Alnylam Presents Results from Natural History Study of Patients with Familial Amyloidotic Cardiomyopathy and Presents Complete Results from Phase 2 Clinical Trial for Revusiran
Mar 15 15
Alnylam Pharmaceuticals, Inc. announced results from a retrospective natural history study evaluating disease progression in transthyretin (TTR)-mediated amyloidosis (ATTR amyloidosis) patients with familial amyloidotic cardiomyopathy (FAC). Amongst other findings, study results showed a mean decline of 140 meters in 6-minute walk distance (6-MWD) over an 18-month period in FAC patients with mild-to-moderate heart failure. These natural history findings support the company’s co-primary endpoint for its Phase 3 ENDEAVOUR clinical study with revusiran. In addition, Alnylam announced that it presented complete results from its Phase 2 clinical trial with revusiran in a poster at the American College of Cardiology (ACC) Annual Scientific Session being held March 14 – 16 in San Diego. Consistent with preliminary results presented last year, revusiran achieved an up to 98.2% knockdown of serum TTR – the disease-causing protein – and was found to be generally well tolerated in the Phase 2 trial in FAC patients. Alnylam is developing revusiran (ALN-TTRsc), an investigational RNAi therapeutic targeting TTR, for the treatment of FAC. ATTR amyloidosis is an inherited, progressively debilitating, and often fatal disease caused by mutations in the TTR gene. These mutations cause misfolding of the TTR protein and the formation of amyloid fibrils that deposit in tissues. One of the clinical manifestations of ATTR amyloidosis is FAC, in which TTR amyloid deposition in the heart leads to cardiac wall thickening and heart failure. FAC is fatal within 2.5 to 5 years of diagnosis and treatment is currently limited to supportive care. Senile systemic amyloidosis (SSA) is a non-hereditary form of TTR cardiac amyloidosis caused by idiopathic deposition of wild-type TTR; its prevalence is generally unknown, but is associated with advanced age. Findings from the natural history study were presented at a meeting with members of the Association of Black Cardiologists (ABC). This study was performed to characterize disease severity and rate of progression in a multinational population of FAC patients. Demographics and time from first visit to death were collected retrospectively on 137 FAC patients from two countries at two large amyloidosis centers: The National Amyloidosis Centre (NAC) in London (N=88); and Columbia University in New York (N=49). The majority of patients had mild-to-moderate heart failure (40% NYHA class II, 43% NYHA class III) and the V122I TTR mutation (85%), with a median age of 72 years. Serial 6-MWD data were collected retrospectively in 39 patients followed at NAC, while hospitalizations were captured in the 49 patients followed at Columbia. Median survival was 34.1 months for the pooled group of 137 patients, and median time to first cardiovascular hospitalization was 26.7 months. There was a clear decline in 6-MWD over 18 months. Specifically, at 12 and 18 months, the mean decline in 6-MWD was 106 +/- 24 meters and 140 +/- 39 meters, respectively. These results are consistent with the 91 meter and 118 meter decline compared to baseline at 12 and 18 months, respectively, observed in 10 FAC patients in the published TRACS study (Ruberg et al., Am Heart J 2012). There was no consistent change over time in NT-proBNP levels among 78 patients from the NAC with data available for analysis. Based on these findings, Alnylam believes that the ongoing Phase 3 ENDEAVOUR trial of revusiran in FAC patients has the potential to show an impact of TTR lowering on the co-primary endpoint of decline from baseline in 6-MWD at 18 months. In addition, Alnylam has assembled natural history data from academic collaborators on approximately 250 patients with SSA and plans to present those findings at a future meeting. The company also announced complete results from its Phase 2 clinical trial with revusiran. The revusiran Phase 2 study was aimed at evaluating the safety, tolerability, pharmacodynamics, and preliminary clinical activity of revusiran in patients with FAC and SSA. Revusiran was found to be generally well tolerated in both FAC and SSA patients with advanced disease. The most common adverse event was a low incidence of transient mild liver function test (LFT) changes in 4 patients (15%) that, in all cases, resolved without discontinuing therapy. In 3 of the 4 patients, these elevations appeared to be clinically insignificant and were less than 1.5 times the upper limit of normal (ULN). One patient had an approximate 4-fold elevation in liver transaminases that was deemed a serious adverse event (SAE) and mild in severity; this event resolved during continued dosing. The next most common adverse event was injection site reactions (ISR) that occurred in 15% of patients. These were all mild in severity and were similar to the ISRs observed and previously reported in the revusiran Phase 1 study. There were no discontinuations and no significant changes in renal function or any other laboratory chemistry or hematologic parameters. Revusiran demonstrated clinical activity in TTR cardiac amyloidosis patients as measured by knockdown of serum TTR, the disease-causing protein. Specifically, administration of revusiran resulted in potent, rapid, and durable knockdown of serum TTR of up to 98.2%, with a mean maximum knockdown of 85.9% +/- 9.2%. After five weeks of treatment in this small study population, there were no significant changes observed in the exploratory clinical measurements performed. Alnylam has also recently initiated its Phase 2 open-label extension (OLE) study of revusiran. The study is designed to evaluate the tolerability and clinical activity of revusiran with long-term dosing for up to two years. The company expects to present results from the revusiran Phase 2 OLE study at least once annually, starting in late 2015. Alnylam is currently enrolling subjects in its ENDEAVOUR Phase 3 trial, 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 at 18-months and the percent reduction in TTR burden between placebo- and revusiran-treated patients over 18 months. The trial is designed to enroll up to 200 FAC patients with a documented TTR mutation, including V122I or other mutations, in addition to amyloid deposits as identified by biopsy. Patients will be randomized 2:1, revusiran:placebo, with revusiran administered subcutaneously at 500 mg daily for five days then weekly for 18 months. The study was designed with 90% power to detect as little as 39% difference in the 18-month change from baseline for 6-MWD between treatment groups, with a significance level of p < 0.05. All patients completing the ENDEAVOUR Phase 3 study will be eligible to enroll in a Phase 3 OLE study.
Alnylam Pharmaceuticals, Inc. Presents at BioCentury 22nd Annual Future Leaders in the Biotech Industry Conference, Mar-20-2015 10:00 AM
Feb 26 15
Alnylam Pharmaceuticals, Inc. Presents at BioCentury 22nd Annual Future Leaders in the Biotech Industry Conference, Mar-20-2015 10:00 AM. Venue: Millennium Broadway Hotel & Conference Center, New York, New York, United States.
Alnylam Pharmaceuticals, Inc. Presents at SunTrust Robinson Humphrey Biotechnology and Pharmaceutical One-on-One Orphan Drug Day, Feb-23-2015
Feb 18 15
Alnylam Pharmaceuticals, Inc. Presents at SunTrust Robinson Humphrey Biotechnology and Pharmaceutical One-on-One Orphan Drug Day, Feb-23-2015 . Venue: JW Marriott Essex House, 160 Central Park South, b/w 6th & 7th Avenue, New York, New York, United States.