Alnylam Pharmaceuticals this week announced positive interim data from a phase I study of its subcutaneously delivered TTR amyloidosis treatment ALN-TTRsc, which show the drug can cut levels of its disease-causing protein by roughly 90 percent.
During a conference call, Alnylam CEO John Maraganore touted the results as establishing "a new benchmark for consistent and sustained TTR knockdown" when it comes to RNA-based ATTR treatments, and that the company would aim for this target in all future studies of ALN-TTRsc.
ATTR is caused by mutations in the TTR gene, which triggers accumulation of abnormal amyloid proteins in the body. ALN-TTRsc is designed to inhibit both the wild-type and mutant forms of the protein and is formulated with the GalNAc technology, which facilitates liver delivery of siRNAs via uptake through the asialoglycoprotein receptors expressed on the surface of hepatocytes.
The 40-subject, ongoing phase I trial included an initial single-ascending dose phase in which subjects received subcutaneous doses of placebo or ALN-TTRsc from 1.25 to 10 mg/kg. In the multiple-ascending dose phase of the study, subjects received 10 subcutaneous doses of placebo or ALN-TTRsc from 2.5 to 10 mg/kg.
This week, Alnylam said that interim data from 28 subjects, which were presented at the Heart Failure Society of America's annual meeting, show that "single- and multi-dose administration of ALN-TTRsc resulted in rapid, dose-dependent, consistent, and durable knockdown of serum TTR levels." Meanwhile, in the multi-dose cohorts, there was a "statistically significant knockdown of serum TTR at all doses tested as compared to placebo."
Specifically, ALN-TTRsc was able to trigger a 94 percent reduction in serum TTR levels and a mean TTR knockdown of 92.4 percent at nadir, although this was at the highest dose level tested.
In the more clinically relevant dose level of 5 mg/kg, ALN-TTRsc administration resulted in up to 93.3 percent knockdown of serum TTR and a mean TTR knockdown of 87.5 percent at nadir.
"During the period of dose administration, TTR levels were essentially clamped down, showing a very consistent effect during dosing," Alnylam CMO Akshay Vaishnaw said during the call. "In addition, we're very pleased to see a rapid onset of action with nadir achieved at about day 15 and then a very durable effect after cessation of drug with a recovery to baseline levels over several weeks after."
In terms of safety, both single and multiple doses of ALN-TTRsc were found to be safe and well-tolerated, with no significant or adverse events associated with the drug at doses through 10 mg/kg.
All adverse events were deemed mild or moderate in severity, and included injection site reactions in a minority of subjects receiving both drug and placebo.
In all cases, these reactions were self-limiting and resolved within approximately two hours of onset, according to Alnylam. There were no study discontinuations, flu-like symptoms, or changes in cytokines, C-reactive protein, liver function tests, renal function, or hematologic parameters.
Notably, the TTR knockdown in humans was closely correlated to results obtained in non-human primates, with an essentially one-to-one relationship on a mg/kg basis — confirming human translation for the GalNAc-siRNA conjugate platform, Alnylam noted.
Viashnaw noted that enrollment continues in the phase I study so that Alnylam can test different dosing regimens of the drug.
"We'll use these additional data to finalize our dose and dose regimen selection for the start of our phase II [trial] later this year," which will enroll ATTR patients with cardiac manifestations of the disease, known as familial amyloidotic cardiomyopathy, he said, adding that the company would likely proceed with either a 5 mg/kg or 7.5 mg/kg doses weekly or every two weeks.
As previously announced, Alnylam anticipates moving ALN-TTRsc into phase III next year.