RNAi Therapy for Porphyrias Yields Positive Results

Positive clinical results from Phase 1 and Phase 1/2 open-label extension (OLE) studies of givosiran were presented by Alnylam Pharmaceuticals at the European Association for the Study of the Liver (EASL) 53^rd Annual International Liver Congress this weekend.

Monthly administration of givosiran at 2.5 mg/kg, an investigational RNA interference (RNAi) therapeutic intended for the treatment of actute hepatic porphyrias (AHPs), is believed to significantly lower aminolevulinic acid synthase 1 (ALAS1) levels in a continual manner and thus decrease neurotoxic heme intermediates, aminolevulinic acid (ALA) and porphobilnogen (PBG) to near normal levels.

In the randomized, double-blind, placebo-controlled Phase 1, the drug exhibited an over 80% decrease of urinary ALA and an over 75% decrease in average annualized porphyria attack rate, compared to placebo.

Serious adverse events (AEs) were reported in 6 patients receiving givosiran in the Phase 1 study; however, none were considered to be related to study drug.

“We view these new results with givosiran as very encouraging, since they demonstrate robust and what we believe to be clinically meaningful reductions in urinary ALA, porphyria attack rate, and hemin administration with continued dosing for up to nearly two years. 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 3 development plan,” said Akin Akinc, Vice President and General Manager, Givosiran Program at Alnylam in a press release.

A robust treatment effect was maintained in givosiran-treated patients with extended dosing in the OLE study, with a total time on treatment across the Phase 1 and OLE studies of up to 22 months.

In patients who received the drug during the Phase 1, and continued through the OLE study, mean reductions in annual attack rate (AAR) of 93% and annualized hemin use of 94% were observed, relative to the AAR and annualized hemin use recorded for these patients in the Phase 1 run-in period. The extent of these reductions in the OLE study surpassed that observed in response to givosiran treatment during the Phase 1 study, suggesting that extended dosing at 2.5 mg/kg monthly potentially leads to enhanced clinical activity.

The safety and efficacy of givosiran are currently being investigated in the ENVISION Phase 3 clinical trial and ongoing Phase 1/2 OLE study and, as of this writing, have not been evaluated by the FDA, the EMA or any other health-related regulatory agency.

Alnylam continues to enroll patients in the ENVISION Phase 3 pivotal study, which was initiated at the end of 2017. It was also announced at the EASL 53^rd Annual International Liver Congress that the company expects to enroll the 30th patient into ENVISION in the coming weeks, in support of the planned interim analysis in mid-2018.

If positive, the results would support a potential NDA filing for givosiran by the end of 2018.

Givosiran has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) and PRIME designation by the European Medicines Agency (EMA). Additionally, the RNAi drug has also been granted orphan drug designations by both the FDA and the EMA for the treatment of AHPs.

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