A group of researchers discuss the clinical features and diagnosis of acute hepatic porphyrias (AHP) as well as their take on the approval of the first small interfering RNA (siRNA)-based therapy for the treatment of these patients.
Seeking to characterize acute hepatic porphyrias (AHP), a group of researchers published their work on the clinical features and diagnosis of the complex inherited metabolic disorders, as well as therapeutic approaches.
Across the subtypes of AHP—acute intermittent porphyria (AIP), hereditary coproporphyria, variegate porphyria, and doss porphyria—acute neurovisceral attacks are considered the most recognized manifestation of disease, although the researchers note that nontraditional manifestations involving the central nervous system, neuropsychiatric disturbances, and photosensitivity complicate accurate and timely diagnosis. In fact, according to the researchers, AHPs are commonly misdiagnosed, sometimes for up to 15 years.
“The group of clinical conditions that make a differential diagnosis with AHPs is broad and can be best evaluated based on the main clinical and neuromuscular signs involved,” wrote the researchers. These signs include:
Once a diagnosis is made, the decision on what therapeutic approach to take varies based on several factors, like whether the goal of treatment is to treat acute neurovisceral attacks, start treatment during the intercritical period or after acute attacks, or to prevent recurrent attacks and chronic long-term complications.
Treatment options vary, ranging from anesthetics to cardiovascular therapies to immunotherapy and vaccines. Of interest, the researchers highlighted some new therapeutic approaches, including N-Acetyl-D-Galactosamine (GalNAc)-conjugated small interfering RNA (siRNA)-based therapies. One, the siRNA-based treatment givosiran, which was approved by the FDA in 2019, is making its mark on the course of disease; the researchers said that the treatment can be considered for refractory or recurrent AP, refractory patients, or patients without access to hemin therapies as a prohyplactic alternative.
“Once-monthly subcutaneous administration of givosiran 2.5 mg/kg promotes a sustained reduction of liver ALAS1 levels by degradation of its mRNA in hepatocytes,” wrote the researchers. “Thus, it decreases the production of neurotoxic intermediates ALA and PBG and prevents recurrent attacks and chronic and acute symptoms of AIP.”
The treatment was studied in a randomized, double-blind, placebo-controlled, global and multicenter trial. Among 6 patients who received once-monthly injections of the treatment, all achieved reductions in ALAS1 mRNA, ALA, and PBG to normal levels, experiencing a 79% decrease in annualized recurrent attack rate at that stage.
Sgobbi de Souza P, Badia B, Farias I, Goncalves E, Pinto W, Oliveira A. Acute hepatic porphyrias for the neurologist: current concepts and perspectives. Arq Neuropsiquiatr. Published online January 6, 2021. doi:10.1590/0004-282x20200096.