OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Givosiran – Givlaari®

DRUG CLASS

Genetic Disorder Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO	MOLECULAR FORMULA	STRUCTURE
Givosiran	1639325-43-1	C78-H139-N11-O30

ANNOTATED BIBLIOGRAPHY

References updated: 27 February 2020

Abbreviations: ALA, aminolevulinic acid; ALAS, aminolevulinic acid synthetase; PBG, porphobilinogen; siRNA, small interfering RNA.

• Yasuda M, Gan L, Chen B, Kadirvel S, Yu C, Phillips JD, New MI, et al. RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice. Proc Natl Acad Sci U S A. 2014;111:7777–82. [PMC free article: PMC4040563] [PubMed: 24821812]

  (Screening of multiple small interfering RNAs [siRNA] for activity in suppressing aminolevulinic acid synthetase [ALAS] in cell culture identified several with potent activity which were formulated into lipid nanoparticles and shown to lower ALAS activity and decrease serum levels of aminolevulinic acid (ALA) and porphobilinogen (PBG) in mice and to protect against acute attacks of porphyria in mouse models of the disease).
• Bonkovsky HL, Maddukuri VC, Yazici C, Anderson KE, Bissell DM, Bloomer JR, Phillips JD, et al. Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. Am J Med. 2014;127:1233–41. [PMC free article: PMC4563803] [PubMed: 25016127]

  (Among 108 subjects with acute porphyria enrolled in a U.S. prospective clinical cohort study, 90 had acute intermittent porphyria, 9 hereditary coproporphyria and 9 variegate porphyria; most were women [81%], non-Hispanic and white, and delay in diagnosis after onset of symptoms was common [mean delay=15 years]).
• Bissell DM, Lai JC, Meister RK, Blanc PD. Role of delta-aminolevulinic acid in the symptoms of acute porphyria. Am J Med. 2015;128:313–7. [PMC free article: PMC4339446] [PubMed: 25446301]

  (32 year old woman using several Ayurvedic medications developed recurrent abdominal pain and had elevations in serum ALA but not PBG, subsequent testing demonstrating lead poisoning and symptoms improving with hemin infusions but ultimately resolving after chelation of excess lead; these results suggest that ALA rather than PBG is the cause of neurologic and visceral symptoms in acute hepatic porphyria).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, no cases were attributed to siRNA therapies or medications for porphyria).
• Sardh E, Harper P, Balwani M, Stein P, Rees D, Bissell DM, Desnick R, et al. Phase 1 Trial of an RNA interference therapy for acute intermittent porphyria. N Engl J Med. 2019;380:549–58. [PubMed: 30726693]

  (A phase 1 trial of ascending, single doses of givosiran followed by studies of the two optimal doses vs placebo either once monthly or quarterly in 40 patients with acute intermittent porphyria demonstrated rapid and marked declines in urinary ALA and PBG levels and decreases in annualized acute attack rates of 75-90%; there were no liver related severe adverse events and “no clinically significant changes in laboratory measures”).
• Setten RL, Rossi JJ, Han SP. The current state and future directions of RNAi-based therapeutics. Nat Rev Drug Discov. 2019;18:421–46. [PubMed: 30846871]

  (Extensive review of gene silencing using RNA interference pathways and the potential of RNAi therapeutics which have promise in many genetic and acquired diseases including transthyretin amyloidosis [transthyretin], HIV infection [CCR5], HBV [HBV mRNA], alpha-1-antitrypsin deficiency [zz A1AT], hypercholesterolemia [PCSK9]).
• Chen B, Whatley S, Badminton M, Aarsand AK, Anderson KE, Bissell DM, Bonkovsky HL, et al. International Porphyria Molecular Diagnostic Collaborative. an evidence-based database of verified pathogenic and benign variants for the porphyrias. Genet Med. 2019;21:2605–13. [PMC free article: PMC7229570] [PubMed: 31073229]

  (Announcement of a collaborative international effort to define phenotypes and genotypes of the 4 acute hepatic porphyrias, 3 being autosomal dominant [acute intermittent porphyria, hereditary coproporphyria and variegate porphyria] and 1 autosomal recessive, the genetic variation and clinical expression of each being highly variable).
• Gouya L, Ventura P, Balwani M, Bissell DM, Rees DC, Stölzel U, Phillips JD, et al. EXPLORE: A prospective, multinational, natural history study of patients with acute hepatic porphyria with recurrent attacks. Hepatology. 2019 Sep 12; [Epub ahead of print] [PMC free article: PMC7255459] [PubMed: 31512765]

  (Among 112 patients with acute hepatic porphyria and recurrent attacks followed for at least 6 months, 98 [88%] had a total of 483 attacks, 371 [77%] requiring hemin therapy and, compared to baseline, urinary levels of ALA, PBG and ALAS mRNA increased during acute attacks).
• Naik H, Overbey JR, Montgomery GH, Winkel G, Balwani M, Anderson KE, Bissell DM, et al. Evaluating the patient-reported outcomes measurement information system scales in acute intermittent porphyria. Genet Med. 2020;22:590–7. [PMC free article: PMC7060090] [PubMed: 31690837]

  (Analysis of symptom scores in a cohort of 259 patients [75% with symptoms] with acute intermittent porphyria).
• Scott LJ. Givosiran: first approval. Drugs. 2020;80:335–9. [PubMed: 32034693]

  (Review of the mechanism of action, history of development, clinical efficacy and safety of givosiran shortly after its approval for use in acute hepatic porphyria in the US and Europe mentions that in the registration trial, the median composite annualized attack rate at 6 months was decreased by 90% and adverse events in treated vs control subjects included nausea [27% vs 11%], injection site reactions [25% vs 0%], rash [17% vs 4%], creatinine increase [15% vs 4%], aminotransferase elevations [13% vs 2%] and fatigue [10% vs 4%]).
• FDA. Givosiran. Multi-Disciplinary Review and Evaluation. 2019. Available at: https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2019/212194Orig1s000MultidisciplineR.pdf.

  (The FDA clinical review of givosiran for efficacy and safety reported ALT elevations above 3 times ULN arose in 6 of 48 [13%] givosiran treated vs 1 of 46 [2%] controls, one patient discontinuing therapy because of enzyme elevations after 3 doses [ALT 172 U/L, AST 95 U/L] which reportedly resolved rapidly upon stopping).