Promising results with PCSK9 siRNA treatment

Effect 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

Literature - Fitzgerald et al., Lancet, Oct. 2013 - The Lancet, Early Online Publication, 3 October 2013

Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S et al.
The Lancet, Early Online Publication, 3 October 2013 doi:10.1016/S0140-6736(13)61914-5


Despite the extensive use and efficacy of statins, the management of raised LDL-c remains inadequate, specifically in individuals with pre-existing coronary heart disease or diabetes, who are at  high risk. It has been estimated that among high-risk individuals, only 50% achieve the target LDL-c of less than 2.59 mmol/L at 6 months after statin treatment, despite close monitoring en optimisation of the drug regimen [1-5]. Thus, the need for new treatments for hypercholesterolaemia is evident.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been identified as a potential therapeutic target, since experimental [6-8] and genetic studies [9-11] suggest that lowering circulating plasma PCSK9 levels should lower LDL-c, and possibly the risk of coronary heart disease. In addition, statins appear to increase circulating PCSK9 levels, which could limit the efficacy of statin treatment [12-15].
Small interfering RNA (siRNA) can cause sequence-specific degradation of messenger RNA, which suppresses the synthesis of the corresponding proteins. This is part of the naturally occurring RNA interference (RNAi) process [16,17]. A PCSK9-specific siRNA has been found to acutely lower hepatocyte-specific synthesis and plasma concentrations of PCSK9 in preclinical models [18], resulting in substantial and durable lowering of LDL-c.
This study investigated the safety and efficacy in human beings of intra-venous administration of ALN-PCS, an siRNA that inhibits PCSk9 synthesis formulated in a novel lipid nanoparticle for delivery [34], in a randomised, single-blind, placebo-controlled, phase I trial.

Main results

  • ALN-PCS was generally safe and well-tolerated; no drug-related serious adverse events occurred. All treatment-emergent adverse events had mild to moderate severity, with similar proportions of patients in the ALN-PCS and placebo groups affected (19 (79%) vs. 7 (88%)). Both patients on ALN-PCS and placebo developed a mild, macular, transient erythematous rash, without pain or pruritus.
  • No clinically significant, dose-dependent changes in laboratory indices (including liver function tests, creatine phosphokinase, C-reactive protein, haematologic measures) were noted, neither in nine measured cytokines.
    No clinically significant safety findings were observed in the 6 month follow-up period.
  • Single-dose administration of ALN-PCS yielded a rapid and dose-dependent reduction in plasma PCSK9 protein. The duration of the PCKS9-lowering effect was dose-dependent.
    At the highest dose of 0.400 mg/kg, PCSK9 dropped with 70% from baseline, as compared to placebo treatment, on day 3 post-dose (P<0.0001). PCSK9 levels increased significantly in the placebo group, attributed to the pre-medication given to all participants. This effect was overcome with ALN-PCS treatment.
  • Reduction of plasma levels of PCSK9 protein was independent of baseline levels, which may vary by a factor of over 100 across a population.
  • Single-dose administration of ALN-PCS also yielded a rapid and dose-dependent drop in LDL-c levels, again with a dose-dependent duration. A mean 40% reduction was obtained with the highest dose.

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This first-in-man study showed that ALN-PCS was well-tolerated; the few mild to moderate adverse that were seen related to the treatment, were observed in both the  ALN-PCS and placebo groups. No other clinically relevant changes in liver function or inflammatory markers were noted.
Despite the fact that this study was underpowered to do so, significant decreases were observed in PCSK9 and LDL-c plasma levels in the higher dose group. The effects were rapid and durable.


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