Spotlight on Givosiran as a Treatment Option for Adults with Acute Hepatic Porphyria: Design, Development, and Place in Therapy

Abstract

Small interfering ribonucleic acids [siRNAs] are short ribonucleic acid (RNA) fragments cleaved from double-stranded RNA molecules that target and bind to specific sequences on messenger RNA (mRNA), leading to their destruction. Therefore, the siRNA down-regulates the formation of selected mRNAs and their protein products. Givosiran is one such siRNA that uses this mechanism to treat acute hepatic porphyrias. Acute hepatic porphyrias are a group of rare, inherited metabolic disorders, characterized by acute potentially life-threatening attacks as well as chronic symptoms with a negative impact on quality of life. It has four types, each associated with distinct enzyme defects in the heme biosynthesis pathway in the liver. By targeting the expression of hepatic 5-aminolevulinic acid [ALA] synthase-1 [ALAS1], givosiran can down-regulate levels of toxic metabolites, leading to biochemical and clinical improvement. Givosiran selectively targets hepatocytes due to its linkage to N -acetylgalactosamine (GalNac) leading to its selective uptake via asialoglycoprotein receptors (ASGPR). We provide an up-to-date literature review regarding givosiran in the context of a clinical overview of the porphyrias, an overview of siRNAs for therapy of human disorders, the design and development of givosiran, key clinical trial results of givosiran for prevention of acute porphyric attacks, emerging concerns regarding chronic use of givosiran, and the overall management of acute hepatic porphyrias. These insights are important not only for the management of acute hepatic porphyrias but also for the emerging field of siRNAs and their role in novel therapies for various diseases.

Idiosyncratic drug-induced liver injury caused by givosiran in a patient with acute intermittent porphyria

“…Based upon this case and those reported by Balwani et al [ 14 ], and Ventura et al [ 6 ], it seems likely that givosiran may give rise to potentially severe immune-mediated acute DILI. Thus, although givosiran represents a welcome advance for the treatment of patients with AIP who are experiencing frequent acute attacks, patients initiating therapy should be monitored closely for DILI or other adverse drug reactions during the first 3–4 months and, if tolerated well, periodically thereafter [ [17] , [18] , [19] ].…”

mRNA in the Context of Protein Replacement Therapy

“…The former act through their interplay with the RNA-induced silencing complex (RISC), leading to RNA interference (RNAi), meaning that a siRNA has the potential to target a prespecified mRNA molecule and induce its degradation, completely blocking the expression of a certain gene [ 5 ]. Drugs based on siRNAs have already been launched to treat TTR-amyloidosis and hepatic porphyria [ 6 , 7 ]. Regarding microRNAs, these molecules inhibit target mRNAs by forming a complex with RISC and downstream suppressing mRNA translation or contributing to its degradation or cleavage.…”

EXPLORE B: A prospective, long‐term natural history study of patients with acute hepatic porphyria with chronic symptoms

“…24 , 26 Other management strategies include trigger avoidance, acute attack treatment with intravenous hemin, and hemin prophylaxis. 26 , 27 Hemin use carries acute (e.g., headache, phlebitis) and chronic risks (e.g., iron overload, venous thrombosis/obliteration, central venous catheter complications). 10 , 27 , 28 , 29 For women with attacks associated with the menstrual cycle's luteal phase, gonadotropin‐releasing hormone (GnRH) analogs have been used prophylactically.…”

“…Givosiran (Givlaari; Alnylam Pharmaceuticals, Cambridge, MA), a once‐monthly subcutaneous injection, is an ALAS1‐directed small interfering RNA approved for AHP treatment in adults in the United States and adults and adolescents age ≥ 12 years in the European Union 24,25 . Givosiran treatment can lead to nausea, fatigue, injection‐site reactions, serum aminotransferase elevations, decreased estimated glomerular filtration rate, increased blood homocysteine, or anaphylactic reactions in some patients 24,26 . Other management strategies include trigger avoidance, acute attack treatment with intravenous hemin, and hemin prophylaxis 26,27 .…”

“…Givosiran treatment can lead to nausea, fatigue, injection‐site reactions, serum aminotransferase elevations, decreased estimated glomerular filtration rate, increased blood homocysteine, or anaphylactic reactions in some patients 24,26 . Other management strategies include trigger avoidance, acute attack treatment with intravenous hemin, and hemin prophylaxis 26,27 . Hemin use carries acute (e.g., headache, phlebitis) and chronic risks (e.g., iron overload, venous thrombosis/obliteration, central venous catheter complications) 10,27–29 .…”