Alnylam reports positive initial phase II data with Revusiran to treat TTR Cardiac Amyloidosis

Initial results are being presented this weekend to clinicians convening during the American Heart Association meeting held in Chicago, including a meeting of the Association of Black Cardiologists.

In the pilot Phase 2 study, revusiran was found to be generally well tolerated in TTR cardiac amyloidosis patients. Revusiran demonstrated clinical activity with an up to 98.2% knockdown of serum TTR – the disease causing protein.

This included similar knockdown effects toward wild type and mutant TTR protein within V122I patients, who represent the most common genotype associated with inherited forms of TTR cardiac amyloidosis. In the five week course of treatment, there were no significant changes observed in a number of exploratory clinical measurements.

Revusiran utilizes Alnylam’s proprietary GalNAc-conjugate delivery platform that enables subcutaneous delivery of RNAi therapeutics with a wide therapeutic index.

"Our pilot Phase 2 study was designed to evaluate the tolerability and initial clinical activity of revusiran in patients with TTR cardiac amyloidosis. These initial results demonstrate that revusiran is generally well tolerated in patients with significant disease burden. In addition, we continue to be impressed with the level of knockdown – up to 98.2% – achieved with revusiran toward both mutant and wild-type TTR. In fact, 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," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam.

"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-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 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.

The revusiran 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.

Revusiran was administered initially as daily subcutaneous doses for five days and then once weekly for five weeks at doses of 5.0 mg/kg or 7.5 mg/kg, 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 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 presented were from 26 patients, including 14 diagnosed with FAC and 12 with SSA. Results being presented are from a 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.

In 3 of 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. There was also a low incidence (15%) of mild, transient, and clinically insignificant monocytosis (increase in percentage monocyte count), which occurred in 4 individuals with elevated baseline monocytosis. There were no discontinuations and no significant changes in renal function or any other laboratory chemistry or hematologic parameters.