Interim Data from a Randomized, Placebo Controlled, Phase 1 Study of Aln-AS1, an Investigational RNAi Therapeutic for the Treatment of Acute Hepatic Porphyria (2016)

Abstract Acute hepatic porphyria (AHP) is a family of rare metabolic disorders including acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP), caused by a deficiency in one of the eight enzymes required for heme biosynthesis in the liver. When ALA synthetase (ALAS1), the first and rate limiting step in the pathway, is induced by triggers such as exposure to certain drugs or fasting, the neurotoxic heme intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG) can accumulate upstream of the deficient enzyme leading to acute and potentially life threatening neurovisceral attacks in AHP patients. RNA interference is a naturally occurring cellular mechanism mediated by small interfering RNA (siRNA) that allows for the inhibition of protein synthesis through the cleavage and degradation of a specific mRNA. ALN-AS1 is an investigational RNAi therapeutic that targets ALAS1 in order to decrease ALA and PBG levels and subsequent porphyria attacks. We are currently conducting a phase 1, multinational, randomized, placebo-controlled, study in 3 parts; Part A single ascending dose (SAD), Part B multiple ascending dose (MAD) and Part C multiple dose (MD) study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics (i.e. changes in ALA, PBG and circulating ALAS1 mRNA levels) of subcutaneously administered ALN-AS1 in AIP patients. Part C also has exploratory analyses of clinical activity, including the impact of ALN-AS1 on porphyria attacks, acute healthcare visits, and heme treatment (ClinicalTrials.gov Identifier: NCT02452372). We previously presented interim SAD data demonstrating that ALN-AS1 was generally well tolerated with no serious adverse events (SAEs) or clinically significant laboratory abnormalities related to study drug, and no discontinuations due to AEs. Circulating ALAS1 mRNA levels had a mean (SEM) maximal reduction of 44% ± 8% relative to baseline (p ≤ 0.01 compared to placebo), with concomitant mean (SEM) maximal reductions in ALA and PBG of 77% ± 7% and 73% ± 6%, respectively (p= 0.03 and 0.06 compared to placebo, respectively) at the 0.35 mg/kg dose. In addition, changes in circulating ALAS1 mRNA were highly correlated with changes in urinary ALA and PBG (R2=0.82, p&lt;10-15). We will now report interim progress and data from all 3 Parts of the phase 1 study including safety, pharmacodynamics, pharmacokinetics and exploratory clinical activity. Disclosures Sardh: Alnylam Pharmaceuticals: Consultancy. Harper:Alnylam Pharmaceuticals: Consultancy. Balwani:ICGG Gaucher Registry (Sanofi Genzyme sponsored): Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; Alnylam Pharmaceuticals: Consultancy. Anderson:Alnylam Pharmaceuticals: Consultancy. Bloomer:Alnylam Pharamceuticals: Consultancy. Bissel:Alnylam Pharmaceuticals: Consultancy. Desnick:Alnylam Pharmaceuticals: Consultancy. Bonkovsky:Alnylam Pharamceuticals: Consultancy. Penz:Alnylam Pharmaceuticals: Employment, Equity Ownership. Chan:Alnylam Pharmaceuticals: Employment, Equity Ownership. Soh:Alnylam Pharmaceuticals: Employment, Equity Ownership. Querbes:Alnylam Pharmaceuticals: Employment, Equity Ownership. Simon:Alnylam Pharmaceuticals: Employment, Equity Ownership. Rees:Alnylam Pharmaceuticals: Consultancy.