GS-14-ENVISION, a phase 3 study to evaluate efficacy and safety of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1, in acute hepatic porphyria patients

Balwani, Manisha; Gouya, Laurent; Rees, David; Stein, Penelope E.; Stölzel, Ulrich; Aguilera, Paula; Bissell, D. Montgomery; Bonkovsky, Herbert L.; Keel, Siobán; Parker, Charles J.; Phillips, John; Silver, Samuel; Windyga, Jerzy; D’Avola, Delia; Ross, Gayle; Stewart, Peter; Ritchie, Bruce; Oh, Jeeyoung; Harper, Pauline; Wang, Jiaan-Der; Langendonk, Janneke G.; Ivanova, Aneta; Horie, Yutaka; Anderson, Karl E.; Ventura, Paolo; Chan, Amy B.W.; Penz, Craig; Simon, Amy; Dinh, Quinn; Liu, Gary; Sardh, Eliane

doi:10.1016/s0618-8278(19)30142-2

Cited by 14 publications

(14 citation statements)

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“…Subcutaneous administration (and a less complex production process) is also the main advantage of GalNAc-siRNA conjugates although currently approved conjugates have to be administered by healthcare professionals. Most recently, the GalNAc-siRNA conjugate Givlaari™ (givosiran, $575,000 per year) was approved for treating acute hepatic porphyria [236,237], while New Drug Applications were filed for lumasiran for treating primary hyperoxaluria type 1, [238,239] and inclisiran for treating hypercholesteremia [240][241][242]. Vutrisiran, a GalNAc-siRNA conjugate for treating ATTRv amyloidosis, is currently undergoing phase 3 trials and has been granted Orphan Drug designation in the U.S. and the European Union [243].…”

Section: Future Perspectivesmentioning

confidence: 99%

Lipid nanoparticle technology for therapeutic gene regulation in the liver

Witzigmann

Kulkarni

Leung

et al. 2020

Advanced Drug Delivery Reviews

257

168

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Hereditary genetic disorders, cancer, and infectious diseases of the liver affect millions of people around the globe and are a major public health burden. Most contemporary treatments offer limited relief as they generally aim to alleviate disease symptoms. Targeting the root cause of diseases originating in the liver by regulating malfunctioning genes with nucleic acid-based drugs holds great promise as a therapeutic approach. However, employing nucleic acid therapeutics in vivo is challenging due to their unfavorable characteristics. Lipid nanoparticle (LNP) delivery technology is a revolutionary development that has enabled clinical translation of gene therapies. LNPs can deliver siRNA, mRNA, DNA, or gene-editing complexes, providing opportunities to treat hepatic diseases by silencing pathogenic genes, expressing therapeutic proteins, or correcting genetic defects. Here we discuss the state-of-the-art LNP technology for hepatic gene therapy including formulation design parameters, production methods, preclinical development and clinical translation.

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Section: Future Perspectivesmentioning

confidence: 99%

Lipid nanoparticle technology for therapeutic gene regulation in the liver

Witzigmann

Kulkarni

Leung

et al. 2020

Advanced Drug Delivery Reviews

257

168

View full text Add to dashboard Cite

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“…While LNP encapsulation has enabled delivery of siRNAs to the liver, due to their poor PK and diffusion coefficients, the NAT field is moving away from LNPs and toward single molecule, targeted conjugates. For liver diseases, the stand out tris-GalNAc targeting domain to deliver siRNAs and ASOs to liver hepatocytes is already showing significant benefit for patients in clinical trials [3,4,5]. While the success of GalNAc conjugates has inspired a gold rush of companies striving to develop liver-targeted therapies, it also raises the possibility of successfully targeting oligonucleotide therapies to extra-hepatic tissues.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, chemical conjugation of siRNA and ASO oligonucleotides to targeting domains has enabled binding to and cellular uptake in a limited number of therapeutically relevant cell types. For example, oligonucleotides bearing tris-GalNAc moieties that target the asialoglycoprotein receptor (ASGPR) on liver hepatocytes have shown significant successes in multiple clinical trials [3,4,5]. These encouraging results show the path forward for the targeted delivery of NATs to other, non-hepatic tissues [6].…”

Section: Introductionmentioning

confidence: 99%

Site Selective Antibody-Oligonucleotide Conjugation via Microbial Transglutaminase

et al. 2019

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Nucleic Acid Therapeutics (NATs), including siRNAs and AntiSense Oligonucleotides (ASOs), have great potential to drug the undruggable genome. Targeting siRNAs and ASOs to specific cell types of interest has driven dramatic improvement in efficacy and reduction in toxicity. Indeed, conjugation of tris-GalNAc to siRNAs and ASOs has shown clinical efficacy in targeting diseases driven by liver hepatocytes. However, targeting non-hepatic diseases with oligonucleotide therapeutics has remained problematic for several reasons, including targeting specific cell types and endosomal escape. Monoclonal antibody (mAb) targeting of siRNAs and ASOs has the potential to deliver these drugs to a variety of specific cell and tissue types. However, most conjugation strategies rely on random chemical conjugation through lysine or cysteine residues resulting in conjugate heterogeneity and a distribution of Drug:Antibody Ratios (DAR). To produce homogeneous DAR-2 conjugates with two siRNAs per mAb, we developed a novel two-step conjugation procedure involving microbial transglutaminase (MTGase) tagging of the antibody C-terminus with an azide-functionalized linker peptide that can be subsequently conjugated to dibenzylcyclooctyne (DBCO) bearing oligonucleotides through azide-alkyne cycloaddition. Antibody-siRNA (and ASO) conjugates (ARCs) produced using this strategy are soluble, chemically defined targeted oligonucleotide therapeutics that have the potential to greatly increase the number of targetable cell types.

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“…These patients are also usually women, some with attacks during the luteal phase of their menstrual cycles. In addition to the acute attack symptoms described above, more than 50% of patients with frequent, recurrent attacks report chronic daily neurologic symptoms, and 35% had a diagnosis of neuropathy, outside of overt attack episodes (40,41). These patients typically have persistently elevated levels of ALA and PBG (42).…”

Section: Recurrent Acute Attacksmentioning

confidence: 99%

The acute hepatic porphyrias

Wang¹

2021

Transl Gastroenterol Hepatol

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Heme and porphyriasPorphyrias are inherited disorders of heme biosynthesis. Heme is an essential molecule that carries out a wide array of functions necessary for aerobic life. It is the prosthetic group for essential molecules including hemoglobin, mitochondrial cytochromes and cytochrome P-450s. Heme is synthesized through eight enzymatic steps, and mutations that lead to defective activity in heme synthesis enzymes result in the eight inherited porphyrias. As a result, there is abnormal accumulation of the intermediates that precede the enzyme deficiency. Symptoms for the porphyrias are due to the specific intermediates that accumulate.The acute hepatic porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP) and 5-aminolevulinic acid dehydratase deficiency porphyria (ALAD) all present with similar episodic acute neurovisceral attacks due to abnormal accumulation of the neurotoxic porphyrin precursors delta-aminolevulinic acid (ALA) and porphobilinogen (PBG).The process of heme synthesis is shown in Figure 1. The conversion of glycine and succinyl coenzyme A to ALA by the mitochondrial enzyme ALA synthase (ALAS) is the first and rate limiting step in heme synthesis. In subsequent reactions, two molecules of ALA combine to form the porphyrin precursor PBG. Four PBGs are linked and cyclized to form the first porphyrin of the pathway, uroporphyrinogen I. Subsequent reactions in the pathway produce porphyrin intermediates of progressively decreasing water solubility until the formation of heme (Figure 1). It's important to note that the first two intermediates, ALA and PBG are porphyrin precursors, not porphyrins. The excretion of the hydrophilic ALA, PBG, and uroporphyrin are entirely in urine, whereas coproporphyrin is in both urine and feces, and protoporphyrin only in feces.Though all cells in the human body synthesize heme, it is predominantly formed by erythroblasts in the bone

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GS-14-ENVISION, a phase 3 study to evaluate efficacy and safety of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1, in acute hepatic porphyria patients

Cited by 14 publications

References 0 publications

Lipid nanoparticle technology for therapeutic gene regulation in the liver

Lipid nanoparticle technology for therapeutic gene regulation in the liver

Site Selective Antibody-Oligonucleotide Conjugation via Microbial Transglutaminase

The acute hepatic porphyrias

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