Date: 2014-10-14
Type of information: Presentation of results at a congress
phase: 1
Announcement: presentation of results at the 10th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS), held October 12 - 15, 2014 in San Diego
Company: Alnylam Pharmaceuticals (USA - MA)
Product: ALN-TTRsc
Action
mechanism: ALN-TTRsc, which is being developed for the treatment of familial amyloidotic cardiomyopathy, is a subcutaneously administered RNAi therapeutic that comprises an siRNA conjugated to a GalNAc ligand that enables receptor-mediated delivery to the liver. ALN-TTRsc is the first GalNAc-siRNA and the first subcutaneously delivered, systemic RNAi therapeutic to enter clinical development stages.
ATTR is an autosomal dominant inherited disease caused by mutations in the TTR gene, which is expressed predominantly in the liver. Pre-clinical studies have shown that subcutaneous administration of ALN-TTRsc resulted in potent and sustained suppression of TTR. In non-human primates, ALN-TTRsc administration resulted in an approximately 80% reduction of TTR at doses as low as 2.5 mg/kg. In single- and multi-dose pre-clinical safety studies in rodents and non-human primates, ALN-TTRsc was found to be generally safe and well tolerated. Specifically, at doses as high as 300 mg/kg in non-human primates, ALN-TTRsc was well tolerated with no clinical signs, no adverse laboratory or histopathologic findings, no elevations in cytokines or complement, and no significant injection site reactions.
Disease: TTR-mediated amyloidosis (ATTR)
Therapeutic area: Rare diseases - Genetic diseases
Country:
Trial details:
Latest
news: * On October 14, 2014, Alnylam, a leading RNAi therapeutics company, announced that it presented new data from multiple clinical and pre-clinical studies at the 10th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS), held October 12 - 15, 2014 in San Diego. Among multiple presentations, the company presented additional data from its Phase 1 trial with ALN-TTRsc, an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with TTR cardiac amyloidosis, showing rapid, dose-dependent, stable, and durable knockdown of serum TTR of up to 96.2%. \"Our Phase 1 study of ALN-TTRsc was the first to demonstrate clinical activity and tolerability for RNAi therapeutics using our proprietary GalNAc-conjugate delivery platform that enables subcutaneous administration with a wide therapeutic index. These new data extend our previous presentation by including results from a 7.5 mg/kg cohort where we observe a mean max TTR knockdown of 87.9%. In addition, we have now completed our chronic toxicology studies with ALN-TTRsc, including 6-month rat and 9-month non-human primate studies, which confirmed the wide safety margin established in previous, shorter duration studies. Importantly, we believe these new toxicology results provide additional de-risking for our broader GalNAc-conjugate platform, where we continue to see favorable tolerability results in pre-clinical and clinical studies across an increasing number of programs," said Akshay Vaishnaw , M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. \"We are currently conducting a Phase 2 trial of ALN-TTRsc in ATTR patients with TTR cardiac amyloidosis, and we look forward to sharing initial data at a meeting to be held during the American Heart Association meeting on November 15 . We remain on track to initiate an open-label extension (OLE) study with ALN-TTRsc in the coming weeks, and expect to begin enrolling patients in our Phase 3 trial in TTR cardiac amyloidosis by the end of this year.\" The new results include TTR knockdown data for an additional cohort (N=6) receiving doses of 7.5 mg/kg, showing a mean max TTR knockdown of 87.9% and a maximum TTR knockdown of 96.2%. As described before, ALN-TTRsc was generally well tolerated with mild or moderate injection site reactions as the most frequent adverse event, consistent with results from previous cohorts. In addition to the updated clinical data, results from new pre-clinical toxicology data with ALN-TTRsc were presented. Data from 6-month toxicology studies in rats and 9-month toxicology studies in non-human primates (NHPs) showed that chronic dosing with ALN-TTRsc was generally well tolerated. In the 6-month rat study, the No Observed Adverse Effect Level (NOAEL) for ALN-TTRsc was determined to be 30 mg/kg, with adverse findings observed at the 100 mg/kg dose including hepatocyte vacuolation with associated minor increases in liver transaminases (less than or equal to 1.6 times control animals); all were reversed after a three-month non-dosing recovery period. The NOAEL in the rat 6-month study was unchanged from that determined in a previously conducted 6-week study, showing the absence of any cumulative toxicologic effects. In the 9-month NHP study, all doses - including the top dose of 200 mg/kg - were generally well tolerated with no meaningful changes in any hematology and laboratory parameters. The NOAEL will be determined upon completion of histopathology, but is expected to be greater than or equal to 200 mg/kg. The completion of these toxicology studies enables the advancement of ALN-TTRsc into a Phase 3 clinical trial, which is expected to begin by the end of this year, and supports the potential filing of the drug candidate\'s New Drug Application (NDA). ALN-TTRsc is currently being evaluated in an open-label, multi-dose pilot Phase 2 clinical trial in ATTR patients with TTR cardiac amyloidosis. Alnylam expects to present initial results from the Phase 2 study at a meeting to be held during the American Heart Association meeting in November.
Updated data were presented from the Phase 1 trial of ALN-TTRsc performed in healthy volunteers. Initial results were presented at the Heart Failure Society of America 17th Annual Scientific Meeting in September 2013 , and showed robust, consistent, and statistically significant (p < 0.01) knockdown of serum TTR protein levels of up to 94%.
