Date: 2014-05-21
Type of information: Publication of results in a medical journal
phase: preclinical
Announcement: publication of preclinical results in the Proceedings of the National Academy of Sciences (PNAS)
Company: Alnylam Pharmaceuticals (USA - MA)
Product: RNAi therapeutics targeting aminolevulinic acid synthase-1 (ALAS-1)
Action mechanism:
Disease: hepatic porphyrias, including acute intermittent porphyria (
Therapeutic area: Rare diseases
Country:
Trial details:
Latest
news: * On May 21, 2014, Alnylam Pharmaceuticals, a leading RNAi therapeutics company, announced the publication in the Proceedings of the National Academy of Sciences (PNAS) of pre-clinical results with RNAi therapeutics targeting aminolevulinic acid synthase-1 (ALAS-1) for the treatment of hepatic porphyrias, including acute intermittent porphyria (AIP). In the paper, titled “RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice,” Alnylam scientists and collaborators at the Icahn School of Medicine at Mount Sinai in New York City documented results from pre-clinical models of the human disease showing that RNAi therapeutics targeting ALAS-1 can completely block the abnormal production of toxic intermediates of the heme biosynthesis pathway that cause the symptoms and disease pathology of AIP. This new paper provides proof of concept for an RNAi therapeutic for the treatment of AIP. The company is now on track to file an Investigational New Drug application for ALN-AS1 in late 2014 or early 2015. In the new paper published in PNAS, Alnylam scientists and collaborators at the Icahn School of Medicine at Mount Sinai documented their results from studies performed in a mouse model of AIP. Prophylactic administration of an ALAS-1 specific siRNA completely protected AIP mice from phenobarbital-induced up-regulation of hepatic ALAS-1 mRNA and protein, as well as the resulting accumulation of the neurotoxic ALA and PBG heme biosynthesis precursors. This protective effect was dose responsive and durable, with a single dose administration resulting in a protective effect that lasted for at least two weeks. This feature provides an advantage over prophylactic hemin – the current standard of care in AIP – which is infused as often as twice a week in patients with frequent attacks. Further, in a treatment model, a single dose of ALAS-1 siRNA rapidly reduced the high levels of plasma ALA and PBG that were elevated during a phenobarbital-induced acute attack. In addition, preliminary comparative studies show that ALAS-1 siRNA administration was more effective than heme administration in the treatment of an acute attack, as seen by the more extensive and rapid lowering of both ALA and PBG with its administration. New results from rotarod studies showed that treatment with an ALAS-1 siRNA was associated with a significant improvement in performance as compared with animals treated with a control siRNA, suggesting that treatment with the drug can protect against symptoms of neuromotor impairment associated with AIP attacks. Finally, data were shown demonstrating that administration of ALAS-1 siRNA was not associated with a hepatic heme deficiency or altered liver hemoprotein activity. Alnylam is currently advancing ALN-AS1, a subcutaneously administered RNAi therapeutic targeting ALAS-1 for the treatment of porphyria, including AIP. ALN-AS1 utilizes the company’s proprietary Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability, and a wide therapeutic index. ESC-GalNAc conjugates are a clinically validated platform based on recent results from the company’s ALN-AT3 program in a Phase 1 study. At the 9th Annual Meeting of the Oligonucleotide Therapeutics Society in October 2013, the company presented results in non-human primates (NHP), showing that multi-dose administration of an ESC-GalNAc-siRNA targeting ALAS-1 led to rapid, dose-dependent, and long-lasting knockdown of the ALAS-1 mRNA in NHPs, with an ED50 of approximately 1.25 mg/kg. Further, in a rat model of AIP, ALN-AS1 administration at doses as low as 2.5 mg/kg resulted in a complete blunting of phenobarbital-induced over-production of PBG and ALA, the toxic heme intermediates in AIP. Alnylam is currently conducting additional studies with ALN-AS1 and expects to file an Investigational New Drug (IND) application or IND equivalent in late 2014 or early 2015.
