In a randomized, double-blind, placebo-controlled study, Givosiran demonstrates a decreased annualized attack rate and hemin usage. Initial results from an ongoing open-label extension (OLE) study show consistent reductions in porphyria attacks with continued Givosiran treatment.
Hepatic porphyrias are a subgroup of of porphyrias in which the enzyme deficiency occurs in the liver. Acute hepatic porphyrias encompass four diseases: acute intermittent porphyria (AIP) (most common), variagate porphyria, hereditary coproporphyria, and hereditary deficit of delta-aminolevulinic acid dehydratase (most rare).
Currently, urgent treatment with an injection of human hemin and/or perfusion of carbohydrates is required when an acute attack is confirmed. Management of the disorder includes avoiding causal factors to prevent attacks and protect the skin from the light in cases of cutaneous manifestations.
Alnylam’s hope in developing Givosiran, a subcutaneously administered, investigational RNAi therapeutic, is for it to become a novel treatment approach for the prevention of recurrent attacks by targeting ALAS1 for the treatment of AHP, including AIP.
"We believe that a long acting therapeutic agent that has the potential to prevent porphyria attacks and that can be administered via a once monthly, low volume, subcutaneous injection could be a potentially transformative treatment option for patients suffering with this debilitating and potentially life-threatening disease," said Jeff Miller, General Manager of the givosiran program.
"Based on these encouraging interim results and with both Breakthrough Therapy and PRIME designations granted, we will continue to work with global regulatory authorities to rapidly advance givosiran toward regulatory filings and, if approved, to patients. To that end, we remain on track to initiate the givosiran Phase 3 program in late 2017."
Per a press release, the continuing part of the Phase 1 study of the drug is being managed as a randomized, double-blind, placebo-controlled study in up to 24 AIP patients who experience recurrent porphyria attacks. Patients are followed in a 3-month run-in phase, where the amount and frequency of attacks and levels of porphobilinogen (PBG) and aminolevulinate (ALA) are measured prospectively.
Patients who experience at least 1 porphyria attack during the run-in phase are then eligible to enter the study’s 6-month treatment phase, where they are randomized to receive 2 once-quarterly doses or 4 once-monthly doses of placebo or givosiran at 2.5 or 5.0 mg/kg. During the treatment phase, the effects of placebo or givosiran on the number and frequency of porphyria attacks, as well as on the levels of ALA and PBG, are measured prospectively in a blinded manner and then compared to run-in phase results.
Additional measures include safety, tolerability, hospitalizations, use of hemin (FDA approved), levels of ALAS1 mRNA, and givosiran pharmacokinetics. Following the treatment phase, all patients are eligible to receive givosiran in an open-label extension study.
Givosiran has already been granted Orphan Drug Designations in both the E.U. and the U.S. for the treatment of acute hepatic porphyrias. Givosiran also received Breakthrough Designation by the U.S. Food and Drug Administration (FDA), and has been granted PRIME designation by the European Medicines Agency (EMA).
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