Givosiran

Givosiran, sold under the brand name Givlaari, is a medication used for the treatment of adults with acute hepatic porphyria.^[3][6][7][8] Givosiran is a small interfering RNA (siRNA) directed towards delta-aminolevulinate synthase 1 (ALAS1),^[9] an important enzyme in the production of heme.

Givosiran

Clinical data
Trade names	Givlaari
AHFS/Drugs.com	Monograph
License data	US DailyMed: Givosiran
Pregnancy category	AU: B3[1]
Routes of administration	Subcutaneous
ATC code	A16AX16 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[1] CA: ℞-only[2] US: ℞-only[3] EU: Rx-only[4][5]
Identifiers
IUPAC name N-[1,3-bis[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]-2-[[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]methyl]propan-2-yl]-12-[(2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl]-12-oxododecanamide
CAS Number	1639325-43-1
PubChem CID	119058042
DrugBank	DB15066
UNII	ROV204583W
KEGG	D11702
Chemical and physical data
Formula	C524H694F16N173O316P43S6
Molar mass	16300.42 g·mol−1
3D model (JSmol)	Interactive image
SMILES C[C@@H]1C[C@H](CN1C(=O)CCCCCCCCCCC(=O)NC(COCCC(=O)NCCCNC(=O)CCCCO[C@H]2[C@@H]([C@H]([C@H]([C@H](O2)CO)O)O)NC(=O)C)(COCCC(=O)NCCCNC(=O)CCCCO[C@H]3[C@@H]([C@H]([C@H]([C@H](O3)CO)O)O)NC(=O)C)COCCC(=O)NCCCNC(=O)CCCCO[C@H]4[C@@H]([C@H]([C@H]([C@H](O4)CO)O)O)NC(=O)C)O
InChI InChI=1S/C78H139N11O30/c1-50-42-54(96)43-89(50)65(104)26-12-10-8-6-5-7-9-11-25-64(103)88-78(47-111-39-27-61(100)82-33-19-30-79-58(97)22-13-16-36-114-75-66(85-51(2)93)72(108)69(105)55(44-90)117-75,48-112-40-28-62(101)83-34-20-31-80-59(98)23-14-17-37-115-76-67(86-52(3)94)73(109)70(106)56(45-91)118-76)49-113-41-29-63(102)84-35-21-32-81-60(99)24-15-18-38-116-77-68(87-53(4)95)74(110)71(107)57(46-92)119-77/h50,54-57,66-77,90-92,96,105-110H,5-49H2,1-4H3,(H,79,97)(H,80,98)(H,81,99)(H,82,100)(H,83,101)(H,84,102)(H,85,93)(H,86,94)(H,87,95)(H,88,103)/t50-,54-,55-,56-,57-,66-,67-,68-,69+,70+,71+,72-,73-,74-,75-,76-,77-/m1/s1 Key:RUPXJRIDSUCQAN-PQNNUJSWSA-N

The most common side effects include nausea and injection site reactions.^[8]

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[10]

Medical uses

Givosiran is indicated for the treatment of adults with acute hepatic porphyria, a genetic disorder resulting in the buildup of toxic porphyrin molecules which are formed during the production of heme (which helps bind oxygen in the blood).^[3][7]

History

In November 2019, givosiran was approved in the United States for the treatment of adults with acute hepatic porphyria (AHP).^[7][11]

Efficacy was evaluated in ENVISION (NCT03338816), a randomized, double‑blind, placebo‑controlled, multinational trial enrolling 94 participants with acute hepatic porphyria.^[8] Participants were randomized (1:1) to receive once monthly subcutaneous injections of givosiran 2.5 mg/kg or placebo during a six‑month double‑blind period.^[8] The performance of givosiran was measured by the rate of porphyria attacks that required hospitalizations, urgent health care visits or intravenous infusion of hemin at home.^[7] Participants who received givosiran experienced 70% fewer porphyria attacks compared to patients receiving a placebo.^[7]

The U.S. Food and Drug Administration (FDA) granted the application for givosiran breakthrough therapy designation, priority review designation, and orphan drug designation.^[7][8] The FDA granted the approval of Givlaari to Alnylam Pharmaceuticals.^[7]

References

1. "Givlaari APMDS". Therapeutic Goods Administration (TGA). 15 December 2023. Archived from the original on 2 January 2024. Retrieved 7 March 2024.
2. "Summary Basis of Decision (SBD) for Givlaari". Health Canada. 23 October 2014. Archived from the original on 30 May 2022. Retrieved 29 May 2022.
3. "Givlaari- givosiran sodium injection, solution". DailyMed. Archived from the original on 8 February 2022. Retrieved 7 February 2022.
4. "Givlaari EPAR". European Medicines Agency. 29 January 2020. Archived from the original on 12 November 2021. Retrieved 4 March 2023.
5. "Givlaari Product information". Union Register of medicinal products. Archived from the original on 5 March 2023. Retrieved 3 March 2023.
6. Syed YY (May 2021). "Givosiran: A Review in Acute Hepatic Porphyria". Drugs. 81 (7): 841–848. doi:10.1007/s40265-021-01511-3. PMID 33871817. S2CID 233292573.
7. "FDA approves first treatment for inherited rare disease". U.S. Food and Drug Administration (FDA) (Press release). 20 November 2019. Archived from the original on 21 November 2019. Retrieved 20 November 2019. This article incorporates text from this source, which is in the public domain.
8. "FDA approves givosiran for acute hepatic porphyria". U.S. Food and Drug Administration (FDA). 20 November 2019. Archived from the original on 21 November 2019. Retrieved 20 November 2019. This article incorporates text from this source, which is in the public domain.
9. Balwani M, Sardh E, et al.; ENVISION Investigators. Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria. N Engl J Med. 2020 Jun 11;382(24):2289-2301. doi: 10.1056/NEJMoa1913147. PMID 32521132.
10. "New Drug Therapy Approvals 2019". U.S. Food and Drug Administration. 31 December 2019. Archived from the original on 18 January 2024. Retrieved 15 September 2020.
11. "Drug Trials Snapshots: Givlaari". U.S. Food and Drug Administration (FDA). 20 November 2019. Archived from the original on 24 January 2020. Retrieved 24 January 2020. This article incorporates text from this source, which is in the public domain.

External links

• Clinical trial number NCT03338816 for "ENVISION: A Study to Evaluate the Efficacy and Safety of Givosiran (ALN-AS1) in Patients With Acute Hepatic Porphyrias (AHP)" at ClinicalTrials.gov