Acute hepatic porphyria (AHP) is a group of inherited metabolic disorders that affect hepatic
heme biosynthesis. They are associated with attacks of neurovisceral manifestations that can be life threatening and constitute what is considered an
acute porphyria attack. Until recently, the sole specific treatment for
acute porphyria attacks consisted of the
intravenous administration of
hemin. Although attacks are often sporadic, some patients develop recurrent acute attacks, with devastating effects on quality of life.
Liver transplantation has historically been the sole curative treatment option. The clinical manifestations of AHP are attributed to the accumulation of the
heme precursor 5-aminolevulinic
acid (ALA) and
porphobilinogen (PBG). Advances in molecular engineering have provided new therapeutic possibilities for modifying the
heme synthetic pathway. We reviewed the background and current status of AHP treatment using liver-directed
small interfering RNA targeting ALAS1. The therapeutic aim was to normalize the levels of ALAS1, which is highly upregulated during
acute porphyria attacks.
Givosiran is now an approved drug for use in adults and adolescents aged 12 years and older. The results of clinical trials have shown that
givosiran treatment leads to a rapid and sustained reduction of ALAS1
mRNA, decreased
heme precursor levels, and a decreased rate of acute attacks compared with placebo. The clinical trials (phases I, II, and III) were all randomized and placebo controlled. Many patients enrolled in the initial clinical trials have continued treatment in open label extension and extended/compassionate-use programs in countries where
givosiran is not yet commercially available.