Clinical Data from ALN-AAT and Non-Clinical Research Demonstrating Continued RNAi Platform Optimization and Leadership in the Field

Clinical Data from ALN-AAT and Non-Clinical Research Demonstrating Continued RNAi Platform Optimization and Leadership in the Field

We presented clinical and non-clinical data in a series of posters and oral presentations at the 12th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS), held September 25 – 28, 2016 in Montreal, Quebec.


Phase 1/2 clinical data were presented from ALN-AAT, an investigational RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease, also known as alpha-1 liver disease. Results as of the data transfer date of June 30, 2016 showed that ALN-AAT administration resulted in potent, dose-dependent and durable knockdown of serum AAT of up to 88.9% in healthy volunteers (N=19).  Pharmacodynamic effects of ALN-AAT were highly durable, where a single dose of 6 mg/kg maintained mean AAT knockdown of about 75% out to approximately six months.

ALN-AAT was shown to be generally well tolerated in healthy adult volunteers. There were no drug-related serious adverse events (SAEs), discontinuations due to adverse events (AEs), or injection site reactions reported. Transient, asymptomatic, and dose-dependent increases in liver enzymes were observed in 3 out of 15 healthy volunteers exposed to single doses of ALN-AAT.  In order to optimize the tolerability profile for this program, we plan to advance a follow-on molecule targeting a different sequence for further development.

Non-clinical data presented at OTS demonstrated significant advances in optimizing the Enhanced Stabilization Chemistry (ESC)-GalNAc platform, including improved potency, duration of activity, and tolerability.  We presented a comprehensive review of non-clinical data from toxicology studies of multiple GalNAc conjugates, which highlighted a wide therapeutic index with no evidence of thrombocytopenia or pro-inflammatory effects across the platform.  In an additional presentation, comparative studies of GalNAc conjugated siRNAs and ASOs revealed differences in efficacy and PK between the two RNA platforms.  Further, early research exploring muscle delivery showed that recent advances in siRNA design from Alnylam’s ESC-GalNAc platform could potentially be translated to robust RNAi-mediated silencing in muscle using cholesterol conjugates, demonstrating the future potential of the platform for extra-hepatic delivery.

We are encouraged by these data supporting the potential to achieve improved potency, durability, and tolerability in RNAi therapeutics. We are dedicated to continuous innovation and optimization of our RNAi platform as we strive to develop transformative treatments for a broad array of human disease.


Receive news and updates on the work at Alnylam that affects you most.