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Alnylam Pharmaceuticals has reported positive clinical results from a Phase I study of ALN-PCS, an RNAi therapeutic targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), for the treatment of severe hypercholesterolemia.

ALN-PCS is a PCSK9 synthesis inhibitor that acts by minimising the intracellular and extracellular levels of PCSK9, thereby lowering plasma levels of low-density lipoprotein cholesterol (LDL-C).

The single-blind placebo-controlled single-ascending dose Phase I trial enrolled a total of 32 subjects into six sequential dose cohorts ranging from 0.015 to 0.400mg/kg in a 3:1 randomisation of drug to placebo.

The trial’s primary objective was to investigate the safety and tolerability of a single dose of ALN-PCS, and secondary objectives included assessment of pharmacodynamic effects of the drug on plasma PCSK9 protein levels and evaluation of clinical efficacy as measured by LDL-C levels.

Treatment with ALN-PCS resulted in rapid, dose-dependent, and durable reductions in LDL-C of up to 50% and plasma of up to 84% relative to baseline and placebo, with a considerable mean reduction of 41% and 68% respectively, at the 0.400mg/kg dose level.

Alnylam senior vice president and chief medical officer Akshay Vaishnaw said the mechanism of action for ALN-PCS, which inhibits the synthesis of PCSK9 in liver cells thereby reducing both its intracellular and extracellular functions, provides a differentiated strategy for PCSK9 antagonism.

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“This mechanism of action for ALN-PCS results in potent and durable LDL-C reductions and consistent clinical activity across a wide range of baseline PCSK9 plasma levels, including individuals with very high PCSK9 levels,” Vaishnaw added.

“These new results show very robust, statistically significant, and dose-dependent lowering of both PCSK9 and LDL-C levels in a single dose study performed in the absence of statin co-administration.

“In addition, ALN-PCS treatment was well tolerated at all dose levels studied to date indicating the potential to even further dose escalate in future studies.”

Alnylam president and chief operating officer Barry Greene said the new data will support continued advancement of ALN-TTR02 for the treatment of therapeutic targeting transthyretin mediated amyloidosis (ATTR), which employs the same second generation lipid nanoparticles (LNP) delivery formulation as ALN-PCS.

“Dosing in our ALN-TTR02 clinical study has recently been initiated and we are on track to report data in the third quarter of this year,” Greene added.