Alnylam seeks MHRA approval for ALN-AAT Phase I/II trial to treat alpha-1 liver disease

ALN-AAT is a subcutaneously administered investigational RNAi therapeutic targeting alpha-1 antitrypsin (AAT). The company said that ALN-AAT employs its Enhanced Stabilization Chemistry (ESC)-GalNAc delivery technology.

The proposed clinical trial of ALN-AAT will be carried out in normal healthy volunteers and then in subjects with alpha-1 liver disease.

Following approval of the CTA, the company will begin the Phase I/II study in later this year, with initial data expected to be reported in early 2016.

Additionally, the company’s scientists presented new pre-clinical data which showed a robust knockdown of serum AAT of up to 93% in non-human primates (NHPs) with monthly subcutaneous dosing and a wide therapeutic index.

Alnylam executive vice-president of R&D and chief medical officer Dr Akshay Vaishnaw said: "We believe ALN-AAT holds considerable promise as a novel therapeutic approach for the treatment of alpha-1 liver disease, an increasingly recognized clinical manifestation of alpha-1-antitrypsin deficiency where there is a significant unmet need and where liver transplantation is the only available treatment option.

"Our pre-clinical results, including new data presented at this year’s DDW meeting, demonstrate that monthly subcutaneous doses of ALN-AAT achieves robust knockdown of serum AAT – the disease-causing protein – of up to 93% in NHPs, with highly durable effects and a wide therapeutic index.

"In earlier reported and recently updated studies, we’ve demonstrated that ALN-AAT can reduce liver levels of mutant AAT, improve histopathology associated with mutant AAT expression, and reduce liver fibrosis and the incidence of tumor formation in a mouse model of alpha-1 liver disease.

"The filing of this new CTA also highlights the reproducible and modular features of Alnylam’s platform, as ALN-AAT now becomes our sixth clinical stage program in our Genetic Medicine STAr, our seventh clinical pipeline program overall, and the fifth clinical program employing our ESC-GalNAc delivery technology."

According to the filed CTA, the Phase I/II trial of ALN-AAT will be a randomized, single-blind, placebo-controlled study conducted in three parts.

A total of 48 healthy adult volunteers will be enrolled in the single-dose (Part A) and multi-dose (Part B), dose-escalation studies, while Part C will be a multi-dose study in adults with the PiZZ mutation in their AAT gene and with mild-to-moderate liver fibrosis.

The trial’s primary objective is to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-AAT, while secondary objectives include evaluation of pharmacokinetics of ALN-AAT and clinical activity for ALN-AAT as measured by knockdown of serum AAT.