Givosiran

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Givosiran
Mass / length primary structure 1711.0031 g mol −1
Identifier
External IDs

Further information on the active ingredient
Non-proprietary name Givosiran
other names ALN-AS1
Molecular formula C 524 H 694 F 16 N 173 O 316 P 43 S 6
Molar mass 16300.49 g mol −1
Mechanism of action Inhibition of aminolevulinic acid synthase

Givosiran is a drug approved as Givlaari (manufacturer Alnylam Pharmaceuticals ) for the treatment of acute intermittent porphyria (AIP). It is a representative of a comparatively new class of active ingredients whose effects are based on RNA interference (RNAi) or RNA silencing ( gene silencing ). In the life sciences, RNA interference has established itself as an experimental possibility for the temporary shutdown of genes (“ gene knockdown ”). This class of substances is referred to as RNAi therapeutics .

Givosiran is a double-stranded, small interfering ribonucleic acid ( small interfering RNA , siRNA).

application areas

Givosiran is indicated for the treatment of acute intermittent porphyria (AIP) in patients aged 12 years and over. Intermittent means phase , see also course of disease . AIP is a very rare disease (ultra rare disease) and a form of porphyria . These are mostly congenital disorders of heme biosynthesis, in which an enzyme defect leads to overproduction, accumulation and increased excretion of intermediate products of heme synthesis, the so-called porphyrins . A distinction is made between erythropoietic (affecting blood formation) and hepatic (affecting the liver) porphyrias.

Mechanism of action

Givosiran inhibits aminolevulinic acid synthase , which plays a relevant role in hemoglobin synthesis .

Chemical structure

Givosiran is a conjugate of an siRNA with a branched GalNAc connection. In the double-stranded siRNA, the base pairs that have been chemically modified by substitution are arranged as follows:

(3'-5 ') C = A = GAAA- G -A- G -U- G -U- C -U- C -AUCUUA- R 1
(5'-3') U = G = G- U - C- U -U- U -C- U -C- A -C- A -G- A -G- U -A- G - A = A = U

Legend:
C ≙ cytidine , A ≙ adenosine , G ≙ guanosine , U ≙ uridine

X ≙ 2'- O -methyl-X,
X ≙ 2'-deoxy-2'-fluoro-X

- ≙ phosphodiester bond
= ≙ phosphorothioate bond (phosphodiester bond in which the hydroxyl group is replaced by a thiol group )

R 1 =Partial structure of givosiran

The GalNAc conjugate technology ("Enhanced Stabilization Chemistry", ESC) enables subcutaneous administration and releases the siRNA in the liver.

Givosiran is used pharmaceutically as the sodium salt, a white to pale yellow, hygroscopic powder that dissolves easily in water.

Studies

  • EXPLORE: A prospective, multinational, observational study characterizing the natural history and clinical management of AHP patients with recurrent attacks (3 or more attacks / year) or who receive hemin or gonadotropin-releasing hormone analogue prophylaxis to prevent attacks.
  • OLE (open-label extension): A Study to Evaluate Long-term Safety and Clinical Activity of ALN-AS1 in Patient With Acute Intermittent Porphyria (AIP)

Admission

Givlaari was approved in the US in November 2019 and in the EU in March 2020.

This was preceded by the granting of Breakthrough Therapy status in the USA in May 2017 for the prophylaxis of acute relapses in patients with acute hepatic porphyria. This means an accelerated approval process that has also given the drug the "priority medicine" ( PRIME ) in the EU European Medicines Agency (EMA). Givosiran has orphan drug status in both the US and the EU .

In the EU, the EMA issued a positive recommendation for approval in January 2020, and a little later approval was granted by the European Commission .

Web links

  • Public Assessment Report (EPAR) of the European Medicines Agency (EMA) on: Givlaari

Individual evidence

  1. ^ A b World Health Organization: International Nonproprietary Names for Pharmaceutical Substances (INN) - Recommended International Nonproprietary Names: List 76 . In: WHO Drug Information . 30, No. 3, 2016.
  2. ↑ Thomas Kia (Ed.): AllEx - Alles fürs Examen . 1st edition. Georg Thieme Verlag KG, 2012, ISBN 978-3-13-146951-9 , p. 345 .
  3. ↑ M. Manoharan: GalNAc-siRNA with Enhanced Stabilization Chemistry , Alnylam Pharmaceuticals, March 2014.
  4. ^ Committee for Medicinal Products for Human Use (CHMP): Assessment report - Givlaari ( PDF ) . Ed .: European Medicines Agency. January 30, 2020.
  5. ↑ Initial Evidence of Clinical Activity Shown with Givosiran (ALN-AS1) in Acute Intermittent Porphyria Patients with Recurrent Attacks ( Memento of February 7, 2017 in the Internet Archive ), PM Alnylam of March 12, 2016, accessed on August 6, 2017
  6. ↑ A Study to Evaluate Long-term Safety and Clinical Activity of ALN-AS1 in Patient With Acute Intermittent Porphyria (AIP) .
  7. ↑ FDA approves first treatment for inherited rare disease. In: FDA. November 20, 2019, accessed March 16, 2020 .
  8. ↑ K. Graefe: First drug for rare hereditary diseases , Pharmazeutische Zeitung , March 10, 2020.
  9. ↑ FDA Grants Breakthrough Therapy Designation for Alnylam's Givosiran for the Prophylaxis of Attacks in Patients with Acute Hepatic Porphyria ( Memento August 7, 2017 in the Internet Archive ), PM Alnylam, May 31, 2017, accessed August 6, 2017.
  10. ↑ Alnylam Receives European Medicines Agency PRIME Designation for Accelerated Assessment of Givosiran, an Investigational RNAi Therapeutic for the Treatment of Acute Hepatic Porphyrias ( Memento August 7, 2017 in the Internet Archive ), PM Alnylam, March 1, 2017, accessed August 6 2017.
  11. ↑ Data Presented at ICPP Show Encouraging Results for Givosiran in AHP Patients ( Memento from August 7, 2017 in the Internet Archive ), RareDiseaseReport from June 26, 2017, accessed on August 6, 2017.
  12. ↑ Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 27-30 January 2020 EMA PM of January 31, 2020, accessed on January 31, 2020