.
        Conditions/situations or laboratory findings such as:
        • (a)
          Any clinically significant abnormality identified at the time of screening that in the judgment of the investigator or any subinvestigator would preclude safe completion of the study or constrain endpoints assessment such as major systemic diseases.
        • (b)
          Patients considered by the investigator or any subinvestigator as inappropriate for this study for any reason, for exapmle:
          • Those deemed unable to meet specific protocol requirements, such as scheduled visits.
          • Those deemed unable to administer or tolerate long-term injections as per the patient or the investigator
          • Presence of any other conditions (eg, geographic, social…) actual or anticipated that the investigator feels would restrict or limit the patient's participation for the duration of the study.
          • Uncooperative behavior or any condition that could make the patient potentially noncompliant to the study procedures.
      • 23.Treatment with any investigational medicinal product (IMP) within 8 weeks or 5 half-lives before the screening period, whichever was longer.
      Note: If half-life was not known, then 8 weeks were to be applied for a nonbiological IMP and 6 months for a biological IMP.

       Exclusion criteria related to mandatory background therapies

      • 24.
        All contraindications to the background statins or other LMTs (as applicable) or warning/precaution of use (when appropriate) as displayed in the respective National Product Labelling.

       Exclusion criteria related to the current knowledge of alirocumab

      • 25.
        Hypersensitivity to alirocumab or to any of the ingredients of alirocumab injections.
      • 26.
        Females who had experienced menarche or females of childbearing potential who were sexually active who were unwilling or unable to be tested for pregnancy.
      • 27.
        Positive pregnancy test in females who had experienced menarche or females of childbearing potential who were sexually active.
      • 28.
        Females who were breastfeeding.
      • 29.
        Females of childbearing potential who were sexually active and not protected by highly effective contraceptive method(s) of birth control (as defined in the informed consent form and/or in a local protocol addendum) and/or who were unwilling or unable to be tested for pregnancy.
      Note: Females of childbearing potential who were sexually active or females who had experienced menarche had to have a confirmed negative pregnancy test at screening and other study visits. Females of childbearing potential who were sexually active had to use an effective contraceptive method throughout the entire duration of the study treatment and for at least 10 weeks after the last injection. The applied methods of contraception had to meet the criteria for a highly effective method of birth control according to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. M3(R2): Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. ICH. 2009 Jun: 1-25.

       Exclusion criteria for the open-label extension treatment period

       Exclusion criteria related to study methodology

      • 30.
        Significant protocol deviation in the main phase based on investigator judgment, such as noncompliance by the patient.
      • 31.
        Patients who experienced an adverse event leading to permanent discontinuation from the main open-label dose-finding treatment period.
      • 32.
        Patients having any new condition or worsening of an existing condition which in the opinion of the investigator would make the patient unsuitable for entry into the extension phase or could interfere with the patient participating in or completing the study.

       Exclusion criteria related to the current knowledge of alirocumab

      • 33.
        Hypersensitivity to alirocumab or to any of the ingredients of alirocumab injections.
      • 34.
        Positive pregnancy test at last visit of the main treatment period (week 14 [cohort 3]/week16 [cohorts 1 and 2], visit 8).
      • 35.
        Females who had experienced menarche or females of childbearing potential not willing to continue highly effective method(s) of birth control (as defined in the informed consent form and/or in a local protocol addendum) and/or who were unwilling or unable to be tested for pregnancy.
      Note for guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals (CPMP/ICH/286/95).

       Diabetes or diabetic complications narratives

      A 17-year old female patient in cohort 1 (50 mg every 2 weeks [Q2W]) was reported to have a treatment-emergent type 1 diabetes mellitus in the open-label extension period before the switch to phase 3 Q2W doses. According to medical history information, this patient had experienced intermittently increased glycemia for 4 years. The patient was reported with increased fasting glucose up to 7.9 mmol/L (clinically significant abnormality value after switch) at week 76 (value at screening was above the upper limit of normal [5.9 mmol/L])). The patient was asymptomatic. No weight changes were observed for this patient during her study participation. The patient was found to be positive for anti-glutamic acid decarboxylase (GAD) antibodies; however, she was negative for anti-tyrosine phosphatase2 (IA2) and anti-insulin antibodies. The patient did not have any other autoimmune disease. Her glycated hemoglobin (HbA1c) value at the time of diagnosis was reported to be increased; however, this value was not provided.
      Subsequently available HbA1c values were within the normal ranges. The event was considered nonserious and not related to study drug by the investigator. The endocrinologist considered that the mildly increased values of glycemia did not require treatment with insulin. The patient was initiated on metformin.
      An 11-year-old male patient in cohort 4 on levothyroxine treatment for autoimmune thyroiditis was reported to have a post-treatment serious adverse event (type 1 diabetes). During the study participation, glucose values were normal. The event was reported approximately 3.5 months after the last dose of study drug (glycemia: 16 mmol/L, HbA1c: 89 mmol/mol and glycosuria 4+). The patient was thus diagnosed with diabetes mellitus type 1 during the screening visit for the pediatric phase 3 study conducted in HeFH patients. Positive anti-GAD antibodies and highly positive anti-thyroid peroxidase (TPO) antibodies were reported.
      Tabled 1List of Study Sites and Investigators
      CountryStudy sitePrincipal investigator
      CanadaClinique des maladies lipidiques de Québec Inc, 2600 boulevard Laurier Suite 880, Quebec G1V 4W2, Quebec, CANADABergeron Jean
      Czech RepublicFN Brno, Pediatricka klinika, Cernopolni 9, Brno 61300, CZECH REPUBLICDostalova Kopecna Lenka
      Krajska nemocnice Tomase Bati a.s., Pediatricka klinika, Havlickovo nabrezi 600, Zlin 76000, CZECH REPUBLICToukalkova Lenka
      Fakultni nemocnice v Motole, Ustav lekarske chemie a klinicke biochemie, V Uvalu 84, Praha 5, 15006, CZECH REPUBLICCepova Jana
      FranceHopital Femme Mere Enfant de Lyon, Service d'hepatologie, gastroenterologie et, nutrition pediatrique, 59 boulevard Pinel, Bron Cedex 69677, FRANCEPeretti Noel
      NetherlandsAmsterdam Universitair Medische Centra, Academisch Medisch Centrum, Meibergdreef 9, Amsterdam 1105AZ, NETHERLANDSHovingh Gerard
      NorwayOslo Universitetssykehus HF ,Rikshospitalet, Lipiklinikken, Visiting adr: Sognsvannsveien 20, 0372 Mail adr. PO box 4950 Nydalen, 0424 Oslo, NORWAYRisstad Hilde/Langslet Gisle (former)
      Russian FederationFederal state budget scientific institution “Scientific res, 6 Sosnovy boul, Kemerovo 650002, RUSSIAN FEDERATIONBarbarash Olga
      St-Petersburg State Pediatric Medical University, 2, Litovskaya Str., Saint-Petersburg 194100, RUSSIAN FEDERATIONChasnyk Vyacheslav
      South AfricaTREAD Research CC, Room 41, 8th Floo, Department of Cardiology, Tygerberg Hospital, Francie van Zyl Drive, Parow 7500, SOUTH AFRICABurgess Lesley
      SpainHospital Infantil Universitario Niño Jesus, Avenida Menéndez Pelayo, 65, Madrid 28009, Madrid, SPAINArgente Oliver Jesús
      Hospital Abente Y Lago, Calle Sir John More S/N, A Coruna 15001, La Coruña, SPAINDiaz Diaz Jose Luis
      SwedenAstrid Lindgren Barnsjukhus Karolinska, Universitetssjukhuset, Barnendokrinologiska kliniken, Karolinska Universitetssjukhuset, Astrid Lindgrens barnsjukhus, Stockholm 17176, SWEDENNergårdh Ricard
      United States of AmericaCincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati 45229, Ohio, UNITED STATESShah Amy
      Washington University School of Medicine, 4921 Parkview Place, St Louis, Missouri 63110, UNITED STATESGoldberg Anne
      Presbyterian Novant Heart & Wellness, 125 Baldwin Avenue, Suite 200, Charlotte, 28204 North Carolina, UNITED STATESBarringer Thomas

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