[42] If we can treat osteoporosis with them, why not use them to lower LDL?

Phase II trial of a Monoclonal antibody to lower LDL
#MP111212
[Koren, Lancet, 12, PCSK9, LDL, 50.9%]

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61771-1/abstract

Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study

Dr Michael J Koren MD a , Rob Scott MD b, Jae B Kim MD b, Beat Knusel PhD b, Thomas Liu PhD b, Lei Lei PhD b, Michael Bolognese MD c, Scott M Wasserman MD b
The Lancet, Volume 380, Issue 9858

Background

Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases serum LDL-cholesterol (LDL-C) concentrations. We assessed the effects of AMG 145, a human monoclonal antibody against PCSK9, in patients with hypercholesterolaemia in the absence of concurrent lipid-lowering treatment.

Methods

In a phase 2 trial done at 52 centres in Europe, the USA, Canada, and Australia, patients (aged 18—75 years) with serum LDL-C concentrations of 2·6 mmol/L or greater but less than 4·9 mmol/L were randomly assigned equally through an interactive voice response system to subcutaneous injections of AMG 145 70 mg, 105 mg, or 140 mg, or placebo every 2 weeks; subcutaneous AMG 145 280 mg, 350 mg, or 420 mg or placebo every 4 weeks; or oral ezetimibe 10 mg/day. The primary endpoint was percentage change from baseline in LDL-C concentration at week 12. Analysis was by modified intention to treat. Study personnel and patients were masked to treatment assignment of AMG 145 or placebo. Ezetimibe assignment was open label. This trial is registered with ClinicalTrials.gov, number NCT01375777.

Findings

406 patients were assigned to AMG 145 70 mg (n=45), 105 mg (n=46), or 140 mg (n=45) every 2 weeks; AMG 145 280 mg (n=45), 350 mg (n=45), or 420 mg (n=45) every 4 weeks; placebo every 2 weeks (n=45) or every 4 weeks (n=45); or ezetimibe (n=45). AMG 145 significantly reduced LDL-C concentrations in all dose groups (mean baseline LDL-C concentration 3·7 mmol/L [SD 0·6]; changes from baseline with every 2 weeks AMG 145 70 mg −41·0% [95% CI −46·2 to −35·8]; 105 mg −43·9% [—49·0 to −38·7]; 140 mg −50·9% [—56·2 to −45·7]; every 4 weeks AMG 145 280 mg −39·0% [—44·1 to −34·0]; 350 mg −43·2% [—48·3 to −38·1]; 420 mg −48·0% [—53·1 to −42·9]; placebo every 2 weeks −3·7% [—9·0 to 1·6]; placebo every 4 weeks 4·5% [—0·7 to 9·8]; and ezetimibe −14·7% [—18·6 to −10·8]; p<0·0001 for all doses vs placebo or ezetimibe). Treatment-emergent adverse events occurred in 136 (50%) of 271 patients in the AMG 145 groups, 41 (46%) of 90 patients in the placebo groups, and 26 (58%) of 45 patients in the ezetimibe group; no deaths or serious treatment-related adverse events were reported.

Interpretation

The results of our study support the further assessment of AMG 145 in long-term studies with larger and more diverse populations including patients with documented statin intolerance.