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Efficacy and Safety of Alirocumab in Patients With Autosomal Dominant Hypercholesterolemia Associated With Proprotein Convertase Subtilisin/Kexin Type 9 Gain-of-Function or Apolipoprotein B Loss-of-Function Mutations

Open AccessPublished:December 27, 2019DOI:https://doi.org/10.1016/j.amjcard.2019.12.028
      Autosomal dominant hypercholesterolemia results from mutations affecting the low-density lipoprotein receptor pathway, including proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GoFm) and apolipoprotein B (APOB) loss-of-function mutations (LoFm). This study examined the long-term efficacy and safety of alirocumab in patients with PCSK9 GoFm and APOB LoFm who participated in the open-label extension to a Phase 2 double-blind study (NCT01604824). Of the 23 patients who completed the 14-week double-blind period and 8-week follow-up, 21 opted to continue in the open-label extension (PCSK9 GoFm, n = 15; APOB LoFm, n = 6). Patients received alirocumab 150 mg every 2 weeks from week 32 up to 3 years for PCSK9 GoFm and 2 years for APOB LoFm. Mean duration of alirocumab exposure was 129 weeks (median: 144 weeks). After initiation of alirocumab treatment, low-density lipoprotein cholesterol (LDL-C) decreased in both groups. At week 80, mean percent reduction in LDL-C from baseline was 58.0% and 47.1% for PCSK9 GoFm and APOB LoFm groups, respectively. Treatment-emergent adverse events were reported in 19 patients (90.5%); no patients discontinued treatment due to treatment-emergent adverse events. In patients with autosomal dominant hypercholesterolemia and elevated LDL-C levels despite receiving maximally tolerated lipid-lowering therapies, alirocumab 150 mg every 2 weeks resulted in clinically meaningful reductions in LDL-C, sustained through to 3 years and 2 years for patients with PCSK9 GoFm and APOB LoFm, respectively. Alirocumab was generally well tolerated with no unexpected safety concerns.
      Autosomal dominant hypercholesterolemia (ADH)
      • Santos RD
      • Gidding SS
      • Hegele RA
      • Cuchel MA
      • Barter PJ
      • Watts GF
      • Baum SJ
      • Catapano AL
      • Chapman MJ
      • Defesche JC
      • Folco E
      • Freiberger T
      • Genest J
      • Hovingh GK
      • Harada-Shiba M
      • Humphries SE
      • Jackson AS
      • Mata P
      • Moriarty PM
      • Raal FJ
      • Al-Rasadi K
      • Ray KK
      • Reiner Z
      • Sijbrands EJ
      • Yamashita S
      Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel.
      results from mutations affecting the low-density lipoprotein receptor pathway, mainly including LDL-receptor gene mutations but also apolipoprotein B (APOB) loss-of-function mutations (LoFm) and, less commonly, proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GoFm).
      • Sjouke B
      • Hovingh GK
      • Kastelein JJ
      • Stefanutti C
      Homozygous autosomal dominant hypercholesterolaemia: prevalence, diagnosis, and current and future treatment perspectives.
      • Andersen LH
      • Miserez AR
      • Ahmad Z
      • Andersen RL
      Familial defective apolipoprotein B-100: a review.
      • Defesche JC
      • Stefanutti C
      • Langslet G
      • Hopkins PN
      • Seiz W
      • Baccara-Dinet MT
      • Hamon SC
      • Banerjee P
      • Kastelein JJP
      Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia.
      APOB LoFm reduce the binding affinity between ApoB and the LDL-receptor,
      • Andersen LH
      • Miserez AR
      • Ahmad Z
      • Andersen RL
      Familial defective apolipoprotein B-100: a review.
      ,
      • Borén J
      • Ekström U
      • Agren B
      • Nilsson-Ehle P
      • Innerarity TL
      The molecular mechanism for the genetic disorder familial defective apolipoprotein B100.
      whereas PCSK9 GoFm may result in reduced LDL receptor levels and concomitant elevated LDL-cholesterol (LDL-C) levels due to increased lysosomal degradation of the LDL receptor.
      • Horton JD
      • Cohen JC
      • Hobbs HH
      PCSK9: a convertase that coordinates LDL catabolism.
      Alirocumab, a fully human monoclonal antibody that inhibits PCSK9, is effective for further lowering of LDL-C in statin-treated patients with ADH and is associated with a reduction in cardiovascular risk.
      • Defesche JC
      • Stefanutti C
      • Langslet G
      • Hopkins PN
      • Seiz W
      • Baccara-Dinet MT
      • Hamon SC
      • Banerjee P
      • Kastelein JJP
      Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia.
      ,
      • Ray KK
      • Ginsberg HN
      • Davidson MH
      • Pordy R
      • Bessac L
      • Minini P
      • Eckel RH
      • Cannon CP
      Reductions in atherogenic lipids and major cardiovascular events: a pooled analysis of 10 ODYSSEY trials comparing alirocumab with control.
      The mutation underlying ADH may influence the response to alirocumab.
      • Defesche JC
      • Stefanutti C
      • Langslet G
      • Hopkins PN
      • Seiz W
      • Baccara-Dinet MT
      • Hamon SC
      • Banerjee P
      • Kastelein JJP
      Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia.
      The results of the long-term efficacy and safety assessment of alirocumab in patients with PCSK9 GoFm and APOB LoFm who participated in the open-label extension (OLE) of a randomized intervention study
      • Hopkins PN
      • Defesche J
      • Fouchier SW
      • Bruckert E
      • Luc G
      • Cariou B
      • Sjouke B
      • Leren TP
      • Harada-Shiba M
      • Mabuchi H
      • Rabes JP
      • Carrie A
      • van Heyningen C
      • Carreau V
      • Farnier M
      • Teoh YP
      • Bourbon M
      • Kawashiri MA
      • Nohara A
      • Soran H
      • Marais AD
      • Tada H
      • Abifadel M
      • Boileau C
      • Chanu B
      • Katsuda S
      • Kishimoto I
      • Lambert G
      • Makino H
      • Miyamoto Y
      • Pichelin M
      • Yagi K
      • Yamagishi M
      • Zair Y
      • Mellis S
      • Yancopoulos GD
      • Stahl N
      • Mendoza J
      • Du Y
      • Hamon S
      • Krempf M
      • Swergold GD
      Characterization of autosomal dominant hypercholesterolemia caused by PCSK9 gain of function mutations and its specific treatment with alirocumab, a PCSK9 monoclonal antibody.
      ,
      • Hopkins P
      • Krempf M
      • Bruckert E
      • Donahue S
      • Yang F
      • Zhang Y
      • DiCoccio A
      Pharmacokinetic and pharmacodymanic assessment of alirocumab in patients with familial hypercholesterolemia associated with proprotein convertase subtilisin/kexin type 9 gain-of-function or apolipoprotein B loss-of-function mutations.
      are presented here.

      Methods

      This study was an OLE of a Phase 2, randomized, double-blind study to evaluate the pharmacodynamics and safety of alirocumab in patients with ADH, and PCSK9 GoFm or APOB LoFm (ClinicalTrials.gov registration: NCT01604824). The study was conducted in accordance with the Declaration of Helsinki and the International Council for Harmonization guidelines for Good Clinical Practice and was approved by an appropriately constituted Institutional Review Board or Independent Ethics Committee. All patients provided written informed consent.
      The study design is shown in Figure 1. Patients continued to take their prestudy lipid-lowering therapy (LLT) throughout the double-blind and follow-up periods. During the OLE, patients were no longer required to remain on a stable LLT regimen, and the investigator could change the patient's LLT if needed. Further details on study design, key exclusion criteria, laboratory assessments, and statistical analyses are given in the Supplementary Methods.
      Figure 1
      Figure 1Study design. Notes: Between week 22 and week 32 patients were off-treatment. EOS = end of study (70 days after the last alirocumab dose); EOT = end of treatment; OLE = open-label extension; Q2W = every 2 weeks; R = randomization.
      Patients who completed the follow-up period of the double-blind part of the study were invited to enter the OLE, during which they received alirocumab 150 mg every 2 weeks (Q2W) from week 32 up to 3 years. A total of 21 patients opted to continue in the OLE (PCSK9 GoFm, n = 15; APOB LoFm, n = 6); 2 patients opted not to continue in the OLE (both PCSK9 GoFm carriers).

      Results

      All 21 patients completed the OLE treatment period; only 1 patient (4.8%) did not attend the end of study follow-up visit (reason given, “other”). Baseline patient characteristics are summarized separately for patients with PCSK9 GoFm and APOB LoFm, and overall, in Table 1. Study-directed genotyping indicated that patients in the PCSK9 GoFm group had 4 different variants (Asp374Tyr; Ser127Arg; Leu108Arg; Arg218Ser), while patients in the APOB LoFm group all had the same variant (Arg3500Gln). The pathogenicity of the variants included in this study was verified based on genetic and molecular evidence from the literature.
      • Borén J
      • Ekström U
      • Agren B
      • Nilsson-Ehle P
      • Innerarity TL
      The molecular mechanism for the genetic disorder familial defective apolipoprotein B100.
      ,
      • Abifadel M
      • Elbitar S
      • El Khoury P
      • Ghaleb Y
      • Chemaly M
      • Moussalli ML
      • Rabes JP
      • Varret M
      • Boileau C
      Living the PCSK9 adventure: from the identification of a new gene in familial hypercholesterolemia towards a potential new class of anticholesterol drugs.
      The proportion of female patients was greater in the PCSK9 GoFm group (80%) compared with the APOB LoFm group (33%). There was a difference in body weight between the 2 groups, possibly due to the greater proportion of females in the PCSK9 GoFm group; however, mean body mass index was similar in the 2 groups. Mean baseline calculated LDL-C was higher in the PCSK9 GoFm group (146 mg/dl) compared with the APOB LoFm group (122 mg/dl).
      Table 1Summary of patient characteristics by group (proprotein convertase subtilisin/kexin type 9 gain-of-function mutations or apolipoprotein B loss-of-function mutations) and overall at baseline (open-label safety analysis set)
      VariablePatients with PCSK9 GoFm variants (n = 15)Patients with APOB LoFm variants (n = 6)All (N = 21)
      Age (years), mean ± SD44.7 ± 12.745.5 ± 4.244.9 ± 10.8
      Sex
       Male3 (20.0%)4 (66.7%)7 (33.3%)
       Female12 (80.0%)2 (33.3%)14 (66.7%)
      Country
       France6 (40.0%)1 (16.7%)7 (33.3%)
       USA9 (60.0%)5 (83.3%)14 (66.7%)
      Race
       White14 (93.3%)6 (100.0%)20 (95.2%)
       Indian Ocean Islander1 (6.7%)01 (4.8%)
      Body weight (kg), mean ± SD78.4 ± 15.191.0 ± 15.782.0 ± 16.0
      Height (cm), mean ± SD164.7 ± 6.4174.1 ± 10.4167.4 ± 8.6
      BMI (kg/m2), mean ± SD29.0 ± 6.330.1 ± 5.329.3 ± 5.9
      HbA1c (%), mean ± SD5.8 ± 0.65.5 ± 0.25.7 ± 0.5
      PCSK9 GoFm variant
      By study-directed genotyping.
       Asp374Tyr9 (60.0%)09 (42.9%)
       Ser127Arg4 (26.7%)04 (19.0%)
       Leu108Arg1 (6.7%)01 (4.8%)
       Arg218Ser1 (6.7%)01 (4.8%)
      APOB LoFm variant
      By study-directed genotyping.
       Arg3500Gln06 (100.0%)6 (28.6%)
      Lipid parameters (mg/dl)
       Total cholesterol, mean ± SD224.2 ± 86.0204.2 ± 27.4218.5 ± 73.8
       Measured LDL-C, mean ± SD154.5 ± 86.8129.8 ± 31.1147.5 ± 75.2
       Calculated LDL-C, mean ± SD
      Calculated using the Friedewald formula.
      146.1 ± 83.2122.3 ± 27.5139.3 ± 71.8
       HDL-C, mean ± SD56.7 ± 14.264.0 ± 8.158.8 ± 13.0
       Triglycerides, median (Q1:Q3)107.0 (55.0:144.0)79.5 (75.0:98.0)89.0 (66.0:131.0)
       Lipoprotein (a), median (Q1:Q3)20.8 (10.0:66.6)111.7 (66.5:188.0)34.4 (10.9:90.3)
      Baseline value is defined as the last available value prior to the first dose in double-blind period. APOB = gene encoding apolipoprotein B100; BMI = body mass index; GoFm = gain-of-function mutation; HbA1c = glycated hemoglobin; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; LoFm = loss-of-function mutation; PCSK9, gene encoding proprotein convertase subtilisin/kexin type 9; SD = standard deviation.
      low asterisk By study-directed genotyping.
      Calculated using the Friedewald formula.
      Adherence with alirocumab was high during the OLE; patients received their alirocumab injections on 99% of planned occasions. The mean duration of alirocumab exposure was 129 weeks (range 82 to 180 weeks; median, 144 weeks). Overall, 100% of patients were exposed to alirocumab for ≥72 weeks, 57.1% for ≥132 weeks, and 28.6% for ≥179 weeks.
      The mean percent change from baseline in measured LDL-C during the OLE is shown in Figure 2 for the PCSK9 GoFm and APOB LoFm groups. In both groups, LDL-C decreased following initiation of alirocumab treatment at week 32 and remained below baseline throughout the duration of the study. At week 44 (12 weeks after the start of the OLE period) mean ± standard deviation (SD) percent reduction from baseline in measured LDL-C was 66.0% ± 19.0% in patients with PCSK9 GoFm variants and 47.0% ± 12.3% in patients in the APOB LoFm group.
      Figure 2
      Figure 2Mean percent change from baseline in measured LDL-C (±SE) during the OLE period, separately for patients with PCSK9 GoFm and APOB LoFm (open-label safety analysis set). Notes: All patients received alirocumab for approximately 3 years or until alirocumab became commercially available, whichever came first, resulting in a reduction in patient numbers from week 116 through to week 200. Baseline value is defined as the last available value prior to the first dose in double-blind period. APOB = gene encoding apolipoprotein B100; EOS = end of study; EOT = end of treatment; GoFm = gain-of-function mutation; LDL-C = low-density lipoprotein cholesterol; LoFm = loss-of-function mutation; OLE = open-label extension; PCSK9 = gene encoding proprotein convertase subtilisin/kexin type 9; SE = standard error.
      The mean percent reduction in LDL-C in patients with PCSK9 GoFm variants was greater than that observed in patients with APOB LoFm variants at all timepoints up to week 80; the mean ± SD percent reduction in LDL-C was 58.0% ± 22.5% and 47.1% ± 8.5% at week 80 in the 2 groups, respectively. Note that only 1 patient from the APOB LoFm group continued the study after study week 104. At the EOT visit the mean ± SD percent reduction from baseline in measured LDL-C was 44.6% ± 26.5% and 48.3% ± 12.7% in the PCSK9 GoFm and APOB LoFm patients, respectively.
      The mean percent change from baseline in LDL-C during the OLE period is shown separately for each PCSK9 GoFm or APOB LoFm variant in Figure 3. For all variants, LDL-C decreased after initiation of alirocumab treatment. In the patient with the PCSK9: Leu108Arg variant, LDL-C level returned to near baseline level by week 56. In the group with the PCSK9: Asp374Tyr variant, there was a gradual decrease in mean percent change in measured LDL-C from week 92.
      Figure 3
      Figure 3Mean percent change from baseline in measured LDL-C (±SE) during the OLE period, separately for each PCSK9 GoFm or APOB LoFm variant. Notes: Baseline value is defined as the last available value prior to the first dose in double-blind period. APOB = gene encoding apolipoprotein B100; GoFm = gain-of-function mutation; LDL-C = low-density lipoprotein cholesterol; LoFm = loss-of-function mutation; OLE = open-label extension; PCSK9 = gene encoding proprotein convertase subtilisin/kexin type 9; SE = standard error.
      Median percent changes in lipoprotein (a) are shown in Figure 4 for PCSK9 GoFm and APOB LoFm variants separately; reductions from baseline were observed for both groups.
      Figure 4
      Figure 4Median (Q1:Q3) percent change from baseline in lipoprotein (a) during the OLE period, separately for patients with PCSK9 GoFm and APOB LoFm (open-label safety analysis set). Notes: All patients received alirocumab for approximately 3 years or until alirocumab became commercially available, whichever came first, resulting in a reduction in patient numbers from week 116 through to week 200. Baseline value is defined as the last available value prior to the first dose in double-blind period. APOB = gene encoding apolipoprotein B100; EOS = end of study; EOT = end of treatment; GoFm = gain-of-function mutation; LDL-C = low-density lipoprotein cholesterol; LoFm = loss-of-function mutation; OLE = open-label extension; PCSK9 = gene encoding proprotein convertase subtilisin/kexin type 9.
      The incidence of treatment-emergent adverse events (TEAEs) during the OLE is summarized in Table 2. TEAEs were reported in 19 patients (90.5%); no deaths occurred, and no patients discontinued treatment due to TEAEs. The most frequently reported TEAEs (>10%) were viral upper respiratory tract infection (28.6%; 6 patients with PCSK9 GoFm), and upper respiratory tract infection (14.3%; 2 patients with PCSK9 GoFm, and 1 patient with APOB LoFm). Three patients (14.3% overall; all PCSK9 GoFm) experienced treatment-emergent serious adverse events, including 2 cardiac disorders (unstable angina and myocardial infarction), 1 gastrointestinal disorder (salivary gland disorder), 1 general disorder (chest pain), and 1 metabolism and nutrition disorder (obesity); none were considered by the investigator to be related to study drug. No patient had a positive treatment-emergent ADA response in the OLE.
      Table 2Summary of treatment-emergent adverse events during the open-label extension by group (proprotein convertase subtilisin/kexin type 9 gain-of-function mutations or apolipoprotein B loss-of-function mutations) and overall (open-label safety analysis set)
      Patients with PCSK9 GoFm variants (n = 15)Patients with APOB LoFm variants (n = 6)All (N = 21)
      Patients with any OLE TEAE15 (100.0%)4 (66.7%)19 (90.5%)
      Patients with any OLE treatment emergent SAE3 (20.0%)03 (14.3%)
      Patients with any OLE TEAE leading to death000
      Patients with any OLE TEAE leading to permanent treatment discontinuation000
      APOB = gene encoding apolipoprotein B100; GoFm = gain-of-function mutation; LoFm = loss-of-function mutation; OLE = open-label extension; PCSK9 = gene encoding proprotein convertase subtilisin/kexin type 9; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

      Discussion

      As patients with ADH may require long-term treatment with LLTs, the evaluation of the long-term maintenance of the LDL-C lowering efficacy and safety of alirocumab in patients with ADH is of importance; particularly as not all monoclonal antibodies developed for PCSK9 inhibition have demonstrated sustained efficacy.
      • Ridker PM
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      • Nissen S
      • Revkin J
      • Rose LM
      • Santos RD
      • Schwartz PF
      • Shear CL
      • Yunis C
      • Investigators Spire
      Lipid-reduction variability and antidrug-antibody formation with bococizumab.
      In this study, alirocumab 150 mg Q2W resulted in clinically meaningful LDL-C reductions (mean reduction from baseline to week 80 of 58.0% vs 47.1% for PCSK9 GoFm vs APOB LoFm, respectively), shown to be sustained through to 3 years for patients with PCSK9 GoFm and 2 years for patients with APOB LoFm. It should be noted that baseline LDL-C represents the parent study baseline (i.e., before alirocumab treatment was started); however, as all patients were on statins (or other LLTs), baseline mean LDL-C was relatively low (139.3 mg/dl) for this ADH population.
      The long-term maintenance of alirocumab efficacy in patients with ADH observed here agrees with previous alirocumab trials of similar duration conducted in differing patient populations. The ODYSSEY OLE study enrolled patients with heterozygous familial hypercholesterolemia (n = 985), receiving maximally tolerated statins, who had completed 1 of 4 Phase 3 parent studies (all 18 months duration); during ODYSSEY OLE, consisting of an additional 2.5 years median treatment duration, alirocumab reduced mean LDL-C from baseline by 47.9% at week 96.
      • Farnier M
      • Hovingh GK
      • Langslet G
      • Dufour R
      • Baccara-Dinet MT
      • Din-Bell C
      • Manvelian G
      • Guyton JR
      Long-term safety and efficacy of alirocumab in patients with heterozygous familial hypercholesterolemia: an open-label extension of the ODYSSEY program.
      The long-term efficacy of alirocumab has also been investigated in the cardiovascular outcomes trial for alirocumab, ODYSSEY OUTCOMES, which enrolled participants (n = 18,924) with recent (4 to 52 weeks) acute coronary syndrome. Following alirocumab treatment during ODYSSEY OUTCOMES, a reduction in mean LDL-C from baseline of 62.7% (vs placebo) was observed at 4 months, sustained through to 48 months (LDL-C reduction of 54.7% vs placebo; on-treatment analysis).
      • Schwartz GG
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      ODYSSEY OUTCOMES Committees Investigators
      Alirocumab and cardiovascular outcomes after acute coronary syndrome.
      The mean percent change from baseline in LDL-C with alirocumab in this study was also generally consistent with previously published findings from pooled analyses of shorter studies with alirocumab (12 to 78 weeks’ duration) in patients with familial hypercholesterolemia.
      • Defesche JC
      • Stefanutti C
      • Langslet G
      • Hopkins PN
      • Seiz W
      • Baccara-Dinet MT
      • Hamon SC
      • Banerjee P
      • Kastelein JJP
      Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia.
      ,
      • Hartgers ML
      • Defesche JC
      • Langslet G
      • Hopkins PN
      • Kastelein JJP
      • Baccara-Dinet MT
      • Seiz W
      • Hamon S
      • Banerjee P
      • Stefanutti C
      Alirocumab efficacy in patients with double heterozygous, compound heterozygous, or homozygous familial hypercholesterolemia.
      The mean percent reduction in LDL-C in patients with PCSK9 GoFm variants was greater than that observed in patients with APOB LoFm variants up to week 80. After that time point, there was a slight decrease in percent LDL-C reduction from baseline over time in the PCSK9 GoFm group. This decrease was particularly apparent in the patient with PCSK9: Leu108Arg variant; although we can confirm this patient was administered study treatment for the duration of the OLE, we are unable to comment on their adherence to other LLTs as this information is not available (further discussion regarding possible causes of variability in LDL-C lowering between the 2 groups is given below). A previous study examined LDL-C reduction with alirocumab in a large cohort of patients (n = 1191) with a wide spectrum of mutations in genes causative for familial hypercholesterolemia.
      • Defesche JC
      • Stefanutti C
      • Langslet G
      • Hopkins PN
      • Seiz W
      • Baccara-Dinet MT
      • Hamon SC
      • Banerjee P
      • Kastelein JJP
      Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia.
      It was observed that LDL-C reduction from baseline was numerically greater in PCSK9 GoFm variants than APOB LoFm; however, this finding was limited by the small numbers of patients with these mutations, particularly PCSK9 GoFm. The authors concluded that the response to alirocumab was similar across genotypes (LDLR, LDLRAP1, APOB, and PCSK9 variants) at 24 weeks.
      • Defesche JC
      • Stefanutti C
      • Langslet G
      • Hopkins PN
      • Seiz W
      • Baccara-Dinet MT
      • Hamon SC
      • Banerjee P
      • Kastelein JJP
      Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia.
      Factors that may contribute to the variability observed in mean percent LDL-C reduction during the course of the OLE include differences in response to alirocumab between different genetic variants. For example, the lower mean percent LDL-C reduction in patients with APOB LoFm compared with PCSK9 GoFm may be a result of the lower affinity of mutated APOB for the LDL-receptor, thereby leading to reduced clearance of LDL-C particles by hepatic uptake through the LDL-receptors.
      • Andersen LH
      • Miserez AR
      • Ahmad Z
      • Andersen RL
      Familial defective apolipoprotein B-100: a review.
      ,
      • Defesche JC
      • Gidding SS
      • Harada-Shiba M
      • Hegele RA
      • Santos RD
      • Wierzbicki AS
      Familial hypercholesterolaemia.
      In addition, given that patients were no longer required to remain on a stable LLT regimen during the OLE, any changes to the background LLT regimen may also contribute to variability in observed response to alirocumab. However, it should be noted that compliance to background LLT use was not monitored during the OLE. Finally, interindividual variation in biological factors not related to treatment or mutation types may also contribute to observed LDL-C reductions.
      No patient in the OLE had a positive treatment-emergent ADA response; therefore, ADAs did not contribute to the variability in mean percent LDL-C reduction over time. Furthermore, alirocumab was well tolerated throughout the duration of the OLE in both the PCSK9 GoFm and APOB LoFm groups.
      Limitations of this analysis include the very small sample sizes; therefore, mean percent change from baseline in LDL-C over time should be interpreted with caution. No formal hypothesis testing was performed, instead the results of this study should be seen as hypothesis-forming. In addition, as only 1 patient remained in the APOB LoFm group after week 104, no conclusions can be made regarding the efficacy and safety of alirocumab in patients with APOB LoFm variants beyond week 104. Furthermore, differences in patient characteristics at baseline existed between the PCSK9 GoFm and APOB LoFm groups, for example, the PCSK9 GoFm group had a higher proportion of females and higher LDL-C levels.
      In summary, the present study demonstrates that in patients with PCSK9 GoFm and APOB LoFm with elevated LDL-C levels despite maximally tolerated LLTs, alirocumab 150 mg Q2W resulted in long-term clinically meaningful LDL-C reductions, with no unexpected long-term safety concerns.

      Author Contributions

      M.F., P.N.H., E.B., S.L. and S.D. contributed to the analysis and interpretation of the data, and critically reviewed and edited the manuscript. M.K., P.N.H. and E.B. were investigators who contributed to the data acquisition. In addition, S.D. contributed to the concept or study design. Medical writing assistance and editorial support, under the direction of the authors were provided by Rachel Dunn, PhD, of Prime (Knutsford, UK), funded by Sanofi and Regeneron Pharmaceuticals, Inc., according to Good Publication Practice guidelines (http://annals.org/aim/article/2424869/good-publication-practice-communicating-company-sponsored-medical-research-gpp3). Sanofi and Regeneron Pharmaceuticals, Inc., were involved in the study design, collection, analysis and interpretation of data, as well as data checking of information provided in the manuscript. However, ultimate responsibility for opinions, conclusions, and data interpretation lies with the authors.

      Acknowledgment

      The authors would like to thank the patients, their families and all investigators involved in this study. In addition, the authors would like to thank Dr Gérald Luc for his early contributions to the development of the manuscript, including data acquisition in his role as study investigator, data analysis and interpretation.

      Disclosures

      Michel Krempf reports grants and personal fees from Sanofi/Regeneron Pharmaceuticals, Inc. during the conduct of the study, personal fees from Abbott, and grants and personal fees from MSD, outside of the submitted work. Paul N. Hopkins reports grants from Sanofi and Amgen, and personal fees from Aegerion, Danone, Genfit, MSD, Sanofi/Regeneron Pharmaceuticals, Inc., AstraZeneca, Servier, Amgen, Akcea, and Unilever. Eric Bruckert reports grants from Sanofi and Amgen, and personal fees from Aegerion, Danone, Genfit, MSD, Sanofi/Regeneron Pharmaceuticals, Inc., AstraZeneca, Servier, Amgen, Akcea and Unilever. Shane Lee and Stephen Donahue are employees of and stockholders in Regeneron Pharmaceuticals, Inc. All authors approved the final version. The authors had unrestricted access to the study data, were responsible for all content and editorial decisions, and received no honoraria related to the development of this publication.

      Appendix. Supplementary materials

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