Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced it has completed enrollment in its Phase 2 clinical trial with revusiran (re-VOO-si-ran), the recommended International Nonproprietary Name (INN) for ALN-TTRsc. Revusiran is an investigational RNAi therapeutic targeting wild-type and all mutant forms of transthyretin (TTR) and utilizes Alnylam's proprietary GalNAc-conjugate delivery platform that enables subcutaneous delivery of RNAi therapeutics with a wide therapeutic index. 

The pilot Phase 2 study enrolled 26 patients with TTR cardiac amyloidosis, who received revusiran for a five week course of treatment. The company also announced today 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 today 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.

“We believe that revusiran has the potential to be an important therapeutic option for the treatment of TTR cardiac amyloidosis – a disease with significant morbidity and mortality, and no approved therapies. Our Phase 1 clinical study demonstrated robust knockdown of circulating TTR – the disease-causing gene – of up to 96%, and was generally well tolerated,” said Jared Gollob, M.D., Vice President, Clinical Research of Alnylam. “We have now completed enrollment in our pilot Phase 2 study in 26 TTR cardiac amyloidosis patients, where revusiran was administered over a five-week period, and we look forward to presenting these initial results in the coming weeks. With the start of our Phase 2 OLE study, we are pleased to be able to provide patients the opportunity to continue receiving revusiran. We believe that longer term treatment with revusiran in the OLE study will provide important data on tolerability with chronic dosing and could provide potential evidence for clinical activity. We plan on presenting data from the OLE study at least once annually starting in 2015. Finally, we are pleased to have completed our discussions with U.S. and EU regulatory authorities on the design of our Phase 3 study, and are on track to initiate the study before year's end.”

TTR-mediated amyloidosis (ATTR) is an inherited, progressively debilitating, and often fatal disease caused by mutations in the TTR gene. These mutations cause misfolding of the protein and the formation of amyloid fibrils that deposit in tissues. One of the clinical manifestations of ATTR is familial amyloidotic cardiomyopathy (FAC), in which TTR amyloid deposition in the heart leads to cardiac wall thickening and heart failure. In addition, wild-type TTR can accumulate as amyloid deposits in the heart of elderly people in a disease known as senile systemic amyloidosis (SSA). FAC and SSA are fatal within 2.5 to 5 years of diagnosis and treatment is currently limited to supportive care.

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. This trial was conducted as an open-label, multi-dose study, and completed enrollment with 26 patients, including 14 diagnosed with FAC and 12 with 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 has now initiated its Phase 2 OLE study of revusiran. All patients that completed dosing in the Phase 2 trial are eligible to be enrolled in the OLE study. Revusiran will be administered at a fixed subcutaneous dose of 500 mg, with once-daily dosing for the first five days followed by weekly dosing thereafter. The study is designed to evaluate the tolerability and clinical activity of revusiran with long-term dosing for up to two years. In addition to data on mortality, hospitalization, general tolerability, and measurement of serum TTR levels, the study will assess every six months the same clinical measures included in the pilot Phase 2 trial noted above as well as additional measures of amyloid burden including technetium imaging of the heart and quantitation of amyloid in abdominal fat pad aspirates. The company expects to present results from the revusiran Phase 2 OLE study at least once annually starting in 2015.

Finally, Alnylam has now completed its meetings with regulatory authorities from the U.S. and EU regarding the design of a Phase 3 trial for revusiran in TTR cardiac amyloidosis. Specifically, the company completed an End-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA) and received scientific advice from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). Alnylam will provide details of the Phase 3 design upon initiation of the study, which is expected by the end of this year.

In January 2014, Alnylam and Genzyme, a Sanofi company, formed an alliance to accelerate and expand the development and commercialization of RNAi therapeutics across the world. The alliance is structured as a multi-product geographic alliance in the field of rare diseases. In the case of revusiran, Alnylam and Genzyme are co-developing and co-commercializing the investigational RNAi therapeutic in North America and Western Europe, while Genzyme is developing and commercializing revusiran in the rest of world.
 

Merrimack Pharmaceuticals, Inc. (Nasdaq:MACK) announced the U.S. FDA has granted orphan drug designation to their investigational drug candidate MM-141 for the treatment of pancreatic cancer. MM-141 is a tetravalent bispecific antibody designed to block tumor survival signals by targeting receptor complexes containing IGF-1R and ErbB3 (HER3). The IGF-1R and HER3 complexes both activate a major cellular signaling pathway that allows tumor cells to grow and develop resistance to therapies.

"Receiving orphan drug designation for MM-141 is an important regulatory advancement in the development of our clinical program," said Ulrik Nielsen, Ph.D., Chief Scientific Officer and Co-Founder of Merrimack. "Pancreatic cancer is an aggressive and devastating disease, with a five year survival rate of 6% and a low early detection rate. Merrimack is dedicated to changing the landscape of this disease for patients across all lines of therapy. We look forward to advancing the clinical development of MM-141 as we believe that it has the potential to significantly inhibit tumor survival signaling and address pathways of therapeutic resistance in this indication."

The FDA's Office of Orphan Products Development (OOPD) designates orphan status to drugs and biologics intended for the safe and effective treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the United States. This orphan drug designation will potentially provide Merrimack Pharmaceuticals with seven-year marketing exclusivity for MM-141 and other benefits if the drug is approved by the FDA.

MM-141 is Merrimack's sixth oncology candidate to enter clinical development and is currently being tested in a Phase 1 dose-escalation clinical study. A Phase 2 study testing MM-141 in combination with nab-paclitaxel and gemcitabine in front line pancreatic cancer is expected to start in 2015.