Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: A Phase II pooled analysis

Figures & data

Figure 1. Dynamic relationship among alirocumab, PCSK9, and LDL-C levels (data from single dose study; NCT01074372) is shown [5]. A. Free PCSK9 and total alirocumab concentration versus time is shown. B. Free PCSK9 and total alirocumab concentration and mean percentage change in LDL-C versus time is shown. The single-dose study (NCT01074372) was conducted in healthy volunteers with no background statin or other lipid-lowering therapy.

Table 1. Summary of alirocumab dosing schedule highlighting doses represented in all three Phase II studies [6-8].

Study	Placebo, n	Q4W dosing, n			Q2W dosing, n
		150 mg	200 mg	300 mg	50 mg	100 mg	150 mg
Study 1003 [8]	15	15	16	15			16
Study 11565 [6]	31		30	30	30	31	31
Study 11566 [7]	31^a						61^a

^aPlacebo and one alirocumab treatment arm included up-titration of atorvastatin from 10 mg to atorvastatin 80 mg.

Abbreviations: Q2W = Every 2 weeks; Q4W = Every 4 weeks.

Figure 2. Patient disposition for the pooled analysis is shown.

Table 2. Pooled baseline characteristics.

	Control (n = 77)	Alirocumab 150 mg Q2W (n = 108)
Mean age, years (SD)	53.8 (9.4)	58.2 (10.1)
Males, %	49.4	43.5
Race, %
White	84.4	88.9
Black or African-American	13.0	11.1
Asian	1.3	0
Other	1.3	0
Hispanic or Latino ethnicity, %	28.6	22.2
Mean BMI, kg/m^2 (SD)	28.9 (4.7)	29.2 (4.6)
Mean lipid parameters, mg/dL
LDL-C (SD)	130.6 (27.5)	127.2 (25.0)
HDL-C (SD)	51.8 (13.8)	53.8 (15.0)
Non-HDL-C (SD)	158.7 (30.8)	154.2 (31.3)
Triglycerides^a (Q1–Q3)	122.5 (91.5–174.0)	123.5 (87.8–168.5)
Lp(a) ^a (Q1–Q3)	19.0 (6.0–77.0)	28.0 (9.0–70.0)
Apo B (SD)	108.8 (22.8)	108.1 (23.9)

^aMedian.

Abbreviations: Apo = Apolipoprotein; BMI = Body mass index; HDL-C = High-density lipoprotein cholesterol; LDL-C = Low-density lipoprotein cholesterol; Lp(a) = Lipoprotein (a); Q2W = Every 2 weeks; SD = Standard deviation.

Table 3. Pooled TEAEs and safety and laboratory parameters.

	Control (n = 77)^a	Alirocumab 150 mg Q2W (n = 108)^a
Any TEAE, n (%)	42 (54.5)	63 (58.3)
Any treatment-emergent SAE	2 (2.6)	1 (0.9)
Any TEAE leading to death	0	0
Any TEAE or treatment-emergent SAE leading to permanent discontinuation	4 (5.2)	2 (1.9)
TEAEs by MeDRA system organ class
Gastrointestinal disorders	12 (15.6)	13 (12.0)
Infections and infestations	11 (14.3)	13 (12.0)
General disorders and administration-site conditions	9 (11.7)	16 (14.8)
Of which, injection-site reactions	4 (5.2)	12 (11.1)
Musculoskeletal disorders	13 (16.9)	13 (12.0)
Nervous system disorders	6 (7.8)	12 (11.1)
Respiratory disorders	3 (3.9)	7 (6.5)
Skin and subcutaneous tissue disorders	0	7 (6.5)
Vascular disorders	2 (2.6)	4 (3.7)
Renal disorders	0	1 (0.9)
Laboratory parameters
Alanine aminotransferase > 3 × ULN	0	0
Aspartate aminotransferase > 3 × ULN	0	1 (0.9)
Alkaline phosphatase > 1.5 × ULN	0	2 (1.9)
Total bilirubin > 1.5 × ULN	0	2 (1.9)
Creatine kinase > 3 × ULN	4 (5.2)	2 (1.9)

^aData include 31 placebo and 30 alirocumab patients with up-titration of atorvastatin from 10 mg to 80 mg.

Abbreviations: Q2W = Every 2 weeks; SAE = Serious adverse event; TEAE = Treatment-emergent adverse event; ULN = Upper limit of normal.

Figure 3. Mean percentage change from baseline in LDL-C at week 8/12, last observation-carried-forward is shown in patients treated with alirocumab 150 mg Q2W. Efficacy data pooled from studies 11565 and 1003: 12-week end points, background therapy of either atorvastatin 10–40 mg (11565), or a statin ± ezetimibe (1003) and study 11566: 8-week end point, patients were on atorvastatin 10 mg/day at baseline; placebo arm and one treatment arm included up-titration of atorvastatin from 10 mg to 80 mg. Least squares (LS) means and P-values come from covariance analysis with treatment group and study as fixed effects and baseline as covariate. P-value is provided for descriptive purposes only.

Figure 4. Attainment of prespecified LDL-C goals at week 8/12, last observation-carried-forward is shown.

Figure 5. Mean percentage change from baseline in Apo B, non-HDL-C, Lp(a), triglycerides, and HDL-C at week 8/12, last observation-carried-forward is shown. P-values are derived from analyses of covariance with treatment group and study as fixed effects, and baseline as covariate, and are provided for descriptive purposes only. Not adjusted for multiplicity.

Figure 6. Mean percentage change from baseline in LDL-C with alirocumab 150 mg Q2W versus control at week 8/12 by stable background lipid-lowering therapy (LOCF) is shown.

Roth EM, Diller P. Alirocumab for hyperlipidemia: physiology of PCSK9 inhibition, pharmacodynamics and Phase I and II clinical trial results of a PCSK9 monoclonal antibody. Future Cardiol 2014;10:183–99.

 PubMedGoogle Scholar

Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 2012;380:29–36.

 PubMed Web of Science ®Google Scholar

McKenney JM, Koren MJ, Kereiakes DJ, et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012;59:2344–53.

 PubMed Web of Science ®Google Scholar

Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012;367:1891–900.

 PubMed Web of Science ®Google Scholar