Blood. 2023 Apr 07. pii: blood.2022018662. [Epub ahead of print]
The acute hepatic porphyrias (AHPs) are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks precipitated by factors that upregulate hepatic 5-aminolevulinic acid synthase 1 (ALAS1) activity. Induction of hepatic ALAS1 leads to accumulation of porphyrin precursors, in particular 5-aminolevulinic acid (ALA), which is thought to be the neurotoxic mediator leading to acute attack symptoms such as severe abdominal pain and autonomic dysfunction. Patients may also develop debilitating chronic symptoms and long-term medical complications including kidney disease and increased risk of hepatocellular carcinoma. Exogenous heme is the historical treatment for attacks and exerts its therapeutic effect by inhibiting hepatic ALAS1 activity. The pathophysiology of acute attacks provided the rationale to develop an RNA interference (RNAi) therapeutic that suppresses hepatic ALAS1 expression. Givosiran is a subcutaneously administered N-acetyl galactosamine (GalNAc)-conjugated small interfering RNA against ALAS1 that is taken up nearly exclusively by hepatocytes via the asialoglycoprotein receptor. Clinical trials established that continuous suppression of hepatic ALAS1 mRNA via monthly givosiran administration effectively reduces urinary ALA and porphobilinogen (PBG) levels and acute attack rates and improves quality of life. Common side effects include injection site reactions and increases in liver enzymes and creatinine. Givosiran was approved by the U.S. Food and Drug Administration and European Medicines Agency in 2019 and 2020, respectively, for treatment of AHP patients. While givosiran has the potential to decrease the risk of chronic complications, long-term data on the safety and effects of sustained ALAS1 suppression in AHP patients are lacking.