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H omozygous familial hypercholes-terolemia (HoFH) is characterizedby extremely elevated low-
density lipoprotein–cholesterol (LDL-C)levels and early-onset atherosclerotic cardio-vascular disease (1–3). Patients with HoFHare usually treated with multiple lipid-lowering therapies, which may include astatin, ezetimibe, proprotein convertase sub-tilisin/kexin type 9 (PCSK9) inhibitor, lomi-tapide, and lipoprotein apheresis (2). HoFHresults from severely impaired low-densitylipoprotein receptor (LDLR) function, mostcommonly due to mutations in both copies
SEE PAGE 143
of the LDLR gene, but mutations in othergenes involved in the LDLR pathway,including apolipoprotein B (APOB), PCSK9,and the LDLR adapter protein 1 (LDLRAP1),
may also be causal. In clinical practice the untreatedLDL-C level and response to therapy may varywidely. The most severe phenotype is typically seenin patients with mutations leading to complete lossof LDLR function in both copies of the LDLR gene (re-ceptor negative/null mutations) (1,4). Patients withresidual LDLR function have some response to thera-pies that upregulate LDLR function, such as statins orPCSK9 inhibitors. Lomitapide inhibits lipoproteinsynthesis and is thus effective irrespective of
epartment of Vascular Medicine, Academic Medical Center, Am
t of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan;
g Ridge, New Jersey, and Clinical Development, R&D, Sanofi, Mon
i, New York, New York. This study was funded by Sanofi and R
the study design, and collection, analysis, and interpretation of d
uscript. The authors had unrestricted access to study data, were re
honoraria related to the development of this publication. Dr. B
a, and Sanofi; and has received consultancy/advisory board fe
ba has received honoraria from Astellas, Astellas Amgen, Sano
a, and The Medicines Company; and has received research gran
Merck Sharp & Dohme. Dr. Rubba has received grants from Rege
ant support from FH Canada, Aegerion (Novelion Therapeutics), A
ticals, Inc., and Sanofi; and has served as a consultant for Amgen,
anofi. Dr. Kastelein has received honoraria from Regeneron Ph
nd Ionis; and has received consultant/advisory board fees from
en, Esperion, and Ionis. Dr. Charng has received honoraria fromM
d research grants from Amgen, Sanofi, and The Medicines Comp
e are employees of and stockholders in Regeneron Pharmaceut
r in Sanofi. Dr. Rosenson has received research grants through h
Company, Novartis, and Regeneron Pharmaceuticals, Inc.; serves
a; has received honoraria from Amgen, Kowa, Pfizer, and Regener
and has stock ownership in MediMergent. Gerald Watts, DSc, MB
Shah, MD, served as Guest Editor-in-Chief for this paper.
s attest they are in compliance with human studies committees
nd Food and Drug Administration guidelines, including patient co
uthor instructions page.
received March 13, 2020; revised manuscript received May 5, 20
residual LDLR function, but tolerability may limitdosing (5).
Alirocumab, a monoclonal antibody to PCSK9, wasshown to be similarly effective at lowering LDL-C inpopulations with heterozygous familial hypercholes-terolemia (i.e., where only 1 copy of the LDLR, APOB,or PCSK9 gene is affected) and nonfamilial hyper-cholesterolemia populations, and was generally well-tolerated (6–8). An analysis of phase 3 clinical trialdata indicated that patients with double or compoundvariants in LDLR, APOB, PCSK9, and/or LDLRAP1 stillhave an LDL-C response following alirocumab ther-apy, although the response was highly variable (9).However, to date alirocumab has not been assessed ina prospective clinical trial in patients with HoFH.
Here, we report results from a randomized, double-blind, placebo-controlled, parallel-group, phase 3study (Study in Participants With Homozygous Fa-milial Hypercholesterolemia [HoFH] [ODYSSEYHoFH]; NCT03156621) that evaluated the efficacy andsafety of alirocumab 150 mg every 2 weeks versusplacebo in adult patients with HoFH.
METHODS
The ODYSSEY HoFH study was performed across 27sites in 13 countries, and was designed to evaluate thereduction in LDL-C with alirocumab 150 mg every2 weeks in adult ($18 years of age) patients withHoFH in comparison to placebo. A full list of all
sterdam, the Netherlands; fDivision of Cardiology,gFaculty of Medicine, School of Medicine, National
Tarrytown, New York; iRegeneron Pharmaceuticals,
tpellier, France; and the jIcahn School of Medicine at
egeneron Pharmaceuticals, Inc. The sponsors were
ata, as well as data checking of information provided
sponsible for all content and editorial decisions, and
lom has received honoraria from Aegerion, Amgen,
es from Akcea, Amgen, Gemphire, and Sanofi. Dr.
fi, Merck Sharp & Dohme, Boehringer Ingelheim,
ts from Aegerion, Astellas, Astellas Amgen, Kaneka,
neron Pharmaceuticals, Inc. Dr. Gaudet has received
An optional 4-week run-in period was conducted for patients whose background lipid-lowering therapy, apheresis schedule, and/or setting were unstable before
screening. At week 32, a follow-up phone call was made to collect adverse event and concomitant medication information. Q2W ¼ every 2 weeks; R ¼ randomization.
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study sites and investigators is provided in theSupplemental Appendix.
The study was conducted in accordance with theDeclaration of Helsinki and the International Con-ference on Harmonization Guidelines for Good Clin-ical Practice. The institutional review board orindependent ethics committee at each study centerapproved the study protocol, and written informedconsent was obtained from each participant. The trialwas registered with clinicaltrials.gov (NCT03156621).
Details on access to study documents and anony-mized participant data can be found in theSupplemental Appendix.
PARTICIPANTS. Participants with a clinical or ge-netic diagnosis of HoFH and LDL-C $70 mg/dl wereeligible (genetic diagnosis was mandatory for partic-ipants receiving low-density lipoprotein [LDL]apheresis). Participants were also required to bereceiving a stable dose of statin at the screening visitor to have documented lack of efficacy with statins/statin intolerance. If patients were undergoingapheresis, they must have received treatment for atleast 3 months and been on a stable schedule (weeklyor biweekly) for at least 8 weeks before the screening
visit. A complete list of inclusion and exclusioncriteria is available in the Supplemental Appendix.
All randomized patients were genotyped for vari-ants in the LDLR, APOB, PCSK9, and LDLRAP1 genesby Ambry Genetics (Aliso Viejo, California) (geno-typing details are provided in the SupplementalAppendix). Residual LDLR activity was assessedfrom literature references and databases (e.g., LeidenOpen Variant Database and ClinVar). Variants wereclassified as null if residual LDLR activity was <2%,non-null if residual LDLR activity was $2%, and un-classified if LDLR activity was yet to be determined byin vitro methods. Documented evidence of a null mu-tation in both LDLR alleles was an exclusion criterion.
STUDY DESIGN. The study design is shown inFigure 1. Briefly, there was an optional run-in periodand a 2-week screening period. Participants werethen randomized 2:1 to receive alirocumab 150 mg orplacebo every 2 weeks (both by subcutaneous injec-tion) during a 12-week double-blind treatment period;randomization was stratified by apheresis treatmentstatus (yes/no). All participants subsequently entereda 12-week open-label treatment period and receivedalirocumab 150 mg every 2 weeks. For patients
Values are mean� SD, n (%), or median (Q1:Q3). *Both alleles carrying the same mutation. †Each allele carrying adifferent mutation. ‡Diagnosed by invasive or noninvasive testing. §A patient can be counted in several cate-gories. kHigh-intensity statin corresponds to atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily.
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receiving apheresis, blood samples were obtainedbefore the apheresis procedure; study treatment wasadministered immediately after completion of theapheresis procedure. For patients not receivingapheresis, study treatment was administered after allsamples for clinical laboratory evaluation had beenobtained. Changes in lipid-lowering therapies,including apheresis, were not allowed throughout thedouble-blind and open-label treatment periods.
A first-step analysis was planned for when all pa-tients had completed the double-blind treatmentperiod (first patient visit occurred on October 3, 2017;last patient visit for the double-blind treatmentperiod occurred on September 26, 2019). The second-step analysis was planned for when all patients hadcompleted the open-label period (ongoing at the timeof this first-step analysis).
ENDPOINTS AND ASSESSMENTS. The primary effi-cacy endpoint was the percent change in LDL-C frombaseline to week 12 in the intention-to-treat popula-tion with alirocumab versus placebo. Key secondaryefficacy endpoints (pre-specified in the study proto-col) included the percent change from baseline toweek 12 in apolipoprotein (Apo) B, non–high-densitylipoprotein cholesterol (non–HDL-C), total choles-terol, lipoprotein(a) (Lp[a]), high-density lipoprotein–cholesterol (HDL-C), triglycerides, and ApoA1 (inten-tion-to-treat population).
Safety was assessed through treatment-emergentadverse event (TEAE) reports, laboratory data, andvital signs. Adverse events of special interest, pre-specified in the study protocol, are detailed in theSupplemental Appendix. Additional assessmentsincluded the pharmacokinetics and pharmacody-namics of alirocumab 150 mg every 2 weeks in pa-tients with HoFH, and the potential development ofanti-alirocumab antibodies. Further details on studymethods are provided in the Supplemental Appendix.
STATISTICAL ANALYSIS. The primary efficacyendpoint was analyzed in the intention-to-treatpopulation; missing data were accounted for using amixed-effect model with a repeated measuresapproach using all post-baseline data available withinthe week 4 to week 12 analysis windows. Furtherdetails on the determination of sample size and thestatistical analyses of efficacy and safety endpoints,including the hierarchical testing procedure for keysecondary efficacy endpoints, are provided in theSupplemental Appendix.
RESULTS
PATIENT DISPOSITION. A total of 69 patients wererandomized to study treatment (24 to placebo and 45
FIGURE 2 Percent Change From Baseline in LDL-C Over Time According to Treatment Randomization (Intention-to-Treat Analysis)LS
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LS mean � SE were calculated using a mixed-effect model with repeated measures approach. LDL-C ¼ low-density lipoprotein cholesterol;
LS ¼ least squares; Q2W ¼ every 2 weeks.
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to alirocumab), and all completed the 12-weekdouble-blind period and were included in the effi-cacy and safety analyses (Supplemental Figure 1).Mean � SD duration of study drug exposure duringthe double-blind period was 12.1 � 0.5 weeks and 11.9� 0.5 weeks for the alirocumab and placebo groups,respectively. During the double-blind treatmentperiod, only 1 patient randomized to alirocumabmissed doses at weeks 4 and 6; overall, there was asimilar injection frequency between the alirocumaband placebo groups (mean � SD: 14.6 � 1.4 days and14.0 � 0.4 days, respectively). All 69 patients enteredthe open-label treatment period: 61 (88.4%) patientscompleted the 12-week open-label treatment period,2 (2.9%) patients discontinued study treatmentbefore completing the open-label treatment period(both due to adverse events; see further detailsbelow), and 6 (8.7%) patients remain in the open-label treatment period at the time of this first-stepanalysis. Of the 10 patients who were receivingapheresis therapy during the double-blind treatmentperiod (see further details below), only 2 patientsmissed an apheresis procedure during the double-blind treatment period (single occurrence for bothpatients). Both patients were receiving weeklyapheresis therapy; 1 patient missed a procedure atweek 3 (alirocumab group) and the other patientmissed a procedure at week 7 (placebo group).
BASELINE CHARACTERISTICS. Baseline characteris-tics according to treatment group are summarized inTable 1. For the overall cohort, background lipid-lowering therapy at baseline included 67 (97.1%) pa-tients on a statin (59 [85.5%] on a high-intensityregimen); 50 (72.5%) on ezetimibe; 10 (14.5%) onlomitapide; and 10 (14.5%) on apheresis. Thirty(43.5%) patients had a history of coronary heart dis-ease. Based on medical history, 42 (60.9%) patients ofthe overall cohort had a genetic diagnosis of HoFHand 27 (39.1%) patients had clinical diagnosis ofHoFH; based on in-study genotyping, a definitediagnosis of HoFH was not possible for 17 (24.6%)patients. Mean baseline LDL-C was 295.0 mg/dl in thealirocumab group and 259.6 mg/dl in the placebogroup. Although documented evidence of a null mu-tation in both LDLR alleles was an exclusion criterion,4 patients (8.9%) in the alirocumab group and 1 pa-tient (4.2%) in the placebo group were subsequentlyfound to have null/null LDLR mutations.EFFICACY (DOUBLE-BLIND TREATMENT PERIOD).
For the primary efficacy endpoint, the least squaresmean � SE percent change in LDL-C from baseline atweek 12 was �26.9% � 4.6% for alirocumab and þ8.6%� 6.3% for placebo (Figure 2), with a difference be-tween groups of �35.6% � 7.8% (p < 0.0001) (Table 2).A sensitivity analysis excluding patients with null/nullmutations in both LDLR alleles resulted in similar
% change from baseline, combined estimate � SE �7.4 � 4.2 3.9 � 5.7 �11.3‡ � 7.1 [�25.2 to 2.6], 0.1112kApoA1
Baseline, mg/dl 125.6 � 4.3 124.8 � 5.0
Week 12, mg/dl 131.5 � 2.6 126.5 � 3.5
% change from baseline 5.0 � 2.1 1.4 � 2.9 3.6 � 3.6 [�3.6 to 10.7], 0.3212k
Values are LS mean � SE, unless otherwise indicated. *LS mean � SE and p values describing the % change in lipid values from baseline to week 12 were calculated using amixed-effect model with repeated measures approach, except for Lp(a) and triglycerides, which were calculated using multiple imputation followed by robust regressionanalysis. The proportion of patients achieving a reduction in LDL-C from baseline of $15% or $30% were calculated using a 2-step multiple imputation procedure to addressmissing values, followed by logistic regression analysis to obtain the combined estimate for odds ratio. The proportion of patients achieving a reduction in LDL-C from baselineof$50% was calculated using a last observation carried forward approach to address missing values, followed by exact conditional logistic regression. †Combined estimate forodds ratio. ‡Combined estimate for adjusted mean difference. §Exact odds ratio estimate. kNominal p values provided for descriptive purposes only. Hierarchical testingterminated at the 8th key secondary endpoint of % change in HDL-C, therefore all subsequent statistical comparisons were not considered statistically significant.
CI ¼ confidence interval; I ¼ infinity; other abbreviations as in Table 1.
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least squares mean � SE percent reductions in LDL-Cfrom baseline at week 12 of �29.4 � 4.8% and 10.3 �6.5% for alirocumab and placebo groups, respectively,with a difference between groups of �39.7 � 8.1%. Ananalysis of the effect of genotype on the observedreduction in LDL-C at week 12 by individual patient isshown in Figure 3. LDL-C changes at week 12 werehighly variable among patients with null/null LDLRmutations (Figure 3). Further details of baseline char-acteristics, genotype, and relative change in LDL-C at
week 12 for individual patients are presented inSupplemental Table 1. The mean change in LDL-C atweek 12 according to apheresis status is presented inSupplemental Table 2.
Alirocumab resulted in significant (all p < 0.0001)least squares mean reductions from baseline to week12 (difference vs. placebo) in levels of Apo B (�29.8%),non–HDL-C (�32.9%), total cholesterol (�26.5%), andLp(a) (�28.4%) (Table 2). At week 12, the proportion ofpatients achieving $15% reduction in LDL-C was
encoding low-density lipoprotein receptor adaptor protein 1; PCSK9 ¼ gene encoding proprotein convertase subtilisin/kexin type 9; other
abbreviations as in Figure 2.
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61.9% in the alirocumab group and 12.5% in the pla-cebo group (p ¼ 0.0004), the proportionachieving $30% reduction in LDL-C was 57.1% in thealirocumab group and 4.2% in the placebo group(p ¼ 0.0010), and the proportion achieving$50% reduction in LDL-C was 26.7% in the alir-ocumab group and 0% in the placebo group(p ¼ 0.0017) (Table 2).
INTERIM EFFICACY ANALYSES (OPEN-LABEL
TREATMENT PERIOD). Overall, the changes frombaseline in lipid levels observed during the double-blind treatment period were maintained during theopen-label treatment period, and similar treatmenteffects with alirocumab were observed for patientswho were switched from placebo to alirocumab onentering the open-label treatment period(Supplemental Figure 2). The mean reduction in LDL-C from baseline to week 24 with alirocumab was27.3% (67.9 mg/dl). For patients who had receivedalirocumab during the double-blind treatment periodand who continued to receive alirocumab during theopen-label treatment period, the mean � SD reduc-tion in LDL-C from baseline at week 24 was 30.7
� 32.2%. For patients who had received placeboduring the double-blind treatment period and thenreceived 12 weeks of alirocumab treatment during theopen-label treatment period (at week 24), mean � SDLDL-C reduction from baseline was 20.6 � 39.3%.Reductions in LDL-C at week 24 according to apher-esis status are summarized in Supplemental Table 2,and the individual changes in LDL-C from baselineover time for patients receiving apheresis treatmentare shown in Supplemental Figure 3. At week 24, withalirocumab treatment there were reductions frombaseline in levels of ApoB (21%), non–HDL-C (25.2%),total cholesterol (20.2%), Lp(a) (11.6%), and tri-glycerides (4.6%); increases in HDL-C and ApoA1 of10.0% and 6.3%, respectively, were also observed.
SAFETY (DOUBLE-BLIND TREATMENT PERIOD).
Safety data are summarized in Table 3; TEAEsoccurred in 20 patients (44.4%) in the alirocumabgroup and 12 patients (50.0%) in the placebo group.No treatment-emergent serious adverse events,treatment discontinuations due to a TEAE, or deathswere reported in either treatment group during thedouble-blind period. Injection-site reactions occurred
TABLE 3 Safety Analysis for the Double-Blind Treatment Period
(Safety Population)
Alirocumab(n ¼ 45)
Placebo(n ¼ 24)
TEAEs
Any TEAE 20 (44.4) 12 (50.0)
Treatment-emergent SAE 0 (0.0) 0 (0.0)
TEAEs leading to death 0 (0.0) 0 (0.0)
TEAEs leading to treatment discontinuation 0 (0.0) 0 (0.0)
TEAEs of special interest
Local injection-site reaction 1 (2.2) 0 (0.0)
General allergic events 1 (2.2) 0 (0.0)
Neurologic events 0 (0.0) 0 (0.0)
Symptomatic overdose 0 (0.0) 0 (0.0)
Neurocognitive events* 0 (0.0) 0 (0.0)
Cataract 0 (0.0) 0 (0.0)
Hepatic disorders 0 (0.0) 0 (0.0)
Diabetes or diabetic complications 0 (0.0) 0 (0.0)
TEAEs in $5% of patients
Upper respiratory tract infection 2 (4.4) 2 (8.3)
Headache 2 (4.4) 2 (8.3)
Diarrhea 3 (6.7) 0 (0.0)
Values are n (%). *Neurocognitive events defined using either the sponsor or FDACMQ lists.
CMQ ¼ custom MedDRA query; FDA ¼ U.S. Food and Drug Administration;TEAE ¼ treatment-emergent adverse event.
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in 1 patient in the alirocumab group and 0 patients inthe placebo group, and general allergic eventsoccurred in 1 patient (nonserious conjunctivitis) inthe alirocumab group and 0 patients in the placebogroup. No patient experienced 2 consecutive LDL-Cvalues <25 mg/dl. Common TEAEs (that occurredin $5% of patients in any treatment group) were up-per respiratory tract infection, headache, and diar-rhea (Table 3). In the alirocumab group, 1 patient hada positive anti-alirocumab antibody response atbaseline (negative response at all later times) and1 patient had a positive treatment-emergent low-titerresponse at week 12 only. No patients in the placebogroup had a positive anti-alirocumab antibodyresponse during the double-blind treatment period.
INTERIM SUMMARY OF OPEN-LABEL SAFETY RESULTS.
During the open-label treatment period, TEAEsoccurred in 22 patients (31.9%) (SupplementalTable 3). The most commonly reported TEAE wasnasopharyngitis (n ¼ 4, 5.8%); headache andinfluenza-like illness were reported for 2 patients(2.9%), and all other TEAEs were singly reported. Oneserious adverse event of arthralgia occurred in 1 pa-tient (1.4%), which was not considered related totreatment (this patient received alirocumab duringthe double-blind period). Two patients (2.9%; bothreceived alirocumab during the double-blind period)discontinued treatment due to TEAEs. The first TEAE
leading to treatment discontinuation was abnormalhepatic function; on study day 99 (14 days after thelast alirocumab dose on day 85 — the start of theopen-label treatment period) the patient had a mod-erate severity abnormal hepatic function (alanineaminotransferase 1.9 times upper limit of normal,aspartate aminotransferase 2.7 times upper limit ofnormal), which was completely resolved on study day169 without treatment. The investigator consideredthis event to be related to the study drug. The secondTEAE leading to treatment discontinuation at week 12was injection-site hypersensitivity (a mild localinjection-site reaction and the third occurrence of thistype of TEAE for the patient). One patient whoreceived placebo during the double-blind treatmentperiod exhibited a neutralizing low-titer anti-alir-ocumab antibody response at week 24. For this pa-tient, the observed reduction in LDL-C from baselineat week 24 was approximately 50%.
PHARMACOKINETICS AND PHARMACODYNAMICS.
In patients randomized to alirocumab, total alir-ocumab concentrations approached steady state byweek 8 of the double-blind treatment period; meanconcentrations were 21.9 mg/l and 23.3 mg/l at weeks8 and 10, respectively, with minimal increasesthereafter (Supplemental Figure 4). In patients ran-domized to placebo during the double-blind treat-ment period, mean concentrations of total alirocumabafter 12 weeks of open-label alirocumab treatmentwere similar to those seen in patients who hadreceived alirocumab throughout the study (26.4 mg/lvs. 25.5 mg/l). In patients randomized to alirocumab,alirocumab reduced free PCSK9 concentrations with acorresponding increase in total PCSK9 (>6-fold in-crease) during the double-blind treatment period,which was sustained during the open-label treatmentperiod (Supplemental Figures 5 and 6). Similarly, inpatients who received placebo during the double-blind treatment period, the administration of alir-ocumab 150 mg every 2 weeks during the open-labeltreatment period resulted in decreases in free PCSK9and increases in total PCSK9 serum concentrations ofa similar magnitude as seen in those who receivedalirocumab treatment throughout the study. Thepharmacokinetics and pharmacodynamics of alir-ocumab according to apheresis status are summarizedin Supplemental Table 2.
DISCUSSION
In the largest randomized, controlled interventionaltrial in HoFH patients to date, treatment with alir-ocumab resulted in significant and clinicallymeaningful reductions in LDL-C at week 12
CENTRAL ILLUSTRATION The ODYSSEY HoFH Trial: Alirocumab Efficacy and Safety in Adults WithHomozygous Familial Hypercholesterolemia
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(n = 45)
Alirocumab 150 mg Q2W(n = 69) Follow-up period
Treatment Received During the Double-BlindTreatment Period:
Double-Blind Treatment Period Open-Label Treatment Period
All Patients Received Open-LabelAlirocumab from Week 12
Open-Label Treatment Period:
Placebo (n = 24)
Alirocumab 150 mg Q2W (n = 69)
Key pointsThe largest randomizedcontrolled interventional trialin patients with HoFH to date
Alirocumab was generallywell tolerated, with no safetyissues compared withplacebo
35.6% reduction in LDL-C atweek 12 with alirocumab(difference vs placebo;p < 0.0001)
•
•
•
4 weeks 2 weeksDouble-blind treatment period
12 weeksOpen-label treatment period
12 weeks 8 weeks
Blom, D.J. et al. J Am Coll Cardiol. 2020;76(2):131–42.
The percent change from baseline in LDL-C over time is shown for patients with HoFH treated with alirocumab 150 mg every 2 weeks or placebo. Patients
who received alirocumab had a marked reduction in LDL-C levels, with an LS mean � SE percent change from baseline at week 12 of �26.9% (4.6%) for
alirocumab and þ8.6% (6.3%) for placebo, with a difference between treatment groups of �35.6% (7.8%; p < 0.0001). LS mean � SE were calculated
using a mixed-effect model with repeated measures approach. HoFH ¼ homozygous familial hypercholesterolemia; ITT ¼ intention-to-treat;
LDL-C ¼ low-density lipoprotein cholesterol; LS ¼ least squares; Q2W ¼ every 2 weeks.
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(Central Illustration). Additionally, alirocumab signif-icantly reduced other elevated atherogenic lipids andlipoproteins (ApoB, total cholesterol, non–HDL-C, andLp[a]). Alirocumab was generally well tolerated, withno significant safety differences versus placebo.Safety results were consistent with previous trials ofalirocumab in heterozygous familial hypercholester-olemia and nonfamilial hypercholesterolemia pop-ulations (10).
Monoclonal antibodies to PCSK9 such as alir-ocumab act via the LDLR pathway, and reduce LDL-Cby blocking the action of PCSK9, leading to increasedLDLR numbers on the liver cell surface and increasedclearance of LDL-C from the circulation (5). Thesmaller relative LDL-C reductions observed in thepresent study compared with previous studies inother populations (e.g., an LDL-C reduction of 61%with alirocumab 150 mg every 2 weeks was observed
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in the ODYSSEY LONG TERM trial including hetero-zygous familial hypercholesterolemia andnonfamilial hypercholesterolemia patients) (8) aretherefore likely due to the genetic deficiencies in theLDLR pathway in this HoFH study population. How-ever, substantial and significant absolute reductionsin LDL-C were observed in the present study withalirocumab. In addition, the LDL-C response to alir-ocumab was more variable in patients with HoFHthan in other forms of hypercholesterolemia, reflect-ing the significant genetic heterogeneity we observedin this HoFH population. However, responses alsovaried markedly between patients with identicalmutations in another study with responses corre-lating with in vitro residual LDLR expression (11). Anopen-label, nonrandomized study of evolocumabshowed a mean LDL-C reduction of 21.2% at 12 weeksin the overall population of patients with HoFH, and areduced and variable response in patients with LDLRnull/null mutations (12). The evolocumab studyallowed for dose adjustment between 420 mg every 2or every 4 weeks, whereas the present study used afixed dose of alirocumab 150 mg every 2 weeks. Adefinite genetic diagnosis was not possible for 17 of 69(24.6%) patients in this study, which is a higher pro-portion than that observed in a previous HoFH studypopulation (1 of 106 patients; 0.9%) (13).
In the present study, LDL-C changes from baselinewere variable, but mostly low or absent, among the 5patients with null/null mutations. PCSK9 inhibitionwould not be expected to be effective in such patients(hence null/null patients were to be excluded fromthe study per protocol). Although the main effect ofstatins is mediated via LDLR upregulation, atorvas-tatin was shown to reduce lipoprotein production inHoFH patients, explaining why modest statin re-sponses are frequently observed in LDLR null/nullpatients (14). Variable statin adherence could thusexplain some of the LDL-C changes observed in null/null patients.
Variable LDL-C changes were also observed amongthe 10 patients undergoing apheresis in this study.Although the overall changes in LDL-C were direc-tionally similar between apheresis subgroups, inter-pretation of the current results is limited by the smallnumber of patients receiving apheresis. In theODYSSEY ESCAPE (Study of Alirocumab [REGN727/SAR236553] in Patients With Heterozygous FamilialHypercholesterolemia [HeFH] Undergoing Low-Density Lipoprotein [LDL] Apheresis Therapy) trial,apheresis was shown not to impact alirocumab effi-cacy in patients with heterozygous familial hyper-cholesterolemia, as the mean change in pre-apheresisLDL-C from baseline at week 6 was �53.7% for the
alirocumab 150 mg every 2 weeks group comparedwith 1.6% for the placebo group (15).
Although modest reductions in LDL-C from addinga statin and PCSK9 inhibitor are helpful, further re-ductions are usually needed in patients with HoFH.Lomitapide operates primarily by reducing lipopro-tein production, and efficacy is not affected by re-sidual LDLR functionality (16). Inhibition ofangiopoietin-like protein 3 may also provide ameans of reducing LDL-C independently of the LDLR,and is currently under investigation (17).There are nocardiovascular outcomes data for HoFH from ran-domized trials; however, the expected cardiovascularbenefit of reducing LDL-C in HoFH is supported byseveral lines of evidence. A retrospective analysis ofthe records of 149 patients with HoFH from 2 lipidclinics in South Africa reported that, despite a limitedmean reduction in LDL-C (26.4%), lipid-loweringtreatment was associated with delayed cardiovascu-lar events and prolonged survival (18). These resultsare supported by a more recent retrospective surveyof the clinical outcomes and lipid levels of patientswith HoFH in South Africa and the United Kingdom,which showed that the magnitude of the reduction inserum cholesterol with lipid-lowering therapies(received between 1990 and 2014) is the majordeterminant of survival (19).
As well as elevated LDL-C, patients with familialhypercholesterolemia often have elevated Lp(a)levels, which is thought to contribute to theirincreased cardiovascular risk; statins are not effectiveat lowering Lp(a) (20). In the current study, althoughLDL-C reductions were lower in the patients withHoFH compared with those seen in other populations,Lp(a) reductions with alirocumab were comparablewith results from previous trials; for example, a 26%reduction in Lp(a) with alirocumab (75 or 150 mgevery 2 weeks) was observed in a pooled analysis ofphase 3 ODYSSEY trials including patients with het-erozygous familial hypercholesterolemia andnonfamilial hypercholesterolemia (21). However,Lp(a) reductions following evolocumab treatment inpatients with HoFH were reported to be smaller thanthose observed in patients with heterozygous familialhypercholesterolemia (12). The differences betweenthe studies may be due to differences in the under-lying genetic variations in Lp(a) and LDLR pathwayphenotypes, and/or differences in use of backgroundtherapies including apheresis. The mechanism bywhich Lp(a) is cleared from the circulation is not fullyunderstood, and may involve both LDLR-dependentand -independent mechanisms (22–24).STUDY LIMITATIONS. Limitations include therelatively short duration of the trial and that
PERSPECTIVES
COMPETENCY IN MEDICAL KNOWLEDGE: Patients with
HoFH typically have very high levels of LDL-C and develop
atherosclerotic cardiovascular disease at young ages. The PCSK9
inhibitor alirocumab upregulates LDL receptor function and,
compared to placebo, safely lowers LDL-C, but reduction of
LDL-C is more limited than generally observed in other patient
populations, possibly due to deficient LDL receptor pathways in
patients with HoFH.
TRANSLATIONAL OUTLOOK: Further research is needed to
assess the impact of PCSK9 inhibition on long-term clinical
outcomes in patients with HoFH and develop therapeutic inter-
ventions that function independently of LDL receptor pathways.
J A C C V O L . 7 6 , N O . 2 , 2 0 2 0 Blom et al.J U L Y 1 4 , 2 0 2 0 : 1 3 1 – 4 2 Alirocumab in Homozygous FH
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patients <18 years of age were not recruited. As pa-tients with familial hypercholesterolemia haveelevated LDL-C from birth, treatment as early aspossible is recommended (1,2). Early initiation ofstatin therapy has been shown to reduce occurrenceof cardiovascular events in patients with heterozy-gous familial hypercholesterolemia (25). A trial ofalirocumab in pediatric patients with HoFH hasrecently completed (An Efficacy and SafetyStudy of Alirocumab in Children and AdolescentsWith Homozygous Familial Hypercholesterolemia;NCT03510715).
CONCLUSIONS
Treatment with alirocumab resulted in significant andclinically meaningful reductions in LDL-C in patientswith HoFH, as well as significant reductions in otherlipoprotein and lipid parameters. Alirocumab wasgenerally well-tolerated, with no clinically significantdifferences between alirocumab and placebo groupswith regards to safety findings; no safety concernswere identified from the open-label data.
ACKNOWLEDGMENTS The authors thank the pa-tients, their families, and all investigators involved inthis study. Medical writing assistance and editorialsupport, under the direction of the authors, wasprovided by Rachel Dunn, PhD, and Rob Campbell,PhD, of Prime (Knutsford, United Kingdom), funded
by Sanofi and Regeneron Pharmaceuticals, Inc.,according to Good Publication Practice guidelines.
ADDRESS FOR CORRESPONDENCE: Dr. Blom, Divi-sion of Lipidology, Department of Medicine, Univer-sity of Cape Town and Hatter Institute forCardiovascular Research in Africa, University of CapeTown, Chris Barnard Building, Anzio Road, 7925 Ob-servatory, Cape Town, South Africa. E-mail: [email protected]. Twitter: @HICRA_UCT.
RE F E RENCE S
1. Cuchel M, Bruckert E, Ginsberg HN, et al. Ho-mozygous familial hypercholesterolaemia: newinsights and guidance for clinicians to improvedetection and clinical management. A positionpaper from the Consensus Panel on FamilialHypercholesterolaemia of the European Athero-sclerosis Society. Eur Heart J 2014;35:2146–57.
2. Hovingh GK, Goldberg AC, Moriarty PM. Man-aging the challenging homozygous familial hy-percholesterolemia patient: academic insights andpractical approaches for a severe dyslipidemia, aNational Lipid Association Masters Summit. J ClinLipidol 2017;11:602–16.
4. Sniderman AD, Tsimikas S, Fazio S. The severehypercholesterolemia phenotype: clinical diag-nosis, management, and emerging therapies. J AmColl Cardiol 2014;63:1935–47.
5. Seidah NG. The PCSK9 revolution and the po-tential of PCSK9-based therapies to reduce LDL-cholesterol. Glob Cardiol Sci Pract 2017;2017:e201702.
6. Farnier M, Gaudet D, Valcheva V, Minini P,Miller K, Cariou B. Efficacy of alirocumab in highcardiovascular risk populations with or without
heterozygous familial hypercholesterolemia:pooled analysis of eight ODYSSEY phase 3 clinicalprogram trials. Int J Cardiol 2016;223:750–7.
7. Kastelein JJ, Ginsberg HN, Langslet G, et al.ODYSSEY FH I and FH II: 78 week results withalirocumab treatment in 735 patients with het-erozygous familial hypercholesterolaemia. EurHeart J 2015;36:2996–3003.
8. Robinson JG, Farnier M, Krempf M, et al. Effi-cacy and safety of alirocumab in reducing lipidsand cardiovascular events. N Engl J Med 2015;372:1489–99.
9. Hartgers ML, Defesche JC, Langslet G, et al.Alirocumab efficacy in patients with double het-erozygous, compound heterozygous, or homozy-gous familial hypercholesterolemia. J Clin Lipidol2018;12. 390–6 e398.
10. Jones PH, Bays HE, Chaudhari U, et al. Safetyof alirocumab (a PCSK9 monoclonal antibody)from 14 randomized trials. Am J Cardiol 2016;118:1805–11.
11. Thedrez A, Blom DJ, Ramin-Mangata S, et al.Homozygous familial hypercholesterolemiapatients with identical mutations variably ex-press the LDLR (low-density lipoproteinreceptor): implications for the efficacy of
12. Santos RD, Stein EA, Hovingh GK, et al. Long-term evolocumab in patients with familial hyper-cholesterolemia. J Am Coll Cardiol 2020;75:565–74.
13. Raal FJ, Hovingh GK, Blom D, et al. Long-termtreatment with evolocumab added to conven-tional drug therapy, with or without apheresis, inpatients with homozygous familial hyper-cholesterolaemia: an interim subset analysis of theopen-label TAUSSIG study. Lancet DiabetesEndocrinol 2017;5:280–90.
14. Marais AD, Naoumova RP, Firth JC, Penny C,Neuwirth CK, Thompson GR. Decreased pro-duction of low density lipoprotein by atorvas-tatin after apheresis in homozygous familialhypercholesterolemia. J Lipid Res 1997;38:2071–8.
15. Moriarty PM, Parhofer KG, Babirak SP, et al.Alirocumab in patients with heterozygous familialhypercholesterolaemia undergoing lipoproteinapheresis: the ODYSSEY ESCAPE trial. Eur Heart J2016;37:3588–95.
16. Khoury E, Brisson D, Roy N, Tremblay G,Gaudet D. Review of the long-term safety oflomitapide: a microsomal triglycerides transfer
21. Ray KK, Vallejo-Vaz AJ, Ginsberg HN,et al. Lipoprotein(a) reductions from PCSK9inhibition and major adverse cardiovascularevents: pooled analysis of alirocumabphase 3 trials. Atherosclerosis 2019;288:194–202.
22. Gaudet D, Watts GF, Robinson JG, et al. Effectof alirocumab on lipoprotein(a) over $1.5 years(from the phase 3 ODYSSEY program). Am J Car-diol 2017;119:40–6.
23. Shapiro MD, Minnier J, Tavori H, et al.Relationship between low-density lipoproteincholesterol and lipoprotein(a) lowering inresponse to PCSK9 inhibition with evolocumab.J Am Heart Assoc 2019;8:e010932.
24. Tavori H, Christian D, Minnier J, et al. PCSK9 as-sociation with lipoprotein(a). Circ Res 2016;119:29–35.
25. Luirink IK, Wiegman A, Kusters DM, et al. 20-year follow-up of statins in children with familialhypercholesterolemia. N Engl J Med 2019;381:1547–56.
KEY WORDS homozygous familialhypercholesterolemia, low-densitylipoprotein, lipoprotein(a), proproteinconvertase subtilisin/kexin type 9 inhibitor
APPENDIX For a list of study investigators,full inclusion and exclusion criteria, expandedMethods and reference section, tables, andfigures, please see the online version of thispaper.
