Alirocumab

Pharmacologic interventions for PCSK9 Adapted from Journal of the American College of Cardiology, 62(16): 1401-1408

For a review of all PCSK9 inhibitors please click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tarek Nafee, M.D. [2],Aysha Anwar, M.B.B.S[3]

Overview

Alirocumab (REGN727 and SAR236553) is an investigational human monoclonal antibody that inhibits PCSK9 for the treatment of hypercholesterolemia.

Mechanism of Action

Alirocumab is a human monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is a protein that attaches to surface LDL receptors and triggers their degradation. This reduces the ability of hepatocytes to uptake LDL cholesterol and subsequently leads to increased levels of circulating LDL. By binding PCSK9, alirocumab inhibits LDL receptor destruction and increases the endocytosis of LDL from the circulation. Pre-clinical studies, and early clinical trials have shown the efficacy and safety of alirocumab in decreasing LDL cholesterol as an add-on agent or as monotherapy.

Approved Indications

In July 2015, the FDA approved the drug Praluent (alirocumab) for patients who have heterozygous familial hypercholesterolemia (FH) and high-risk patients who have had a stroke or myocardial infarction in the past and cannot take statins because of negative side effects. The EU is expected to make a decision by the end of September 2015.

Contraindications

Alirocumab is contraindicated in patients with history of serious hypersensitivity reactions including hypersensitivity vasculitis and reactions requiring hospitalizations.

Investigational Indications

• Diabetes mellitus
• Mixed dyslipidemia
• Metabolic syndrome
• Moderate to high cardiovascular risk
• Hypertriglyceridemia

Known Adverse Effects

• Local injection site reactions
• Allergic reactions
• Derranged LFTS
• Nasopharyngitis
• Influenza
• UTI
• Bronchitis
• Myalgia
• Muscle spasms
• Sinusitis
• Cough
• Contusion
• Musculoskeletal pain
• Low LDL -C value
• Anti drug antibodies

Major Trials

Synopsis

Trial Name	Year	NCT Identifier	Phase	N	Study Population	Primary Endpoint	Secondary Endpoints	Safety Endpoints	Randomization	Intervention Arm	Control Arm(s)	Study Duration	Follow up	Main Study Findings	Other Findings
		NCT 01288469	II	92
Linked to FH		NCT 01266876	II	77
		NCT 01288443	II	183
COMBO I	2012-2013	NCT 01644175	III	316	Patients > 18 years Moderate to high CV risk with LDL>100mg/dl Very high CV risk with LDL>70mg/dl 4 weeks of maximal statin therapy	% change in LDL at week 24 in ITT population	% change in LDL at different timepoints in "on-treatment" population	AE reporting	2:1	75mg SQ Alirocumab Q2W increased to 150 mg if LDL ≥70mg/dl by week 12	Matched Placebo	52 weeks	8 weeks	-48.2% vs. -2.3% (Δ:45.9%; 95% CI: 39.3-52.5; p<0.0001)	Substantial drop in first 4 weeks of treatment and sustained at 52 weeks 75% vs. 9.0% of patients reached LDL target of <70mg/dL On-treatment analysis demonstrated similar results (numerically larger difference) Similar AEs in both groups Similar AEs between 75mg and 150mg
COMBO II	2012-2013	NCT 01644188	III	720	Patients > 18 years Moderate to high CV risk with LDL>100mg/dl Very high CV risk with LDL>70mg/dl 4 weeks of maximal statin therapy	% change in LDL at week 24 in ITT population	% change in LDL at week 12(ITT or OT), 24 (OT), 52 (ITT or OT)	AE reporting	2:1	75mg SQ Alirocumab Q2W increased to 150 mg if LDL ≥70mg/dl by week 12	Ezetimibe 10mg PO QD	104 weeks	8 weeks	-50.6% vs. -20.7% (Δ:29.8%; 95% CI: 25.3-34.4; p<0.0001)	Substantial drop in first 4 weeks of treatment and sustained at 52 weeks On-treatment analysis demonstrated similar results (numerically larger difference) Similar AEs in both groups ALI>EZE in AEs leading to Tx discontinuation (7.5% vs. 5.4%)
ALTERNATIVE	2012-2013	NCT 01709513	III	314	Patients > 18 years Moderate to high CV risk with LDL>100mg/dl Very high CV risk with LDL>70mg/dl Washout of lipid lowering therapy for 2 weeks prior	% change in LDL at week 24 in ITT population compared to ezetimibe	% change in LDL at week 12 and 24 in "on-treatment" population compared to ezetimibe	All Adverse events during the study and the optional open label study extension	2:2:1	75mg SQ Alirocumab Q2W	Ezetimibe 10mg PO QD OR Atorvastatin 20mg PO QD	24 weeks	8 week follow up with option to extend to 3 year open label study	-45.0% vs. -14.6% (Δ:30.4%; 95% CI: 24.2-36.6; p<0.0001)	Substantial drop in first 4 weeks of treatment. 41.9% vs. 4.4% of patients reached LDL target of <70mg/dL. On-treatment analysis demonstrated similar results (numerically larger difference) Similar rates of any AEs between the groups. Rates of skeletal muscle associated AEs: ATV>EZE>ALI HR:0.61 (0.38-0.99; p=0.042) HR:0.71 (0.47-1.06)
MONO	2012-2013	NCT 01644474	III	103	Patients > 18 years 10-year risk of fatal CV event ≥ 1% and <5%. LDL>100mg/dl No Hx of established CHD or CHD risk equivalents Not receiving lipid lowering therapy for 4 weeks prior	% change in LDL at week 24 in ITT population	% change in LDL at week 12 in ITT population	AE reporting up to 10 weeks after last dose	1:1	75mg SQ Alirocumab Q2W increased to 150 mg if LDL ≥100 mg/dl by week 12 (70mg/dl was utilized instead of 100mg/dl due to admin error)	Ezetimibe 10mg PO QD	24 weeks	8 weeks	-47.2% vs. -15.6% (Δ:31.6%; 95% CI: 23.0-40.2; p<0.0001)	Substantial drop in first 4 weeks of treatment and sustained for 24 weeks. On-treatment analysis demonstrated similar results (numerically larger difference) More AEs in ezetemibe arm compared to alirocumab Disposable autoinjector resulted in low rate of injection related AEs
FHI	2012-2014	NCT 01623115	III	486	Adult patients HeFH patients LDL ≥ 70 mg/dL if no hx of CVD LDL ≥ 100 mg/dL if hx of CVD Not receiving lipid lowering therapy for 4 weeks prior	% change in LDL at week 24 in ITT population	% change in LDL at week 24 in "on-treatment" population % change in LDL at week 12 (ITT and OT)	AE reporting	2:1	75mg SQ Alirocumab Q2W increased to 150 mg if LDL ≥70mg/dl by week 12	Placebo	78 weeks	8 weeks	-48.8% vs. 9.1% (Δ:57.9%; 95% CI: 52.6-63.3; p<0.0001)	Substantial drop in first 4 weeks of treatment and sustained for 78 weeks. Similar AE profile between arms in both trials Disposable autoinjector resulted in low rate of injection related AEs
FHII	2012-2014	NCT 01709500	III	249										-48.7% vs. 2.8% (Δ:51.4%; 95% CI: 44.8-58.1; p<0.0001)
Long Term	2012-2014	NCT 01507831	III	2314	Adult patients HeFH or CHD or CHD risk equivalents LDL ≥ 70 mg/dL 4 weeks of maximal Statin therapy and continued throughout the study	% change in LDL at week 24 in ITT population	% change in LDL at week 12 and 24 in "on-treatment" population	Adverse Events up to 10 weeks after last dose	2:1	Single 150mg SQ Alirocumab Q2W	Matched Placebo	78 weeks	8 weeks	-61.0% vs. 0.8% (Δ:61.9%; 95% CI: 59.4-64.3; p<0.001)	Similar rates of any Adverse event between the groups.
OPTIONS I	2012-2014	NCT 01730040	III	355	Patients with very high CVD risk with LDL ≥70mg/dl Patients with high CVD risk with LDL ≥100mg/dl Taking baseline atorvastatin 20-40mg for 4 weeks (run-in period)	% change in LDL at week 24 in ITT population compared to any of the five control arms	% change in LDL at week 12 and 24 in "on-treatment" population	AE reporting	1:1:1 (for 20mg baseline atorvastatin) N=169	Add on therapy to 20mg ATV: 75mg SQ Alirocumab Q2W increased to 150 mg if LDL ≥70mg/dl (with CVD) or ≥100mg/dl (without CVD) by week 12	Add-on Ezetimibe 10mg PO QD OR Doubling Atorvastatin to 40mg PO QD	24 weeks	8 weeks	-44.1 vs. -20.5 vs. -5.0 (ALI vs. EZE vs. ATV)	Substantial drop in first 4 weeks of treatment and sustained for 24 weeks with both "entry doses" of statin Pooled statin therapy from all arms show higher incidence of AEs compared to pooled Alirocumab and pooled Ezetimibe arms 79.2% vs. 50.3% vs. 16.0% achieving LDL goals (ALI vs. EZE vs. ATV) Low immunogenicity by Antidrug antibodies
									1:1:1:1 (for 40mg baseline atorvastatin) N=186	Add on therapy to 40mg ATV: 75mg SQ Alirocumab Q2W increased to 150 mg if LDL ≥70mg/dl (with CVD) or ≥100mg/dl (without CVD) by week 12	Add-on Ezetimibe 10mg PO QD OR Doubling Atorvastatin to 80mg PO QD OR Switching to Rosuvastatin 40mg PO QD			-54.0 vs. -22.6 vs. -4.8 vs. -21.4 (ALI vs. EZE vs. ATV vs. RSV)	Substantial drop in first 4 weeks of treatment and sustained for 24 weeks with both "entry doses" of statin Pooled statin therapy from all arms show higher incidence of AEs compared to pooled Alirocumab and pooled Ezetimibe arms 77.2% vs. 54.2% vs. 10.2% vs. 42.2% achieving LDL goals (ALI vs. EZE vs. ATV vs. RSV) Low immunogenicity by Antidrug antibodies
OPTIONS II	2012-2014	NCT 01730053	III	305	Patients with very high CVD risk with LDL ≥70mg/dl Patients with high CVD risk with CHD or no CHD but 10 year CV risk of ≥ 5% need LDL ≥100mg/dl Taking baseline Rosuvastatin 10-20mg for 4 weeks (run-in period) Not receiving any other lipid lowering therapy	% change in LDL at week 24 in ITT population compared to any of the four control arms	% change in LDL at week 24 in "on-treatment" population compared to any of the four control arms	AE reporting	1:1:1	Add on therapy to RSV: 75mg SQ Alirocumab Q2W increased to 150 mg if LDL ≥70mg/dl (with CVD) or ≥100mg/dl (without CVD) by week 12	Add-on Ezetimibe 10mg PO QD OR Doubling Rosuvastatin from 10mg to 20mg	24 weeks	8 weeks	-50.6% vs. -14.4% vs. -16.3% (ALI vs. EZE vs. RSV)	On-treatment analysis demonstrated similar results Similar AE profile between all three arms 77.8% vs. 43.1%vs. 31.3% of patients reaching LDL targets (ALI vs. EZE vs. RSV)
											Add-on Ezetimibe 10mg PO QD OR Doubling Rosuvastatin from 20mg to 40mg			-36.3% vs. -11.0% vs. -15.9% (ALI vs. EZE. vs. RSV)	On-treatment analysis demonstrated similar results Similar AE profile between all three arms 60.1% vs. 43.6%vs. 29.9% of patients reaching LDL targets (ALI vs. EZE vs. RSV)
CHOICE I	2013-2014	NCT 01926782	III	803	Adults>18 years Uncontrolled hypercholesterolemia Moderate to very high CVD risk and receiving the maximally tolerated dose of statins Moderate to very high CVD and with statin associated muscle symptoms Moderate risk CVD risk and no statins	% change in LDL at week 24 AND % change in LDL to average at weeks 21-24 weeks in ITT population	% change in LDL at week 12 % of patients achieving LDL targets by week 24	AE reporting	4:2:1	300mg SQ Alirocumab Q4W decreased to 150 mg Q4W if LDL ≥70mg/dl (with very high CVD risk) or ≥100mg/dl (with moderate CVD) by week 12	75mg SQ Alirocumab Q2W increased to 150 mg if LDL ≥70mg/dl (with very high CVD risk) or ≥100mg/dl (with moderate CVD risk) by week 12 OR Placebo	48 weeks	8 weeks	-52.7% vs-0.3% in pts not on statins -58.8%vs -0.1% in pts on statins	Substantial drop in first 4 weeks of treatment and sustained for 24 weeks Free PCSK9 reduction by 12 weeks and sustained for 24 weeks 78.9% (statin) vs 85.2 (nonstatin) of patients reaching LDL targets in the 300mg group Similar AE profile between all three cohorts
CHOICE II	2013-2014	NCT 02023879	III	233	Adults>18 years Uncontrolled hypercholesterolemia Not receiving statins (may receive other lipid lowering therapies but discontinued throughout the study). Patients with SAMS must have Moderate, high, or very high cardiovascular risk Patients without SAMS may only have moderate cardiovscular risk	% change in LDL at week 24 in ITT population compared to placebo	% change in LDL at week 24 in "on-treatment" population % of patients achieving LDL targets All comparisons with the ALI 75mgQ2W arm	AE reporting	2:1:1 (75mgQ2W:150mgQ4W:Placebo)	150 mg SQ alirocumab Q4W increased to 150 mg Q2W (300mg total) in patients if LDL ≥70mg/dl (with CVD) or ≥100mg/dl (without CVD) at 12 week	Placebo (Primary endpoint) Alirocumab SQ 75 mg Q2W (Secondary endpoint)	24 weeks	8 weeks with option to extend	-51.7% vs 4.7% (Δ:56.4%; 95% CI; p<0.0001)	The larger Q4W dose resulted in a more sustained reduction of free PCSK9 which is further reduced by an increase in dose. The 75mgQ2W demonstrates a higher efficacy vs. placebo, compared with the 150mgQ2W -53.5% vs. 4.7% (Δ:58.2%; 95% CI; p<0.0001) 63.9% vs. 1.8% vs. 70.3% achieved their LDL targets (150Q4W vs. Placebo vs. 75mgQ2W) Similar AEs across groups Despite patients experiencing SAMS pre-trial, there was low incidence of MSK symptoms; thus ruling out causality with LDL lowering. More injection site AEs with 150Q4W
HIGH FH	2012-2015	NCT 01617655	III	107	Adults>18 years Patients with HeFH Uncontrolled hypercholesterolemia On maximum stable statin dose for at least 4 weeks prior LDL≥160mg/dl	% change in LDL at week 24 in ITT population	% change in LDL at week 24 in "on-treatment" population % of patients achieving LDL targets % change in LDL at weeks 12, 52, and 78 (in ITT population)	AE reporting	2:1	150 mg SQ Alirocumab Q2W	Placebo	78 weeks	8 weeks	-45.7% vs -6.6% (Δ:39.1%; p<0.0001)	On-treatment analysis demonstrated similar results 41.0% vs. 5.7% of patients reaching LDL targets (ALI vs. Placebo)
JAPAN	2014-2015	NCT 02107898	III	216	Adults>18 years (in 31 sites in Japan) Patients with HeFH +/- CAD Patients with no HeFH at high CV risk with Hx of CAD Uncontrolled hypercholesterolemia despite lipid lowering therapy for at least 4 weeks prior Patients with HeFH: LDL≥100mg/dl Non-FH patients: LDL≥120mg/dl	% change in LDL at week 24 in ITT population	% change in LDL at week 24 in "on-treatment" population % of patients achieving LDL targets % change in LDL at weeks 12 (ITT or OT)	AE reporting	2:1	75 mg SQ Alirocumab Q2W increased to 150 mg Q2W in patients if LDL≥100mg/dl (without CVD) at 12 week	Placebo	52 weeks	8 weeks	-62.5% vs 1.6% (Δ:64.1%; 95% CI; 59.8-68.5; p<0.0001)	Substantial drop in first 4 weeks of treatment and sustained for 52 weeks On-treatment analysis demonstrated similar results (numerically larger) 96.7% vs. 10.2% of patients reaching LDL targets by week 24 (ALI vs. Placebo) SAEs occur less frequently in ALI vs. placebo (7.0%vs.12.5%)
ESCAPE	2015	NCT 02326220	III	62	Adults>18 years Patients with HeFH High CV risk patients with previous statin treatment Currently undergoing apheresis therapy QW or Q2W for at least 4 weeks prior	Rate of apheresis during 12 week period from week 7-18 compared to number of planned apheresis tx	% change in LDL at week 6 in ITT population Rate of apheresis from week 15 to 18	AE reporting up to 10 weeks after last dose	2:1	150 mg SQ Alirocumab Q2W	Placebo	18 weeks	8 weeks	75% reduction in rate of apheresis weeks 7-18 (ALI vs. Placebo) HR:67%-83%, p<0.0001	Substantial drop in LDL for first 2 weeks of treatment and sustained for 52 weeks 50% reduction in rate of apheresis weeks 15-18 (ALI vs. Placebo) HR:50%-100%, p<0.0001 Similar AEs across groups

Phase II Trials

Safety and efficacy of atorvastatin with or without alirocumab in primary hypercholesterolemia (NCT 01288469)

This randomized, double-blind, placebo-controlled phase 2 trial of 92 patients with LDL-C≥100 mg/dL after treatment with 10 mg of atorvastatin for at least 7 weeks randomized patients to 8 weeks of therapy with either 80 mg of atorvastatin daily plus 150 mg SC alirocumab once every 2 weeks, 10 mg of atorvastatin daily plus 150 mg alirocumab once every 2 weeks, or 80 mg of atorvastatin daily plus SC placebo once every 2 weeks. The trial demonstrated a significant 73.2% reduction from baseline serum LDL-C cholesterol with 80 mg of atorvastatin plus alirocumab compared with 17.3% with the 80 mg atorvastatin plus placebo. Ninety percent of the patients who received alirocumab reached LDL-C concentrations lower than 70 mg/dL compared with 17% of those receiving atorvastatin alone. There were no significant safety signals and the drug was well tolerated.

Safety and efficacy in heterozygous familial hypercholesterolaemia with ongoing stable-dose statin with or without ezetimibe therapy (NCT 01266876)

This randomized, double-blind, placebo-controlled phase 2 trial of 77 adults with heterozygous familial hypercholesterolaemia and LDL-C concentrations of ≥100 mg/dL or higher on stable diet and statin dose, with or without ezetimibe therapy were randomized (1:1:1:1:1) to 5 different treatment arms for 12 weeks: 150 mg SC alirocumab every 4 weeks, 200 mg SC alirocumab every 4 weeks, 300 mg SC alirocumab every 4 weeks, 150 mg SC alirocumab every 2 weeks, or SC placebo. Randomization was stratified by baseline use of ezetimibe. Alirocumab demonstrated a significant reduction in LDL-C at week 12 (28.9%, 31.5%, and 42.5% for the 150, 200, and 300 mg every 4 weeks respectively, and 67.9% for the 150 mg every 2 weeks dose, compared with 10.7% in the placebo arm) with no significant safety signal. There were no increases >3 x ULN in hepatic transaminases or creatine kinase (CK).

Safety and efficacy in primary hypercholesterolemia with ongoing stable atorvastatin therapy (NCT 01288443)

This randomized, double-blind, placebo-controlled phase 2 trial of 183 patients with LDL-C ≥100 mg/dL on stable-dose atorvastatin for 6 or more weeks randomized patients to a 12 week treatment course in either one of 6 arms (1:1:1:1:1:1): subcutaneous (SC) placebo every 2 weeks, 50 mg SC alirocumab every 2 weeks, 100 mg SC alirocumab every 2 weeks, 150 mg SC alirocumab every 2 weeks, 200 mg SC alirocumab every 4 weeks alternating with placebo, or 300 mg SC alirocumab every 4 weeks alternating with placebo. Alirocumab demonstrated a significant dose-related reduction in serum LDL-C (40%, 64%, and 72% with 50, 100, and 150 mg respectively, and 43% and 48% with 200 and 300 mg respectively compared with 5% in placebo) with no major safety signals.

Phase III Trials

ODYSSEY - COMBO I

COMBO I was a randomized, double blind, trial that randomized 316 adult patients with moderate to very high CV risk and elevated LDL-C despite maximal statin use to either SC alirocumab 75mg every 2 weeks for 52 weeks or a matched placebo. Alirocumab dose was increased at week 12 to 150mg every two weeks if LDL targets failed to be met by week 8. Alirocumab was generally well tolerated, with no reported safety signals in the 75mg or 150mg dose. Alirocumab treatment was associated with a significantly higher reduction in LDL-C from baseline to 24 weeks ( -48.2% for alirocumab vs. -2.3% for placebo; Δ:45.9%; 95% CI: 39.3-52.5; p<0.0001). Patients on alirocumab were more likely to reach LDL targets (75% for alirocumab vs. 9% for placebo). Patients on alirocumab demonstrated a substantial drop in LDL-C within the first 4 weeks, which was sustained to week 52.

ODYSSEY - COMBO II

COMBO II was a randomized, double-blind, double-dummy, trial that randomized 720 patients with elevated CV risk and LDL-C despite maximal statins use to either SC alirocumab 75 mg every 2 weeks (and PO placebo) or PO ezetimibe 10 mg daily (and SC placebo). Alirocumab was generally well tolerated, with no reported safety signals. Alirocumab treatment was associated with a significantly higher reduction in mean LDL-C values from baselines at week 24 (50.6 ± 1.4% for alirocumab vs. 20.7 ± 1.9% for ezetimibe; P < 0.0001). Patients on alirocumab were more likely to achieve LDL-C <1.8 mmol/L (77.0% vs. 45.6%; P < 0.0001). At week 24, mean LDL-C levels were 1.3 ± 0.04 mmol/L among patients receiving alirocumab, and 2.1 ± 0.05 mmol/L among patients receiving ezetimibe.

ODYSSEY -ALTERNATIVE

ALTERNATIVE was a randomized, double blind, double dummy trial that randomized 314 adult patients with moderate to very high CV risk and who underwent 2 weeks washout from lipid lowering therapies in a 2:1:1 ratio to 75mg alirocumab every two weeks, or 10mg oral ezetimibe daily, or 20mg oral atorvastatin daily for 24 weeks. Alirocumab was associated with the lowest rates of skeletal muscle associated AEs, followed by ezetimibe and atorvastatin, respectively. Alirocumab was generally well tolerated, with no significant safety signals. Alirocumab treatment was associated with a significantly higher reduction in mean LDL-C from baseline to week 24 compared to ezetimibe (-45.0% for alirocumab vs. -14.6% for ezetimibe; Δ:30.4%; 95% CI: 24.2-36.6; p<0.0001). Patients on alirocumab were more likely to achieve LDL targets (41.9% vs. 4.4%). Alirocumab patients demonstrated a substantial drop in LDL-C in the first 4 weeks, which was sustained for 24 weeks.

ODYSSEY - MONO

ODYSSEY- MONO was a randomized, double blind, double dummy trial that enrolled 103 adult patients with a 10 year fatal CV risk of 1.00% to 4.99% and LDL-C>100mg/dl. Patients had no established history of coronary heart disease or any CHD risk equivalents. Additionally, patients were not receiving lipid lowering therapy for 4 weeks prior to randomization. Patients were randomized to receive 75mg of SC alirocumab twice weekly or oral ezetimibe 10mg once daily. Alirocumab dose was increased at week 12 to 150mg every two weeks if LDL targets failed to be met by week 8. Alirocumab treatment was associated with a significantly higher reduction in mean LDL-C from baseline to week 24 compared to ezetimibe (-47.2% for alirocumab vs. -15.6% for ezetimibe; Δ:31.6%; 95% CI: 23.0-40.2; p<0.0001). Alirocumab patients demonstrated a substantial drop in LDL-C in the first 4 weeks, which was sustained for 24 weeks. Alirocumab was well tolerated with no safety signals.

ODYSSEY - FH I & FH II

ODYSSEY FHI and FH II were multicenter, double-blind, placebo-controlled trials that enrolled a total of 735 heterozygous familial hypercholesterolemia patients and randomized them to either SC alirocumab 75-150 mg every 2 weeks or matching placebo for a total of 78 weeks, on top of a background of lipid lowering therapy.The primary endpoint was the prrcent change in LDL-C from baseline to week 24. Alirocumab administration was associated with a 57.9% reduction compared to placebo in the FH I population (P<0.0001), and a 51.4% reduction compared to placebo in the FH II population (P<0.0001). Alirocumab was well tolerated and there were no safety concerns.

ODYSSEY - Long Term

Long term was a randomized, double-blind, placebo-controlled trial that enrolled 2341 patients at high risk for CV events with baseline LDL-C ≥70 mg/dL. Patients were randomized in 2:1 ratio to receive either 150mg SC alirocumab or equivalent placebo once every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24. Alirocumab treatment was associated with a 62% reduction in LDL-C compared to placebo (P<0.001). In an exploratory analysis, alirocumab was associated with a significant reduction in the rate of major adverse cardiovascular events (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P=0.02). Alirocumab treatment was associated with a significantly higher incidence of myalgia (5.4% vs. 2.9%; P=0.006).

ODYSSEY - OPTIONS I

OPTIONS I was a randomized, double blind, trial that enrolled 355 patients with high or very high CVD risk and elevated LDL-C. All patients were receiving 20 or 40 mg of atorvastatin for at least 4 weeks prior to study enrollment. Patients were stratified by their baseline dose of 20mg atorvastatin vs. 40mg atorvastatin prior to randomization. Patients receiving 20mg of atorvastatin were randomized in a 1:1:1 ratio to receive add-on therapy of 75mg SC alirocumab twice weekly, or add-on therapy of 10mg oral ezetimibe once daily, or doubling the atorvastatin dose to 40mg once daily. Patients receiving a baseline 40mg of atorvastatin were randomized in a 1:1:1:1 ratio to receive add-on therapy of 75mg SC aloricumab twice weekly, or add-on therapy of 10mg oral ezetimibe once daily, or doubling atorvastatin dose to 80mg once daily, or switching to 40mg oral rosuvastatin once daily. Patients were followed for 24 weeks.

Among patients receiving a 20mg baseline dose of atorvastatin , add-on therapy of alirocumab was associated with a 44.1% reduction in mean LDL-C compared to 20.5% for ezetimibe, and 5.0% for 40mg atorvastatin. Patients on alirocumab add-on treatment were most likely to achieve LDL-C targets (79.2% for alirocumab vs. 50.3% for ezetimibe vs. 16.0% for 40mg atorvastatin).

Among patients receiving 40mg baseline dose of atorvastatin, add-on therapy of alirocumab was associated with a 54.0% reduction in mean LDL-C compared to 22.6% for ezetimibe, 4.8% for atorvastatin, and 21.5% for rosuvastatin. Patients on alirocumab add-on treatment were most likely to achieve LDL-C targets (77.2% for alirocumab vs. 54.2% for ezetimibe vs. 10.2% for 80mg atorvastatin, and 42.2% for rosuvastatin).

Alirocumab was well tolerated and showed no safety signals. Regardless of baseline dose of atorvastatin, patients experienced a substantial drop in mean LDL-C within the first 4 weeks which was sustained for 24 weeks.

ODYSSEY - OPTIONS II

OPTIONS II was a randomized, double blind, trial that enrolled 305 patients with high or very high CVD risk and elevated LDL-C. All patients were receiving 10 or 20 mg of rosuvastatin for at least 4 weeks prior to study enrollment. Patients were stratified by their baseline dose of 10mg rosuvastatin vs. 20mg rosuvastatin prior to randomization. Patients receiving 10mg of rosuvastatin were randomized in a 1:1:1 ratio to receive add-on therapy of 75mg SC alirocumab twice weekly, or add-on therapy of 10mg oral ezetimibe once daily, or doubling the rosuvastatin dose to 20mg once daily. Patients receiving a baseline 20mg of rosuvastatin were randomized in a 1:1:1 ratio to receive add-on therapy of 75mg SC aloricumab twice weekly, or add-on therapy of 10mg oral ezetimibe once daily, or doubling rosuvastatin dose to 40mg once daily, Patients were followed for 24 weeks.

Among patients receiving a 10mg baseline dose of rosuvastatin , add-on therapy of alirocumab was associated with a 50.6% reduction in mean LDL-C compared to 14.4% for ezetimibe, and 16.3% for 20mg rosuvastatin. Patients on alirocumab add-on treatment were most likely to achieve LDL-C targets (77.8% for alirocumab vs. 43.1% for ezetimibe vs. 31.3% for 20mg rosuvastatin).

Among patients receiving 20mg baseline dose of rosuvastatin, add-on therapy of alirocumab was associated with a 36.3% reduction in mean LDL-C compared to 11.0% for ezetimibe, and 15.9% for rosuvastatin. Patients on alirocumab add-on treatment were most likely to achieve LDL-C targets (60.1% for alirocumab vs. 43.6% for ezetimibe vs. 29.9% for 40mg rosuvastatin). Results of the 20mg group missed the mark for statistical significance.

Alirocumab was well tolerated and showed no safety signals.

ODYSSEY - CHOICE I

CHOICE I was a randomized, double blind, placebo controlled clinical trial that enrolled 803 adult patients with uncontrolled hypercholesterolemia and moderate to very high CVD risk receiving maximum dose of statins, have skeletal muscle symptoms associated with statin use or discontinued statin use. Patients were randomized in a 4:2:1 ratio to receive 300mg SC alirocumab every 4 weeks, or 75mg SC alirocumab every 2 weeks, or placebo for 48 weeks. Alirocumab treatment was well tolerated and showed no significant safety signals.

Among patients not receiving statins at baseline; those receiving alirocumab demonstrated a 52.7% reduction in mean LDL-C compared to 0.3% in placebo. Among patients receiving statins at baseline; those receiving alirocumab demonstrated a 48.8% reduction in mean LDL-C compared to 0.1% in placebo.

ODYSSEY - CHOICE II

CHOICE II was a randomized, double blind, placebo controlled clinical trial that enrolled 233 adult patients with uncontrolled hypercholesterolemia and discontinued statins. This trial enrolled a large subgroup of patients who previously experienced statin associated myopathy. Patients were randomized in a 2:1:1 ratio to receive 150mg SC alirocumab every four weeks, or placebo, or 75mg SC alirocumab every two weeks. Primary effficacy endpoint was the percent change in mean LDL-C from baseline to week 24 in the ITT population compared to placebo. Alirocumab was well tolerated and demonstrated no safety signals. There was a low incidence of musculoskeletal symptoms across all groups. More injection site reactions were associated with the 150mg dose compared to placebo or the 75mg dose.

Patients receiving alirocumab had a 51.7% mean reduction in LDL-C compared to 4.7% in patients receiving placebo. The 75mg twice weekly dose demonstrated a higher efficacy against placebo compared to the 150mg every 4 weeks dose. More patients achieved target LDL-C levels in the 75mg dose group compared to 150mg and placebo groups (70.3% vs. 63.9% vs. 1.8%, respectively).

ODYSSEY - HIGH FH

HIGH FH was a randomized, double blind, placebo controlled clinical trial that enrolled 107 adult patients with heterozygous familial hypercholesterolemia with poorly controlled cholesterol levels (LDL>150mg/dl) despite maximum stable dose of statins. Patients were randomized in a 2:1 fashion to receive 150mg SC alirocumab every two weeks or placebo for 78 weeks. Alirocumab was well tolerated and demonstrated no safety signals.

Patients on alirocumab had a 45.7% reduction in LDL-C from baseline to week 24 compared to 6.6% reduction in the placebo group. 41.0% of patients in the alirocumab group achieved LDL targets compared to 5.7% in the placebo group.

ODYSSEY - JAPAN

ODYSSEY JAPAN was a randomized, double blind, placebo controlled clinical trial that enrolled 216 adult patients at 31 sites in Japan. Patients had heterozygous familial hypercholesterolemia and those with high cardiovascular risk with a history of coronary artery disease. Patients had uncontrolled hypercholesterolemia with an elevated LDL-C despite lipid lowering therapy. Eligible patients were randomized in a 2:1 fashion to receive 75mg SC alirocumab every two weeks or placebo, for a duration of 52 weeks. Surprisingly, patients receiving placebo experienced more SAEs compared to patients in the alirocumab group (12.5% for placebo and 7.0% for alirocumab). Alirocumab was well tolerated, and no safety concerns were observed.

Patients receiving alirocumab demonstrated a 62.5% reduction in mean LDL-C from baseline to week 24 compared to placebo; 1.6%. This was demonstrated with a substantial drop in the first 4 weeks and sustained for 52 weeks. 96.7% of patients receiving alirocumab achieved LDL-C targets compared to 10.2% of patients in the placebo group.

ODYSSEY - ESCAPE

ESCAPE is a

Cost-Effectiveness

Doses are administered every two weeks with a cost of $40 a day or $14,600 a year, substantially higher than some generic statins, which can cost as little as $0.10 a day. Praluent is more expensive to manufacture than statins because it is made in live genetically engineered cells. Manufacturers argue that the drug is cost-effective because it will reduce medical costs of hospitalizations from stroke or myocardial infarction and that the price of the drug reflects its value. Praluent used in combination with statins can lower cholesterol 40-70% compared to statins that lower LDL an average of 40% . Still, further research into the actual ability of the drug to reduce risk and complications is ongoing. Reduced prices and plans through insurers should help make the drug accessible to patients with lower ability to pay.

References

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