Skip to main content
SpringerLink
Log in

Givosiran: A Review in Acute Hepatic Porphyria

  • Adis Drug Evaluation
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Givosiran (Givlaari®) is an δ-aminolevulinic acid synthase 1 (ALAS1)-directed small interfering RNA (siRNA) approved for the treatment of acute hepatic porphyria (AHP). In the phase 3 ENVISION trial, givosiran significantly reduced the annualized rate of composite porphyria attacks (i.e. attacks requiring hospitalization, urgent healthcare visit or intravenous hemin administration at home) compared with placebo in patients with recurrent acute intermittent porphyria (the most common type of AHP) attacks. Givosiran also improved several other outcomes, including hemin use and pain (the cardinal symptom of AHP). While generally well tolerated with an acceptable safety profile, the drug may increase the risk of hepatic and kidney adverse events. Givosiran offers the convenience of once-monthly subcutaneous administration. Available evidence indicates that givosiran is an important newer therapeutic option for patients with AHP and severe recurrent attacks.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Wang B, Rudnick S, Cengia B, et al. Acute hepatic porphyrias: review and recent progress. Hepatol Commun. 2019;3(2):193–206.

    Article  Google Scholar 

  2. Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017;377(9):862–72.

    Article  CAS  Google Scholar 

  3. Kazamel M, Desnick RJ, Quigley JG. Porphyric neuropathy: pathophysiology, diagnosis, and updated management. Curr Neurol Neurosci Rep. 2020;20(12):56.

    Article  Google Scholar 

  4. Chen B, Solis-Villa C, Hakenberg J, et al. Acute intermittent porphyria: predicted pathogenicity of HMBS variants indicates extremely low penetrance of the autosomal dominant disease. Hum Mutat. 2016;37(11):1215–22.

    Article  CAS  Google Scholar 

  5. Bonkovsky HL, Maddukuri VC, Yazici C, et al. Acute porphyrias in the USA: features of 108 subjects from Porphyrias Consortium. Am J Med. 2014;127(12):1233–41.

    Article  Google Scholar 

  6. Bissell DM, Lai JC, Meister RK, et al. Role of delta-aminolevulinic acid in the symptoms of acute porphyria. Am J Med. 2015;128(3):313–7.

    Article  CAS  Google Scholar 

  7. Balwani M, Wang B, Anderson KE, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017;66(4):1314–22.

    Article  Google Scholar 

  8. Stein P, Badminton M, Barth J, et al. Best practice guidelines on clinical management of acute attacks of porphyria and their complications. Ann Clin Biochem. 2013;50(Pt 3):217–23.

    Article  Google Scholar 

  9. Gouya L, Ventura P, Balwani M, et al. EXPLORE: a prospective, multinational, natural history study of patients with acute hepatic porphyria with recurrent attacks. Hepatology. 2020;71(5):1546–58.

    Article  CAS  Google Scholar 

  10. Simon A, Pompilus F, Querbes W, et al. Patient perspective on acute intermittent porphyria with frequent attacks: a disease with intermittent and chronic manifestations. Patient. 2018;11(5):527–37.

    Article  Google Scholar 

  11. Puy H, Gouya L, Deybach JC. Porphyrias. Lancet. 2010;375(9718):924–37.

    Article  CAS  Google Scholar 

  12. Schmitt C, Lenglet H, Yu A, et al. Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver. J Intern Med. 2018;284(1):78–91.

    Article  CAS  Google Scholar 

  13. European Porphyria Network. Acute porphyria. 2020. https://porphyria.eu. Accessed 16 Mar 2021.

  14. de Paula Brandao PR, Titze-de-Almeida SS, Titze-de-Almeida R. Leading RNA interference therapeutics part 2: silencing delta-aminolevulinic acid synthase 1, with a focus on givosiran. Mol Diagn Ther. 2020;24(1):61–8.

    Article  Google Scholar 

  15. Debacker AJ, Voutila J, Catley M, et al. Delivery of oligonucleotides to the liver with GalNAc: from research to registered therapeutic drug. Mol Ther. 2020;28(8):1759–71.

    Article  CAS  Google Scholar 

  16. Gonzalez-Aseguinolaza G. Givosiran—running RNA interference to fight porphyria attacks. N Engl J Med. 2020;382(24):2366–7.

    Article  CAS  Google Scholar 

  17. European Medicines Agency. Givlaari: public assessment report. 2020. https://www.ema.europa.eu. Accessed 16 Mar 2021.

  18. Alnylam Pharmaceuticals. How GIVLAARI® (givosiran) works? 2020. https://www.givlaarihcp.com. Accessed 16 Mar 2021.

  19. Yasuda M, Gan L, Chen B, 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 USA. 2014;111(21):7777–82.

    Article  CAS  Google Scholar 

  20. Chan A, Liebow A, Yasuda M, et al. Preclinical development of a subcutaneous ALAS1 RNAi therapeutic for treatment of hepatic porphyrias using circulating RNA quantification. Mol Ther Nucleic Acids. 2015;4:e263.

    Article  CAS  Google Scholar 

  21. Sardh E, Harper P, Balwani M, et al. Phase 1 trial of an RNA interference therapy for acute intermittent porphyria. N Engl J Med. 2019;380(6):549–58.

    Article  Google Scholar 

  22. Alnylam Pharmaceuticals. Givlaari (givosiran) injection, for subcutaneous use: US prescribing information. 2019. https://www.fda.gov. Accessed 16 Mar 2021.

  23. European Medicines Agency. Givlaari 189 mg/mL solution for injection: summary of product characteristics. 2020. https://www.ema.europa.eu. Accessed 16 Mar 2021.

  24. Agarwal S, Simon AR, Goel V, et al. Pharmacokinetics and pharmacodynamics of the small interfering ribonucleic acid, givosiran, in patients with acute hepatic porphyria. Clin Pharmacol Ther. 2020;108(1):63–72.

    Article  CAS  Google Scholar 

  25. Agarwal S, Sardh E, Harper P, et al. A drug-drug interaction study investigating the effect of givosiran on activity of five drug metabolizing CYP450 enzymes in acute hepatic porphyria (AHP) patients [abstract no. PII-088]. Clin Pharm Ther. 2020;107(Suppl 1):S59.

  26. Stein P, Rees D, Anderson K, et al. A phase 1/2 open label extension study of givosiran, an investigational RNAi therapeutic, in patients with acute intermittent porphyria [abstract no. FRI310 plus poster]. J Hepatol. 2020;73(Suppl 1):S553–S4.

  27. Balwani M, Sardh E, Ventura P, et al. Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. N Engl J Med. 2020;382(24):2289–301.

    Article  CAS  Google Scholar 

  28. Sardh E, Balwani M, Rees D, et al. Twelve-month interim analysis of efficacy and safety of givosiran, and investigational RNAi therapeutic for acute hepatic porphyria, in the envision open label extension. 2020. https://www.alnylam.com. Accessed 23 Dec 2020.

  29. Bonkovsky HL, et al. Clinical outcomes in patients with acute hepatic porphyria treated with givosiran who stopped hemin prophylaxis at study entry: a post hoc analysis of data from the phase 3 ENVISION study through month 12 [abstract no. P2094 (S1154)]. In: American College of Gastroenterology 2020 Annual Scientific Meeting. 2020.

  30. Kauppinen R, Kuo HC, Oh J, et al. Reduction in pain during and between attacks in patients with acute hepatic porphyria treated with givosiran: a posthoc analysis of the phase 3 ENVISION study [abstract no. O4015]. In: 6th Congress of the European Academy of Neurology. 2020.

  31. Kuter D, Keel S, Parker C, et al. Eighteen-month interim analysis of efficacy and safety of givosiran, an RNAi therapeutic for acute hepatic porphyria, in the envision open label extension [abstract no. 222]. In: 62nd American Society of Hematology Annual Meeting and Exposition. 2020.

  32. Thapar M, Rudnick S, Bonkovsky HL. Givosiran, a novel treatment for acute hepatic porphyrias. Expert Rev Precis Med Drug Dev. 2021;6(1):9–19.

    Article  Google Scholar 

  33. Bustad HJ, Kallio JP, Vorland M, et al. Acute intermittent porphyria: an overview of therapy developments and future perspectives focusing on stabilisation of HMBS and proteostasis regulators. Int J Mol Sci. 2021;22(2).

  34. Ventura P, Corradini E, Di Pierro E, et al. Hyperhomocysteinemia in patients with acute porphyrias: a potentially dangerous metabolic crossroad? Eur J Intern Med. 2020;79:101–7.

    Article  CAS  Google Scholar 

  35. American Porphyria Foundation. Treatment options. 2020. https://porphyriafoundation.org. Accessed 16 Mar 2021.

  36. National Organization for Rare Disorders. Acute intermittent porphyria. 2019. https://rarediseases.org. Accessed 16 Mar 2021.

  37. Honor A, Rudnick SR, Bonkovsky HL. Givosiran to treat acute porphyria. Drugs Today. 2021;57(1):47–59.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

During the peer review process the manufacturer of givosiran was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

Author information

Authors and Affiliations

  1. Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New Zealand

    Yahiya Y. Syed

Authors
  1. Yahiya Y. Syed
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yahiya Y. Syed.

Ethics declarations

Funding

The preparation of this review was not supported by any external funding.

Authorship and Conflict of interest

Yahiya Y. Syed is a salaried employee of Adis International Ltd/Springer Nature, and declares no relevant conflicts of interest. All authors contributed to the review and are responsible for the article content.

Ethics approval, Consent to participate, Consent to publish, Availability of data and material, Code availability

Not applicable.

Additional information

The manuscript was reviewed by: P. Berraondo, Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain; H. L. Bonkovsky, Wake Forest University School of Medicine/NC Baptist Hospital, Winston-Salem, NC, USA; E. I. Minder, Municipal Hospital Triemli, Institute of Laboratory Medicine, Zurich, Switzerland; E. Sardh, Department of Endocrinology and Centre for Inherited Metabolic Disease, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; A. K. Singal, Avera McKennan University Hospital Transplant Institute, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, USA.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file2 (MP4 8696 kb)

Supplementary file3 (PPTX 1099 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Syed, Y.Y. Givosiran: A Review in Acute Hepatic Porphyria. Drugs 81, 841–848 (2021). https://doi.org/10.1007/s40265-021-01511-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-021-01511-3

Search

Navigation