Praluent - Pharmacology alirocumab

Alirocumab is a human monoclonal antibody (IgG1 isotype) that targets proprotein convertase subtilisin kexin type 9 (PCSK9). Alirocumab is a PCSK9 inhibitor produced by recombinant DNA technology in Chinese Hamster Ovary cell suspension culture. Alirocumab consists of two disulfide-linked human heavy chains, each covalently linked through a disulfide bond to a human kappa light chain. A single N-linked glycosylation site is located in each heavy chain within the CH2 domain of the Fc constant region of the molecule. The variable domains of the heavy and light chains combine to form the PCSK9 binding site within the antibody. Alirocumab has an approximate molecular weight of 146 kDa.

PRALUENT is a sterile, preservative-free, clear, colorless to pale yellow solution for subcutaneous injection. PRALUENT 75 mg/mL or 150 mg/mL solution for subcutaneous injection in a single-dose pre-filled pen or single-dose pre-filled syringe is supplied in a siliconized 1 mL Type-1 clear glass syringe. The needle shield is not made with natural rubber latex.

Each 75 mg/mL pre-filled pen or pre-filled syringe contains 75 mg alirocumab, histidine (8 mM), polysorbate 20 (0.1 mg), sucrose (100 mg), and Water for Injection USP, to pH 6.0.

Each 150 mg/mL pre-filled pen or pre-filled syringe contains 150 mg alirocumab, histidine (6 mM), polysorbate 20 (0.1 mg), sucrose (100 mg), and Water for Injection USP, to pH 6.0.

Alirocumab is a human monoclonal antibody that binds to proprotein convertase subtilisin kexin type 9 (PCSK9). PCSK9 binds to the low-density lipoprotein receptors (LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver. LDLR is the primary receptor that clears circulating LDL, therefore the decrease in LDLR levels by PCSK9 results in higher blood levels of LDL-C. By inhibiting the binding of PCSK9 to LDLR, alirocumab increases the number of LDLRs available to clear LDL, thereby lowering LDL-C levels.

Alirocumab reduced free PCSK9 in a concentration-dependent manner. Following a single subcutaneous administration of alirocumab 75 or 150 mg, maximal suppression of free PCSK9 occurred within 4 to 8 hours. Free PCSK9 concentrations returned to baseline when alirocumab concentrations decreased below the limit of quantitation.

Absorption

After subcutaneous (SC) administration of 75 mg to 300 mg alirocumab, median times to maximum serum concentrations (t_max) were 3–7 days. The pharmacokinetics of alirocumab after single SC administration of 75 mg into the abdomen, upper arm, or thigh were similar. The absolute bioavailability of alirocumab after SC administration was about 85% as determined by population pharmacokinetics analysis. A slightly greater than dose proportional increase was observed, with a 2.1-fold to 2.7-fold increase in total alirocumab concentrations for a 2-fold increase in dose from 75 mg every 2 weeks to 150 mg every 2 weeks. Monthly dose normalized exposure with 300 mg every 4 weeks treatment was similar to that of 150 mg every 2 weeks. Steady state was reached after 2 to 3 doses with an accumulation ratio up to a maximum of about 2-fold.

Distribution

Following IV administration, the volume of distribution was about 0.04 to 0.05 L/kg indicating that alirocumab is distributed primarily in the circulatory system.

Metabolism and Elimination

Specific metabolism studies were not conducted, because alirocumab is a protein. Alirocumab is expected to degrade to small peptides and individual amino acids. In clinical studies where alirocumab was administered in combination with atorvastatin or rosuvastatin, no relevant changes in statin concentrations were observed in the presence of repeated administration of alirocumab, indicating that cytochrome P450 enzymes (mainly CYP3A4 and CYP2C9) and transporter proteins such as P-gp and OATP were not affected by alirocumab.

Two elimination phases were observed for alirocumab. At low concentrations, the elimination is predominately through saturable binding to target (PCSK9), while at higher concentrations the elimination of alirocumab is largely through a non-saturable proteolytic pathway.

Based on a population pharmacokinetic analysis, the median apparent half-life of alirocumab at steady state was 17 to 20 days in patients receiving alirocumab at subcutaneous doses of 75 mg Q2W or 150 mg Q2W.

Specific Populations

A population pharmacokinetic analysis was conducted on data from 2799 patients. Age, body weight, gender, race, and creatinine clearance were found not to significantly influence alirocumab pharmacokinetics. No dose adjustments are recommended for these demographics.

Pediatric

PRALUENT has not been studied in pediatric patients [see Use in Specific Populations (8.4) ].

Renal impairment

Since monoclonal antibodies are not known to be eliminated via renal pathways, renal function is not expected to impact the pharmacokinetics of alirocumab.

No data are available in patients with severe renal impairment.

Hepatic impairment

Following administration of a single 75 mg SC dose, alirocumab pharmacokinetic profiles in patients with mild and moderate hepatic impairment were similar to those in patients with normal hepatic function.

No data are available in patients with severe hepatic impairment.

Drug-Drug Interactions

The median apparent half-life of alirocumab is reduced to 12 days when administered with a statin; however, this difference is not clinically meaningful and does not impact dosing recommendations.

Carcinogenicity studies have not been conducted with alirocumab. The mutagenic potential of alirocumab has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.

There were no adverse effects on surrogate markers of fertility (e.g., estrous cyclicity, testicular volume, ejaculate volume, sperm motility, or total sperm count per ejaculate) in a 6-month chronic toxicology study in sexually-mature monkeys subcutaneously administered at 5, 15, and 75 mg/kg/week at systemic exposures up to 103-fold the 150 mg every two weeks subcutaneous clinical dose based on serum AUC. In addition, there were no adverse alirocumab-related anatomic pathology or histopathology findings in reproductive tissues in rat or monkey toxicology studies at systemic exposures up to 11-fold and 103-fold respectively, in the 6-month studies, compared to clinical systemic exposure following a 150 mg every two weeks dose, based on serum AUC.

During a 13-week toxicology study of 75 mg/kg once weekly alirocumab in combination with 40 mg/kg once daily atorvastatin in adult monkeys, there were no effects of PRALUENT on the humoral immune response to keyhole limpet hemocyanin (KLH) after one to two months at exposures 100-fold greater than the exposure at the maximum recommended human dose of 150 mg every two weeks, based on AUC.

Study 1 (ODYSSEY OUTCOMES, NTC01663402) was a multicenter, double-blind, placebo-controlled trial in 18,924 adult patients (9462 PRALUENT; 9462 placebo) followed for up to 5 years. Patients had an acute coronary syndrome (ACS) event 4 to 52 weeks prior to randomization and were treated with a lipid-modifying–therapy (LMT) regimen that was statin-intensive (defined as atorvastatin 40 or 80 mg, or rosuvastatin 20 or 40 mg) or at maximally tolerated dose of a statin, with or without other LMT. Patients were randomized to receive either PRALUENT 75 mg once every two weeks (Q2W) or placebo Q2W. The PRALUENT 300 mg Q4W dose [see Dosage and Administration (2.1) ] was not evaluated in this study.

At month 2, if additional LDL-C lowering was required based on pre-specified LDL-C criteria (LDL-C ≥50 mg/dL), PRALUENT was adjusted to 150 mg Q2W. For patients who had their dose adjusted to 150 mg Q2W and who had two consecutive LDL-C values below 25 mg/dL, down-titration from 150 mg Q2W to 75 mg Q2W was performed. Patients on 75 mg Q2W who had two consecutive LDL-C values below 15 mg/dL were switched to placebo in a blinded fashion. Approximately 2615 (27.7%) of 9451 patients treated with PRALUENT required dose adjustment to 150 mg Q2W. Of these 2615 patients, 805 (30.8%) were down-titrated to 75 mg Q2W. Overall, 730 (7.7%) of 9451 patients switched to placebo.

A total of 99.5% of patients were followed for survival until the end of the trial. The median follow-up duration was 33 months.

The mean age at baseline was 59 years (range 39–92), with 25% women, and 27% at least 65 years old. The trial population was 79% Caucasian, 3% Black, and 13% Asian; 17% identified as Hispanic/Latino ethnicity. The index ACS event was a myocardial infarction in 83% of patients and unstable angina in 17% of patients. Prior to the index ACS event, 19% had prior myocardial infarction and 23% had coronary revascularization procedures (CABG/PCI). Selected additional baseline risk factors included hypertension (65%), diabetes mellitus (25%), New York Association class I or II congestive heart failure (15%), and eGFR <60 mL/min/1.73 m² (13%). Most patients (89%) were receiving statin-intensive therapy with or without other LMT at randomization. The mean LDL-C value at baseline was 92.4 mg/dL.

PRALUENT significantly reduced the risk for the primary composite endpoint (time to first occurrence of coronary heart disease death, non-fatal myocardial infarction, fatal and non-fatal ischemic stroke, or unstable angina requiring hospitalization: p=0.0003). The results are presented in Table 2.

The Kaplan-Meier estimates of the cumulative incidence of the primary endpoint over time is presented in Figure 1.

Figure 1: Primary Composite Endpoint Cumulative Incidence over 4 Years in ODYSSEY OUTCOMES

Study 2 (ODYSSEY LONG TERM, NCT01507831) was a multicenter, double-blind, placebo-controlled trial that randomly assigned 1553 patients to PRALUENT 150 mg Q2W and 788 patients to placebo. All patients were taking maximally tolerated doses of statins with or without other lipid-modifying therapy, and required additional LDL-C reduction. The mean age was 61 years (range 18–89), 38% were women, 93% were Caucasian, 3% were Black, and 5% were Hispanic/Latino. The average LDL-C at baseline was 122 mg/dL.

The proportion of patients who prematurely discontinued study drug prior to the 24-week primary endpoint was 8% among those treated with PRALUENT and 8% among those treated with placebo.

At week 24, the treatment difference between PRALUENT and placebo in mean LDL-C percent change was -58% (95% CI: -61%, -56%; p-value: ˂0.0001).

For additional results see Table 3 and Figure 2.

a The means were estimated based on all randomized patients, with multiple imputation of missing data taking into account treatment adherence. b Number of patients with observed data.

Figure 2: Mean Percent Change from Baseline in LDL-C Over 52 Weeks in Patients on Maximally Tolerated Statin Treated with PRALUENT 150 mg Q2W and Placebo Q2W (ODYSSEY LONG TERM)a

Study 3 (ODYSSEY COMBO I, NCT01644175) was a multicenter, double-blind, placebo-controlled trial that randomly assigned 209 patients to PRALUENT and 107 patients to placebo. Patients were taking maximally tolerated doses of statins with or without other lipid-modifying therapy, and required additional LDL-C reduction.

The mean age was 63 years (range 39–87), 34% were women, 82% were Caucasian, 16% were Black, and 11% were Hispanic/Latino. Mean baseline LDL-C was 102 mg/dL.

The proportion of patients who prematurely discontinued study drug prior to the 24-week primary endpoint was 11% among those treated with PRALUENT and 12% among those treated with placebo.

At week 12, the mean percent change from baseline in LDL-C was -45% with PRALUENT compared to 1% with placebo, and the treatment difference between PRALUENT 75 mg Q2W and placebo in mean LDL-C percent change was -46% (95% CI: -53%, -39%).

At week 12, if additional LDL-C lowering was required based on pre-specified LDL-C criteria, PRALUENT was up-titrated to 150 mg Q2W for the remainder of the trial. The dose was up-titrated to 150 mg Q2W in 32 (17%) of 191 patients treated with PRALUENT for at least 12 weeks. At week 24, the mean percent change from baseline in LDL-C was -44% with PRALUENT and -2% with placebo, and the treatment difference between PRALUENT and placebo in mean LDL-C percent change was -43% (95% CI: -50%, -35%; p-value: <0.0001).

Studies 4 (ODYSSEY FH I, NCT01623115) and 5 (ODYSSEY FH II, NCT01709500) were multicenter, double-blind, placebo-controlled trials that, combined, randomly assigned 490 patients to PRALUENT and 245 patients to placebo. The trials were similar with regard to both design and eligibility criteria. All patients had HeFH, were taking a maximally tolerated dose of statin with or without other lipid-modifying therapy, and required additional LDL-C reduction. The diagnosis of HeFH was made either by genotyping or clinical criteria ("definite FH" using either the Simon Broome or WHO/Dutch Lipid Network criteria). The mean age was 52 years (range 20–87), 45% were women, 94% were Caucasian, 1% were Black, and 3% were Hispanic/Latino. The average LDL-C at baseline was 141 mg/dL.

Considering both trials together, the proportion of patients who prematurely discontinued study drug prior to the 24-week primary endpoint was 6% among those treated with PRALUENT and 4% among those treated with placebo.

At week 12, the treatment difference between PRALUENT 75 mg Q2W and placebo in mean LDL-C percent change was -48% (95% CI: -52%, -44%).

At week 12, if additional LDL-C lowering was required based on pre-specified LDL-C criteria, PRALUENT was up-titrated to 150 mg Q2W for the remainder of the trials. The dose was up-titrated to 150 mg Q2W in 196 (42%) of 469 patients treated with PRALUENT for at least 12 weeks. At week 24, the mean treatment difference between PRALUENT and placebo in mean LDL-C percent change from baseline was -54% (95% CI: -59%, -50%; p-value: ˂0.0001). The LDL-C-lowering effect was sustained to week 52.

For additional results see Table 4 and Figure 3.

a The means were estimated based on all randomized patients, with multiple imputation of missing data taking into account treatment adherence. b Number of patients with observed data.

Figure 3: Mean Percent Change from Baseline in LDL-C Over 52 Weeks in Patients with HeFH on Maximally Tolerated Statin Treated with PRALUENT 75/150 mg Q2W and Placebo Q2W (ODYSSEY FH I and FH II Pooled)a

Study 6 (ODYSSEY HIGH FH, NCT01617655) was a multicenter, double-blind, placebo-controlled trial that randomly assigned 72 patients to PRALUENT 150 mg Q2W and 35 patients to placebo. Patients had HeFH with a baseline LDL-C ≥160 mg/dL while taking a maximally tolerated dose of statin with or without other lipid-modifying therapy. The mean age was 51 years (range 18–80), 47% were women, 88% were Caucasian, 2% were Black, and 6% were Hispanic/Latino. The average LDL-C at baseline was 198 mg/dL.

The proportion of patients who discontinued study drug prior to the 24-week primary endpoint was 10% among those treated with PRALUENT and 0% among those treated with placebo.

At week 24, the mean percent change from baseline in LDL-C was -43% with PRALUENT and -7% with placebo, and the treatment difference between PRALUENT and placebo in mean LDL-C percent change was -36% (95% CI: -49%, -24%; p-value: <0.0001).

Study 7 (ODYSSEY CHOICE I, NCT01926782) was a multicenter, double-blind, placebo-controlled trial that randomly assigned 458 patients with primary hyperlipidemia to PRALUENT 300 mg Q4W, 115 patients to PRALUENT 75 mg Q2W, and 230 patients to placebo. Patients were stratified based on whether or not they were treated concomitantly with statin.

The mean age was 61 years (range 21–88), 42% were women, 87% were Caucasian, 11% were Black, and 3% were Hispanic/Latino.

The proportion of patients who discontinued study drug prior to the 24-week primary endpoint was 12% among those treated with PRALUENT 300 mg Q4W, 14% among those treated with PRALUENT 75 mg Q2W, and 15% among those treated with placebo.

In the cohort of patients on background statin, the mean LDL-C at baseline was 113 mg/dL. At week 12, the treatment difference between PRALUENT 300 mg Q4W and placebo in mean percent change in LDL-C from baseline was -54% (97.5% CI: -61%, -48%), and the treatment difference between PRALUENT 75 mg Q2W and placebo in mean percent change in LDL-C was -44% (97.5% CI: -53%, -35%) (Figure 4).

Figure 4: Mean Percent Change from Baseline in LDL-C up to Week 12 in Patients on Concomitant Statin Treated with PRALUENT 75 mg Q2W, PRALUENT 300 mg Q4W or Placebo The means were estimated based on all randomized patients, with multiple imputation of missing data taking into account treatment adherence.

At week 12, if additional LDL-C lowering was required based on pre-specified LDL-C criteria, PRALUENT was adjusted to 150 mg Q2W for the remainder of the trial. The dose was adjusted to 150 mg Q2W in approximately 20% of patients treated with PRALUENT 75 mg Q2W or 300 mg Q4W for at least 12 weeks.

At week 24, the treatment difference between initial assignment to PRALUENT 300 mg Q4W and placebo in mean percent change in LDL-C from baseline was -56% (97.5% CI: -62%, -49%; p-value: <0.0001), and the treatment difference between initial assignment to PRALUENT 75 mg Q2W and placebo in mean percent change in LDL-C from baseline was -48% (97.5% CI: -57%, -39%).

In the cohort of patients not treated with a concomitant statin, the mean LDL-C at baseline was 142 mg/dL. The treatment difference between PRALUENT and placebo were similar to the cohort of patients treated with a concomitant statin.

Study 8 (ODYSSEY ESCAPE, NCT02326220) was a multicenter, double-blind, placebo-controlled trial that randomly assigned patients with HeFH who were undergoing LDL apheresis to PRALUENT 150 mg Q2W (N=41) or placebo (N=21). Patients were treated in combination with their usual LDL apheresis schedule for 6 weeks. The mean age was 59 years (range 27–79), 42% were women, 97% were Caucasian, 3% were Black, and 0% were Hispanic/Latino. The mean LDL-C at baseline, measured before the apheresis procedure, was 181 mg/dL. The proportion of patients who discontinued study drug prior to the 6-week endpoint was 2% among those treated with PRALUENT 150 mg Q2W and 5% among those treated with placebo. At week 6, the mean percent change from baseline in pre-apheresis LDL-C was -53% in patients in the PRALUENT group compared to 1% in patients who received placebo.

Study 9 (ODYSSEY COMBO II, NCT01644188) was a multicenter, double-blind, ezetimibe-controlled trial that randomly assigned 479 patients to PRALUENT 75 mg Q2W/150 mg Q2W and 241 patients to ezetimibe 10 mg/day. Patients were taking a maximally tolerated dose of a statin and required additional LDL-C reduction.

The mean age was 62 years (range 29–88), 26% were women, 85% were Caucasian, 4% were Black, and 3% were Hispanic/Latino. Mean baseline LDL-C was 107 mg/dL.

The proportion of patients who prematurely discontinued study drug prior to the 24-week primary endpoint was 9% among those treated with PRALUENT and 10% among those treated with ezetimibe.

At week 12, the mean percent change from baseline in LDL-C was -50% with PRALUENT compared to -22% with ezetimibe, and the treatment difference between PRALUENT and ezetimibe in mean LDL-C percent change was -28% (95% CI: -32%, -23%).

At week 12, if additional LDL-C lowering was required based on pre-specified LDL-C criteria, PRALUENT was up-titrated to 150 mg Q2W for the remainder of the trial. The dose was up-titrated to 150 mg Q2W in 82 (18%) of 446 patients treated with PRALUENT for at least 12 weeks. At week 24, the mean percent change from baseline in LDL-C was -48% with PRALUENT and -20% with ezetimibe, and the treatment difference between PRALUENT and ezetimibe in mean LDL-C percent change was -28% (95% CI: -33%, -23%; p-value: <0.0001).

Study 10 (ODYSSEY MONO, NCT01644474) was a multicenter, double-blind, ezetimibe-controlled trial in patients with a moderate CV risk, not taking statins or other lipid-modifying therapies, and a baseline LDL-C between 100 mg/dL to 190 mg/dL that randomly assigned 52 patients to PRALUENT 75 mg Q2W and 51 patients to ezetimibe 10 mg/day.

The mean age was 60 years (range 45–72), 47% were women, 90% were Caucasian and 10% were Black. Mean baseline LDL-C was 140 mg/dL.

The proportion of patients who prematurely discontinued study drug prior to the 24-week endpoint was 15% among those treated with PRALUENT and 14% among those treated with ezetimibe.

At week 12, the mean percent change from baseline in LDL-C was -48% with PRALUENT compared to -19% with ezetimibe, and the treatment difference between PRALUENT 75 mg Q2W and ezetimibe in mean LDL-C percent change was -29% (95% CI: -37%, -22%). At week 12, if additional LDL-C lowering was required based on pre-specified LDL-C criteria, PRALUENT was up-titrated to 150 mg Q2W for the remainder of the trial. The dose was up-titrated to 150 mg Q2W in 14 (30%) of 46 patients treated with PRALUENT for at least 12 weeks. At week 24, the mean percent change from baseline in LDL-C was -45% with PRALUENT and -14% with ezetimibe, and the treatment difference between PRALUENT and ezetimibe in mean LDL-C percent change was -31% (95% CI: -40%, -22%; p-value: <0.0001).