Lancet：RNAi基因治疗新药ALN-PCS明显降低患者胆固醇水平（临床I期研究）

胆固醇高者通常需要服用他汀类药物以降低心脏病风险，但此类药物副作用较明显。最新完成的临床试验显示，一种通过调控基因来降低胆固醇的药物同样有效，且无明显副作用。

由Alnylam 公司研发，在英国盖氏医院研究人员与美国同行一起，在英国新一期《柳叶刀》杂志上报告说，一种被称为“ALN-PCS”的新药，可通过干扰核糖核酸来抑制PCSK9 基因的表达，使身体清除有害胆固醇的能力恢复正常。

研究人员招募了英美两国３２名１８至６５岁的志愿者进行了首期临床试验，结果显示，新药可将服药者的平均胆固醇水平降低４０％，与他汀类药物的效用相当，并且服用新药的志愿者均未出现抗药性或明显副作用。

据介绍，目前英国有超过５００万人服用他汀类降胆固醇药物，但有约五分之一的患者对这类药物有抗药性，且不少服用者产生肌肉酸痛、健忘等副作用。

研究人员说，下一步他们将开展更大规模的临床试验，重点考察服用这种新药的长期安全性及耐药性。英国心脏基金会专家彼得·韦斯伯格说，胆固醇过高会显着增加心脏病风险，但有些病人因抗药性或副作用不能服用常规药物，这项研究再次证实，基因技术可为开发有效、低副作用的新型药物提供新希望。

但是MedSci认为，目前该药仅在临床I期，未进行大规模的有效性和安全性研究，目前还不宜过于乐观。但是基因治疗确实是未来重要的新药研究方向。

原始出处：

Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR, Sutherland JE, Hutabarat RM, Clausen VA, Karsten V, Cehelsky J, Nochur SV, Kotelianski V, Horton J, Mant T, Chiesa J, Ritter J, Munisamy M, Vaishnaw AK, Gollob JA, Simon A.
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.Lancet. 2013 Oct 1. pii: S0140-6736(13)61914-5.

有关ALN-PCS

ALN-PCS: Hypercholesterolemia

Alnylam is developing ALN-PCS, an RNAi therapeutic for the treatment of hypercholesterolemia, or high levels of cholesterol in the blood. Hypercholesterolemia contributes to many diseases, most notably cardiovascular disease - the leading cause of death in the U.S.

ALN-PCS02

ALN-PCS is a systemically delivered RNAi therapeutic targeting the gene proprotein convertase subtilisn/kexin type 9, or PCSK9, a genetically validated target involved in the metabolism of LDL cholesterol (LDL-C), or "bad" cholesterol. Our RNAi therapeutic has the potential to lower tissue and circulating PCSK9 levels resulting in higher LDL receptor levels in the liver, and subsequently lower LDL-C levels.

Pre-clinical data with ALN-PCS have shown specific silencing of PCSK9 mRNA and PCSK9 serum protein levels of up to 90%, with an ED50 (the dose that provides a 50% silencing effect) of approximately 0.06 mg/kg for both mRNA and protein reduction. These studies have also demonstrated a greater than 50% reduction in levels of LDL-C, which is rapid and durable, lasting for weeks after a single dose.

In September 2011, Alnylam initiated the Phase I clinical trial with ALN-PCS. Positive results from this study were presented in April 2012. The Phase I study was conducted as a randomized, single-blind, placebo-controlled, single-ascending dose study in healthy volunteer subjects with elevated baseline LDL-C (>116mg/dL). A total of 32 subjects were enrolled into six sequential dose cohorts ranging from 0.015 to 0.400 mg/kg. Results showed that ALN-PCS, in the absence of concomitant lipid-lowering agents such as statins, resulted in statistically significant and durable reductions of PCSK9 plasma levels of up to 84% and lowering of LDL-C of up to 50%. The effects of a single dose of ALN-PCS support a once-monthly dose administration regimen for future studies. Importantly, ALN-PCS demonstrated consistent clinical activity toward both PCSK9 and LDL-C independent of baseline levels of PCSK9, highlighting the unique mechanism of action for a PCSK9 synthesis inhibitor.

ALN-PCS was shown to be safe and well tolerated in this study and there were no serious adverse events related to study drug administration.

ALN-PCSsc

ALN-PCSsc is a subcutaneously administered RNAi therapeutic also targeting PCSK9 for the potential treatment of hypercholesterolemia.

In October 2013, new data were presented at the Oligonucleotide Therapeutics Society meeting showing that ALN-PCSsc led to an up to 90% PCSK9 knockdown and an up to 68% lowering of LDL-C in absence of statins.

Based on these findings we have selected our ALN-PCSsc Development Candidate and expect to file an IND in late 2014.

In early 2013, The Medicines Company and Alnylam announced an exclusive global alliance to advance the ALN-PCS program. The collaboration includes program includes both ALN-PCS02 and ALN-PCSsc. Alnylam will continue the program while funded by The Medicines Company for an estimated one to two years to complete certain pre-clinical and Phase I clinical studies. The Medicines Company will then lead and fund development from Phase II forward and commercialize the ALN-PCS program if successful.