Clinical Trials

* On October 5, 2016, Alnylam Pharmaceuticals announced that upon the recommendation of the ENDEAVOUR Phase 3 study Data Monitoring Committee (DMC) to suspend dosing, the company has decided to discontinue development of revusiran, an investigational RNA interference (RNAi) therapeutic that was being developed for the treatment of hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM). This decision was made yesterday evening and has been communicated to investigators, study sites, and regulatory authorities. Following recent reports in the Phase 2 OLE study of new onset or worsening peripheral neuropathy, the ENDEAVOUR DMC assembled yesterday at the Company's request to review these reports and ENDEAVOUR data on an unblinded basis. The DMC did not find conclusive evidence for a drug-related neuropathy signal in the ENDEAVOUR trial, but informed Alnylam that the benefit-risk profile for revusiran no longer supported continued dosing. Alnylam subsequently reviewed unblinded ENDEAVOUR data which revealed an imbalance of mortality in the revusiran arm as compared to placebo. "Patient safety comes first. We have stopped all dosing and are actively monitoring patients across revusiran studies to ensure their safety. We will also continue to evaluate ENDEAVOUR data to understand the potential cause of these findings," said John Maraganore , Ph.D., Chief Executive Officer at Alnylam. The decision to discontinue development of revusiran does not affect patisiran, which is currently in Phase 3 development for the treatment of hATTR amyloidosis with polyneuropathy (hATTR-PN), or any other Alnylam investigational RNAi therapeutic program in development. Based on a current assessment of the safety data across the Company's other programs, which include the ALN-PCSsc program partnered with The Medicines Company, there is no evidence of a drug-related neuropathy signal in over 800 treated subjects and patients with exposure of up to 34 months. This includes patisiran, which utilizes a lipid nanoparticle delivery formulation, and the seven other clinical programs in Alnylam's pipeline, which all use Enhanced Stabilization Chemistry (ESC) GalNAc delivery technology. ESC-GalNAc conjugates enable dose and exposure levels that are 12-30 times lower than revusiran, which uses Standard Template Chemistry (STC) GalNAc delivery technology.

* On August 8, 2016, Alnylam Pharmaceuticals announced that it has completed enrollment in its ENDEAVOUR Phase 3 study with revusiran for the treatment of hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM), also known as familial amyloidotic cardiomyopathy (FAC). The ENDEAVOUR trial enrolled 206 patients with hATTR-CM, above the enrollment target of 200 patients. The Company expects to report data from the study in early 2018.

* On November 3 , 2015, Alnylam Pharmaceuticals announced new results from its ongoing Phase 2 open-label extension (OLE) study with revusiran for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis). These new clinical data were presented at the 1st European Congress on Hereditary ATTR amyloidosis (EC-ATTR) held November 2 - 3, 2015 in Paris. Initial data from the revusiran Phase 2 OLE study showed robust and sustained knockdown of serum TTR, and was found to be generally well tolerated in the majority of patients with TTR cardiac amyloidosis - including patients with Familial Amyloidotic Cardiomyopathy (FAC) and Senile Systemic Amyloidosis (SSA) - out to 10 months of treatment.
Sustained and Clamped TTR Knockdown out to 10 Months in Revusiran OLE Study Represents Longest Dosing Experience for a GalNAc-siRNA Conjugate Reported to Date: Initial results were presented for patients (N=18) who reached the 6-month endpoint as of a data transfer date of October 12, 2015 . Repeat dosing with revusiran achieved robust and sustained TTR knockdown over the 6-month period, with an up to 98% maximal and 87% mean maximum knockdown of TTR. For patients with an evaluable 6-minute walk distance (6-MWD) measurement at 6 months (N=15), the majority exhibited stable performance compared to baseline. On average, evaluable patients with FAC (N=8) exhibited a mean decline of 20 ± 14 meters and those with SSA (N=7) exhibited a mean decline of 24 ± 20 meters over 6 months.
Weekly dosing with revusiran appeared to be generally well tolerated in the majority of ATTR cardiac amyloidosis patients. Serious adverse events (SAEs) were observed in eight patients (32%), including one death due to infiltrative cardiomyopathy; none of the SAEs were deemed to be related to study drug. The majority of the adverse events (AEs) were mild or moderate in severity; injection site reactions (ISRs) were reported in 11 patients (44%). As previously reported, three patients discontinued due to recurrent localized reactions at the injection site or a diffuse rash; no further discontinuations due to ISRs have occurred.

* On March 15, 2015, Alnylam Pharmaceuticals 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.

* On November 5, 2014, Alnylam Pharmaceuticals announced that it has completed enrollment in its Phase 2 clinical trial with revusiran, the recommended International Nonproprietary Name (INN) for ALN-TTRsc. The pilot Phase 2 study enrolled 26 patients with TTR cardiac amyloidosis, who received revusiran for a five week course of treatment.The pilot Phase 2 study was aimed at evaluating the safety, tolerability, pharmacodynamic and preliminary clinical activity of revusiran in patients with FAC and SSA. Revusiran was administered initially as daily subcutaneous doses for five days and then once weekly at doses of 5 mg/kg or 7.5 mg/kg over a period of five weeks for a total of 10 doses. The primary objective of the study was to evaluate the safety and tolerability of revusiran. The secondary objectives were to assess the pharmacodynamic effect on serum levels of TTR and characterize the pharmacokinetic profile. In addition, exploratory clinical endpoint data were collected at baseline and days 42 and 90 after start of dosing; this includes 6-MWD, echocardiogram and cardiac MRI to assess cardiac amyloid burden and function, circulating cardiac biomarkers including NT-proBNP and troponin to assess heart wall stress and injury, and questionnaires to assess cardiomyopathy symptoms and quality of life. 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.

The company also announced that its open-label extension (OLE) study with revusiran is now open for enrollment for patients who participated previously in the Phase 2 clinical trial. The Phase 2 OLE study will evaluate the safety and tolerability of long-term dosing with revusiran for up to two years, and will also measure effects of treatment on clinical endpoints, including mortality, hospitalization, and 6-minute walk distance (6-MWD), in addition to cardiac amyloid burden and function, and cardiac biomarkers. The company intends to report clinical data from this study about once per year, with initial data expected in 2015. Finally, Alnylam is also announcing that it has completed its discussions with regulatory authorities in the U.S. and EU regarding the design of a Phase 3 study for revusiran in TTR cardiac amyloidosis patients; the company remains on track to initiate the study before year's end.

* On December 16, 2013, Alnylam Pharmaceuticals has announced  that it has initiated a pilot Phase II study with ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting the transthyretin (TTR) gene in development for the treatment of TTR-mediated amyloidosis (ATTR). The Phase II trial, which is now open for enrollment, is aimed at evaluating the tolerability and preliminary clinical activity of ALN-TTRsc in TTR cardiac amyloidosis patients with familial amyloidotic cardiomyopathy (FAC) – which is caused by autosomal dominant mutations in the TTR gene, or senile systemic amyloidosis (SSA) – which is caused by idiopathic accumulation of wild-type TTR in the heart. The company expects to present data from the Phase II trial in late 2014, and assuming positive results, begin a Phase III trial in TTR cardiac amyloidosis patients by the end of 2014.