Efficacy and Safety of Alirocumab in Japanese Patients With Heterozygous Familial Hypercholesterolemia or at High Cardiovascular Risk With Hypercholesterolemia Not Adequately Controlled With Statins　– ODYSSEY JAPAN Randomized Controlled Trial –

Abstract

Background: The ODYSSEY Japan study was designed to demonstrate the reduction in low-density lipoprotein cholesterol (LDL-C) by alirocumab as add-on to existing lipid-lowering therapy in Japanese patients with heterozygous familial hypercholesterolemia (heFH) or non-FH at high cardiovascular risk who require additional pharmacological management to achieve their LDL-C treatment goal (<2.6 or <3.1 mmol/L, depending on risk category).

Methods and Results: This randomized, double-blind, parallel-group, 52-week study was conducted in Japan. Patients (n=216) with heFH, non-FH at high cardiovascular risk with coronary disease, or classified as category III were enrolled. The prespecified safety analysis was done after the last patient completed 52 weeks. Patients were randomized (2:1, alirocumab:placebo) with stratification for heFH to s.c. alirocumab (75 mg every 2 weeks [Q2 W] with increase to 150 mg if week 8 LDL-C ≥2.6/3.1 mmol/L) or placebo for 52 weeks plus stable statin therapy. At week 24, mean±SE change in LDL-C from baseline was –62.5±1.3% in the alirocumab group and 1.6±1.8% in the placebo group (difference, –64.1±2.2%; P<0.0001); the reduction was sustained to week 52 (alirocumab, –62.5±1.4%; placebo, –3.6±1.9%). No patterns were evident between treatment groups for adverse events at 52 weeks.

Conclusions: In high-risk Japanese patients with hypercholesterolemia on stable statin therapy, alirocumab markedly reduced LDL-C vs. placebo and was well tolerated over 52 weeks. (Circ J 2016; 80: 1980–1987)

Elevated low-density lipoprotein cholesterol (LDL-C) is a causal factor of coronary artery disease (CAD)¹ and is the primary target of lipid-lowering therapy (LLT).² Lowering LDL-C reduces the risk of CAD, with a direct correlation between LDL-C concentration and CAD events.³ The IMPROVE-IT study showed that the addition of ezetimibe to statin therapy provided a statistically significant and well-tolerated further cardiovascular benefit in high-risk patients when compared with statin treatment alone, but the reduction in LDL-C provided by ezetimibe and the overall treatment effect were modest.⁴

Editorial p 1903

According to the 2012 Japan Atherosclerosis Society (JAS) guidelines, drug therapy in parallel with lifestyle modification is required for dyslipidemic patients with a history of CAD or with familial hypercholesterolemia (FH). The target treatment goal is <2.6 mmol/L (<100 mg/dl) for LDL-C, or a decrease ≥50% from baseline, and the target non-high-density lipoprotein cholesterol (non-HDL-C) goal is <3.1 mmol/L (<130 mg/dl).⁵ For primary prevention in patients at high cardiovascular risk (classified as category III), the target LDL-C is <3.1 mmol/L (<120 mg/dl) and the target non-HDL-C is <3.9 mmol/L (<150 mg/dl).⁵ Data collected between 2009 and 2012, however, show that 38% of treated high-risk Japanese patients fail to achieve the target LDL-C concentration.⁶

Alirocumab is a fully human monoclonal antibody against proprotein convertase subtilisin/kexin 9 (PCSK9). Alirocumab as monotherapy or in combination with other LLT reduces LDL-C concentration by 40–73%.^7–18 The ODYSSEY Japan study (NCT02107898) was designed to demonstrate the reduction in LDL-C by alirocumab vs. placebo as add-on to stable daily statin treatment with or without other LLT in Japanese patients with heterozygous FH (heFH) or non-FH at high cardiovascular risk who require additional pharmacological management because their current statin therapy failed to achieve their LDL-C treatment goal. The effect of alirocumab on additional lipid parameters and its safety and tolerability over 52 weeks were also evaluated.

Methods

This was a randomized, double-blind, placebo-controlled, parallel-group, phase 3 study conducted at 31 sites in Japan. The subjects consisted of adults with heFH (diagnosed on genotyping or clinical criteria⁵) with or without a history of documented CAD (myocardial infarction, unstable angina, coronary revascularization procedure, or clinically significant CAD diagnosed on invasive or non-invasive testing), or patients with non-FH at high cardiovascular risk with a history of documented CAD, or classified as JAS category III (primary prevention).⁵ Patients were required to have hypercholesterolemia that was not adequately controlled despite taking a stable daily dose of statin therapy with or without other LLT. Inadequately controlled LDL-C was defined as concentration ≥2.6 mmol/L (≥100 mg/dl) at the screening visit in heFH patients or in non-FH patients with CAD, or ≥3.1 mmol/L (≥120 mg/dl) in category III patients. The stable daily dose of statin must have been taken for ≥4 weeks before the screening visit. The full study criteria are given in the Supplementary Online Material. The first patient was enrolled in March 2014 and the last patient completed the study in September 2015.

The study was performed in accordance with the 18th World Medical Assembly and all applicable amendments laid down by the World Medical Assemblies, and the International Conference on Harmonization guidelines for good clinical practice, all applicable laws, rules and regulations. The protocol was approved by the institutional review boards of participating centers. All patients gave written informed consent.

Intervention

The study consisted of a screening period of up to 3 weeks, a 52-week double-blind treatment period, and an 8-week off-treatment follow-up period (Figure S1). Patients were randomized (2:1, alirocumab:placebo), with stratification for heFH, to receive s.c. alirocumab 75 mg or placebo (1-ml injection volumes) every 2 weeks (Q2W) for 52 weeks on top of stable daily statin therapy (neither type nor dose of statin was prespecified) with or without other LLT. All study drugs were given via autoinjector by staff at the study site up to week 24, at which point the patient could choose to self-inject the study medication, without supervision, provided the investigator felt the patient was able to carry out the injection correctly. Patients choosing to self-inject could do so either at home or at the study site, with the exception of week 36, at which time blood sampling was undertaken at the study site, after which the patient could inject the medication.

Per protocol, the alirocumab dose was automatically increased at week 12 to 150 mg Q2W (1-ml injection volume) if week 8 LDL-C was ≥2.6 mmol/L (≥100 mg/dl) in heFH patients or in non-FH patients with a history of CAD, or ≥3.1 mmol/L (≥120 mg/dl) in category III patients. Investigators and patients remained blinded to any dose increase.

Patients were instructed to remain on a stable dose of statin or LLT and on a stable diet (JAS guidelines⁵ or equivalent) throughout the study, from screening onwards. Patients were not allowed to take fibrates (other than fenofibrate) or red yeast rice products.

Lipid variables were measured by a central laboratory. LDL-C concentration was calculated using the Friedewald formula.¹⁹ For patients whose triglycerides exceeded 4.5 mmol/L (400 mg/dl), the central laboratory automatically measured LDL-C using the β-quantification method (Covance-BML Clinical Trial Laboratory, Saitama, Japan, and Covance Central Laboratory Services, Singapore). Patients who achieved 2 consecutive calculated LDL-C levels <0.65 mmol/L (25 mg/dl) were particularly monitored.

Study Endpoints

The primary endpoint was the percent change in calculated LDL-C from baseline to week 24 using all LDL-C from week 24 regardless of adherence to treatment (intent-to-treat [ITT] approach). Principal secondary objectives included percent change in calculated LDL-C from baseline to week 24 (on-treatment analysis), calculated LDL-C from baseline to week 12 (ITT/on-treatment analysis), apolipoprotein B and non-HDL-C from baseline to week 24 (ITT/on-treatment analysis), total cholesterol, lipoprotein(a), fasting triglycerides, HDL-C and apolipoprotein A-1 from baseline to week 24 (ITT), apolipoprotein B, non-HDL-C, total cholesterol, lipoprotein(a), fasting triglycerides, HDL-C and apolipoprotein A-1 from baseline to week 12 (ITT); and the proportion of patients reaching the LDL-C goal at week 24 (<2.6 mmol/L [<100 mg/dl] for heFH patients or non-FH patients with a history of CAD, or <3.1 mmol/L [<120 mg/dl] for category III patients; ITT/on-treatment analysis).

Safety was assessed by analyzing adverse event reports (including adjudicated cardiovascular events and serious adverse events), laboratory analysis and vital signs assessed from the time of signed informed consent until the end of the study.

Statistical Analysis

A total sample size of 27 patients would have 90% power to detect a difference in mean percent change in LDL-C of 30% at a 0.05 2-sided significance level and assuming a common standard deviation of 20% and a 5% rate of a non-evaluable primary efficacy endpoint. To meet regulatory requirements, however, the sample size was set at 216 to assess the long-term safety of alirocumab. With this sample size, 100 patients were expected to be exposed to alirocumab for a minimum of 12 months, assuming a 12-month dropout rate of 30%, allowing adverse events with a rate ≥0.03 to be detected with 95% probability.

The subjects for the primary efficacy analysis consisted of randomized patients with calculated LDL-C at baseline and at least one of the planned time-points (from weeks 4 to 24), regardless of treatment adherence (ITT group). The on-treatment group (modified ITT) was defined as all randomized patients who took at least 1 dose or partial dose (in the event that <1 ml was injected) of the randomized treatment and had an evaluable primary efficacy endpoint during the treatment period. The treatment period was defined as the time from the first double-blind injection up to 21 days after the last double-blind injection. The safety group consisted of the randomized population who received at least 1 dose or partial dose of study medication. The safety group was analyzed according to the treatment actually received.

The primary endpoint was analyzed using a mixed effect model with a repeated measures (MMRM) approach to account for missing data. All available post-baseline data at planned time-points from weeks 4 to 24 regardless of status on or off treatment were used in the MMRM approach for the ITT analysis, with the model used to provide least-squares (LS) mean±SE estimates and comparison between treatment arms of LDL-C reductions at week 24. The models included fixed categorical effects of treatment group, time-point, randomization strata, treatment-by-time-point interaction, and randomization strata-by-time-point interaction, as well as the continuous fixed covariates of baseline LDL-C and baseline value-by-time-point interaction.

A hierarchical procedure was used to control type I error and handle multiple endpoints. Given that the primary endpoint analysis was significant at the 5% α level, key secondary efficacy endpoints were tested sequentially in the order defined in the Supplementary Online Material.

Secondary endpoints consisting of continuous variables with a normal distribution were analyzed using the MMRM model. Secondary endpoints with a non-normal distribution (lipoprotein(a) and triglycerides) and the binary (non-continuous) variable secondary endpoints were analyzed using a multiple imputation approach for handling of missing values followed by robust regression (for lipoprotein(a) and triglycerides) or logistic regression (for the binary endpoints).

Data from the safety analysis (adverse events, laboratory findings, and vital signs) are reported descriptively. The treatment-emergent adverse event (TEAE) period was defined as the time from the first double-blind dose to the last double-blind dose of study treatment +70 days (10 weeks). TEAEs were adverse events that developed or worsened or became serious during the TEAE period.

The analysis was performed using SAS version 9.2 (SAS Institute, Cary, NC, USA).

Results

Of the 319 patients screened, 216 met the eligibility criteria; 144 were randomly allocated to receive alirocumab and 72 to receive placebo (Figure 1). One patient in the alirocumab arm was randomized twice and did not have an LDL-C measurement within one of the analysis windows up to week 24 and was excluded from the safety and ITT groups (no adverse events were reported for this patient). Two patients (one in each treatment arm) who lacked LDL-C measurements were excluded from the on-treatment group.

Figure 1.

Disposition of patients in the ODYSSEY JAPAN Trial. ITT, intention to treat; Q2 W, every 2 weeks.

The mean±SD age of the study group was 60.8±9.5 years, 60.6% were men, 68.5% had diabetes mellitus, and 49.5% had body mass index ≥25 kg/m². Overall, 19.0% (n=41) had heFH, 18.5% (n=25) had a history of CAD, and 69.4% (n=150) were categorized as JAS category III.⁵ The mean calculated LDL-C at baseline was 3.7±0.7 mmol/L (141.2±26.7 mg/dl). The baseline characteristics of the two randomized groups were generally well matched (Table 1). All patients were receiving a stable daily dose of statin as background LLT, and 14.4% were receiving additional LLT.

Table 1. Baseline Characteristics

Characteristic	Alirocumab (n=144)	Placebo (n=72)
Age (years)	60.3±9.7	61.8±9.0
Men, n (%)	84 (58.3)	47 (65.3)
Body mass index (kg/m2)	25.6±4.3	25.4±3.2
Heterozygous familial hypercholesterolemia	27 (18.8)	14 (19.4)
Cardiovascular history and risk factors
Myocardial infarction	12 (8.3)	4 (5.6)
Unstable angina	6 (4.2)	4 (5.6)
Coronary revascularization procedure	18 (12.5)	13 (18.1)
Other clinically significant CAD	10 (6.9)	10 (13.9)
Ischemic stroke	2 (1.4)	1 (1.4)
Peripheral artery disease	0	0
Chronic kidney disease	8 (5.6)	5 (6.9)
Diabetes mellitus	105 (72.9)	43 (59.7)
Other risk factors	98 (68.1)	51 (70.8)
10-year fatal CAD risk ≥2%	2 (1.4)	1 (1.4)
10-year fatal CAD risk ≥0.5% and <2%	83 (57.6)	44 (61.1)
Hypo-HDL cholesterolemia	9 (6.3)	7 (9.7)
Family history of premature CAD	13 (9.0)	6 (8.3)
Impaired glucose tolerance	8 (5.6)	6 (8.3)
Laboratory values
Lipid parameters
LDL-C (Friedewald formula) (mmol/L)	3.7±0.7	3.7±0.7
Range	2.4–6.4	2.4–5.6
Apolipoprotein B (g/L)	1.1±0.2	1.1±0.2
Total cholesterol (mmol/L)	5.8±0.8	5.9±0.9
Non-HDL-C (mmol/L)	4.4±0.8	4.4±0.8
Lipoprotein (a) (mg/dl)	16.8 (10.1–35.9)	14.7 (8.5–33.7)
Triglycerides (fasted) (mmol/L)	1.4 (1.1–2.0)	1.5 (0.9–2.0)
HDL-C (mmol/L)	1.4±0.3	1.4±0.4
Background lipid-lowering therapy at randomization
Statin therapy
Pravastatin (5–20 mg/day)	60 (41.7)	37 (51.4)
Rosuvastatin (2.5–20 mg/day)	31 (21.5)	9 (12.5)
Atorvastatin (5–40 mg/day)	21 (14.6)	14 (19.4)
Pitavastatin (0.5–4 mg/day)	22 (15.3)	10 (13.9)
Simvastatin (5–10 mg/day)	7 (4.9)	1 (1.4)
Fluvastatin (20–30 mg/day)	3 (2.1)	1 (1.4)
Any non-statin lipid-lowering therapy	19 (13.2)	12 (16.7)

Data given as mean±SD, n (%) or median (IQR). CAD, coronary artery disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

The alirocumab dose was increased (per protocol) to 150 mg Q2 W at week 12 in 2/140 (1.4%) patients in the alirocumab arm who had received at least 1 injection at or after week 12; both patients had heFH. Baseline LDL-C in these patients was 5.9 mmol/L (227 mg/dl) and 6.2 mmol/L (240 mg/dl).

One hundred and thirty-three patients (93.0%) in the alirocumab arm and 66 (91.7%) in the placebo arm remained on treatment throughout the double-blind period. The primary reason for treatment discontinuation was occurrence of an adverse event (Figure 1).

Lipid and Lipoprotein Response

For the primary ITT efficacy analysis, LS mean±SE change in LDL-C concentration from baseline to week 24 was –62.5±1.3% in the alirocumab group and 1.6±1.8% in the placebo group, with a difference between groups of –64.1±2.2% (P<0.0001; Table 2). Mean on-treatment LDL-C at week 24 was 1.3±0.04 mmol/L (52.0±1.7 mg/dl) with alirocumab and 3.7±0.1 mmol/L (143.6±2.4 mg/dl) with placebo; the LS mean±SE change from baseline was –63.7±1.2% for alirocumab and 1.7±1.7% for placebo (LS mean±SE difference, –65.3±2.1%, P<0.0001). In the ITT group, mean LDL-C concentration in the alirocumab group had decreased by 61.7% from baseline over the first 4 weeks, and the reduction was maintained up to week 52 (62.5%; Figure 2). A statistically significant decrease in LDL-C from baseline to week 12 (before possible up-titration; ITT analysis) was observed in the alirocumab group (LS mean±SE, –64.2±1.1%) compared with the placebo group (–2.7±1.6%), with an LS mean difference of –61.5% (95% CI: –65.3 to –57.7; P<0.0001; Table 2). By week 24, 96.7% of patients on alirocumab had achieved the LDL-C goal vs. 10.2% on placebo (P<0.0001). Similar results were observed in the on-treatment analysis (97.9% vs. 10.6%, respectively; P<0.0001).

Table 2. Percent Change in LDL-C and Secondary Lipid Variables

	ITT or OT	Baseline to week 12 or 24	Alirocumab	Placebo	Alirocumab vs. placebo
					LS difference (%)	95% CI	P-value
Primary endpoint: LDL-C
LS change from baseline (%)	ITT	24	n=143, −62.5±1.3	n=72, 1.6±1.8	−64.1±2.2	−68.5 to −59.8	<0.0001
Baseline LDL-C (mmol/L)†	OT	24	n=143, 3.7±0.7	n=71, 3.7±0.7	–	–	–
Range			2.4–6.4	2.4–5.6
LS change from baseline (%)			−63.7±1.2	1.7±1.7	−65.3±2.1	−69.4 to −61.3	<0.0001
Secondary lipid parameters, LS change from baseline (%)			n=143	n=72
LDL-C	ITT	12	−64.2±1.1	−2.7±1.6	−61.5±1.9	−65.3 to −57.7	<0.0001
LDL-C	OT	12	−64.8±1.1	−2.8±1.5	−62.1±1.9	−65.8 to −58.3	<0.0001
Apolipoprotein B	ITT	24	−55.0±1.2	−1.6±1.7	−53.3±2.1	−57.5 to −49.1	<0.0001
Apolipoprotein B	OT	24	−55.9±1.2	−2.1±1.7	−55.9±1.2	−57.8 to −49.8	<0.0001
Non-HDL-C	ITT	24	−54.9±1.2	2.6±1.6	−57.5±2.0	−61.5 to −53.5	<0.0001
Non-HDL-C	OT	24	−56.0±1.1	2.6±1.6	−58.6±1.9	−62.3 to −54.8	<0.0001
Total cholesterol	ITT	24	−39.5±0.9	2.0±1.3	−41.5±1.6	−44.6 to −38.4	<0.0001
Apolipoprotein B	ITT	12	−54.6±1.1	−3.3±1.5	−51.2±1.8	−54.9 to −47.6	<0.0001
Non-HDL-C	ITT	12	−56.3±1.0	−1.7±1.4	−54.5±1.7	−57.9 to −51.1	<0.0001
Total cholesterol	ITT	12	−41.1±0.8	−2.1±1.1	−39.0±1.4	−41.7 to −36.4	<0.0001
Lipoprotein (a)‡	ITT	24	−39.5±1.8	2.5±2.5	−42.0±3.1	−48.0 to −36.0	<0.0001
Triglycerides (fasted)‡	ITT	24	−15.3±2.6	6.7±3.7	−22.0±4.5	−30.9 to −13.1	<0.0001
HDL-C	ITT	24	7.9±1.1	2.1±1.5	5.8±1.8	2.1 to 9.4	0.0020
Apolipoprotein A-1	ITT	24	1.4±1.1	−2.6±1.6	4.0±1.9	0.2 to 7.9	0.0382
Lipoprotein (a)‡	ITT	12	−41.9±1.7	−0.5±2.4	−41.4±2.9	−47.0 to −35.7	<0.0001
Triglycerides (fasted)‡	ITT	12	−13.1±2.6	2.4±3.7	−15.5±4.5	−24.4 to −6.6	0.0007
HDL-C	ITT	12	4.7±0.8	−1.8±1.2	6.5±1.4	3.7 to 9.3	<0.0001
Apolipoprotein A-1	ITT	12	1.5±0.8	−4.8±1.1	6.3±1.4	3.6 to 9.0	<0.0001

Data given as mean±SE or ^†mean±SD. ^‡Combined estimate obtained by combining adjusted means±SE from robust regression model analysis of the different imputed datasets (multiple imputation). ITT, intention-to-treat; LS, least squares; OT, on treatment. Other abbreviations as in Table 1.

Figure 2.

Calculated low-density lipoprotein cholesterol (LDL-C) achieved vs. study time points (intention-to-treat analysis). Percentages at week 24 and 52 indicate least squares (LS) mean±SE percent change from baseline.

The absolute LS mean±SE change from baseline in calculated LDL-C was greater in the alirocumab group (ITT analysis) at weeks 12 (–2.3±0.04 mmol/L [–89.9±1.6 mg/dl] vs. –0.1±0.06 mmol/L [–4.7±2.2 mg/dl] placebo; P<0.001) and 24 (–2.3±0.05 mmol/L [–87.7±1.8 mg/dl] vs. 0.06±0.07 mmol/L [2.1±2.5 mg/dl]; P<0.001). The LS mean difference for alirocumab vs. placebo at week 12 was –2.2 mmol/L (95% CI: –2.3 to –2.1; –85.2 mg/dl, 95% CI: –90.6 to –79.8). Corresponding data at week 24 were –2.3 mmol/L (95% CI: –2.5 to –2.2; –89.9 mg/dl, 95% CI: –96.1 to –83.8). Mean achieved on-treatment LDL-C at week 24 was 1.3±0.04 mmol/L (52.0±1.7 mg/dl) with alirocumab and 3.7±0.1 mmol/L (143.6±2.4 mg/dl) with placebo.

The reductions in apolipoprotein B, non-HDL-C, total cholesterol, lipoprotein(a) and fasting triglycerides at weeks 12 and 24 were all significant vs. placebo (all P<0.001; Table 2). Statistically significant increases in mean HDL-C and apolipoprotein A-1 with alirocumab vs. placebo were also observed.

Safety

Overall, 90.9% of patients on alirocumab and 83.3% on placebo experienced 1 or more adverse event by 52 weeks, none of which was fatal (Table 3). The overall rate of serious adverse events was less frequent in the alirocumab arm (7.0% vs. 12.5% on placebo). The rates of TEAEs leading to treatment discontinuation were similar (4.9% on alirocumab and 5.6% on placebo).

Table 3. TEAEs and Laboratory Variables^† at 52 Weeks

	Alirocumab (n=143)	Placebo (n=72)
Any TEAE	130 (90.9)	60 (83.3)
Treatment-emergent SAE	10 (7.0)	9 (12.5)
TEAE leading to death	0	0
TEAE leading to treatment discontinuation	7 (4.9)	4 (5.6)
TEAE (primary system organ class level) occurring in ≥1% of patients in either group
Infections and infestations	85 (59.4)	36 (50.0)
Musculoskeletal disorders and connective tissue disorders	48 (33.6)	24 (33.3)
Gastrointestinal disorders	41 (28.7)	20 (27.8)
Injury, poisoning and procedural complications	32 (22.4)	10 (13.9)
General disorders and administration site conditions	29 (20.3)	10 (13.9)
Metabolism and nutrition disorders	23 (16.1)	7 (9.7)
Nervous system disorders	22 (15.4)	8 (11.1)
Skin and subcutaneous tissue disorders	17 (11.9)	9 (12.5)
Respiratory, thoracic and mediastinal disorders	13 (9.1)	6 (8.3)
Laboratory investigations‡	12 (8.4)	0
Eye disorders	11 (7.7)	9 (12.5)
Vascular disorders	11 (7.7)	8 (11.1)
Renal and urinary disorders	10 (7.0)	4 (5.6)
Cardiac disorders	10 (7.0)	2 (2.8)
Hepatobiliary disorders	6 (4.2)	3 (4.2)
Reproductive system and breast disorders	6 (4.2)	1 (1.4)
Neoplasms, benign, malignant and unspecified (including cysts and polyps)	5 (3.5)	3 (4.2)
Immune system disorders	4 (2.8)	5 (6.9)
Psychiatric disorders	3 (2.1)	1 (1.4)
Ear and labyrinth disorders	3 (2.1)	2 (2.8)
Blood and lymphatic system	1 (0.7)	0
Endocrine disorders	1 (0.7)	0
TEAE (preferred term level) in ≥1% of patients in either group
Nasopharyngitis	65 (45.5)	26 (36.1)
Back pain	18 (12.6)	4 (5.6)
Injection site reaction	18 (12.6)	3 (4.2)
Hypertension	9 (6.3)	5 (6.9)
Arthralgia	4 (2.8)	6 (8.3)
Headache	5 (3.5)	2 (2.8)
Dizziness	5 (3.5)	0
Myalgia	2 (1.4)	3 (4.2)
Influenza	1 (0.7)	6 (8.3)
Sinusitis	0	1 (1.4)
Adjudicated cardiovascular events (any patient with treatment-emergent event)	3 (2.1)	1 (1.4)
Non-fatal myocardial infarction	1 (0.7)	1 (1.4)
Congestive heart failure requiring hospitalization	1 (0.7)	0
Ischemia-driven coronary revascularization procedure	2 (1.4)	1 (1.4)
Laboratory parameters
Alanine aminotransferase >3×ULN	5 (3.5)	1 (1.4)
Aspartate aminotransferase	2 (1.4)	1 (1.4)
Bilirubin >2×ULN	0	1 (1.4)
Creatine kinase >3×ULN	5 (3.5)	0

Data given as n (%). ^†Safety group. ^‡Alanine aminotransferase increased, liver function test abnormal, blood creatine phosphokinase increased. SAE, serious adverse event; TEAE, treatment-emergent adverse event; ULN, upper limit of normal.

The most common TEAEs (occurring in ≥10% of patients in either group) by primary system organ class were infections and infestations; musculoskeletal or connective tissue disorders; gastrointestinal disorders; injury, poisoning and procedural complications; general disorders and administration site conditions; metabolism and nutrition disorders; nervous system disorders; skin and subcutaneous tissue disorders; eye disorders; and vascular disorders (Table 3). Adjudicated cardiovascular events were infrequent, occurring in 2.1% of patients on alirocumab and in 1.4% on placebo. Most frequently reported TEAEs for the alirocumab group at the preferred term level were nasopharyngitis, back pain, and injection site reactions. One case of prostatitis and one of nephrotic syndrome (both in the placebo group) were judged related to the study treatment by the investigator. A relationship between alirocumab and a case of congestive heart failure was not ruled out by the investigator. No relevant abnormalities were observed for any potentially clinically significant laboratory abnormality.

Seventeen patients (12.1%) in the alirocumab arm (none in the placebo arm) had 2 consecutive LDL-C measurements <0.65 mmol/L (<25 mg/dl) during the treatment period, including 3 (2.1%) whose calculated LDL-C was <0.39 mmol/L (15 mg/dl). Rates of TEAEs in this group are detailed in Table S1. The overall rate of TEAEs was similar to that in the placebo arm (82.4% and 83.3%, respectively).

Sixty-two of 205 patients (30.2%) chose to self-inject the study medication from week 24. The overall rates of TEAEs occurring from week 24 onwards were lower among patients who self-injected vs. those whose study medication was injected by study personnel, in the alirocumab (68.3% vs. 81.9%) and the placebo (57.1% vs. 77.6%) groups (Table S2). In the alirocumab group, 2 patients had 2 adverse events each and the third had 1 event; 1 patient discontinued self-injection. Injection site reactions were infrequent and were of mild intensity among patients who chose to self-inject.

Discussion

The results of this randomized, double-blind, phase 3 study demonstrate a marked reduction in LDL-C with alirocumab in Japanese patients with heFH or non-FH at high cardiovascular risk with inadequately controlled hypercholesterolemia on statins with or without other LLT. The mean difference in LDL-C with alirocumab vs. placebo was 64.1% at week 24, and the reduction was sustained to week 52. By week 24, 96.7% of the patients in the alirocumab group achieved the target LDL-C concentration compared with 10.2% of the patients on placebo.

At week 24, alirocumab also resulted in beneficial effects on other lipids, including a marked reduction in lipoprotein(a), an independent predictor of CAD,^20,21 and an increase in HDL-C. In a pooled analysis of three double-blind phase 2 trials, alirocumab 150 mg Q2W produced a 30% reduction vs. placebo (P<0.0001) in lipoprotein(a).²² An even greater reduction (–43.3%) was observed in a Japanese phase 2 study in hypercholesterolemic patients on alirocumab 150 mg Q2W.¹⁴ The mechanism by which alirocumab reduces lipoprotein(a) is as yet unclear, but Gaudet et al postulated that upregulation of LDL receptors by statins and alirocumab, combined with very low concentrations of LDL-C and apolipoprotein B, resulted in the uptake of lipoprotein(a) by LDL receptors.²² Unlike other ODYSSEY studies, in which the medication was self-administered from the outset,^11,13 in this Japanese study all patients were injected by the study personnel up to week 24, at which point they could choose to self-inject the medication. The overall rate of subsequent TEAEs was lower among patients who chose to self-inject, and no differences were apparent in the rates of injection site reactions between patients who self-administered the medication and patients in whom the injections were given by site personnel.

The phase 3 YUKAWA-2 study showed that the PCSK9 monoclonal antibody evolocumab reduced LDL-C by ≥67% vs. placebo at 12 weeks, and was well tolerated in Japanese patients with hyperlipidemia or mixed dyslipidemia and high cardiovascular risk on atorvastatin 5 or 20 mg/day.²³ The present study provides evidence that the efficacy of alirocumab is sustained up to 52 weeks, and has an acceptable safety profile. The overall rate of TEAEs was similar in the alirocumab and placebo groups, and was driven by non-serious events. Serious events were infrequent, occurring in 7.0% of patients on alirocumab and in 12.5% on placebo. Seventeen patients (12.1%) on alirocumab had 2 consecutive LDL-C measurements <0.65 mmol/L (<25 mg/dl). In the phase 2 YUKAWA study, 90 of 205 (43.9%) statin-treated patients on evolocumab reported LDL-C <0.65 mmol/L.²⁴ In the present study, 12.1% of patients in the alirocumab arm had 2 consecutive LDL-C measurements <0.65 mmol/L (<25 mg/dl), including 2.1% with LDL-C <0.39 mmol/L (<15 mg/dl); the overall rate of TEAEs was similar to that in the placebo arm. A pooled analysis was conducted with data from 14 trials involving 3,340 patients on alirocumab. No safety signals were observed in patients with pharmacologically induced LDL-C <0.65 mmol/L (<25 mg/dl; 23.8% of patients) or <0.39 mmol/L (15 mg/dl; 8.6% of patients). The consequences of lowering LDL-C to very low levels are still under investigation, and the ongoing ODYSSEY OUTCOMES study will extend these findings.²⁵ Given that the background statin therapy in ODYSSEY JAPAN was not restricted to one specific statin treatment or dose, the findings are more broadly applicable to current clinical practice for the management of hyperlipidemia in Japan.

A report from the 2002 Japan Lipid Assessment Program found that nearly half of patients failed to reach the JAS target goals for LDL-C despite receiving statin treatment.²⁶ While more recent data show an improvement in goal attainment (62% on target),⁶ a substantial proportion of patients still require additional LLT. Shioji et al demonstrated that switching from atorvastatin to rosuvastatin increased the proportion of patients who attained the goals (P=0.010), but half of the patients on the more potent statin still had elevated LDL-C.²⁷ There is therefore a clear need for new therapies that offer clinically meaningful incremental reductions in LDL-C to those afforded by existing LLT. The PCSK9 monoclonal antibodies have demonstrated clear therapeutic potential in the treatment of hypercholesterolemia, including patients with FH, exhibiting potent ability to lower LDL-C concentration, with an acceptable safety profile.²⁸ Preliminary findings, based on study-level data, also suggest a potential reduction in the risk of all-cause death, cardiovascular death, and myocardial infarction.²⁹ Cardiovascular outcomes with alirocumab are currently being investigated in a large ongoing study (http://clinicaltrials.gov/show/NCT01663402),³⁰ and will be assessed in a pooled analysis from the overall ODYSSEY program.

Conclusions

In Japanese patients with heFH or non-FH at high cardiovascular risk with hypercholesterolemia not adequately controlled on stable statin therapy, a dose-increase approach with alirocumab resulted in large reductions vs. placebo in LDL-C, with a similar long-term safety profile.

Acknowledgments

We thank the participants and investigators, and the following persons from the sponsors for their contributions to data collection and analysis, assistance with statistical analysis, or critical review of the manuscript: Regeneron: William J. Sasiela, PhD; Lisa Collins, BSc; Jaman Maroni, MD; Michael Louie, MD, MPH; and Carol Hudson, BPharm; Sanofi: Jay Edelberg, MD, PhD; L. Veronica Lee, MD; Holly C. Schachner, MD; Guillaume Lecorps, MSc; and Michael Howard, MBA. Writing support was provided by Sophie K. Rushton-Smith, PhD, funded by Sanofi and Regeneron Pharmaceuticals. This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc. The sponsor was involved in the study design; in the writing of the report; and in the decision to submit the article for publication.

Disclosures

T.T., remuneration by Sanofi; T.H., research funding by Sanofi; A.N., endowed departments by commercial entities by Sanofi. M.K., Y.T., K.U., and M.T.B.-D. are employees of Sanofi. The other authors declare no conflicts of interest.

Supplementary Files

Supplementary File 1

Supplementary Online Material

Figure S1. Study design.

Table S1. TEAEs (Safety Group) at 52 weeks in patients with 2 consecutive LDL-C <0.65 mmol/L (25 mg/dl)

Table S2. TEAEs from week 24 vs. self-injection status

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-16-0387

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