Rare Disease Report

Alnylam Announces Promising Results with Their RNAi Therapy

NOVEMBER 14, 2014
James Radke

Every decade or so, a major scientific breakthrough happens.  This may be happening now, according to Alnylam Pharmaceuticals who announced positive initial Phase 2 data with revusiran (ALN-TTRsc) for the treatment of TTR cardiac amyloidosis being presented at the American Heart Association meeting held in Chicago.

In the pilot Phase 2 study, the RNAi therapy was found to be generally well tolerated in TTR cardiac amyloidosis patients and equally important, the treatment demonstrated clinical activity with up to 98.2% knockdown of serum TTR – the disease causing protein.  Aside from serum TTR, no other secondary outcome measures were found to be different in this 5 week study.

Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam said:

“This level of knockdown is the greatest ever reported for an RNAi therapeutic in clinical studies. As would be expected with the short treatment duration of five weeks, there were no significant changes in the exploratory clinical measurements performed.”

“We look forward to further evaluation of revusiran in our Phase 2 open-label extension (OLE) study that is now enrolling patients who participated in the Phase 2 study. We believe long-term dosing with revusiran could provide us with important data on tolerability, in addition to the potential for activity toward clinical endpoints. We plan on sharing data from the OLE study about once annually, beginning in 2015. In addition, having now concluded favorable regulatory discussions in the U.S. and Europe, we expect to begin our Phase 3 trial in TTR cardiac amyloidosis before year’s end.”

TTR Cardiac Amyloidosis

Transthyretin (TTR) is a protein that helps control the transportation of vitamin A in the body. Mutations of the TTR gene can lead to abnormal folding of the TTR protein that in turn results in deposits of the amyloid fibril proteins in various organs and tissues. Where they deposit will determine the symptoms. For example, patients with familial amyloidotic cardiomyopathy (FAC) have cardiac deposits and may show symptoms of congestive heart failure and/or severe postural hypotension whereas patients with familial amyloidotic polyneuropathy  (FAP) have neuropathic deposits.  Senile systemic amyloidosis (SSA) is a non-hereditary form of TTR cardiac amyloidosis caused by idiopathic deposition of wild-type TTR.

Study Details

The open-label, multi-dose 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 5 days and then once weekly for 5 weeks at doses of 5.0 mg/kg or 7.5 mg/kg, for a total of 10 doses. The primary objective was to evaluate the safety and tolerability of revusiran. The secondary objectives were to assess the clinical activity of revusiran toward serum levels of TTR and characterize the drug’s pharmacokinetic profile. In addition, a number of exploratory clinical measurements were performed at baseline and days 42 and 90 after start of dosing.

The initial Phase 2 results  were from 26 patients (14 diagnosed with FAC and 12 with SSA; data cutoff date of October 3, 2014). Revusiran was found to be generally well tolerated in both FAC and SSA patients. The most common adverse event was injection site reactions (ISR) that occurred in 23% of patients. These were all mild in severity and were similar to the ISRs observed and previously reported in the revusiran Phase 1 study. The next most common adverse event was a low incidence of transient mild liver function test (LFT) changes (15%) that, in all cases, resolved without discontinuing therapy.

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 87.2% +/- 9.1%.  After five weeks of treatment in this small study population, there were no significant changes observed in the exploratory clinical measurements performed, including 6-minute walk distance (6-MWD), modified body mass index (mBMI), echocardiogram and cardiac MRI, circulating cardiac biomarkers including NT-proBNP and troponin, and questionnaires to assess cardiomyopathy symptoms and quality of life. Alnylam expects to present the full data set from this Phase 2 trial in early 2015.

Julian Gillmore, M.D., Ph.D., of the National Amyloidosis Centre, University College London said:

“TTR cardiac amyloidosis represents a significant unmet medical need with no approved therapies, and I believe that revusiran holds promise as a potential new treatment option for patients. I am very encouraged by these initial Phase 2 results, showing a favorable tolerability profile, in addition to potent and rapid knockdown of circulating levels of serum TTR, the disease-causing protein.”


As the phase 2 study continues, the company has also 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, and expects to initiate the study by the end of the 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. In the case of revusiran, Alnylam and Genzyme are co-developing and co-commercializing the treastment in North America and Western Europe, while Genzyme is developing and commercializing revusiran in the rest of world.

Image of clinical results obtained from November 15th Alynam report available at http://www.alnylam.com/web/assets/Revusiran_Ph2-AHA_ABC_11152014.pdf

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