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]

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.

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
		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 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			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)
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
OPTIONS II	2012-2014	NCT 01730053	III	305
CHOICE I	2013-2014	NCT 01926782	III	803
CHOICE II	2013-2014	NCT 02023879	III	233
HIGH FH	2012-2015	NCT 01617655	III	107
JAPAN	2014-2015	NCT 02107898	III	216
ESCAPE	2015	NCT 02326220	III	62

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 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 - 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).

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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