Alnylam Pharmaceuticals last week released preclinical data demonstrating proof of concept for its porphyria treatment ALN-AS1.
The drug is designed to silence ALAS-1, a liver-expressed rate-limiting enzyme upstream of porphobilinogen deaminase. Inhibition of ALAS-1 has been shown to reduce the accumulation of heme precursors that cause the clinical manifestations of acute intermittent porphyria — a form of porphyria Alnylam is focusing on.
The new data show that ALN-AS1 “completely protected mice from phenobarbital-induced up-regulation of hepatic ALAS-1 mRNA and the resulting accumulation of the neurotoxic ALA and PBG heme biosynthesis precursors,” Alnylam said.
This protective effect was dose responsive and durable, lasting for at least two weeks after a single administration.
“Further, in a treatment model, a single dose of ALAS-1 siRNA rapidly reduced the high levels of plasma ALA and PBG that were elevated during a phenobarbital-induced acute attack,” Alnylam said. Meanwhile, preliminary comparative studies show that the drug was more effective than heme administration in the treatment of an acute attack.
Alnylam said that efforts to develop its GalNAc conjugation technology for use with ALN-AS1 have been promising, and that it remains on track to file an investigational new drug application for the compound in 2014.