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432 Cardio Diabetes Medicine 2017

• In two studies (ODYSSEY FH I, n = 486; FH II, n = and in those without an identified LDLR mutation.24
249), patients were randomized 2 : 1 to alirocumab Thus, both alirocumab and evolocumab are highly eff
75 mg or placebo every 2 weeks. Alirocumab dose ective in further reducing LDL cholesterol in patients
was increased at Week 12 to 150 mg if Week 8 with heterozygous familial hypercholesterolaemia
LDL was ≥70 mg/dL. Mean LDL decreased from when added to high-intensity statin therapy. 15
144.7 mg/dL to 71.3 mg/dL ( -57.9% vs. placebo) at
Week 24 in patients randomized to alirocumab in Homozygous Familial
FH I and from 134.6 mg/dL to 67.7 mg/dL ( -51.4% Hypercholesterolaemia (HoFH)
vs. placebo) in FH II (P < 0.0001). These reductions
were maintained through Week 78. LDL-C <71.3 HoFH is characterised by very high LDL and result-
mg/dL was achieved at Week 24 by 59.8 and ing atherosclerotic CVD early in life. It occurs due
68.2% of alirocumab-treated patients in FH I and to loss-of-function mutations in both alleles of the
FH II, respectively. In patients with HeFH and inad- LDLR gene (in most cases) or in other genes encod-
equate LDL control at baseline despite maximally ing proteins in the LDL-receptor pathway. Because
tolerated statin therapy, alirocumab treatment re- of very low or absent residual LDL-receptor activity,
sulted in significant LDL reduction and was well standard lipid-lowering therapies that work through
tolerated. Alirocumab also significantly reduced the common pathway of LDL-receptor upregulation
apolipoprotein B concentration by about 40% and (statins, ezetimibe, bile acid sequestrants) are much
non-HDL cholesterol concentration by about 50% less effective or completely ineffective in patients
compared with placebo (both p<0·0001). with HoFH. Even with optimised therapy including
15
high-intensity statin with or without ezetimibe, plus
Alirocumab (150 mg every 2 weeks) was also as- LDL apheresis, LDL remain raised and the mean age
sessed in a cohort of patients with severe hetero- of death is 33 years.
zygous familial hypercholesterolaemia (mean LDL
cholesterol 5 mmol/L) in ODYSSEY-HIGH, a phase In an open-label, single-arm study (TESLA part A),
3, 78-week study, in which treatment with alirocumab evolocumab (420 mg monthly) reduced LDL by a
15
led to a 40% placebo-corrected reduction in LDL cho- mean of 16·5% in HoFH. In a subsequent 12-week,
lesterol from baseline (p<0·0001), which was main- placebo-controlled RCT with 49 participants (TESLA
15
tained for 52 weeks. part B), evolocumab treatment significantly reduced
16
mean LDL cholesterol by 31%. Evolocumab is ap-
In a 12-week phase 2 trial (RUTHERFORD), more than proved for use in patients with homozygous famil-
160 patients with heterozygous familial hypercholes- ial hyper cholesterolaemia who are at least 13 years
tero laemia and an LDL cholesterol concentration of old, in addition to optimised standard therapy, and
2·6 mmol/L or more despite optimum lipid-lowering for most of these patients represents a reasonable
therapy were randomly assigned to evolocumab (350 next step beyond standard therapy.
mg or 420 mg monthly) or placebo.62 By week 12,
compared with placebo, evolocumab at both doses INCLISIRAN
signifi cantly reduced LDL cholesterol (44% reduction Inclisiran is a small interfering RNA that binds to
with 350 mg dose; 56% reduction with 420 mg dose; RNA-induced silencing complex (RISK), leading to
p<0·001); non-HDL cholesterol and apolipoprotein B degradation of the mRNA of PCSK9, reducing its
were also signifi cantly reduced in the evolocumab translation, and subsequently decreasing the degra-
groups versus placebo (p<0·001). In the phase 3 tri- dation of LDL receptors.
al of this series (RUTHERFORD-2), more than 300
patients with heterozygous familial hypercholestero- Inclisiran (ALN-PCSSC) has been evaluated in phase
laemia and similar lipid profi les at baseline were II trials and found to be well tolerated. Inclisiran re-
randomly assigned to evolocumab (140 mg every sults in dose-dependent reductions in PCSK9 and
2 weeks or 420 mg monthly) and followed up for LDL levels. At day 180, the least-squares mean re-
12 weeks, with similar results to the phase 2 trial: ductions in LDL levels were 27.9 to 41.9% after a
compared with placebo, evolocumab significantly single dose of inclisiran and 35.5 to 52.6% after two
reduced mean LDL cholesterol by 60% (p<0·0001), doses. Maximum reduction in LDL was seen after 2
non- HDL cholesterol by 55% (p<0·0001), and apo- doses of 300 mg (at day 1 and 90), approximately
lipoprotein B by 50% (p<0·0001).24 Roughly 80% of 48% of the patients had LDL <50 mg/dl at day 180.
the participants in this study were reported to have At day 240, PCSK9 and LDL levels remained signifi-
an LDLR mutation. The effects of evolocumab were cantly lower than at baseline. Serious adverse events
similar across the different LDLR mutation classes occurred in 11% of the patients in inclisiran arm (8% in

GCDC 2017