Initial Evidence of Clinical Activity Shown with Givosiran (ALN-AS1) in Acute Intermittent Porphyria Patients with Recurrent Attacks

We reported positive initial results from Cohorts 1 and 2 in Part C of our Phase 1 study with givosiran (gi-VOH-si-ran), the International Nonproprietary Name for ALN-AS1, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias.  These results were presented at the 58th Annual Meeting of the American Society of Hematology (ASH), held December 3 – 6, 2016 in San Diego, California.

Initial results from Part C, which is a randomized, double-blind, placebo-controlled (3:1, drug:placebo) study in patients with acute intermittent porphyria (AIP) experiencing recurrent attacks, showed robust and durable lowering of aminolevulinic acid (ALA) and porphobilinogen (PBG), the toxic heme intermediates that are believed to mediate porphyria symptoms and acute attacks.  Further, in Cohort 1 (N=4, 2.5 mg/kg given once-quarterly), givosiran demonstrated initial evidence for clinical activity in AIP patients with meaningful reductions in the number and frequency of porphyria attacks.  Specifically, as compared with the run-in phase, there was a 74% mean decrease in the annualized attack rate and a 75% mean reduction in annualized hemin administration, with the maximum attack-free interval (i.e., the greatest period of time between porphyria attacks) approximately 10.5 times that observed during the run-in phase.  In Cohort 2 (N=4, 2.5 mg/kg given once-monthly), which remains blinded as patients are still in the treatment phase of the study, aggregated data provided additional evidence of clinical activity.

As of the data transfer on November 7, 2016, there were no drug-related serious adverse events (SAEs) reported in Cohorts 1-4.  In Cohort 3, which remains blinded, one death was reported after the data transfer date due to acute pancreatitis, complicated by a pulmonary embolism; the death was considered to be unlikely related to givosiran or placebo by the investigator and the study’s Safety Review Committee.  Of note, increases in pancreatic enzymes and acute pancreatitis have been reported in the literature in patients with acute hepatic porphyria (Shen et al., Acta Neurol Taiwan, 2008;17:177-183; Shiraki et al., Nihon Rinsho, 1995;53:1479-1483).  In Cohorts 1 and 2, there were no discontinuations due to adverse events (AEs).  Possibly or definitely related AEs reported in two or more cases were injection site reactions and myalgia; all of these events were mild. There were no other clinically significant changes in vital signs, electrocardiograms, clinical laboratory parameters, or physical examination.

We look forward to the continued advancement of givosiran as we work to provide what we believe could be a potentially transformative treatment option for patients with acute hepatic porphyrias, a group of ultra-rare orphan diseases with enormous unmet medical need.