Introduction: Acute hepatic porphyrias (AHPs) are a family of rare inherited disorders characterized by enzyme dysfunctions in the hepatic pathway of heme biosynthesis. In AHPs, accumulation of the neurotoxic porphyrin precursors delta-aminolevulinic acid and porphobilinogen, caused by enhanced activity of hepatic aminolevulinate synthase 1 (ALAS1), is associated with acute, potentially life-threatening neurovisceral attacks. Symptoms during and between attacks dramatically reduce patients' quality of life (QoL). Givosiran is the first mRNA-targeted treatment for AHPs, silencing ALAS1 expression.
Areas covered: For givosiran, this review summarizes its chemistry, mechanism of action, pharmacokinetics, pharmacodynamics, safety, preclinical and clinical data in AHP, postmarketing surveillance, and regulatory status. A literature search of public and internal databases was performed, bibliographies of retrieved articles were manually searched to identify additional studies of relevance, and information was also provided by Alnylam Pharmaceuticals.
Expert opinion: Givosiran is a small interfering RNA (siRNA) therapeutic that reduces hepatic activity of ALAS1 and decreases accumulation of neurotoxic porphyrin precursors in patients with AHPs, ultimately reducing the number of acute attacks and improving symptoms and QoL between attacks. As AHPs are lifelong diseases, long-term safety data are needed for givosiran as an siRNA-based therapy.
Keywords: Givosiran; acute hepatic porphyrias; acute intermittent porphyria; delta-aminolevulinate synthase; delta-aminolevulinic acid; hereditary coproporphyria; metabolic diseases; porphobilinogen; small interfering RNA; variegate porphyria.