Praluent Drug Information
Generic name: ALIROCUMAB
PCSK9 Inhibitor [EPC]
Uses of Praluent
- ® is indicated: To reduce the risk of major adverse cardiovascular (CV) events (coronary heart disease death, myocardial infarction, stroke, or unstable angina requiring hospitalization) in adults at increased risk for these events. As an adjunct to diet and exercise to reduce low- density lipoprotein cholesterol (LDL-C) in: adults with hypercholesterolemia. adults and pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH). adults with homozygous familial hypercholesterolemia (HoFH). PRALUENT is a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor indicated: To reduce the risk of major adverse cardiovascular (CV) events (coronary heart disease death, myocardial infarction, stroke, or unstable angina requiring hospitalization) in adults at increased risk for these events. As an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in : adults with hypercholesterolemia adults and pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia (HeFH). adults with homozygous familial hypercholesterolemia (HoFH).
Dosage & Administration of Praluent
Recommended Dosage in Adults Hypercholesterolemia, including HeFH
The recommended starting dosage of PRALUENT is either 75 mg once every 2 weeks or 300 mg once every 4 weeks administered subcutaneously . For patients receiving PRALUENT 300 mg every 4 weeks, measure LDL-C just prior to the next scheduled dose, because LDL-C can vary between doses in some patients . If the LDL-C response is inadequate, the dosage may be adjusted to 150 mg subcutaneously every 2 weeks. HeFH undergoing LDL apheresis or with HoFH: The recommended dosage of PRALUENT is 150 mg once every 2 weeks administered subcutaneously . PRALUENT can be administered without regard to the timing of LDL apheresis. Assess LDL-C when clinically appropriate.
The LDL-lowering effect of PRALUENT may be measured as early as 4 weeks after initiation.
Recommended Dosage in Pediatric Patients Aged 8 years and Older With HeFH
The recommended dosage of PRALUENT for patients with a body weight less than 50 kg is 150 mg once every 4 weeks administered subcutaneously . If the LDL-C lowering response is inadequate, the dosage may be adjusted to 75 mg subcutaneously once every 2 weeks . The recommended dosage of PRALUENT for patients with a body weight of 50 kg or more is 300 mg once every 4 weeks administered subcutaneously . If the LDL-C lowering response is inadequate, the dosage may be adjusted to 150 mg subcutaneously once every 2 weeks . Assess LDL-C when clinically appropriate. The LDL-lowering effect of PRALUENT may be measured as early as 4 weeks after initiation.
Missed Doses
If a dose is missed: Within 7 days from the missed dose, instruct the patient to administer PRALUENT and resume the patient's original schedule. More than 7 days after the missed dose: For every 2-week dosage, instruct the patient to wait until the next dose on the original schedule. For every 4-week dosage, instruct the patient to administer the dose and start a new schedule based on this date.
Important
Administration Instructions Train patients and/or caregivers on how to prepare and administer PRALUENT, according to the Instructions for Use and instruct them to read and follow the Instructions for Use each time they use PRALUENT. In children aged 12 to 17 years, it is recommended that PRALUENT be given by or under the supervision of an adult. In children aged 8 to 11 years, PRALUENT should be given by a caregiver. Prior to use, allow PRALUENT to warm to room temperature for 30 to 40 minutes if PRALUENT has been refrigerated.
Visually inspect PRALUENT prior to administration. PRALUENT is a clear, colorless to pale yellow solution. Do not use if the solution is cloudy, discolored, or contains particles.
Administer PRALUENT subcutaneously into areas of the thigh, abdomen, or upper arm that are not tender, bruised, red, or indurated. Rotate injection sites for each administration. It may take up to 20 seconds to inject PRALUENT. To administer the 300 mg dose, give two 150 mg PRALUENT injections consecutively at two different injection sites.
Side Effects of Praluent
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Adults with Hypercholesterolemia The data in Table 1 are derived from 9 primary hypercholesterolemia placebo-controlled trials that included 2,476 adult patients treated with PRALUENT 75 mg and/or 150 mg every 2 weeks, including 2,135 exposed for 6 months and 1,999 exposed for more than 1 year (median treatment duration of 65 weeks). The mean age of the population was 59 years, 40% of the population were female, 90% were White, 4% were Black or African American, 3% were Asian, and 3% other races; 6% identified as Hispanic or Latino ethnicity. Adverse reactions reported in at least 2% of PRALUENT-treated patients, and more frequently than in placebo-treated patients, are shown in Table 1. Table 1: Adverse Reactions Occurring in >2% of PRALUENT-Treated Adult Patients and ≥1% More Frequently Than with Placebo Adverse Reactions Placebo (N=1,276) % PRALUENT 75 mg every 2 weeks and 150 mg every 2 weeks combined (N=2,476) % Injection site reactions Includes erythema/redness, itching, swelling, pain/tenderness 5 7 Influenza 5 6 Diarrhea 4 5 Myalgia 3 4 Muscle spasms 2 3 Contusion 1 2 Adverse reactions led to discontinuation of treatment in 5.3% of patients treated with PRALUENT and 5.1% of patients treated with placebo.
The most common adverse reactions leading to treatment discontinuation in patients treated with PRALUENT were allergic reactions (0.6% versus 0.2% for PRALUENT and placebo, respectively) and elevated liver enzymes (0.3% versus <0.1%). In an analysis of ezetimibe-controlled trials in which 864 patients were exposed to PRALUENT for a median of 27 weeks and 618 patients were exposed to ezetimibe for a median of 24 weeks, the types and frequencies of common adverse reactions were similar to those listed above. Adverse Reactions in a Cardiovascular Outcomes Trial in Adults In a CV outcomes trial in which 9,451 patients were exposed to PRALUENT for a median of 31 months and 9,443 patients were exposed to placebo for a median of 32 months, common adverse reactions (greater than 5% of patients treated with PRALUENT and occurring more frequently than placebo) included myalgia (6% PRALUENT, 5% placebo). Adverse Reactions in Pediatric Patients with HeFH In a 24-week placebo-controlled clinical trial in which 101 pediatric patients aged 8 to 17 years with HeFH were exposed to PRALUENT and 52 pediatric patients with HeFH were exposed to placebo, the safety profile of PRALUENT observed in this population was consistent with the safety profile observed in adults with HeFH. Other Adverse Reactions Local Injection Site Reactions In a pool of placebo-controlled trials evaluating PRALUENT 75 mg and/or 150 mg administered every 2 weeks in adults, local injection site reactions including erythema/redness, itching, swelling, and pain/tenderness were reported more frequently in patients treated with PRALUENT (7.2% versus 5.1% for PRALUENT and placebo, respectively). Few patients discontinued treatment because of these reactions (0.2% versus 0.4% for PRALUENT and placebo, respectively), but patients receiving PRALUENT had a greater number of injection site reactions, had more reports of associated symptoms, and had reactions of longer average duration than patients receiving placebo. In a 48-week placebo-controlled trial evaluating PRALUENT 300 mg every 4 weeks and 75 mg every 2 weeks in adults, in which all patients received an injection of drug or placebo every 2 weeks, local injection site reactions were reported more frequently in patients treated with PRALUENT 300 mg every 4 weeks as compared to those receiving PRALUENT 75 mg every 2 weeks or placebo (16.6%, 9.6%, and 7.9%, respectively). Three patients (0.7%) treated with PRALUENT 300 mg every 4 weeks discontinued treatment due to local injection site reactions versus no patients (0%) in the other 2 treatment groups.
In a CV outcomes trial in adults, local injection site reactions were reported in 3.8% of patients treated with PRALUENT versus 2.1% patients treated with placebo, and led to permanent discontinuation in 26 patients (0.3%) versus 3 patients (<0.1%), respectively. In the trial of pediatric patients with HeFH, local injection site reactions were reported in 5% of patients treated with PRALUENT versus 0% patients treated with placebo; no patients discontinued treatment due to injection site reactions. Hypersensitivity Reactions in Adults Hypersensitivity reactions were reported more frequently in adult patients treated with PRALUENT than in those treated with placebo (8.6% versus 7.8%). The most common hypersensitivity reaction was pruritus (1.1% versus 0.4% for PRALUENT and placebo, respectively). The proportion of patients who discontinued treatment due to allergic reactions was higher among those treated with PRALUENT (0.6% versus 0.2%). Serious allergic reactions, such as hypersensitivity, nummular eczema, and hypersensitivity vasculitis were reported in patients using PRALUENT in controlled clinical trials.
Liver Enzyme Abnormalities in Adults In the hypercholesterolemia trials in adults, liver-related disorders (primarily related to abnormalities in liver enzymes) were reported in 2.5% of patients treated with PRALUENT and 1.8% of patients treated with placebo, leading to treatment discontinuation in 0.4% and 0.2% of patients, respectively. Increases in serum transaminases to greater than 3 times the upper limit of normal occurred in 1.7% of patients treated with PRALUENT and 1.4% of patients treated with placebo.
Postmarketing Experience
The following adverse reactions have been reported during post-approval use of PRALUENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions: Angioedema Influenza-like illness
Warnings & Cautions for Praluent
Hypersensitivity Reactions Hypersensitivity reactions, including hypersensitivity vasculitis, angioedema, and other hypersensitivity reactions
requiring hospitalization, have been reported with PRALUENT treatment. If signs or symptoms of serious hypersensitivity reactions occur, discontinue treatment with PRALUENT, treat according to the standard of care, and monitor until signs and symptoms resolve. PRALUENT is contraindicated in patients with a history of a serious hypersensitivity reaction to alirocumab or any excipient in PRALUENT .
Pregnancy Safety for Praluent
Pregnancy Risk Summary Available data from clinical trials and postmarketing reports on PRALUENT use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, there were no effects on embryo-fetal development when rats were subcutaneously administered alirocumab during organogenesis at dose exposures up to 12-fold the exposure at the maximum recommended human dose of 150 mg every two weeks. In monkeys, suppression of the humoral immune response was observed in infant monkeys when alirocumab was dosed during organogenesis to parturition at dose exposures 13-fold the exposure at the maximum recommended human dose of 150 mg every two weeks.
No additional effects on pregnancy or neonatal/infant development were observed at dose exposures up to 81-fold the maximum recommended human dose of 150 mg every two weeks. Measurable alirocumab serum concentrations were observed in the infant monkeys at birth at comparable levels to maternal serum, indicating that alirocumab, like other IgG antibodies, crosses the placental barrier. Monoclonal antibodies are transported across the placenta in increasing amounts especially near term; therefore, alirocumab has the potential to be transmitted from the mother to the developing fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. There is a pregnancy safety study for PRALUENT. If PRALUENT is administered during pregnancy, healthcare providers should report PRALUENT exposure by contacting Regeneron at 1-844-734-6643. Data Animal data In Sprague Dawley rats, no effects on embryo-fetal development were observed when alirocumab was dosed at up to 75 mg/kg/dose by the subcutaneous route on gestation days 6 and 12 at exposures 12-fold the maximum recommended human dose of 150 mg every two weeks, based on serum AUC. In cynomolgus monkeys, suppression of the humoral immune response to keyhole limpet hemocyanin (KLH) antigen was observed in infant monkeys at 4 to 6 months of age when alirocumab was dosed during organogenesis to parturition at 15 mg/kg/week and 75 mg/kg/week by the subcutaneous route, corresponding to 13-fold and 81-fold the human exposure at the maximum recommended human dose of 150 mg every two weeks, based on serum AUC. The lowest dose tested in the monkey resulted in humoral immune suppression; therefore, it is unknown if this effect would be observed at clinical exposure.
No study designed to challenge the immune system of infant monkeys was conducted. No additional embryo-fetal, prenatal or postnatal effects were observed in infant monkeys, and no maternal effects were observed, when alirocumab was dosed at up to 75 mg/kg/week by the subcutaneous route, corresponding to maternal exposure of 81-fold the exposure at the maximum recommended human dose of 150 mg every two weeks, based on serum AUC.
Pediatric Use of Praluent
Pediatric Use The safety and effectiveness of PRALUENT as an adjunct to diet and other LDL-C-lowering therapies for the treatment of HeFH have been established in pediatric patients aged 8 years and older. Use of PRALUENT for this indication is based on data from a 24-week, randomized, placebo-controlled, double-blind trial in pediatric patients with HeFH. In the trial, 101 patients received PRALUENT and 52 patients received placebo; 26 patients (17%) were 8 to 9 years of age. This indication is supported by evidence from controlled trials in adults.
The safety and effectiveness of PRALUENT have not been established in pediatric patients with HeFH who are younger than 8 years of age or in pediatric patients with other types of hypercholesterolemia.
Contraindications for Praluent
is contraindicated in patients with a history of a serious hypersensitivity reaction to alirocumab or any of the excipients in PRALUENT. Hypersensitivity vasculitis, angioedema, and hypersensitivity reactions requiring hospitalization have occurred. History of a serious hypersensitivity reaction to alirocumab or any of the excipients in PRALUENT.
Clinical Studies of Praluent
Cardiovascular Outcome Trial in Adult Patients with Established Cardiovascular Disease Trial 1
(ODYSSEY OUTCOMES, NTC01663402) was a multicenter, double-blind, placebo-controlled trial in 18,924 adult patients (9,462 PRALUENT; 9,462 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 or placebo once every two weeks. 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 every 2 weeks.
For patients who had their dose adjusted to 150 mg every 2 weeks and who had two consecutive LDL-C values below 25 mg/dL, down-titration from 150 mg every 2 weeks to 75 mg every 2 weeks was performed. Patients on 75 mg every 2 weeks who had two consecutive LDL-C values below 15 mg/dL were switched to placebo in a blinded fashion. Approximately 2,615 (27.7%) of 9,451 patients treated with PRALUENT required dose adjustment to 150 mg every 2 weeks.
Of these 2,615 patients, 805 (30.8%) were down-titrated to 75 mg every 2 weeks. Overall, 730 (7.7%) of 9,451 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. Baseline Disease and Demographic Characteristics The mean age at baseline was 59 years (range 39-92), with 25% female, and 27% at least 65 years old. The trial population was 79% White, 3% Black or African American and 13% Asian; 17% identified as Hispanic or 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 Heart Association class I or II congestive heart failure (15%), and eGFR <60 mL/min/1.73 m 2 (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. Endpoint Results 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. Table 2: Cardiovascular Outcomes in Adult Patients with Established Cardiovascular Disease Endpoint PRALUENT N=9,462 Placebo N=9,462 Hazard Ratio (95% CI) Cox-proportional hazards model with treatment as a factor and stratified by geographic region n (%) Incidence Rate per 100 Patient Years (95% CI) n (%) Incidence Rate per 100 Patient Years (95% CI) Primary composite endpoint Primary composite endpoint defined as: time to first occurrence of coronary heart disease death, non-fatal myocardial infarction, fatal and non-fatal ischemic stroke, or unstable angina requiring hospitalization 903 (9.5%) 3.5 (3.3 to 3.8) 1052 (11.1%) 4.2 (3.9 to 4.4) 0.85 Components of the Primary Composite Endpoint First occurrence of specified event at any time; patients may have experienced more than one adjudicated event CHD death 205 (2.2%) 0.8 (0.7 to 0.9) 222 (2.3%) 0.8 (0.7 to 0.9) 0.92 Non-fatal MI Statistical testing performed outside hierarchy; therefore not considered statistically significant 626 (6.6%) 2.4 (2.2 to 2.6) 722 (7.6%) 2.8 (2.6 to 3.0) 0.86 Fatal or non-fatal ischemic stroke 111 (1.2%) 0.4 (0.3 to 0.5) 152 (1.6%) 0.6 (0.5 to 0.7) 0.73 Unstable angina requiring hospitalization 37 (0.4%) 0.1 (0.1 to 0.2) 60 (0.6%) 0.2 (0.2 to 0.3) 0.61 Mortality Endpoint (not statistically significant per pre-specified method to control for type I error) All-cause mortality 334 (3.5%) 1.2 (1.1 to 1.4) 392 (4.1%) 1.5 (1.3 to 1.6) 0.85 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 Figure 1
Clinical Trials in Adult Patients with Primary Hypercholesterolemia (including HeFH) and HoFH
Primary Hypercholesterolemia Trial 2 (ODYSSEY LONG TERM, NCT01507831) was a multicenter, double-blind, placebo-controlled trial that randomly assigned 1,553 adult patients to PRALUENT 150 mg every 2 weeks and 788 adult 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. Baseline Disease and Demographic Characteristics The mean age was 61 years (range 18-89), 38% were female, 93% were White, 3% were Black or African American, and 5% identified as Hispanic or Latino ethnicity.
The average LDL-C at baseline was 122 mg/dL. Endpoint Results 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). The proportion of patients who prematurely discontinued trial drug prior to the 24-week primary endpoint was 8% among those treated with PRALUENT and 8% among those treated with placebo. For additional results see Table 3 and Figure 2. Table 3: Mean Percent Change from Baseline and Difference Difference is PRALUENT minus Placebo from Placebo in Lipid Parameters at Week 24 in ODYSSEY LONG TERM A pattern-mixture model approach was used with multiple imputation of missing post-treatment values based on a patient's own baseline value and multiple imputation of missing on-treatment values based on a model including available on-treatment values Treatment Group LDL-C Total-C Non-HDL-C Apo B Week 24 (Mean Percent Change from Baseline) Placebo (n=788) 1 0 1 1 PRALUENT 150 mg (n=1,553) -58 -36 -49 -50 Difference from placebo (LS Mean) (95% CI) -58 (-61, -56) -36 (-37, -34) -50 (-52, -47) -51 (-53, -48) 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 Adult Patients on Maximally Tolerated Statin Treated with PRALUENT 150 mg Every 2 Weeks and Placebo Every 2 Weeks (ODYSSEY LONG TERM) a Trial 3 (ODYSSEY COMBO I, NCT01644175) was a multicenter, double-blind, placebo-controlled trial that randomly assigned 209 adult patients to PRALUENT and 107 adult patients to placebo. Patients were taking maximally tolerated doses of statins with or without other lipid-modifying therapy and required additional LDL-C reduction.
Figure 2 Baseline Disease and Demographic Characteristics The mean age was 63 years (range 39-87), 34% were female, 82% were White, 16% were Black or African American, and 11% were Hispanic or Latino. Mean baseline LDL-C was 102 mg/dL. Endpoint Results 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 every 2 weeks 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 every 2 weeks for the remainder of the trial. The dose was up-titrated to 150 mg every 2 weeks 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). The proportion of patients who prematurely discontinued trial drug prior to the 24-week primary endpoint was 11% among those treated with PRALUENT and 12% among those treated with placebo. Trials 4 (ODYSSEY FH I, NCT01623115) and 5 (ODYSSEY FH II, NCT01709500) were multicenter, double-blind, placebo-controlled trials that, combined, randomly assigned 490 adult patients to PRALUENT and 245 adult 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). Baseline Disease and Demographic Characteristics The mean age was 52 years (range 20-87), 45% were female, 94% were White, 1% were Black or African American, and 3% identified as Hispanic or Latino ethnicity. The average LDL-C at baseline was 141 mg/dL. Endpoint Results At week 12, the treatment difference between PRALUENT 75 mg every 2 weeks 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 every 2 weeks for the remainder of the trials.
The dose was up-titrated to 150 mg every 2 weeks 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. Considering both trials together, the proportion of patients who prematurely discontinued trial drug prior to the 24-week primary endpoint was 6% among those treated with PRALUENT and 4% among those treated with placebo. For additional results see Table 4 and Figure 3. Table 4: Mean Percent Change from Baseline and Difference Difference is PRALUENT minus Placebo from Placebo in Lipid Parameters at Week 12 and Week 24 in Adult Patients with HeFH (ODYSSEY FH I and FH II Pooled) A pattern-mixture model approach was used with multiple imputation of missing post-treatment values based on a patient's own baseline value and multiple imputation of missing on-treatment values based on a model including available on-treatment values Treatment Group LDL-C Total-C Non-HDL-C Apo B Week 12 (Mean Percent Change from Baseline) Placebo (n=245) 5 4 5 2 PRALUENT 75 mg (n=490) -43 -27 -38 -34 Difference from placebo (LS Mean) (95% CI) -48 (-52, -44) -31 (-34, -28) -42 (-46, -39) -36 (-39, -33) Week 24 (Mean Percent Change from Baseline) Placebo (n=245) 7 5 7 2 PRALUENT 75 mg/150 mg Dose was up-titrated to 150 mg every 2 weeks in 196 (42%) patients treated for at least 12 weeks (n=490) -47 -30 -42 -40 Difference from placebo (LS Mean) (95% CI) -54 (-59, -50) -36 (-39, -33) -49 (-53, -45) -42 (-45, -39) 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 Adult Patients with HeFH on Maximally Tolerated Statin Treated with PRALUENT 75/150 mg Every 2 Weeks and Placebo every 2 weeks (ODYSSEY FH I and FH II Pooled) a Trial 6 (ODYSSEY HIGH FH, NCT01617655) was a multicenter, double-blind, placebo-controlled trial that randomly assigned 72 adult patients to PRALUENT 150 mg every 2 weeks and 35 adult 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. Figure 3 Baseline Disease and Demographic Characteristics The mean age was 51 years (range 18-80), 47% were female, 88% were White, 2% were Black or African American, and 6% identified as Hispanic or Latino ethnicity. The average LDL-C at baseline was 198 mg/dL. Endpoint Results 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). The proportion of patients who discontinued trial drug prior to the 24-week primary endpoint was 10% among those treated with PRALUENT and 0% among those treated with placebo.
Trial 7 (ODYSSEY CHOICE I, NCT01926782) was a multicenter, double-blind, placebo-controlled trial that randomly assigned 458 adult patients with hypercholesterolemia to PRALUENT 300 mg every 4 weeks, 115 adult patients to PRALUENT 75 mg every 2 weeks, and 230 adult patients to placebo. Patients were stratified based on whether or not they were treated concomitantly with statin. Baseline Disease and Demographic Characteristics The mean age was 61 years (range 21-88), 42% were female, 87% were White, 11% were Black or African American, and 3% identified as Hispanic or Latino ethnicity.
Endpoint Results 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 every 4 weeks 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 every 2 weeks 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 Adult Patients on Concomitant Statin Treated with PRALUENT 75 mg Every 2 Weeks, PRALUENT 300 mg Every 4 Weeks 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 every 2 weeks for the remainder of the trial. The dose was adjusted to 150 mg every 2 weeks in approximately 20% of patients treated with PRALUENT 75 mg every 2 weeks or 300 mg every 4 weeks for at least 12 weeks. At week 24, the treatment difference between initial assignment to PRALUENT 300 mg every 4 weeks 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 every 2 weeks 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.
The proportion of patients who discontinued trial drug prior to the 24-week primary endpoint was 12% among those treated with PRALUENT 300 mg every 4 weeks, 14% among those treated with PRALUENT 75 mg every 2 weeks, and 15% among those treated with placebo. Trial 8 (ODYSSEY ESCAPE, NCT02326220) was a multicenter, double-blind, placebo-controlled trial that randomly assigned adult patients with HeFH who were undergoing LDL apheresis to PRALUENT 150 mg every 2 weeks (N=41) or placebo (N=21). Patients were treated in combination with their usual LDL apheresis schedule for 6 weeks. Figure 4 Baseline Disease and Demographic Characteristics The mean age was 59 years (range 27-79), 42% were female, 97% were White, 3% were Black or African American, and 0% identified as Hispanic or Latino ethnicity.
The mean LDL-C at baseline, measured before the apheresis procedure, was 181 mg/dL. Endpoint Results 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. The proportion of patients who discontinued study drug prior to the 6-week endpoint was 2% among those treated with PRALUENT 150 mg every 2 weeks and 5% among those treated with placebo. Trial 9 (ODYSSEY COMBO II, NCT01644188) was a multicenter, double-blind, ezetimibe-controlled trial that randomly assigned 479 adult patients to PRALUENT 75 mg every 2 weeks/150 mg every 2 weeks and 241 adult patients to ezetimibe 10 mg/day.
Patients were taking a maximally tolerated dose of a statin and required additional LDL-C reduction. Baseline Disease and Demographic Characteristics The mean age was 62 years (range 29-88), 26% were female, 85% were White, 4% were Black or African American, and 3% identified as Hispanic or Latino ethnicity. Mean baseline LDL-C was 107 mg/dL. Endpoint Results 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 every 2 weeks for the remainder of the trial.
The dose was up-titrated to 150 mg every 2 weeks 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). The proportion of patients who prematurely discontinued trial drug prior to the 24-week primary endpoint was 9% among those treated with PRALUENT and 10% among those treated with ezetimibe. Trial 10 (ODYSSEY MONO, NCT01644474) was a multicenter, double-blind, ezetimibe-controlled trial in adult 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 every 2 weeks and 51 patients to ezetimibe 10 mg/day.
Baseline Disease and Demographic Characteristics The mean age was 60 years (range 45-72), 47% were female, 90% were White and 10% were Black or African American, and 1% identified as Hispanic or Latino ethnicity. Mean baseline LDL-C was 140 mg/dL. Endpoint Results 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 every 2 weeks 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 every 2 weeks for the remainder of the trial. The dose was up-titrated to 150 mg every 2 weeks 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). The proportion of patients who prematurely discontinued trial drug prior to the 24-week endpoint was 15% among those treated with PRALUENT and 14% among those treated with ezetimibe. Adult Patients with HoFH Trial 11 (ODYSSEY HoFH, NCT03156621) was a multicenter, double-blind, placebo-controlled trial that randomly assigned 45 adult patients to PRALUENT 150 mg every 2 weeks and 24 adult patients to placebo. Patients were taking maximally tolerated doses of statins with or without other lipid-lowering therapy and required additional LDL-C reduction.
Randomization was stratified by LDL apheresis treatment status. The diagnosis of HoFH was made by either clinical diagnosis, which included a history of an untreated total cholesterol concentration >500 mg/dL together with either xanthoma before 10 years of age or with a history of total cholesterol >250 mg in both parents, or by genetic testing. Baseline Disease and Demographic Characteristics The mean age was 43 years (range 19-81), 51% were female, 78% were White, 3% were Black or African American, 17% were Asian, and 3% identified as Hispanic or Latino ethnicity.
Mean baseline LDL-C was 283 mg/dL with 97% on statins, 72% on ezetimibe, and 14% on lomitapide. Endpoint Results At week 12, the treatment difference between PRALUENT and placebo in mean LDL-C percent change from baseline was -36% (95% CI: -51% to -20%; p <0.0001) (see Figure 5 ). For the effect of PRALUENT on lipid parameters as compared to placebo, see Table 5. No patient discontinued from the trial prior to the 12-week primary endpoint. Patients with two LDL-receptor negative alleles (little to no residual function) had a minimal to absent response to PRALUENT. Figure 5: LS Mean Percent Change from Baseline in LDL-C Over 12 Weeks in Adult Patients with HoFH (ODYSSEY HoFH) Table 5: Effect of PRALUENT on Lipid Parameters in Adult Patients with HoFH (LS Mean Percent Change from Baseline to Week 12 in ODYSSEY HoFH) Treatment Group LDL-C Apo B Non-HDL-C Total Cholesterol Placebo (n=24) 9 7 8 7 PRALUENT 150 mg every 2 weeks (n=45) -27 -23 -25 -20 Difference from placebo (LS Mean) (95% CI) -36 (-51, -20) -30 (-42, -17) -33 (-48, -18) -27 (-39, -14) Figure 5
Clinical Trials in Pediatric Patients with HeFH Trial 12 (EFC14643
NCT03510884) was a randomized, multicenter, placebo controlled, double blind, 24 week trial in 153 pediatric patients aged 8 to 17 years with HeFH. Patients were on a low-fat diet and receiving background lipid-lowering therapy. Patients were randomized in a 2:1 ratio to receive PRALUENT or placebo. In the PRALUENT group dosed every 2 weeks, 49 patients received a dose of 40 mg for body weight less than 50 kg or 75 mg for body weight 50 kg or more.
The 40 mg dosage every 2 weeks is not approved. In the PRALUENT group dosed every 4 weeks, 52 patients received a dose of 150 mg for body weight less than 50 kg or 300 mg for body weight 50 kg or more. Dose adjustment of PRALUENT to 75 mg every 2 weeks for body weight less than 50 kg or 150 mg every 2 weeks for body weight 50 kg or more occurred at week 12 in patients with LDL-C ≥110 mg/dL. Baseline Disease and Demographic Characteristics The diagnosis of HeFH was made based on criteria from Simon Broome Register Group or by genetic testing.
The mean age was 13 years (range: 8 to 17 years); 57% female; 82% White, 2% Black or African American, 10% American Indian or Alaska Native, and <1% not reported; 18% Hispanic/Latino ethnicity. Mean body weight was 53 kg. The mean LDL-C at baseline was 174 mg/dL; Of the patients receiving PRALUENT once every 2 weeks with an optional up-titration, 99% were on statins and 7% were on ezetimibe at baseline.
Of the patients receiving PRALUENT once every 4 weeks with an optional up-titration, 91% were on statins and 20% were on ezetimibe at baseline. Endpoint Results At week 24 in the group receiving treatment every 4 weeks, the treatment difference between the PRALUENT and placebo groups in LS mean LDL-C percent change from baseline was -31.4% (97.5% CI: -45.0 to -17.9; p<0.0001) (see Table 6 and Figure 6 ). For the effect of PRALUENT on lipid parameters as compared to placebo see Table 6. a A pattern-mixture approach was used with multiple imputation of missing post-treatment values based on a patient's own baseline value and multiple imputation of missing on-treatment values based on a model including available on-treatment values b Number of patients with observed data Figure 6: LDL-C LS Mean Percent Change from Baseline Over Time Through Week 24 in Pediatric Patients (aged 8 to 17 years) with HeFH Treated with PRALUENT Every 4 Weeks or Placebo a Table 6: Mean Percent Change from Baseline and Difference from Placebo in Lipid Parameters at Week 24 in Pediatric Patients (aged 8 to 17 years) Treatment Group The percent of missing data was 5% in the every 2 week group and 13% in the every 4 week group LDL-C Apo B Non-HDL-C Total Cholesterol PRALUENT once every 4 weeks (150 mg for body weight less than 50 kg or 300 mg for body weight 50 kg or more) In the PRALUENT group 52 patients received a dose of 150 mg every 4 weeks (body weight less than 50 kg) or 300 mg every 4 weeks (body weight 50 kg or more). At week 12, a total of 15 (28.8%) patients had an automatic blinded dose adjustment to 75 mg every 2 weeks (body weight less than 50 kg) or 150 mg every 2 weeks (body weight 50 kg or more). LS Mean: Placebo (n=27) -5.2 -3.3 -4.1 -
LS Mean
PRALUENT (n=52) -36.6 -33.0 -34.2 -
LS Mean Difference from Placebo
A pattern-mixture approach was used with multiple imputation of missing post-treatment values based on a patient's own baseline value and multiple imputation of missing on-treatment values based on a model including available on-treatment values (97.5% CI) -31.4 (-45.0, -17.9) -29.7 (-41.1, -18.2) -30.1 (-43.0, -17.2) -22.3 (-33.0, -11.6) PRALUENT once every 2 weeks (40 mg for body weight less than 50 kg or 75 mg for body weight 50 kg or more) In the PRALUENT group dosed every 2 weeks, 49 patients received a dose of 40 mg for body weight less than 50 kg or 75 mg for body weight 50 kg or more. At week 12, a total of 22 (44.9%) patients had an automatic blinded dose adjustment to 75 mg every 2 weeks (body weight less than 50 kg) or 150 mg every 2 weeks (body weight 50 kg or more)., The 40 mg dosage every 2 weeks is not approved LS Mean: Placebo (n=25) 9.7 10.4 9.7
LS Mean
PRALUENT (n=49) -31.9 -25.7 -29.5 -
LS Mean Difference from Placebo (97.5% CI) -41.7 (-54.2, -29.1) -36.2 (-45.8
-26.5) -39.2 (-50.6, -27.8) -29.8 (-38.7, -21.0) Figure 6
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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