With Positive Support from Early Studies Alnylam Looks to File NDA for Second RNAi Therapeutic by the End of 2018

Fueled by positive Phase I and Phase I/II results from an open-label extension (OLE) study of RNAi therapeutic givosiran, as well as an ongoing Phase III trial, Cambridge, Mass.-based Alnylam said it is eying a possible New Drug Application by the end of the year.

This morning Alnylam released the additional results from its OLE study of givosiran, a treatment for acute hepatic porphyrias (AHPs). Alnylam said its extended Phase I data showed that monthly doses of givosiran at 2.5 mg/kg led to mean reductions in annualized attack rate (AAR) of 83 percent and annualized hemin use of 88 percent, relative to placebo. The company said monthly dosing generated greater and more lasting results than quarterly dosing. Alnylam noted the results are encouraging because they demonstrate robust and clinically meaningful reductions in urinary ALA, porphyria attack rate, and hemin administration with continued dosing for up to two years.

Data from the Phase I/II trial showed that patients who received givosiran during the Phase 1 study and continued with givosiran dosing in the OLE study saw mean reductions of annualized attack rates by 93 percent and annualized hemin use of 94 percent. Alnylam said the data suggests that extended dosing of givosiran at 2.5 mg/kg potentially leads to enhanced clinical activity. Not only that, but Alnylam said placebo patients in the Phase I trial who “crossed over” to givosiran in the OLE study saw mean reductions of more than 90 percent in AAR and annualized hemin use.

Alnylam’s new data was initially presented last week at the European Association for the Study of the Liver’s Annual International Liver Congress in Paris. The company said treatment with givosiran led to rapid, dose-dependent, and durable lowering of induced ALAS1 mRNA in patients with recurrent attacks. With the lowering of ALAS1, Alnylam said that corresponded to reductions in both aminolevulinic acid (ALA), which is believed to be the primary neurotoxic intermediate responsible for disease manifestations, and porphobilinogen (PBG). Alnylam said the data showed that monthly dosing with givosiran led to “consistent and sustained lowering of ALA and PBG of greater than 80 percent, relative to baseline.”

“We also believe our new data support use of a monthly dosing regimen for sustained reductions in ALAS1 mRNA and urinary ALA, with improved clinical activity. In sum, we believe the clinical activity and overall safety profile for givosiran continue to support an accelerated Phase II development plan,” Akin Akinc, head of Alnylam’s givosiran program said in a statement.

The company did note there were some safety concerns during the trial with one patient discontinuing following an anaphylactic reaction.

Akinc said the company enrolled its 30th patient in the Phase III Envision study. The company expects that interim data from that trial will support a potential NDA filing for givosiran. If so, that would give Alnylam two shots on goal within a year. In February the FDA accepted Alnylam’s New Drug Application for patisiran, its investigational RNAi therapy targeting transthyretin (TTR) for the treatment of hereditary ATTR (hATTR) amyloidosis. The FDA granted Alnylam a Priority Review and set a target action date of Aug. 11.