Introduction
The structure and function of PCSK9
Synthesis and structure
LDL receptor cycling
Regulation
Mechanism of action
PCSK9 inhibitors
Inhibition strategies
Pharmaceutical company | Drug class | Agent | Phase |
---|---|---|---|
Sanofi/Regeneron | Human mAb | Alicocumab (SAR236553/REGN727) | 3 |
Amgen | Human mAb | Evolocumab (AMG 145) | 3 |
Pfizer/Rinat | mAb | Bococizumab (RN316) | 3 |
Novartis | mAb | LGT-209 | 2 |
Roche/Genetech | mAb | RG7652 | 2 |
Alnylam Pharmaceuticals/The Medicines Company | siRNA oligonucleotide | ALN-PCS02 | 1 |
Bristol-Myers Squibb/Adnexus | Monobody | BMS-962476 | 1 |
Idera Pharmaceuticals | Antisense Oligonucleotide | TBD | PC |
Merck | mAb | 1D05-IgG2 | PC |
Schering-Plough | Mimetic peptides | LDL EGF-AB peptide fragment | PC |
Evolocumab
Evolocumab in primary hypercholesterolemia
Evolocumab in familial hypercholesterolemia
Evolocumab in statin-intolerant patients
Evolocumab and cardiovascular outcomes
Author, trial name (reference) | Year | Comparator | Study group |
n
| Evolocumab dose(s) | Percentage change vs. placebo group | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
LCL-C | HDL-C | Non-HDL | TG | ApoB | Lp(a) | ||||||
Giugliano et al., LAPLACE-TIMI 57 [50] | 2012 | Statin ± ezetimibe | LDL-C > 85 mg mL−1 on-treatment | 236 | 70 mg, 105 mg, 140 mg two-weekly | −41.8 to −66.1 | 6.6 to 8.1 | −38.4 to −61.4 | −18.1 to −33.7 | −34.7 to −56.4 | NA |
238 | 280 mg, 350 mg, 420 mg four-weekly | −41.8 to −50.3 | 1.6 to 5.5 | −37.8 to −47.6 | −13.4 to −19.4 | −34.4 to −42.0 | NA | ||||
Koren et al., MENDEL [48] | 2012 | Placebo only | 100 ≤ LDL-C < 189 mg dL−1
| 135 | 70 mg, 105 mg, 140 mg two-weekly | −37.3 to −47.2 | 4.2 to 10.2 | −35.1 to −45.2 | −7.4 to −12.0 | −32.3 to −44.2 | −11.1 to −29.3 |
136 | 280 mg, 350 mg, 420 mg four-weekly | −43.6 to −52.5 | 3.3 to −5.8 | −37.7 to −47.1 | −1.7 to −5.3 | −33.2 to −42.5 | −21.6 to −29.2 | ||||
Raal et al., RUTHERFORD [54] | 2012 | Statin ± ezetimibe | HeFH; LDL-C ≥ 100 mg dL−1 on-treatment | 111 | 350 mg, 420 mg four-weekly | −43.8 to −55.2 | 6.8 to 7.8 | −41.8 to −53.5 | −15.0 to −19.9 | −34.8 to −46.2 | −23.1 to 31.5 |
Sullivan et al., GAUSS [61] | 2012 | Statin, ezetimibe or other agent | Statin intolerance, LDL-C ≥ 100 mg dL−1
| 95 | 280 mg to 420 mg four-weekly | −26.0 to −35.9 | 6.6 to 8.5 | 24.8 to −33.6 | −8.7 to −13.8 | −21.4 to −29.9 | −12.4 −18.0 |
30 | 420 mg every four-weekly | −47.3 | 13.1 | −44.8 | −4.0 | −36.9 | −21.2 | ||||
Hirayama et al., YUKAWA-1 [85] | 2014 | Statin ± ezetimibe | High CVD risk, LDL-C ≥ 116 mg dL−1
| 101 | 70 mg to 140 mg two-weekly | −52.9 to −68.9 | 4.4 to 9.1 | −49.5 to −62.6 | −14.3 to −16.6 | −46.8 to −60.7 | −41.5 to 50.6 |
104 | 280 mg to 420 mg four-weekly | −58.2 to −63.9 | 13.2 to 16.3 | −53.5 to −58.1 | −17.1 to −20.2 | −47.4 to −53.4 | −32.3 to −39.6 |
Alirocumab
Effect of alirocumab in primary hypercholesterolemia
Alirocumab in familial hypercholesterolemia
Author (reference) | Year | Comparator | Study group |
n
| Evolocumab dose(s) | Percentage change vs. placebo group | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
LCL-C | HDL-C | Non-HDL | TG | ApoB | Lp(a) | ||||||
McKenney et al. [78] | 2012 | Atorvastatin 10, 20 or 40 mg | LCL-C ≥ 100 mg dL−1 on-treatment | 92 | 50 mg, 100 mg, 150 mg two-weekly | −34.5 to −67.3 | 5.1 to 7.7 | −31.4 to −60.3 | −15.2 to −28.6 | −29.5 to −58.3 | −13.3 to −28.6 |
200 mg, 300 mg four-weekly | −38.1 to −42.6 | 7.3 to 9.5 | −35.2 to −38.5 | −18.1 to −20.5 | −30.9 to −35.3 | −7.9 to −16.7 | |||||
Roth et al. [77] | 2012 | Atorvastatin 10 or 80 mg | LCL-C ≥ 100 mg dL−1 on-treatment | 60 | 150 mg two-weekly | −48.9 | 6.2 | −36.0 | 7.9 | −42.4 | −32.0 |
150 mg four-weekly | −55.9 | 9.4 | −41.6 | −12.8 | −46.0 | −28.2 | |||||
Stein et al. [64] | 2012 | Statin ± ezetimibe | HeFH; LCL-C ≥ 100 mg dL−1 on-treatment | 31 | 150 mg two-weekly | −18.2 to −31.9 | 4.3 to 7.8 | −15.5 to −27.6 | −6.2 to 5.6 | −14.5 to −22.0 | −3.54 to −11.4 |
150 mg, 200 mg, 300 mg four-weekly | −57.3 | 10.1 | −46.6 | −5.7 | −43.8 | −19.47 |
The safety of PCSK9 inhibition
Author, trial name (reference) | Year |
n
| Agent | Population and study design | FU (w) | Percentage change vs. placebo group | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
LDL-C | ApoB | Non-HDL-C | TG | HDL-C | Lp(a) | ||||||
Farnier et al., ODYSSEY MONO [65] | 2014 | 103 | Alirocumab | Patients with hypercholesterolemia on no statins vs. ezetimibe | 24 | −31.6 | −25.8 | −25.5 | −1.2 | 4.4 | −4.4 |
Kereiakes et al., ODYSSEY COMBO I [66] | 2015 | 311 | Alirocumab | Patients with hypercholesterolemia not adequately controlled and high CVD risk | 24 | −45.9 | −35.8 | −37.5 | −0.6 | 7.3 | −14.6 |
Colhoun et al., ODYSSEY COMBO II [67] | 2015 | 707 | Alirocumab | Patients with hypercholesterolemia not adequately controlled and high CVD risk | 24 | −29.7 | −22.4 | −22.9 | −0.3 | 8.1 | −21.7 |
Robinson et al., ODYSSEY LONG TERM [73] | 2015 | 2341 | Alirocumab | Patients with hypercholesterolemia not adequately controlled and high CVD risk | 24 | −61.9 | −54.0 | −52.3 | −17.3 | 4.6 | −25.6 |
Blom et al., DESCARTES [53] | 2014 | 901 | Evolocumab | Patients with hyperlipidaemia had four-weekly 420 mg evolocumab in addition to diet alone, diet and atorvastatin or to diet plus atorvastatin plus ezetimibe | 52 | −57.0 | −44.2 | −50.3 | −11.5 | 5.4 | −22.4 |
Robinson et al., LAPLACE-2 [52] | 2014 | 2067 | Evolocumab | Patients with hyperlipidaemia had either 140 mg fortnightly or 420 mg every 4 weeks evolocumab added to statin therapy compared with ezetimibe | 12 | −59.2 to −70.6 | −47.0 | −54.9 | −9.3 to −31.4 | 3.2 to 9.8 | −19.8 to −36.5 |
Stroes et al., GAUSS-2 [62] | 2014 | 307 | Evolocumab | Patients with statin intolerance given 140 mg fortnightly or 420 mg every 4 weeks evolocumab and were compared to those on ezetimibe | 12 | −68.8 to −69.7 | −32.9 | NR | NR | 3.6 to 4.8 | −25.3 to −27.9 |
Koren et al., MENDEL-2 [49] | 2014 | 614 | Evolocumab | Patients with hypercholesterolemia on no statins 140 mg fortnightly or 420 mg every 4 weeks evolocumab and were compared to those on ezetimibe | 12 | −54.8 to −57.1 | −47.8 | −49.8 to −51.2 | −6.2 to −17.7 | 5.9 to 9.3 | −17.8 to −20.4 |
Raal et al., RUTHERFORD-2 [55] | 2015 | 329 | Evolocumab | Patients with heterozygous FH given 140 mg fortnightly or 420 mg every 4 weeks | 12 | −59.2 to −61.3 | −49.1 | −54.8 to −55.0 | −11.6 to −19.6 | 9.1 to 9.2 | −28.2 to −31.6 |
Sabatine et al., OSLER-2 [79] | 2015 | 4465 | Evolocumab | Hypercholesterolemia or mixed dyslipidaemia who had participated in the previous OSLER study | 12 | −61.0 | −47.3 | −52.0 | −12.6 | 7.0 | −25.5 |
Raal et al., TESLA Part B [57] | 2015 | 49 | Evolocumab | Patients with homozygous FH not on apheresis were given 420 mg every 4 weeks of evolocumab | 12 | −30.9 | −23.1 | NR | 0.3 | −0.1 | −11.8 |
Future directions
Title | Description | Study identifier |
---|---|---|
Trial assessing efficacy, safety and tolerability of PCSK9 inhibition in paediatric subjects with genetic LDL disorders | 10–17 year olds with outcomes focused on cardiovascular risk | NCT02392559 |
Effects of selective inhibition of cholesterol absorption with ezetimibe on intestinal cholesterol homeostasis in dyslipidemic men with insulin-resistance—a pilot study | Aged 18–60 and has metabolic syndrome | NCT01849068 |
Evaluating PCSK9 binding antibody influence on cognitive health in high cardiovascular risk subjects | Testing spatial working memory in those aged 40 to 85 taking evolocumab | NCT02207634 |
Further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk | 5 year cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, or coronary revascularization | NCT01764633 |
The evaluation of bococizumab (PF-04950615; RN316) in reducing the occurrence of major cardiovascular events in high risk subjects | Effect of bococizumab on number of Cardiovascular Events | NCT01975389 |
A phase 1 study of an investigational drug, ALN-PCSSC, in subjects with elevated low density lipoprotein cholesterol (LDL-C) | Safety | NCT02314442 |
A 2-part, phase 1, single and multiple ascending dose study to assess the safety, pharmacokinetics, and pharmacodynamics of CAT-2054 in healthy subjects | Frequency and severity of adverse events | NCT02374047 |
Open label study of long term evaluation against LDL-C trial-2 | Incidence of adverse events | NCT01854918 |
ODYSSEY outcomes: evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with alirocumab SAR236553 (REGN727) | To evaluate the effect of alirocumab on any adverse cardiovascular event | NCT01663402 |