Alnylam Pharmaceuticals Inc. Initiates the ENDEAVOUR Phase 3 Clinical Trial of Revusiran in Transthyretin - Mediated Familial Amyloidotic Cardiomyopathy
Dec 11 14
Alnylam Pharmaceuticals Inc. announced it has initiated the ENDEAVOUR Phase 3 clinical trial of revusiran in transthyretin (TTR)-mediated familial amyloidotic cardiomyopathy (FAC). FAC is one of the predominant clinical manifestations of TTR-mediated amyloidosis (ATTR), and afflicts an estimated 40,000 people worldwide. The ENDEAVOUR trial is a randomized, double-blind, placebo-controlled, global study designed to evaluate the efficacy and safety of revusiran in patients with FAC. The co-primary endpoints of the study are the change compared to baseline in 6-minute walk distance (6-MWD) and the per cent reduction in TTR burden between placebo-and revusiran-treated patients at 18 months. This study is now open for enrollment. Alnylam is eligible to receive a $25 million milestone from Genzyme when the first patient is dosed in the ENDEAVOUR study. The ENDEAVOUR Phase 3 trial is a randomized, double-blind, placebo-controlled, global study designed to evaluate the efficacy and safety of revusiran in patients with FAC. The co-primary endpoints of the study are the change compared to baseline in 6-MWD and the percent reduction in TTR burden between placebo- and revusiran-treated patients at 18 months. Secondary endpoints include a composite endpoint of cardiovascular mortality and cardiovascular hospitalization, New York Heart Association (NYHA) class, Kansas City Cardiomyopathy Questionnaire (KCCQ), CV mortality, CV hospitalization and all-cause mortality.
Alnylam Pharmaceuticals, Inc. - Special Call
Dec 9 14
To discuss these new results with ALN-AT3 for the treatment of hemophilia and rare bleeding disorders
Alnylam Pharmaceuticals, Inc. Announces Positive Initial Phase 1 Data for ALN-AT3, an Investigational RNAi Therapeutic Targeting Antithrombin for the Treatment of Hemophilia and Rare Bleeding Disorders
Dec 9 14
Alnylam Pharmaceuticals, Inc. announced positive initial Phase 1 data for ALN-AT3, an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders. Preliminary results were presented at the Annual Meeting of the American Society of Hematology from a single dose cohort in healthy volunteers (n=4) and from the initial multiple dose cohorts of hemophilia subjects (n=4) in the ongoing Phase 1 clinical trial. Amongst other data presented, subcutaneous administration of ALN-AT3 given once weekly for three weeks at low doses of 15 or 45 micrograms/kg (mcg/kg) resulted in an up to 57% knockdown of AT in hemophilia subjects. The effects of ALN-AT3 lasted for about 60 days after a single dose. ALN-AT3 was found to be well tolerated in both healthy volunteers and hemophilia subjects enrolled in the study. These initial results show preliminary evidence for potency and durability of RNAi therapeutics at mcg/kg subcutaneous doses in human studies, and are the first clinical data to be reported for Alnylama Enhanced Stabilization Chemistry (ESC)-GalNAc conjugate technology. These early results for ALN-AT3 from ongoing Phase 1 study demonstrate knockdown of antithrombin of up to 57% at low microgram/kg subcutaneous doses of drug. As such, these data provide preliminary evidence for a high level of potency for RNAi therapeutics in humans with the improved pharmacologic properties for ESC-GalNAc conjugate delivery technology. The ongoing Phase 1 trial of ALN-AT3 is being conducted in Bulgaria, Switzerland, and the U.K. as a single- and multi-dose, dose-escalation study comprised of two parts. Part A which is complete was a randomized, single-blind, placebo-controlled, single-dose, dose-escalation study (n=4 per cohort; 3:1 randomization of ALN-AT3:placebo) in healthy volunteer subjects. The primary objective of this part of the study was to evaluate the safety and tolerability of a single dose of ALN-AT3, with the potential secondarily to show changes in AT plasma levels at sub-pharmacologic doses. Part A of the study evaluated only low doses of ALN-AT3, with a dose-escalation stopping rule at no more than a 40% knockdown of AT. Based on the level of AT knockdown achieved in this part of the study, only the first and lowest 30 mcg/kg dose cohort of 4 healthy volunteers was enrolled. Part B of the study which is ongoing and at early stages is an open-label, multi-dose, dose-escalation study enrolling up to 18 subjects with moderate or severe hemophilia A or B. The primary objective of this part of the study is to evaluate the safety and tolerability of multiple doses of subcutaneously administered ALN-AT3 in hemophilia subjects. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels and increase in thrombin generation at pharmacologic doses of ALN-AT3; thrombin generation is known to be a biomarker for bleeding frequency and severity in people with hemophilia. In this part of the study, dose-escalation is allowed to proceed beyond the 40% AT knockdown level. Initial results from the ongoing study presented include safety, tolerability, and clinical activity data from: the single cohort of healthy volunteers in Part A; the lowest (15 mcg/kg), multi-dose cohort of three hemophilia subjects from Part B; and the initial hemophilia subject enrolled in the second multi-dose cohort (45 mcg/kg) from Part B. For the four subjects currently in Part B, three have severe hemophilia A (less than 1% levels of Factor VIII) and one has severe hemophilia B (less than 1% levels of Factor IX).
Preliminary results from the Phase 1 study to date show that ALN-AT3 was well tolerated in both healthy volunteers and hemophilia subjects. There were no serious adverse events, no discontinuations, no injection site reactions, and no significant changes in physical exams, vital signs, or electrocardiography. In the ongoing Part B of the study, which is in early stages of dose escalation, hemophilia subjects are receiving three weekly subcutaneous doses of ALN-AT3. All clinical activity results presented at the meeting are from a data cutoff date of December 5, and are subject to change upon final analysis. In the first, lowest dose cohort of 15 mcg/kg, ALN-AT3 administration resulted in an up to 52% knockdown of AT in the most advanced subject, with nadir achieved on day 35. The mean maximum knockdown for this group was 27% Â±13% through day 28, and is expected to increase when all subjects reach nadir levels. In the first subject in the second multi-dose cohort of 45 mcg/kg, ALN-AT3 administration resulted in an up to 57% knockdown of AT as measured on day 14; knockdown in this subject has not yet reached expected nadir levels. Plasma samples from the 15 mcg/kg cohort were also evaluated for potential increases in thrombin generation. Excluding increases in thrombin generation observed around the time of replacement factor administration, no conclusions can be drawn from thrombin generation measurements at this dose and level of AT knockdown. This result is in line with data from an induced hemophilia model in non-human primates, where levels of AT knockdown greater than or equal to 60% were required to achieve consistent and significant increases in thrombin generation in the background of reduced levels of factor VIII. The ALN-AT3 Phase 1 study is continuing to enroll hemophilia subjects in the second dose cohort of 45 mcg/kg, and additional multi-dose cohorts are planned. The company expects to present complete results from the Phase 1 study in mid-2015.