PCSK9 monoclonal antibonody therapy as an adjunct to statins

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Macrovascular Residual Risk Studies

6 February 2013

Two recent phase II trials indicate that monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) may have potential in managing atherogenic dyslipidemia, in addition to low-density lipoprotein cholesterol (LDL-C), in statin-treated patients.

Giugliano RP, Desai NR, Kohli P, et al on behalf of the LAPLACE-TIMI 57 Investigators. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study.
Lancet 2012;380:2007-17.

STUDY SUMMARY

Objective:

The primary objective of both studies was to evaluate the LDL-C lowering efficacy of PCSK9 moncolonal antibody therapy – either AMG 1451 or SAR236553/REGN727 (SAR236553)2 in patients with elevated LDL-C levels on stable atorvastatin therapy

Study design:

Multicentre, randomized, double-blind placebo-controlled, parallel group studies

Study population:

Study 1: Patients with hypercholesterolemia and fasting LDL-C levels >2·2 mmol/ L (85 mg/dL) while on a stable dose of atorvastatin (±ezetimibe) for ³4 weeks.
Patients had a median age of 62 years, 51% were female and 65% had LDL-C <3.4 mmol/L (130 mg/dL) at baseline.

Study 2: Patients with LDL-C levels ³2.59 mmol/L (100 mg/dL) while on a stable dose of atorvastatin 10, 20, or 40 mg daily for ³6 weeks. Patients had a mean age of 56.7 years and 52% were female.

In both trials, concomitant treatment with other lipid-modifying therapy was prohibited.

Primary outcome:

In both studies, the primary outcome was the percentage change from baseline in LDL-C levels after 12 weeks on study treatment

Other efficacy variables:

Study 1:

Absolute change from baseline to 12 weeks in LDL-C
Percentage change from baseline to 12 weeks in non-high-density lipoprotein cholesterol (non-HDL-C), HDL-C, triglycerides, very low-density lipoprotein cholesterol (VLDL-C), apolipoproteins (apo) B and A-I, and the ratios of total cholesterol/HDL-C and apoB/A-I

Study 2:

Percentage change from baseline to 12 weeks in total cholesterol, HDL-C, triglycerides, non-HDL-C, apo B and A-I, and lipoprotein(a) [Lp(a)]
Percentage of patients achieving LDL-C treatment goals of <2.59 mmol/L (100 mg/dL) and <1.81 mmol/L (70 mg/dL)

Safety variables:

Treatment-emergent adverse events; and LA PLACE TIMI 57 also evaluated the formation of antibody to treatment

Method:

Study 1: After a screening phase (up to 6 weeks), eligible patients were randomized equally to one of the following groups:

subcutaneous (sc) AMG 145 70 mg, 105 mg, or 140 mg or matching placebo every 2 weeks; or
sc AMG 145 280 mg, 350 mg, or 420 mg or matching placebo every 4 weeks.

The duration of treatment was 12 weeks.
Study 2: Eligible patients were randomized equally to:

SAR236553 50, 100, or 150 mg or placebo every 2 weeks; or
SAR236553 200 or 300 mg every 4 weeks alternating with placebo to mimic twice-weekly dosing. Randomization was stratified by atorvastatin dose.

The total duration of treatment was 12 weeks and there was an 8-week follow-up.

Efficacy results:

At 12 weeks, both treatments reduced LDL-C levels by more than 60%. Maximal LDL-C lowering efficacy was observed with AMG 145 140 mg every 2 weeks (Table 1) and SAR236553 150 mg every 2 weeks (Table 2). Both treatments also lowered triglycerides (by up to 33.7% with AMG 145 and 18.9% with SAR236553), and raised HDL-C. Neither treatment influenced apoA-I.

Table 1: Effect of AMG 145 140 mg every 2 weeks (Study 1)

	LDL-C	apoB	Non-HDL-C	TG	VLDL-C	HDL-C
% change at 12 weeks	¯66.1	¯56.4	¯61.4	¯33.7	¯44.3	8.1
LDL-C <1.8 mmol/L	93.5%
Statistical significance: all p<0.0001 except HDL-C where p=0·0007

Table 2. Effect of SAR236553 150 mg every 2 weeks (Study 2)

	LDL-C	apoB	Non-HDL-C	TG	Lp(a)	HDL-C
% change at 12 weeks	¯ 72.4	¯56.1	¯62.5	¯18.9	¯28.6	5.5
LDL-C <1.8 mmol/L	100%
Statistical significance: all p<0.0001 except TG (p=0.0006) and HDL-C (p=0.057)

Safety results:

Study 1: The most common adverse events were nasopharyngitis (10% with AMG 145 vs 7% with placebo), cough (3% vs 2%], nausea (3% vs 0·6%) and injection site reactions (2% in each group). No patients developed anti-AMG 145 antibodies, neutropenia, or vasculitis.

Study 2: The profile of adverse events was similar in each group. Mild injection site reactions were most common. One patient on SAR236553 experienced a serious adverse event of leukocytoclastic vasculitis.

COMMENT

Understanding the role of PCSK9 in the regulation of LDL-C concentration has paved the way for the development of novel therapeutic approaches. PCSK9 binds the LDL receptor (LDLR) and promotes its degradation in the endosomal/lysosomal pathway.1 Thus, increased activity of PCSK9 leads to lower liver LDLR levels, reduction in LDL-uptake from the circulation, and hypercholesterolemia. In contrast, inhibiting PCSK9 would offer the possibility of lowering LDL-C concentration, a rationale which is now supported by clinical trials.2

Monoclonal antibody therapy targeting PCSK9 holds promise for improving achievement of LDL-C targets in statin-treated patients, a major unmet clinical need. Data from clinical trials, including those reported here, show that there is a reduction of >60% in LDL-C levels for at least 2 weeks after a single injection of a humanized PCSK9 monoclonal antibody therapy, with or without statin therapy.

While LDL-C is the primary treatment priority, there is clear evidence that targeting LDL-C still leaves a high residual cardiovascular risk. The Residual Risk Reduction Initiative (r3i) has emphasised the burden of residual cardiovascular risk associated with elevated atherogenic triglyceride-rich lipoproteins and low HDL-C.3

In the light of recent failed trials, such as AIM-HIGH4 and HPS2-THRIVE5 with niacin and continuing controversy about the role of cholesteryl ester transfer protein inhibition following termination of dalcetrapib, the second agent in this class,6 it is clear that additional treatments are needed. In the trials reported here, treatment with AMG-145 or SAR236553/REGN727 improved LDL-C goal achievement and also lowered triglycerides and raised HDL-C. SAR236553/REGN727 also reduced Lp(a) another atherogenic target. Both treatments appeared to be well tolerated. These findings support the ongoing development of this treatment modality in Phase-III trials to fully characterise their long-term efficacy and safety and effects on cardiovascular outcomes.

References

1. Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism, Trends in Biochem Sci 2007;32:71-7.
2. Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK. The PCSK9 decade. J Lipid Res 2012;53:2515-24.
3. Fruchart JC, Sacks FM, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res 2008;5:319-35.
4. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67.
5. Merck Announces HPS2-THRIVE Study of TREDAPTIVE™ (Extended-Release Niacin/Laropiprant) Did Not Achieve Primary Endpoint. Available from: http://www.mercknewsroom.com/press-release/prescription-medicine-news/merck-announces-hps2-thrive-study-tredaptive-extended-relea, December 20, 2012.
6. Schwartz GC, Olsson AG, Abt M et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. New Engl J Med 2012; 367:2089-99.

Key words

PCSK9; AMG 145; SAR236553/REGN727; atherogenic dyslipidemia; triglycerides; residual cardiovascular risk