NEW YORK (GenomeWeb) – Alnylam Pharmaceuticals last week released data from a Phase II pilot study of its subcutaneously administered TTR-mediated amyloidosis (ATTR) drug revusiran, showing that the agent could knock down levels of its target protein by as much as 98.2 percent.
While treatment with revusiran, formerly known as ALN-TTRsc, was generally well tolerated, Alnylam disclosed that a number of patients in the open-label study experienced a variety of adverse events including one deemed serious.
However, these were transient and did not result in any patients dropping out of the study, Alnylam said. The company remains on track to initiate a Phase III trial of revusiran before the end of 2014.
ATTR is a condition characterized by the accumulation of amyloid deposits in tissues due to mutations in the TTR gene. Revusiran, like its intravenously administered Phase III counterpart patisiran, is designed to silence both mutant and wild-type TTR.
But Alnylam is developing patisiran to treat a form of the disease called familial amyloidotic polyneuropathy, which primarily affects the nervous system. Revusiran is designed for a manifestation of ATTR called familial cardiac amyloidosis (FAC), which primarily affects heart tissue, and senile systemic amyloidosis (SSA), wherein wild-type TTR protein accumulates in the hearts of elderly patients.
Shortly after releasing positive Phase I data on revusiran about a year ago, Alnylam kicked off the Phase II trial to primarily examine its safety and tolerability, although it also performed exploratory clinical measurements. The study enrolled 14 patients with FAC and 12 with SSA who received five daily subcutaneous doses of revusiran, followed by once weekly doses for five weeks for a total of 10 doses. Patients were treated with either 5 mg/kg or 7.5 mg/kg doses.
There were no observed changes in clinical measurements, but Alnylam CEO John Maraganore noted during a conference call held to discuss the data that this was expected given the short duration of treatment in the trial.
Still, the TTR inhibition of nearly 99 percent is encouraging and marks the greatest target protein knockdown reported with any RNAi therapeutic in human studies, he added.
Alnylam CMO Akshay Vaishnaw said during the call that 23 percent of patients in the study experienced injection site reactions, but that these were mild in severity and consistent to those reactions observed and reported in the Phase I trial.
"The next most common adverse event was a low incidence of transient mild liver function test changes," which occurred in four patients, he added. In three of the patients, these changes were clinically insignificant and were less than 1.5 times the upper limit of normal.
One patient, however, experienced a roughly four-fold elevation in liver transaminases, which was categorized as a serious adverse event (SAE), although it was graded as mild in severity.
Notably, the elevation in liver enzymes occurred during the loading phase of the trial when the patient received five daily doses of revusiran, and returned to normal during the maintenance portion of the study, Vaishnaw said.
"In other words, this event resolved with the patient continuing therapy," he said.
Further, the SAE was discovered during the course of routine liver function tests and not as a result of any symptoms from the patient. "The patient felt completely well throughout [the study], so really [this was] a laboratory phenomenon," Vaishnaw added.
Noting that this issue was not observed in patients receiving higher doses of revusiran, he said that "this was probably just an isolated phenomenon. We've very comfortable with the profile here … and I think that this is not going to be an issue generally in the Phase III study."
Finally, mild, transient, and clinically insignificant monocytosis was observed in four patients, Alnylam said. There were no discontinuations and no significant changes in renal function or any other laboratory chemistry or hematologic parameters.
With the release of the data, Maraganore said that Alnylam is continuing an open-label extension study for patients who completed dosing in the Phase II trial. Revusiran will be administered at a fixed 500 mg dose in this study, with an initial five-day once-daily loading phase followed by once a week treatment thereafter.
The extension study is designed to provide tolerability and clinical activity data around long-term dosing for up to two years. In addition to data on mortality, hospitalization, general tolerability, and knockdown of serum TTR, the study will assess a number of clinical endpoints every six months. Data from the open-label extension trial is expected to be presented once a year beginning in 2015.
Alnylam said that it will provide details around its planned Phase III trial for revusiran once it announces the start of the study.