ArticlesEffect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial
Introduction
LDL cholesterol is one of the major risk factors for coronary heart disease, with a continuous and graded association between its plasma concentration and risk—for every 0·78 mmol/L (30 mg/dL) change in LDL cholesterol, the relative risk for coronary heart disease changes by roughly 30%.1, 2 Additionally, in a large meta-analysis3 of 21 statin studies, the investigators concluded that for every 1·01 mmol/L (39 mg/dL) reduction in LDL cholesterol with statin treatment, cardiovascular events were reduced by about 22%.3 Despite the extensive use of statins, existing treatments for the management of raised LDL cholesterol remain inadequate. This is especially true for individuals with pre-existing coronary heart disease or diabetes, who are at the highest risk and require the most aggressive management of hypercholesterolaemia.4 Among high-risk individuals, it is estimated that only 50% achieve the target LDL cholesterol of less than 2·59 mmol/L at 6 months after statin treatment, despite close monitoring and optimisation of the drug regimen.5, 6, 7, 8, 9 With the LDL cholesterol target of less than 1·81 mmol/L in high-risk individuals, the number who reach their LDL cholesterol goals is even lower at 30%.9, 10 Thus, a clear unmet medical need exists for hypercholesterolaemia treatments, especially in high-risk patient populations.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the serine protease family and was first connected to cholesterol metabolism when gain-of-function mutations in PCSK9 were identified in people with familial hypercholesterolaemia who did not have mutations in the LDL receptor (LDLR) or apolipoprotein B (APOB) genes.11 Animal studies subsequently determined that PCSK9 binds hepatocyte LDLRs both intracellularly and extracellularly, leading to their lysosomal degradation (figure 1).12, 13 Loss-of-function mutations in PCSK9 have also been described in human beings, and are associated with reductions in LDL cholesterol and risk of coronary heart disease.14, 15 Several individuals with no circulating PCSK9 due to compound heterozygous loss-of-function mutations have also been identified. These individuals have very low LDL cholesterol (<0·52 mmol/L), but are otherwise healthy.16, 17 In loss-of-function mouse models for PCSK9, reductions in total cholesterol have been noted,18 consistent with the human phenotype. Collectively, these genetics studies support the hypothesis that lowering of circulating plasma PCSK9 by inhibiting its synthesis in hepatocytes should lower LDL cholesterol, potentially resulting in reduced risk of coronary heart disease. Additionally, some evidence suggests that statin treatment increases circulating plasma PCSK9, which could limit the effectiveness of statins as the dose is increased.19, 20, 21, 22 Human clinical trials with PCSK9-blocking antibodies have shown significant reductions in LDL cholesterol in healthy volunteers23, 24 and in individuals with hypercholesterolaemia, with and without statins.25, 26, 27, 28, 29, 30
Small interfering RNA (siRNA) can direct sequence-specific degradation of messenger RNA, leading to suppression of synthesis of the corresponding proteins, as part of the natural biological process known as RNA interference (RNAi).31, 32 Our group has previously reported the acute, hepatocyte-specific lowering of synthesis and plasma concentrations of PCSK9 by treatment with a PCSK9-specific siRNA formulated in a lipid nanoparticle in several preclinical models.33 This treatment resulted in substantial and durable lowering of LDL cholesterol, without an effect on HDL cholesterol. Additionally, we confirmed in these models that the reduction in PCSK9 was based on an RNAi mechanism and resulted in increased numbers of LDLRs on hepatocyte membranes.33 We aimed to investigate the safety and efficacy in human beings of ALN-PCS, an siRNA that inhibits PCSK9 synthesis formulated in a novel lipid nanoparticle for delivery.34
Section snippets
Study design and participants
We undertook a randomised, single-blind, placebo-controlled, phase 1 clinical trial at two phase 1 units in the UK (Covance Clinical Research Unit, Leeds, and Quintiles Drug Research Unit at Guy's Hospital, London). Eligible participants were healthy adults aged 18–65 years with an LDL cholesterol higher than 3·00 mmol/L. Inclusion criteria required that they had received no lipid-lowering treatments in the 30 days before screening and that they had fasting triglyceride concentrations of 2·8
Results
32 eligible participants were recruited between Sept 21, 2011, and Sept 11, 2012. 24 were randomly assigned to receive ALN-PCS and eight to receive placebo (figure 2). One participant was excluded after random assignment because their lipid concentrations proximal to dosing were outside of those defined by the inclusion criteria. Table 1 lists the baseline characteristics of all participants who received study treatment and therefore were included in the analyses.
Overall, ALN-PCS was safe and
Discussion
ALN-PCS was well tolerated, with similar proportions of mild to moderate treatment-emergent adverse events occurring in the treatment and placebo groups. Although some participants developed a rash, it was mild, resolved spontaneously, and occurred with equal frequency in the in placebo and ALN-PCS-treated participants. The rash was identical in appearance and nature in both groups, and was probably a result of the premedications given to all participants, which can cause skin flushing (due to
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