Clinical Trials

Date: 2015-09-01

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the ESC Congress 2015 in London

Company: Sanofi (France) Regeneron Pharmaceuticals (USA - NY)

Product: Praluent™ (alirocumab - SAR236553/REGN727)

Action mechanism:

• monoclonal antibody/RNAi/PCSK9 inhibitor. Alirocumab (SAR236553 / REGN727) is a subcutaneously administered, fully-human antibody targeting PCSK9 (proprotein convertase subtilisin/kexin type 9) in clinical development. By inhibiting PCSK9, a determinant of circulating LDL-cholesterol levels in the blood, REGN727 increases the number of free LDL receptors which can bind to circulating LDL and clear it from the bloodstream. REGN727 was created using Regeneron's pioneering VelocImmune® technology and is being developed by Regeneron in collaboration with Sanofi.

Disease: patients with hypercholesterolemia who are at high or very-high cardiovascular (CV) risk, including patients with an inherited form of high cholesterol known as heterozygous familial hypercholesterolemia (HeFH)

Therapeutic area: Cardiovascular diseases - Genetic diseases - Rare diseases

Country: Argentina, Austria, Belgium, Bulgaria, Canada, Chile, Colombia, Czech Republic, Denmark, Finland, France, Germany, Hungary, Israel, Italy, Republic of Korea, Mexico, Netherlands, Norway, Poland, Portugal, Romania, Russian Federation, South Africa, Spain, Sweden, Ukraine, UK, USA

Trial details:

• ODYSSEY LONG TERM is an ongoing 2,341-patient, double-blind trial designed to evaluate the long-term safety and efficacy of 150 milligrams (mg) alirocumab every two weeks versus placebo in patients with hypercholesterolemia who are at high or very-high cardiovascular (CV) risk, including patients with an inherited form of high cholesterol known as heterozygous familial hypercholesterolemia (HeFH). Both study groups are treated with statins at a maximally-tolerated dose and some patients also receive additional lipid-lowering therapies. A pre-specified interim analysis was performed when all patients reached one year and approximately 25 percent of patients reached 18 months of treatment. (NCT01507831)
• ODYSSEY COMBO II is a double-blind, 720-patient trial designed to evaluate the safety and efficacy of alirocumab compared to ezetimibe in patients with hypercholesterolemia who are at high CV risk and had inadequate LDL-C reduction at baseline despite stable maximally-tolerated statin therapy. (NCT01644188)
• The ODYSSEY FH I (NCT01623115) and FH II (NCT01709500) trials enrolled a total of 738 HeFH patients and compare alirocumab to placebo. All patients are on maximally-tolerated daily statin therapy and the majority of patients also receive ezetimibe. Despite receiving this high level of background therapy, patients in these studies had mean baseline LDL-C levels of 145 mg/dL (FH I) and 134 mg/dL (FH II).

Latest news:

• • On September 1, 2015, Regeneron Pharmaceuticals and Sanofi announced that, in a new pooled analysis of heterozygous familial hypercholesterolemia (HeFH) patients included in the ODYSSEY clinical trial program, Praluent® (alirocumab) significantly reduced low-density lipoprotein cholesterol (LDL-C). This analysis included 1,257 HeFH patients. At week 24, when the primary efficacy endpoint was assessed, patients treated with Praluent® had an average 56 percent greater reduction in LDL-C compared to placebo (p less than 0.0001) in both arms. Reductions were observed as early as week 4 and were maintained for the duration of therapy, until week 78. Results of this analysis were presented at the ESC Congress 2015 in London, and the 78 week results from two of the four trials included in the analysis, ODYSSEY FH I and II, were concurrently published online in the European Heart Journal.
• The analysis presented at ESC Congress 2015 evaluated the efficacy and safety of Praluent compared to placebo in 1,257 patients with HeFH. Data from four Phase 3 ODYSSEY trials, LONG TERM (HeFH patients only), HIGH FH, FH I, and FH II, were included in the analysis. In these trials, patients either received Praluent or placebo, in addition to standard-of-care, which included maximally-tolerated statins with or without other lipid-lowering therapies such as ezetimibe. In ODYSSEY LONG TERM and HIGH FH, patients were treated with Praluent 150 mg (n=348) every two weeks administered as a single 1-milliliter (mL) injection or placebo (n=174).1 In these patients, the average LDL-C at baseline was 168 mg/dL and 162 mg/dL in the Praluent and placebo groups respectively.1 In ODYSSEY FH I and FH II, patients were treated with Praluent 75 mg (n=490) every two weeks administered as a single 1-mL injection or placebo (n=245).1 In ODYSSEY FH I and FH II, patients had their dose adjusted to 150 mg at week 12 if they did not achieve their pre-specified LDL-C goal at week 8. In these patients, the average LDL-C level at baseline was 141 mg/dL in both the Praluent and placebo groups.1
• Across all primary and secondary endpoints assessed, there were statistical differences in favor of Praluent compared to placebo.1 Patients treated with Praluent achieved average LDL-C levels of less than 85 mg/dL at week 12,6 and maintained reductions through 78 weeks of therapy.
• Summary of Primary and Select Secondary Endpoints

• 		Baseline LDL-C	% LDL-C reduction from baselinea (week 24)	% achieved LDL-C goalb (week 24)	Greater % reduction for Praluent vs. placebo groups (on-treatment analysis)c
  					Week 24	Week 52	Week 78
  Initially treated with 75 mg (FH I and FH II)	Praluent	141	49d	75d	56d	58d	56d
  	Placebo	141	-7	5
  Initially treated with 150 mg (LONG TERM and HIGH FH)	Praluent	168	55	64.5	57	60	63
  	Placebo	162	-1	4

• Note: p less than 0.0001 vs. placebo for all data points a Primary efficacy endpoint b LDL-C goal either 70 mg/dL or 100 mg/dL depending on baseline CV risk c On-treatment analysis (all other data is intention-to-treat) d Includes 42 percent of patients treated with Praluent who had their dose adjusted to 150 mg at week 12
• • On March 15, 2015, Regeneron Pharmaceuticals and Sanofi announced that 18-month (78-week) results of a Phase 3 trial of Praluent™ (alirocumab), involving 2,341 high risk patients with hypercholesterolemia were published online in The New England Journal of Medicine. In the ODYSSEY LONG TERM trial, Praluent 150 mg every two weeks reduced low-density lipoprotein cholesterol (LDL-C or "bad" cholesterol) by an additional 62 percent at week 24 when compared to placebo, the primary efficacy endpoint of the study, with consistent LDL-C lowering maintained over 78 weeks.
• 18-Month (78-Week) Safety and Efficacy Results: ODYSSEY LONG TERM evaluated Praluent™ 150 mg (n=1,553) every two weeks compared to placebo (n=788) in patients who were at high cardiovascular (CV) risk and who were receiving maximally-tolerated statin therapy with or without other lipid-lowering treatment. The trial included patients with heterozygous familial hypercholesterolemia (HeFH) (n=276 Praluent, n=139 placebo). Patients received 78 weeks of treatment followed by an eight-week safety assessment. Patients self-administered a subcutaneous injection every two weeks via a pre-filled syringe.
• Key results include: At week 24, Praluent™ reduced LDL-C from baseline by an additional 62 percent versus placebo (p less than 0.0001) when added to the current standard of care, which included maximally-tolerated statins. Efficacy remained consistent throughout treatment, and, at week 78 there was a 56 percent reduction from baseline in LDL-C for Praluent™ versus placebo (p less than 0.0001). At week 24, 81 percent of patients in the Praluent™ group achieved their pre-specified LDL-C goal (either 70 mg/deciliter [mg/dL] or 100 mg/dL depending on baseline CV risk) compared to 8.5 percent for placebo (p less than 0.0001).
• Adverse events (AEs) occurred in 81 percent of Praluent™ and 83 percent of placebo patients, leading to discontinuation in 7.2 percent and 5.8 percent of patients, respectively. AEs were similar between groups, apart from differences in injection site reactions (5.9 percent Praluent, 4.2 percent placebo), myalgia (5.4 percent Praluent™, 2.9 percent placebo), neurocognitive events (1.2 percent Praluent, 0.5 percent placebo), and ophthalmological events (2.9 percent Praluent, 1.9 percent placebo). In a 3,759-patient, pooled safety analysis of nine placebo-controlled Praluent™ studies to be presented on Monday, March 16 at ACC.15, rates of skeletal muscle-related and neurocognitive events were generally balanced between Praluent and placebo.
• At week 78, positively adjudicated pre-specified CV adverse events (including additional CV AEs1 beyond those in the pre-specified ODYSSEY OUTCOMES endpoint of 'major adverse cardiac events' described below) occurred in 4.6 percent and 5.1 percent of Praluent and placebo patients, respectively. In a post hoc analysis using a pre-specified endpoint that included coronary heart disease death, myocardial infarction, stroke, or unstable angina requiring hospitalization, a lower rate of adjudicated major adverse cardiac events was observed in the Praluent™ group (27 of 1550 patients, 1.7 percent) compared with the placebo group (26 of 788 patients, 3.3 percent; hazard ratio 0.52; 95% percent CI, 0.31 to 0.90; nominal p less than 0.01). The cumulative incidence curves diverged progressively over time.
• Positive results from the ODYSSEY CHOICE I and CHOICE II trials, which evaluated monthly dosing of Praluent™ 300 mg and Praluent 150 mg, were presented at ACC.15, in San Diego. Investigators have also presented a pooled analysis of adverse events from five Phase 3 and four Phase 2 double-blind, placebo-controlled trials exploring multiple Praluent doses and regimens involving 3,759 patients with hypercholesterolemia who also received statins.
• • On August 31, 2014, Regeneron Pharmaceuticals and Sanofi announced detailed positive results from four Phase 3 ODYSSEY trials of alirocumab in people with hypercholesterolemia.
• The ongoing 2,341-patient, double-blind ODYSSEY LONG TERM trial is designed to evaluate the long-term safety and efficacy of 150 mg alirocumab every two weeks versus placebo in patients with hypercholesterolemia who are at high or very-high cardiovascular risk. On the primary efficacy endpoint of the trial, at 24 weeks, there was a 61 percent reduction from baseline in LDL-C levels in the alirocumab group as compared to a 1 percent increase in the placebo group (62 percent reduction in alirocumab group compared to placebo), p less than 0.0001. At 52 weeks, there was a 57 percent reduction from baseline in LDL-C levels in the alirocumab group as compared to a 4 percent increase in the placebo group (61 percent reduction in alirocumab group compared to placebo), p less than 0.0001. 81 percent of alirocumab patients achieved their pre-specified LDL-C goal (either 70 milligrams/deciliter [mg/dL] or 100 mg/dL depending on patients' baseline CV risk) compared to 9 percent for placebo (p less than 0.0001).
• In a post hoc safety analysis, there was a lower rate of adjudicated major cardiovascular events (cardiac death, myocardial infarction, stroke, and unstable angina requiring hospitalization) in the alirocumab group compared to placebo (1.4 percent compared to 3.0 percent, nominal p-value less than 0.01). These  events comprise the composite primary endpoint of the ongoing 18,000-patient ODYSSEY OUTCOMES trial, which is prospectively evaluating the potential of alirocumab to demonstrate CV benefit.
• ODYSSEY COMBO II trial is designed to evaluate the safety and efficacy of alirocumab compared to ezetimibe in patients with hypercholesterolemia who are at high CV risk and had inadequate LDL-C reduction at baseline despite stable maximally-tolerated statin therapy. On the primary endpoint of the trial, at 24 weeks, there was a 51 percent reduction from baseline in LDL-C levels in the alirocumab group compared to a 21 percent reduction in the ezetimibe group (30 percent reduction in alirocumab group compared to ezetimibe group), p less than 0.0001. At 52 weeks, there was a 50 percent reduction from baseline in LDL-C levels in the alirocumab group compared to an 18 percent reduction in the ezetimibe group (32 percent reduction in alirocumab group compared to ezetimibe group), p less than 0.0001. 77 percent of patients in the alirocumab group achieved an LDL-C level of 70 mg/dL at 24 weeks.
• Approximately 80 percent of patients in the alirocumab group remained on the initial 75 mg alirocumab dose. The most common adverse events (greater than or equal to 5 percent of patients) were upper respiratory tract infection (6.5 percent alirocumab; 6 percent ezetimibe), accidental overdose (6 percent alirocumab; 7 percent ezetimibe), dizziness (5 percent alirocumab; 5 percent ezetimibe), and myalgia (4 percent alirocumab; 5 percent ezetimibe).
• The ODYSSEY FH I and FH II trials enrolled a total of 738 HeFH patients and compare alirocumab to placebo. On the primary endpoint of the trials, at 24 weeks, there was a 49 percent reduction from baseline in LDL-C levels in both FH I and FH II alirocumab groups compared to an increase of 9 percent in FH I and 3 percent in FH II in the placebo groups (58 and 51 percent reduction compared to placebo), p less than 0.0001. At 52 weeks, in FH I, there was a 47 percent reduction from baseline and, in FH II, a 50 percent reduction from baseline in LDL-C levels in the alirocumab groups compared to an increase of 9 and 8 percent in the placebo groups, respectively (56 and 58 percent reduction compared to placebo), p less than 0.0001. 72 percent of alirocumab-treated patients in FH I, and 81 percent of alirocumab-treated patients in FH II, achieved their pre-specified LDL-C goal (either 70 mg/dL or 100 mg/dL) at 24 weeks compared to 2 and 11 percent in the placebo groups, respectively (p less than 0.0001). Approximately 50 percent of patients in the alirocumab groups remained on the 75 mg dose.In pooled data from both trials, the most common adverse events (greater than or equal to 5 percent of patients) were injection site reactions (11.5 percent alirocumab; 9 percent placebo), nasopharyngitis (10 percent alirocumab; 11 percent placebo), influenza (9 percent alirocumab; 6 percent placebo), and headache (5.5 percent alirocumab; 7 percent placebo).
• These four ODYSSEY trials reported here, along with results from six other Phase 3 studies, encompass more than 5,000 patients studied in double-blind trials for 24-104 weeks. Sanofi and Regeneron anticipate alirocumab regulatory submissions in the U.S. and EU by the end of 2014. In the U.S., the companies intend to use a Priority Review Voucher to obtain priority review status for the alirocumab regulatory submission.

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