2023 Volume 87 Issue 6 Pages 834-846
Background: This study evaluated the safety and effectiveness of alirocumab in Japanese patients with familial hypercholesterolemia (FH) or non-FH in a real-world clinical setting.
Methods and Results: This post-marketing surveillance study had a 2-year standard observation period. The study included Japanese patients with hypercholesterolemia who were treatment naïve to alirocumab, had a high risk of developing cardiovascular events, and had an insufficient response to, or were unsuitable for, treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Alirocumab was administered at a dose of 75 or 150 mg via subcutaneous injection every 2 or 4 weeks. Overall, 1,177 and 1,038 patients were included in the safety and effectiveness analysis populations, respectively. The incidence of adverse drug reactions (ADRs) was 3.4% (40/1,177). The time to ADR occurrence was within 4 weeks in half the patients experiencing ADRs (n=20). There were no meaningful differences in the ADRs experienced in the FH and non-FH groups. The mean (±SE) percentage changes in low-density lipoprotein cholesterol from baseline to last observation carried forward were −46.9±2.1% and −42.7±2.0% in the non-FH and FH groups, respectively. Total cholesterol, triglycerides, apolipoprotein B/E, and lipoprotein(a) concentrations were decreased at Week 4 and maintained until Week 104 in the overall population.
Conclusions: Alirocumab was well tolerated and showed effectiveness in Japanese patients with hypercholesterolemia in a real-world clinical setting.
Primary hypercholesterolemia is associated with an underlying genetic cause and may be categorized as non-familial hypercholesterolemia (non-FH) or familial hypercholesterolemia (FH). Non-FH can occur as a result of several risk factors, such as physical inactivity, smoking, hypertension, and diabetes, whereas FH occurs because of a specific genetic defect.1–3 FH is a common autosomal genetic disorder of low-density lipoprotein cholesterol (LDL-C) metabolism-related genes, such as those encoding the low-density lipoprotein (LDL) receptor, apolipoprotein (Apo) B-100, and proprotein convertase subtilisin/kexin type 9 (PCSK9). FH is characterized by the presence of high LDL-C (≥180 mg/dL), a family history of or premature coronary artery disease and myocardial infarction, and tendon/cutaneous xanthoma.4–7 Regardless of ethnicity, the prevalence of the FH-causing allele is approximately 0.2–0.5% in the general population.6 In a recent retrospective observational study using electronic healthcare databases, the estimated prevalence of FH in Japan was 0.8%.8 The underdiagnosis of FH remains an issue both globally and in Japan.5,9
The risk of developing coronary artery disease is associated with increased LDL-C and is 20-fold higher in untreated FH patients than in those treated with cholesterol-lowering medications, such as statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors).10 LDL-C is a major target for cholesterol-lowering therapy. Based on patient risk, the LDL-C target level has been set by the Japan Atherosclerosis Society (JAS) guidelines for preventing atherosclerotic cardiovascular diseases.11 However, among patients undergoing pharmacotherapy, only 62.4% in the secondary prevention group and 72.5% in the primary prevention group achieved target LDL-C levels.12 Although LDL-C lowering with statin monotherapy is recommended as first-line treatment,4 statins alone may be insufficient to treat patients with severe dyslipidemia, such as patients with FH; concomitant use of other lipid-lowering drugs is required.
Alirocumab is a human monoclonal antibody that inhibits PCSK9, an LDL-C receptor-binding protein in the liver, leading to enhanced clearance of serum LDL-C by free LDL-C receptors.13 Alirocumab is the first PCSK9 inhibitor approved by the US Food and Drug Administration to treat patients with hypercholesterolemia.14 In 2016, alirocumab was approved in Japan to treat patients with hypercholesterolemia and FH who are at high risk of cardiovascular events and in whom treatment with statins was insufficient.15 In 2018, the indication was expanded to patients with hypercholesterolemia who are intolerant of HMG-CoA reductase inhibitors.16
These approvals were based on the results of Phase 3 randomized controlled trials (ODYSSEY LONG TERM [Long-term Safety and Tolerability of Alirocumab (SAR236553/REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in High Cardiovascular Risk Patients With Hypercholesterolemia] and ODYSSEY JAPAN [Efficacy and Safety Evaluation of Alirocumab in Patients With Heterozygous Familial Hypercholesterolemia or High Cardiovascular Risk Patients With Hypercholesterolemia on Lipid Modifying Therapy]).17,18 In ODYSSEY LONG TERM, patients at high risk of cardiovascular events who had an LDL-C concentration ≥70 mg/dL and were undergoing treatment with statins at the maximum tolerated dose were randomly assigned 2 : 1 to treatment with alirocumab 150 mg or placebo.17 In the alirocumab group, LDL-C decreased significantly from baseline to Week 24 (mean±SE change −61.0±0.7%; least-squares mean (LSM) difference vs. placebo −61.9±1.3%; P<0.001); this reduction was maintained up to Week 78. In ODYSSEY JAPAN, high-risk Japanese patients with hypercholesterolemia undergoing stable statin therapy treated with alirocumab showed a significant decrease in LDL-C from baseline to Week 24 (mean±SE change −62.5±1.3%; LSM difference vs. placebo −65.3±2.1%, P<0.0001); this reduction remained until Week 52.18
Despite evidence from randomized control trials, the safety and effectiveness of alirocumab in patients with hypercholesterolemia in the real-world setting in Japan are currently unknown. Therefore, the aim of the present study was to evaluate the safety and effectiveness of alirocumab in Japanese patients with FH or non-FH in a real-world clinical setting. We evaluated the occurrence of adverse drug reactions (ADRs), determined factors associated with the safety and effectiveness of alirocumab, and investigated previously unknown ADRs to alirocumab.
This post-marketing surveillance study was planned with 4-year enrollment and 2-year observation periods and started on December 1, 2016. The standard observation period was 2 years; however, following alirocumab sales discontinuation, patients observed until November 2020 were analyzed. This survey was conducted at 303 sites. Data were collected and registered using an electronic data capture system. This study was conducted in compliance with the Japanese Ministerial Ordinance on Good Post-Marketing Study Practice. All participants provided written informed consent.
PatientsThis study included Japanese, alirocumab-treatment-naïve patients with hypercholesterolemia with a high risk of developing cardiovascular events who had an insufficient response to statins or for whom treatment with statins was considered unsuitable. Patients enrolled in other post-marketing clinical trials of alirocumab were excluded. Patients were classified as non-FH or FH by the investigators.
TreatmentPer the approved label,19 alirocumab 75 or 150 mg via subcutaneous injection (prefilled pen or syringe) was administered every 2 weeks (Q2W) or every 4 weeks (Q4W) at the investigators’ discretion. For patients with an insufficient response to HMG-CoA reductase inhibitors, 75 mg alirocumab was administered Q2W. If the LDL-C response was insufficient, the dose was increased to 150 mg Q2W. For patients considered unsuitable for statin treatment, 150 mg alirocumab was administered Q4W. If the LDL-C response to alirocumab was insufficient, the dose was increased to 150 mg Q2W. The treatment interval (days) was calculated using the last observation carried forward (LOCF) method, and changes in the interval (Q2W or Q4W) between baseline and the LOCF were observed based on the LOCF data up to 52 weeks because of the case report form structure.
SafetyThe incidence of ADRs, the severity of ADRs, unexpected ADRs that were not listed in the approved package insert, and the relationship of ADRs with alirocumab were evaluated. Definitions of ADRs and the ADRs of special interest are provided in the Supplementary Methods.
EffectivenessThe effectiveness endpoints included: changes from baseline in serum LDL-C (direct method), high-density lipoprotein cholesterol, total cholesterol, triglycerides, Apo A-I/B/E, and lipoprotein(a) (Lp(a)) in the overall study population. Patients achieving an LDL-C concentration <100 mg/dL at the LOCF were also assessed as responders. Factors associated with effectiveness were evaluated according to baseline characteristics using the same factors described in the safety section.
Statistical AnalysisSystemic hypersensitivity reactions were observed in 0.7% and 0.8% of patients in the integrated data from previous placebo-controlled trials (overseas Phase 2/3 trials and a domestic Phase 2 trial) and ezetimibe-controlled trials (overseas Phase 3 trials), respectively.19 Although no cases of systemic hypersensitivity reactions have been observed in clinical trials in Japan,16,18 assuming 0.7% of patients would develop systemic hypersensitivity reactions when treated under similar conditions to those in overseas clinical trials, a total of 427 cases would be needed to generate a confidence interval (CI) ≥95%.
To collect sufficient safety information under actual use conditions, as well as an adequate number of cases to evaluate effectiveness and safety in patients with hepatic dysfunction and older patients (age ≥75 years), we set the target number of cases to 3,000 for the safety analysis and 3,300 for enrollment. It was planned that ≥300 patients, each with hepatic failure and age ≥75 years, would be enrolled in the safety population. With a sample size of 3,000 cases, the 2-sided 95% CI for the incidence of systemic hypersensitivity would be 0.40–1.00%, and that for the incidence of cataracts and neurocognitive events would be 0.64–1.36% and 0.48–1.12%, respectively.
The safety population was defined as all patients who had survey records, except those who were inappropriate for inclusion in the safety evaluation. The effectiveness population was defined as patients included in the safety population, excluding those who were inappropriate for inclusion in the effectiveness evaluation.
Patients’ background characteristics are summarized using descriptive statistics, with continuous variables presented as the mean±SD and categorical variables presented as numbers and percentages. The incidence of ADR according to baseline characteristics was tested using Fisher’s exact test for nominal variables and the Cochran–Armitage test for ordinal variables. Multivariable logistic regression analysis was used to determine the relationship between baseline characteristics and ADR incidence, using baseline characteristics for which the univariate analysis indicated significant differences in the incidence of ADRs (i.e., P<0.05). A multivariable logistic regression analysis using a stepwise method for selecting predictor variables was performed with a cut-off of P<0.15.
The effectiveness rate was calculated using patients whose LDL-C concentration at the LOCF was <100 mg/dL (responders). Paired t-tests were performed for changes in continuous variables from baseline. For between-subgroup comparisons, Fisher’s exact test was used for nominal variables and the Cochran–Armitage test was used for ordinal variables. All tests were performed at a 2-sided significance level of 5%.
All statistical analyses were performed using SAS version 9.1 or later (SAS Institute, Cary, NC, USA).
Patient disposition is shown in Figure 1. Initially, it was planned that 3,300 patients would be enrolled; however, following the discontinuation of alirocumab sales, 1,535 patients were enrolled until May 2020. Among those patients observed until November 2020, case report forms were collected from 1,251. Seventy-four patients were excluded from the safety analysis, leaving 1,177 patients in the safety population. In the effectiveness analysis, 139 patients were excluded, leaving 1,038 patients in the effectiveness population.
Patient disposition. CRF, case report form.
The reasons for study discontinuation are presented in Table 1. In total, 627 patients (53.3%) discontinued the study, with the most common reason being discontinued alirocumab sales (n=173; 27.6%). Forty-six (7.3%) patients discontinued alirocumab due to adverse events (AEs). None of the 7 (1.1%) deaths reported were due to ADRs.
| Reasons for discontinuation/drop outA | Patients (n=1,177) |
% of patients who discontinued or dropped out (n=627) |
|---|---|---|
| Total discontinued or dropped out | 627 (53.3) | 100.0 |
| Discontinued alirocumab sales | 173 (14.7) | 27.6 |
| Primary or target disease improved | 123 (10.5) | 19.6 |
| No further visit from a certain time point | 111 (9.4) | 17.7 |
| Switched to another drug | 77 (6.5) | 12.3 |
| Switched after discontinuation of alirocumab sales | 63 (5.4) | 10.1 |
| Adverse events | 46 (3.9) | 7.3 |
| Financial reasons | 36 (3.1) | 5.7 |
| Patient’s preference | 35 (3.0) | 5.6 |
| Insufficient effectiveness | 13 (1.1) | 2.1 |
| Death | 7 (0.6) | 1.1 |
| No visit after the first administration | 5 (0.4) | 0.8 |
| Physician’s decision | 4 (0.3) | 0.6 |
| Days from first administration to discontinuation (n=627) | ||
| Mean±SD | 226.5±187.1 | |
| Minimum | 1 | |
| Maximum | 828 | |
| First quartile | 78.0 | |
| Third quartile | 357.0 | |
Unless indicated otherwise, data are given as the mean±SD or n (%). AThere may be more than 1 reason for discontinuation or drop out.
The baseline demographic and clinical characteristics of the safety population and of the non-FH and FH groups are summarized in Table 2. Among the 1,177 patients in the safety population, 801 (68.1%) were classified as non-FH and 376 (32.0%) were classified as FH. In the non-FH and FH groups, respectively, the mean age was 67.5 and 61.2 years, the proportion of patients aged ≥75 years was 30.3% and 15.7%; the mean duration of disease was 8.4 and 21.8 years; the mean LDL-C concentration at baseline was 115.7 and 134.3 mg/dL; and the proportion of patients with renal dysfunction was 23.6% and 14.4%. The mean values of other lipid profile parameters at baseline were higher in the FH than non-FH group (Table 2). The prevalence of diabetes and hypertension complications and the percentage of patients concomitantly using antidiabetic and antihypertensive drugs were higher in the non-FH than FH group (Table 2).
| Items used for stratification | Overall | Non-FH group | FH group |
|---|---|---|---|
| Safety population | 1,177 | 801 (68.1) | 376 (32.0) |
| Homozygous | 25 | – | 25 (6.7) |
| Heterozygous | 348 | – | 348 (92.6) |
| Unknown | 3 | – | 3 (0.8) |
| Age (years) | |||
| Mean±SD | 65.5±12.0 | 67.5±11.2 | 61.2±12.7 |
| Age ≥75 years | 302 | 243 (30.3) | 59 (15.7) |
| Female sex | 364 | 227 (28.3) | 137 (36.4) |
| Time since diagnosis (years) | 14.4±17.3 | 8.4±8.1 | 21.8±22.3 |
| Diabetes (complication) | |||
| Absent | 691 | 427 (53.3) | 264 (70.2) |
| Present | 481 | 369 (46.1) | 112 (29.8) |
| Unknown | 5 | 5 (0.6) | 0 (0) |
| Hypertension (complication) | |||
| Absent | 309 | 164 (20.5) | 145 (38.6) |
| Present | 863 | 632 (78.9) | 231 (61.4) |
| Unknown | 5 | 5 (0.6) | 0 (0) |
| Stroke (complication) | |||
| Absent | 976 | 629 (78.5) | 347 (92.3) |
| Present | 196 | 167 (20.9) | 29 (7.7) |
| Unknown | 5 | 5 (0.6) | 0 (0) |
| Coronary artery disease (complication) | |||
| Absent | 340 | 197 (24.6) | 143 (38.0) |
| Present | 832 | 599 (74.8) | 233 (62.0) |
| Unknown | 5 | 5 (0.6) | 0 (0) |
| Hepatic dysfunction (complication) | |||
| Absent | 1,077 | 746 (93.1) | 331 (88.0) |
| Present | 95 | 50 (6.2) | 45 (12.0) |
| Unknown | 5 | 5 (0.6) | 0 (0) |
| Renal dysfunction (complication) | |||
| Absent | 929 | 607 (75.8) | 322 (85.6) |
| Present | 243 | 189 (23.6) | 54 (14.4) |
| Unknown | 5 | 5 (0.6) | 0 (0) |
| Concomitant agents (other) | |||
| Absent | 274 | 170 (21.2) | 104 (27.7) |
| Present | 903 | 631 (78.8) | 272 (72.3) |
| Antidiabetic | |||
| Absent | 607 | 400 (63.4) | 207 (76.1) |
| Present | 296 | 231 (36.6) | 65 (23.9) |
| Antihypertensive | |||
| Absent | 303 | 191 (30.3) | 112 (41.2) |
| Present | 600 | 440 (69.7) | 160 (58.8) |
| Concomitant agents for hypercholesterolemia | |||
| Absent | 237 | 178 (22.2) | 59 (15.7) |
| Present | 940 | 623 (77.8) | 317 (84.3) |
| Statins | |||
| Absent | 67 | 55 (8.8) | 12 (3.8) |
| Present | 873 | 568 (91.2) | 305 (96.2) |
| Rosuvastatin | |||
| Present | 390 | 242 (38.8) | 148 (46.7) |
| Atorvastatin | |||
| Present | 245 | 151 (24.2) | 94 (29.7) |
| Simvastatin | |||
| Present | 1 | 0 (0.0) | 1 (0.3) |
| Pitavastatin | |||
| Present | 208 | 156 (25.0) | 52 (16.4) |
| Pravastatin | |||
| Present | 39 | 25 (4.0) | 14 (4.4) |
| Fluvastatin | |||
| Present | 20 | 10 (1.6) | 10 (3.2) |
| Fibrates | |||
| Absent | 902 | 598 (96.0) | 304 (95.9) |
| Present | 38 | 25 (4.0) | 13 (4.1) |
| Fenofibrate | |||
| Present | 7 | 3 (0.5) | 4 (1.3) |
| Bezafibrate | |||
| Present | 9 | 7 (1.1) | 2 (0.6) |
| Clinofibrate | |||
| Present | 0 | 0 (0) | 0 (0) |
| Clofibrate | |||
| Present | 0 | 0 (0) | 0 (0) |
| Bemafibrate | |||
| Present | 23 | 15 (2.4) | 8 (2.5) |
| Small intestine cholesterol transporter inhibitors | |||
| Absent | 556 | 404 (64.9) | 152 (48.0) |
| Present | 384 | 219 (35.2) | 165 (52.1) |
| Ezetimibe | |||
| Present | 384 | 219 (35.2) | 165 (52.1) |
| Probucol | |||
| Absent | 929 | 622 (99.8) | 307 (96.9) |
| Present | 11 | 1 (0.2) | 10 (3.2) |
| Other dyslipidemia drugs | |||
| Absent | 851 | 572 (91.8) | 279 (88.0) |
| Present | 89 | 51 (8.2) | 38 (12.0) |
| Other | |||
| Absent | 852 | 565 (90.7) | 287 (90.5) |
| Present | 88 | 58 (9.3) | 30 (9.5) |
| Antiplatelet drugs | |||
| Absent | 517 | 322 (40.2) | 195 (51.9) |
| Present | 660 | 479 (59.8) | 181 (48.1) |
| Biomarker results at baseline | |||
| DBP (mmHg) | 74.5±13.2 | 75.1±14.0 | 73.1±11.0 |
| SBP (mmHg) | 129.7±19.8 | 131.2±20.8 | 126.1±16.9 |
| Pulse rate (beats/min) | 73.1±12.4 | 73.8±12.8 | 71.4±11.1 |
| HbA1c (%) | 6.5±1.2 | 6.6±1.2 | 6.3±1.1 |
| Fasting blood glucose (mg/dL) | 113.0±31.7 | 116.7±35.8 | 106.4±21.1 |
| TC (mg/dL) | 201.9±60.5 | 195.2±55.6 | 216.2±67.6 |
| LDL-C (direct) (mg/dL) | 121.2±50.6 | 115.7±44.5 | 134.3±60.9 |
| HDL-C (mg/dL) | 53.5±18.1 | 53.0±18.9 | 54.4±16.5 |
| TG (mg/dL) | 155.1±106.4 | 159.7±112.4 | 145.6±92.3 |
| Apo A-I (mg/dL) | 133.6±39.2 | 131.6±37.1 | 136.3±42.1 |
| Apo B (mg/dL) | 110.7±38.8 | 99.8±26.9 | 124.6±46.6 |
| Apo E (mg/dL) | 4.8±2.0 | 4.2±1.8 | 5.5±2.1 |
| Lp(a) (mg/dL) | 36.5±33.2 | 37.6±34.2 | 34.5±31.5 |
| eGFR (mL/min/1.73 m2) | 63.7±20.1 | 61.4±20.7 | 69.4±17.6 |
In the overall study population, data are given as the mean±SD or n; in the familial hypercholesterolemia (FH) and non-FH groups, data are given as the mean±SD or n (%). Apo, apolipoprotein; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride.
The use of concomitant drugs for the primary disease and changes in treatment throughout the study period are presented in Supplementary Table 1.
Alirocumab Treatment PatternDuring the observation period, the respective percentage of patients who received alirocumab with a mean treatment interval of 2 and 4 weeks was 71.4% (n=572) and 16.1% (n=129) in the non-FH group, and 67.0% (n=252) and 18.4% (n=69) in the FH group. The percentage receiving alirocumab with an interval of >4 weeks was higher in the FH than non-FH group (n=32 [8.5%] vs. n=31 [3.9%], respectively). The median duration of alirocumab treatment was 127.0 days (interquartile range [IQR] 85.0–377.0 days) for the safety analysis set. In the non-FH and FH groups, the median duration of alirocumab treatment was 113.0 days (IQR 77.0–365.0 days) and 183.0 days (85.0–454.5 days), respectively.
Among patients with an initial alirocumab dose of 75 mg, 76.3% (n=751) continued alirocumab 75 mg Q2W and 0.6% (n=6) had a final dose of 150 mg Q2W. Among patients with an initial alirocumab dose of 150 mg, 5.8% (n=57) continued alirocumab 150 mg Q4W and 0.3% (n=3) had a final dose of 150 mg Q2W.
SafetyIn the safety population, 167 patients experienced AEs (14.2%), and 40 presented ADRs (3.4%; Table 3). In half the patients experiencing ADRs (n=20), the time to ADR occurrence was within 4 weeks. Unexpected ADRs not described in the package insert included malaise in 4 patients, and dizziness, somnolence, diarrhea, nausea, myalgia, and pain in an extremity in 2 patients each. None of the reported ADRs was serious. No ADRs were observed in patients who underwent treatment for ≥52 weeks.
| Safety population (n=1,177) |
Non-FH group (n=801) | FH group (n=376) | |||
|---|---|---|---|---|---|
| Serious | Overall | Serious | Overall | ||
| No. patients with ADRs | 40 | 0 | 17 | 0 | 23 |
| ADR incidence rate (%) | 3.4 | 0.0 | 2.1 | 0.0 | 6.1 |
| ADR System Organ Class and Preferred Term | |||||
| Nervous system disorders | 5 (0.4) | 0 (0.0) | 2 (0.3) | 0 (0.0) | 3 (0.8) |
| Dizziness | 2 (0.2) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 1 (0.3) |
| Hypoesthesia | 1 (0.1) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 0 (0.0) |
| Sensory disturbance | 1 (0.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.3) |
| Somnolence | 2 (0.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (0.5) |
| Vascular disorders | 1 (0.1) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 0 (0.0) |
| Blood pressure inadequately controlled | 1 (0.1) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 0 (0.0) |
| Gastrointestinal disorders | 8 (0.7) | 0 (0.0) | 2 (0.3) | 0 (0.0) | 6 (1.6) |
| Constipation | 1 (0.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.3) |
| Diarrhea | 2 (0.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (0.5) |
| Gastrointestinal disorder | 1 (0.1) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 0 (0.0) |
| Nausea | 2 (0.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (0.5) |
| Oral discomfort | 1 (0.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.3) |
| Feces soft | 1 (0.1) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 0 (0.0) |
| Hepatobiliary disorders | 5 (0.4) | 0 (0.0) | 2 (0.3) | 0 (0.0) | 3 (0.8) |
| Abnormal hepatic function | 2 (0.2) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 1 (0.3) |
| Liver disorder | 3 (0.3) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 2 (0.5) |
| Skin and subcutaneous tissue disorders | 10 (0.9) | 0 (0.0) | 4 (0.5) | 0 (0.0) | 6 (1.6) |
| Dermatitis allergic | 1 (0.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.3) |
| Drug eruption | 2 (0.2) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 1 (0.3) |
| Eczema | 1 (0.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.3) |
| Eczema nummular | 1 (0.1) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 0 (0.0) |
| Pruritus | 4 (0.3) | 0 (0.0) | 2 (0.3) | 0 (0.0) | 2 (0.5) |
| Rash | 1 (0.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.3) |
| Skin swelling | 1 (0.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.3) |
| Musculoskeletal and connective tissue disorders | 4 (0.3) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 3 (0.8) |
| Arthralgia | 1 (0.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.3) |
| Myalgia | 2 (0.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (0.5) |
| Pain in extremity | 2 (0.2) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 1 (0.3) |
| General disorders and administration site conditions |
9 (0.8) | 0 (0.0) | 4 (0.5) | 0 (0.0) | 5 (1.3) |
| Injection site erythema | 2 (0.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (0.5) |
| Injection site pain | 1 (0.1) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 0 (0.0) |
| Injection site rash | 1 (0.1) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 0 (0.0) |
| Malaise | 4 (0.3) | 0 (0.0) | 2 (0.3) | 0 (0.0) | 2 (0.5) |
| Thirst | 1 (0.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.3) |
| Investigations | 5 (0.4) | 0 (0.0) | 5 (0.6) | 0 (0.0) | 0 (0.0) |
| Blood creatine phosphokinase increased | 2 (0.2) | 0 (0.0) | 2 (0.3) | 0 (0.0) | 0 (0.0) |
| Blood glucose increased | 1 (0.1) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 0 (0.0) |
| Glycosylated hemoglobin increased | 1 (0.1) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 0 (0.0) |
| Low-density lipoprotein decreased | 1 (0.1) | 0 (0.0) | 1 (0.1) | 0 (0.0) | 0 (0.0) |
Unless indicated otherwise, data are given as n (%). Serious ADRs were defined as adverse reactions judged by the investigator as leading to one of the following serious events: death, life-threatening, hospitalization or prolongation of hospitalization to treat the events; permanent or significant disability or damage; congenital anomaly/birth defect; other serious medical conditions. ADR, adverse drug reactions; FH, familial hypercholesterolemia.
Regarding ADRs of special interest in the risk management plan in Japan (RMP),19 systemic hypersensitivity (Hypersensitivity with Standardised MedDRA Queries broad and narrow) occurred in 11 patients. The outcome for all these patients was recovered or recovering/resolving. Other events of special interest in the RMP, such as immunogenicity, cataracts, and neurocognitive events, were not observed. In addition, cardiovascular-related ADRs were not observed in addition to those of special interest in the RMP, and anaphylaxis was not reported.
Factors Associated With ADR DevelopmentThe univariate analysis for ADR development (data not shown) identified the following as risk factors: diagnosis; sex; inpatient/outpatient status; malignancy (complication); presence of cutaneous nodular xanthomas; complications other than diabetes, hypertension, stroke, coronary artery disease, hepatic dysfunction, and renal dysfunction; duration of treatment; and observation period.
Multivariable logistic regression analysis identified the following baseline participant characteristics as being significantly associated with an increased risk of ADRs (P<0.05): FH diagnosis (odds ratio [OR] 3.20; 95% CI 1.66–6.17), malignancy (complication; OR 3.19; 95% CI 1.25–8.10) and complications other than diabetes, hypertension, stroke, coronary artery disease, hepatic dysfunction, and renal dysfunction (OR 2.49; 95% CI 1.27–4.87).
In total, 3.1% of patients without malignancy and 8.5% with malignancy developed ADRs, and 6.1% of patients with FH and 2.1% without FH developed ADRs. The incidence of ADRs without other complications was 2.2%, whereas that with other complications was 5.0%; thus, ADRs were more commonly observed with other complications.
No significant associations were noted for patients with hepatic dysfunction, patients who achieved an LDL-C concentration <25 mg/dL once during long-term administration, patients aged ≥75 years, and patients from the homozygous group in univariate analyses.
ADRs According to FH StatusThe incidence of ADRs was 2.1% and 6.1% in the non-FH and FH groups, respectively. ADRs by system organ class that occurred in ≥1% of patients in the FH group were gastrointestinal disorders, skin and subcutaneous tissue disorders, and general disorders and administration site conditions. The incidence was balanced between the 2 groups, and only 1 or 2 patients developed each of the reported ADRs (Table 3). ADRs in the non-FH group and the heterozygous and homozygous groups are presented in Supplementary Table 2. Few events occurred for each ADR, and there were no marked differences in the incidence of ADRs in either non-FH group (heterozygous or homozygous).
EffectivenessIn the overall study population, the mean LDL-C concentration decreased from 119.9±49.3 mg/dL at baseline to 59.7±40.2 mg/dL at Week 4. The mean LDL-C concentration was maintained until Weeks 52 and 104, at 58.8±36.4 and 62.5±35.0 mg/dL, respectively (Figure 2A). The respective mean and percentage change in LDL-C concentration at baseline to the LOCF was −59.8±43.8 mg/dL and −46.9±2.1% in the non-FH group, and −59.1±51.5 mg/dL and −42.7±2.0% in the FH group (Figure 2B). Total cholesterol, triglyceride, Apo B/E, and Lp(a) levels were decreased at Week 4 and maintained until Weeks 52 and 104 (Table 4).
Mean (±SD) change in low-density lipoprotein cholesterol (LDL-C) throughout the observation period in (A) the overall study population and (B) patients with and without familial hypercholesterolemia separately (effectiveness population). LOCF, last observation carried forward.
| Measure (mg/dL) |
Baseline | Week 4 | Week 12 | Week 24 | Week 36 | Week 52 | Week 104 | LOCF | Change (LOCF– baseline) |
P value | % Change (LOCF– baseline) |
P value |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall study population | ||||||||||||
| LDL-CA | 119.9±49.3 (850) | 59.7±40.2 (768) | 57.7±37.5 (729) | 56.7±35.3 (410) | 58.8±36.7 (372) | 58.8±36.4 (337) | 62.5±35.0 (119) | 60.0±41.0 (920) | −59.6±46.2 (838) | <0.001 | −45.6±1.6 | <0.001 |
| TC | 200.6±58.9 (783) | 135.8±47.9 (686) | 134.5±46.0 (681) | 135.6±45.9 (371) | 138.4±49.7 (329) | 136.4±44.6 (294) | 144.4±43.4 (114) | 136.2±47.2 (841) | −62.3±51.0 (754) | <0.001 | −29.2±0.8 | <0.001 |
| HDL-C | 52.9±15.8 (958) | 55.0±14.9 (852) | 55.7±15.6 (822) | 55.4±15.3 (454) | 56.1±15.9 (412) | 55.8±15.6 (366) | 57.2±15.3 (128) | 55.9±15.6 (1,007) | 3.1±9.9 (951) | <0.001 | 8.0±0.6 | <0.001 |
| TG | 151.9±99.3 (952) | 128.7±72.3 (850) | 131.3±77.6 (834) | 128.6±115.4 (473) | 127.3±98.4 (422) | 128.2±81.7 (375) | 121.4±71.4 (135) | 128.5±78.3 (1,016) | −21.9±82.0 (945) | <0.001 | −4.9±1.7 | 0.004 |
| Apo A-I | 134.0±37.7 (120) | 136.6±30.2 (113) | 149.1±32.0 (99) | 141.8±36.0 (57) | 146.2±28.5 (48) | 153.9±29.1 (41) | 151.2±32.9 (15) | 141.6±32.7 (188) | 8.5±25.8 (83) | 0.003 | 9.8±2.8 | <0.001 |
| Apo B | 110.0±36.5 (128) | 58.1±31.1 (118) | 60.8±31.3 (106) | 62.1±46.9 (61) | 63.4±34.7 (53) | 59.6±33.6 (43) | 64.3±33.9 (17) | 58.6±35.0 (192) | −41.5±34.3 (87) | <0.001 | −37.6±3.2 | <0.001 |
| Apo E | 4.8±2.1 (104) | 3.1±3.1 (99) | 3.6±3.4 (94) | 3.4±1.9 (45) | 3.4±2.1 (38) | 3.5±2.0 (36) | 3.1±1.3 (13) | 3.3±3.4 (168) | −1.4±1.5 (75) | <0.001 | −28.7±2.9 | <0.001 |
| Lp(a) | 36.1±33.0 (150) | 28.2±33.9 (139) | 25.6±30.9 (105) | 29.3±28.0 (67) | 29.3±30.2 (60) | 29.1±29.7 (49) | 27.2±27.7 (18) | 28.5±32.6 (221) | −7.2±15.9 (92) | <0.001 | −10.1±7.5 | 0.180 |
| Non-FH | ||||||||||||
| TC | 194.2±56.0 (524) | 126.7±41.1 (454) | 126.8±39.8 (450) | 130.3±45.0 (248) | 131.0±45.3 (212) | 129.8±43.5 (196) | 136.0±40.1 (67) | 128.3±41.4 (566) | −63.3±47.5 (500) | <0.001 | −30.4±1.0 | <0.001 |
| TG | 156.3±105.3 (631) | 129.2±71.0 (570) | 133.1±78.4 (545) | 129.1±131.7 (313) | 131.4±108.0 (269) | 131.3±86.9 (243) | 117.8±76.1 (79) | 129.5±79.4 (680) | −24.6±83.5 (626) | <0.001 | −6.5±2.0 | <0.001 |
| Apo B | 98.5±23.5 (68) | 48.6±19.1 (88) | 45.7±22.0 (64) | 43.7±24.8 (36) | 46.3±27.0 (29) | 52.8±33.6 (29) | 57.1±32.8 (9) | 47.6±23.4 (134) | −50.8±26.6 (46) | <0.001 | −50.5±3.3 | <0.001 |
| Apo E | 4.2±1.9 (57) | 2.7±3.4 (74) | 2.9±4.0 (59) | 2.7±1.3 (29) | 2.4±1.0 (21) | 2.9±1.6 (24) | 2.7±1.5 (7) | 2.9±3.8 (119) | −1.5±1.4 (43) | <0.001 | −34.4±4.1 | <0.001 |
| Lp(a) | 38.4±35.3 (93) | 26.3±28.1 (113) | 23.3±25.8 (75) | 32.4±29.8 (46) | 30.1±30.8 (41) | 30.5±31.8 (33) | 31.2±30.7 (12) | 26.4±27.6 (166) | −8.6±17.5 (63) | <0.001 | −5.9±10.7 | 0.587 |
| FH group | ||||||||||||
| TC | 213.6±62.4 (259) | 153.6±55.0 (232) | 149.6±53.1 (231) | 146.2±46.0 (123) | 151.8±54.5 (117) | 149.6±43.9 (98) | 156.4±45.5 (47) | 152.5±53.9 (275) | −60.4±57.2 (254) | <0.001 | −26.7±1.4 | <0.001 |
| TG | 143.2±85.7 (321) | 127.9±74.8 (280) | 127.7±76.0 (289) | 127.6±74.3 (160) | 120.2±78.8 (153) | 122.8±71.0 (132) | 126.5±64.6 (56) | 126.3±76.1 (336) | −16.5±78.8 (319) | <0.001 | −1.6±3.2 | 0.613 |
| Apo B | 123.0±43.8 (60) | 85.7±41.7 (30) | 83.6±29.7 (42) | 88.6±58.0 (25) | 84.0±32.1 (24) | 73.7±29.8 (14) | 72.4±35.5 (8) | 84.1±43.4 (58) | −31.1±39.0 (41) | <0.001 | −23.2±4.7 | <0.001 |
| Apo E | 5.5±2.1 (47) | 4.3±1.5 (25) | 4.8±1.7 (35) | 4.7±2.2 (16) | 4.7±2.3 (17) | 4.7±2.2 (12) | 3.5±1.1 (6) | 4.3±1.6 (49) | −1.4±1.7 (32) | <0.001 | −20.9±3.5 | <0.001 |
| Lp(a) | 32.2±28.7 (57) | 36.4±52.0 (26) | 31.5±40.9 (30) | 22.6±22.8 (21) | 27.7±29.8 (19) | 26.0±25.5 (16) | 19.1±20.1 (6) | 34.8±44.1 (55) | −4.3±11.2 (29) | 0.051 | −19.5±4.9 | <0.001 |
Data are mean±SD with n values in parentheses, except for percentage changes, which are the mean±SE. ADirect method. LOCF, last observation carried forward. Other abbreviations as in Tables 2,3.
Changes in lipid profiles throughout the observation period in FH patients are presented in Supplementary Table 3; the lipid profile was improved in patients in both the heterozygous and homozygous groups.
Factors Associated With the Effectiveness of AlirocumabPatient background factors that were significantly associated with alirocumab effectiveness were: diagnosis; non-FH and FH classification (homozygous and heterozygous); diagnostic method; presence of tendon xanthomas; presence of cutaneous nodular xanthomas; age; complications of diabetes, hypertension, coronary artery disease, and renal dysfunction; baseline total cholesterol, LDL-C, triglyceride, Apo B/E, and estimated glomerular filtration rate; previous drug use (lipid-lowering, anticoagulant, and antiplatelet drugs); presence of a pretreatment agent for the underlying disease; dose at baseline; mean drug dose during the observation period; and drug dose interval at baseline in the univariate analysis (data not shown).
According to patient background factors, the effectiveness rates were 87.2% (212/243 patients) and 86.1% (583/677 patients) among patients aged ≥75 and <75 years, respectively (P=0.744); 90.7% (185/204 patients) and 85.2% (609/715 patients) in patients with and without renal dysfunction, respectively (P=0.049); and 79.2% (57/72 patients) and 87.0% (737/847 patients) in patients with and without hepatic dysfunction, respectively (P=0.072).
Treatment-related factors associated with alirocumab effectiveness are presented in Table 5. Comparing effectiveness according to a single administration dose, the rates (proportion of patients who achieved LDL-C <100 mg/dL) were 88.1% in patients who received a single dose of 75 mg and 66.7% in those who received a single dose of 150 mg (P<0.001). Patients who received alirocumab 150 mg were those who required a dose increase due to an insufficient response to 75 mg Q2W or those for whom 150 mg Q4W was selected as the initial treatment due to statin intolerance. When comparing effectiveness according to treatment interval, the rate was significantly higher in patients receiving alirocumab Q2W than in those receiving alirocumab Q4W or longer than Q4W (90.3% vs. 72.0% and 82.6%, respectively; P<0.001).
| Items used for stratification | Baseline | Week 52 | LOCF | No. (%) achieving LDL-C <100 mg/dL |
P value | |||
|---|---|---|---|---|---|---|---|---|
| n | Mean±SD | n | Mean±SD | n | Mean±SD | |||
| Effectiveness population | 850 | 119.9±49.3 | 337 | 58.8±36.4 | 920 | 60.0±41.0 | 795 (86.4) | |
| Single dose administered at baseline | ||||||||
| 75 mg | 772 | 117.5±46.5 | 317 | 56.2±33.5 | 840 | 57.1±38.5 | 740 (88.1) | <0.001 |
| 150 mg | 70 | 147.9±68.7 | 20 | 99.1±54.5 | 72 | 94.4±52.8 | 48 (66.7) | |
| Unknown | 8 | 104.0±34.1 | 0 | – | 8 | 64.0±41.6 | 7 (87.5) | |
| Single dose administered at LOCF | ||||||||
| 75 mg | 731 | 115.9±46.4 | 311 | 56.8±35.0 | 790 | 55.6±37.8 | 706 (89.4) | <0.001 |
| 150 mg | 73 | 149.1±65.0 | 24 | 85.7±44.0 | 76 | 94.4±51.0 | 51 (67.1) | |
| Unknown | 46 | 137.8±45.8 | 2 | 34.5±20.5 | 54 | 77.4±44.1 | 38 (70.4) | |
| Treatment interval at baseline | ||||||||
| Q2W | 668 | 115.7±47.3 | 293 | 56.5±34.7 | 718 | 54.5±37.1 | 648 (90.3) | <0.001 |
| Q4W | 115 | 136.7±56.2 | 39 | 77.2±43.9 | 125 | 83.3±48.6 | 90 (72.0) | |
| >Q4W | 21 | 123.2±51.3 | 3 | 59.0±47.6 | 23 | 65.6±50.8 | 19 (82.6) | |
| Unknown | 46 | 137.8±45.8 | 2 | 34.5±20.5 | 54 | 77.4±44.1 | 38 (70.4) | |
| Treatment interval at LOCF | ||||||||
| Q2W | 651 | 115.1±47.6 | 280 | 54.8±34.2 | 701 | 53.4±37.1 | 638 (91.0) | <0.001 |
| Q4W | 115 | 135.6±51.3 | 43 | 76.3±34.6 | 125 | 84.3±41.7 | 89 (71.2) | |
| >Q4W | 38 | 132.8±58.1 | 12 | 93.0±56.6 | 40 | 76.8±58.5 | 30 (75.0) | |
| Unknown | 46 | 137.8±45.8 | 2 | 34.5±20.5 | 54 | 77.4±44.1 | 38 (70.4) | |
| Mean treatment interval | ||||||||
| Q2W | 646 | 115.6±47.5 | 279 | 54.8±34.4 | 697 | 53.8±37.5 | 632 (90.7) | <0.001 |
| Q4W | 130 | 131.3±52.1 | 46 | 79.0±36.0 | 137 | 78.9±40.2 | 104 (75.9) | |
| >Q4W | 36 | 130.1±59.7 | 10 | 80.8±56.4 | 40 | 81.1±62.0 | 28 (70.0) | |
| Unknown | 38 | 144.9±45.1 | 2 | 34.5±20.5 | 46 | 79.7±44.5 | 31 (67.4) | |
Mean±SD values indicate the LDL-C concentrations at the specified time points. Q2W, every 2 weeks; Q4W, every 4 weeks; >Q4W, longer than 4 weeks. Other abbreviations as in Tables 2,4.
Figure 3 shows LDL-C changes in patients receiving alirocumab Q2W and Q4W. The LDL-C concentration during the observation period was higher in patients receiving alirocumab Q4W. Both the changes and percentage changes in LDL-C concentration were lower in the Q4W group than in the Q2W group.
Mean (±SD) change in low-density lipoprotein cholesterol (LDL-C) throughout the observation period in groups administered alirocumab via subcutaneous injection every 2 (Q2W) or 4 (Q4W) weeks (effectiveness population). LOCF, last observation carried forward.
The J-POSSIBLE post-marketing survey aimed to evaluate the safety and effectiveness of the PCSK9 inhibitor alirocumab in patients with FH and non-FH in a real-world clinical setting in Japan. The sample size in the present study (n=1,535) was considerably smaller than the planned sample size (n=3,300). Furthermore, the discontinuation or drop-out rate was >50%, with approximately 30% of patients dropping out once the sale of alirocumab (Praluent®) was suspended after an injunction issued by the Tokyo District Court was enforced in May 2020. Thereafter, the statistical analyses were based on data collected from survey forms.
Regarding patient characteristics, patients in the FH group were younger and had a longer time since diagnosis. Moreover, in the FH group, a higher proportion of patients were women, and patients had higher mean LDL-C, triglyceride, and Apo B/E concentrations at baseline than patients in the non-FH group. The longer time since diagnosis in this group suggests that patients with FH are diagnosed earlier. There was a higher frequency of complications, such as diabetes and hypertension, in the non-FH than FH group, which may be explained by the higher proportion of older patients in the non-FH group.
Regarding safety, the incidence of AEs was 14.2% (167/1,177) among patients with FH and non-FH treated with alirocumab. In comparison, the incidence of AEs was 81.0% (1,255/1,550) in patients treated with alirocumab in ODYSSEY LONG TERM,17 and the incidence of treatment-emergent AEs was 90.9% (130/143) in patients treated with alirocumab in ODYSSEY JAPAN.18 Although it is difficult to compare the results of studies with different methodologies and safety event definitions, the incidence of AEs was lower in the present study than in ODYSSEY LONG TERM.17
ADRs were reported in 40 (3.4%) patients, but no serious ADRs were observed. Half the patients who developed ADRs developed these events within 4 weeks, suggesting that alirocumab ADRs develop in a relatively short time.
Diagnosis (FH or non-FH), presence of cutaneous tuberous xanthomas, sex, in-/outpatient status, presence of comorbid malignancy, other complications, duration of treatment, and observation period were background factors significantly associated with ADR development in the univariate analysis. However, there were no meaningful differences in ADRs experienced according to FH status. Nonetheless, severe disease was a factor commonly associated with increased ADR occurrence. Thus, it can be inferred that complications of malignancy and other comorbidities increased the occurrence of ADRs in the present study.
Regarding effectiveness, the mean percentage change in LDL-C concentration at baseline to the LOCF in the overall study population was −45.6%. This change is lower than that reported at 24 weeks in ODYSSEY LONG TERM (alirocumab group, −61.0%) and ODYSSEY JAPAN (alirocumab group, −62.5%).17,18 Compared with other interventional Phase 3 trials, the percentage change in LDL-C tended to be lower in the present study, possibly because the baseline LDL-C concentration was lower than in ODYSSEY JAPAN18 and alirocumab was used at a lower dose than in ODYSSEY LONG TERM.17 Interestingly, the percentage change in LDL-C was similar between the non-FH and FH groups in the present study.
There was no significant difference between the doses selected and prescribed between patients with FH and non-FH. The effectiveness rates were higher with single doses of alirocumab 75 than 150 mg, and with a treatment interval of Q2W than with a treatment interval of Q4W. Most patients treated with alirocumab Q2W received 75 mg, whereas a few received 150 mg. Conversely, approximately 40% of patients treated Q4W received 150 mg alirocumab, whereas approximately 60% received 75 mg (off-label use).
Alirocumab 75 mg Q4W is a non-approved dose; according to the approved label,19 the dose recommended for patients with statin intolerance is 150 mg Q4W. However, alirocumab should not be used concomitantly with statins. Because there were no limitations restricting the concomitant use of statins, this factor may have affected the results. Patients who received 150 mg Q2W were statin intolerant or demonstrated poor effectiveness with 75 mg Q2W. The high effectiveness rate in patients who received a single dose of 75 mg may be because the dose given to the patients who were treated Q2W was increased to 150 mg due to insufficient effectiveness (inadequate response) or statin intolerance. In patients receiving alirocumab Q4W, baseline LDL-C was higher, but the change and percentage change in LDL-C were lower than in patients treated with alirocumab Q2W.
When comparing alirocumab effectiveness according to other factors, such as age and complications (renal and hepatic dysfunction), there were no significant differences according to age or the presence/absence of hepatic dysfunction, although alirocumab was significantly more effective in patients with than without renal dysfunction. However, because the effectiveness rate was still >80% in those without renal dysfunction, this finding does not raise any clinically relevant concerns. Thus, alirocumab effectiveness was confirmed regardless of age and complications. Younger patients without complications showed lower effectiveness, but more FH patients were included in this population, which possibly led to the observed result. Moreover, patients with homozygous FH were less responsive to alirocumab than patients with heterozygous FH. Conversely, there was no difference in the percentage change in LDL-C, and alirocumab effectiveness was confirmed regardless of age and complications.
Generally, it is expected that patients with FH will have higher baseline LDL-C concentrations, greater absolute reductions in LDL-C concentrations upon anti-PCSK9 antibody administration,20 and lower LDL-C reduction rates. However, in the present study, the mean baseline LDL-C concentration (132.1±56.5 vs. 114.5±44 .7 mg/dL in the FH and non-FH groups, respectively) and the rate of LDL-C reduction after treatment were almost the same in the FH and non-FH groups. This may be because of the difference in the rate of concomitant statin use at baseline (96.2% vs. 91.2% in the FH and non-FH groups, respectively), the influence of prior treatment and concomitant medications, the level of PCSK9 expression induced by concomitant statin use, and the pathological condition of patients in the FH group. These factors may have resulted in difficulty in lowering LDL-C in the FH group. Thus, the present study confirmed that PCSK9 inhibitors have a similar LDL-C-lowering effect in the FH and non-FH groups.
In the present study, a decrease in Lp(a) was observed after medication (mean −7.2±15.9 mg/dL). The average rate of change was −10% in the present study, compared with −40% in ODYSSEY JAPAN,18 −25% in ODYSSEY OUTCOMES,21 and −26.9% in the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) study,22 but the amount of change was approximately the same. Although it was originally expected that the FH group would have a higher Lp(a) concentration at baseline than the non-FH group, the FH group had a slightly lower mean Lp(a) concentration than the non-FH group (32.2±28.7 vs. 38.4±35.3 mg/dL, respectively) in the present study. This may have been because of the small number of patients in whom Lp(a) was measured and its large variability. Lp(a) is a risk factor for myocardial infarction and cerebral infarction.23 In the present study, the non-FH group had a very high incidence of cerebral infarction. Myocardial infarction was included in coronary diseases, in which angina pectoris was also included; this may have influenced the results.
The present study has limitations. First, this was an observational study and there were no strict eligibility or limitation requirements regarding concomitant drug use. These factors may have affected alirocumab treatment effectiveness and reflect the real-world treatment of Japanese patients with hypercholesterolemia. Second, >50% of patients dropped out, with 30% dropping out because of the discontinuation of alirocumab sales. Third, this was not a controlled study; thus, causation cannot be ascertained. Fourth, the clinical and genetic diagnoses of FH were made by physicians in accordance with JAS diagnostic criteria, and patients who did not meet these criteria were considered non-FH. However, the Exploration into the Lipid Management and Persistent Risk in the Patients Hospitalized for Acute Coronary Syndrome in Japan (EXPLORE-J)24 and an associated subanalysis25 showed that the sensitivity of the 2017 JAS diagnostic criteria for FH is low. Therefore, a certain number of patients with FH in the present study were possibly not diagnosed with FH because they did not meet the JAS criteria for FH and were thus allocated to the non-FH group. Finally, because this study included only Japanese patients, the generalizability of the findings is limited to the Japanese population.
In conclusion, alirocumab was well tolerated and effective in Japanese patients with hypercholesterolemia in a real-world clinical setting. The long-term effectiveness of alirocumab in lowering LDL-C (percentage change in LDL-C) was maintained regardless of non-FH or FH status, age, and complications. Other lipid profile parameters (total cholesterol, triglycerides, Apo B/E, and Lp(a)) also demonstrated long-term improvement. The most effective alirocumab dose and treatment interval were 75 mg and Q2W, respectively.
The authors thank all the physicians who participated in this study, as well as Masayuki Senda from Sanofi, Japan, who provided operational assistance in conducting the study. The authors also acknowledge assistance from CMIC, Co., Ltd., Japan, in conducting the analysis. The authors thank Michelle Belanger, MD, of Edanz (www.edanz.com) for providing medical writing support, which was funded by Sanofi (Tokyo, Japan).
This study was funded by Sanofi (Tokyo, Japan).
A.K. has received lecture fees from Sumitomo Dainippon Pharma, Daiichi-Sankyo, Ono Pharmaceutical Co., Ltd., AstraZeneca, and Takeda. H.A. has received lecture fees from MSD, Sanofi, Pfizer, Daiichi Sankyo, Kowa, Takeda, and Otsuka. S.Y. has received lecture fees from Bristol-Meyers Squibb, Bayer, and Daiichi-Sankyo, and is affiliated with endowed departments from Abbott, Terumo, Nihon-Kohden, Medtronic, Japan Lifeline, Otsuka, Ono, Boehringer Ingelheim, Takeda, Kowa, Zeon, Shionogi, Nippon-Shinyaku, Mochida, and Tesco. A.T., M.U. are employees of Sanofi.
H.A. participated in study design. All authors participated in data analysis and interpretation, writing or reviewing the manuscript, and final approval of the manuscript for submission.
This study was conducted in compliance with the Japanese ministerial ordinance Good Post-Marketing Study Practice. Under this regulation, this study did not require review or approval by the ethics committees of participating sites. All study participants provided written informed consent. All data were collected anonymously to protect personal information and the study sponsor had no access to individual participant medical records.
Qualified researchers may request access to patient-level data and related documents, including, for example, the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient-level data will be anonymized, and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi’s data sharing criteria, eligible studies, and process for requesting access can be found at https://www.vivli.org/.
Please find supplementary file(s);
https://doi.org/10.1253/circj.CJ-22-0445
