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Alnylam

Positive Initial Clinical Data from Phase 1 Trial with ALN-AS1

We reported positive initial results from our ongoing Phase 1 clinical trial with ALN-AS1, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias. Study results showed that single subcutaneous doses of ALN-AS1 resulted in an up to 82% lowering of ALA and an up to 93% lowering of PBG in asymptomatic “high excreter” (ASHE) patients, who carry the genetic mutation of acute intermittent porphyria (AIP) and have elevated levels of aminolevulinic acid (ALA) and porphobilinogen (PBG), the toxic heme intermediates that mediate porphyria attacks. Furthermore, analysis of exosomal mRNA preparations from serum and urine revealed that treatment resulted in potent, dose-dependent, and durable silencing of liver ALAS1 mRNA.  Importantly, ALN-AS1 was found to be generally well tolerated with no clinically significant drug-related adverse events to date. These data provide human proof-of-concept for ALN-AS1 as a potential therapy for AIP and other acute hepatic porphyrias.



We also reported initial data from our EXPLORE study, a multinational, prospective observational study of patients with hepatic porphyrias suffering from recurrent attacks. Initial data from 68 patients provided meaningful insights into the natural history and substantial disease burden of patients. In baseline evaluations, patients reported a poor quality of life. A total of 101 porphyria attacks were documented in 41/68 (60%) of patients in the study. During acute attacks, there were increases in ALAS1 liver mRNA levels as well as in urinary levels of ALA and PBG.



We believe that ALN-AS1 has the potential to be a transformative therapy for patients with acute hepatic porphyrias. We very much look forward to the continued advancement of ALN-AS1 and hope to ultimately bring a safe and effective therapy to this patient population with enormous unmet medical need.