Drotrecogin

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Drotrecogin
other names

Drotrecogin alfa, activated, human vitamin K-dependent protein C variant

Existing structure data : PDB  1AUT , PDB  1LQV , PDB  1PCU

Properties of human protein
Mass / length primary structure 461 amino acids , 52,071 Da
Identifier
External IDs
Enzyme classification
EC, category 3.4.21.69
Orthologue (human)
Entrez 5624
Ensemble ENSG00000115718
UniProt P04070
Refseq (mRNA) NM_000312.3
Refseq (protein) NP_000303.1
PubMed search 5624

Drotrecogin (trade name: Xigris ® , manufactured by Lilly ) is a recombinant form of the naturally in the blood plasma occurring activated protein C , rhAPC (recombinant activated protein C), from which it differs only by individual oligosaccharides in the carbohydrate portion of the molecule. Drotrecogin belongs to the serine proteases . It was intended in intensive care medicine in adults in the case of severe sepsis with multiple organ failure in addition to standard therapy and recommended under certain conditions. The drug was withdrawn from the market in 2011 after the initial positive benefit-risk assessment could not be maintained.

Drotrecogin is genetically engineered from an established human cell line . It differs from the naturally occurring activated protein C in plasma in that it has individual oligosaccharides bound to this protein.

Mechanism of action

The properties of drotrecogin are comparable to those of endogenous human activated protein C. The body's own protein has an antithrombotic effect by blocking factors Va and VIIIa. The active ingredient promotes fibrinolysis by inhibiting PAI-1 . Activated protein C also suppresses the release of the pro-inflammatory cytokines interleukin-1 and TNF-α .

Withdrawal from the market

Xigris was approved in 2002 under "Exceptional Circumstances". Such a procedure is used when the applicant can demonstrate that it is not possible to provide comprehensive data on the efficacy and safety of the drug, either due to the rarity of the disease, limited scientific knowledge in the field of application concerned or ethical considerations. The results of the PROWESS study (PROtein-C Worldwide Evaluation in Severe Sepsis) available at the time showed a significant improvement in 28-day all-cause mortality. The study on 1,690 patients with severe sepsis was then terminated prematurely, and approval was granted with the condition for an annual reassessment. In 2007, the EMA found that subsequent studies could not reproduce the efficacy found in the PROWESS pivot study and requested further clinical data.

A Cochrane analysis published in April 2011 showed that another five clinical, randomized studies showed no significant survival benefit for patients with sepsis from treatment with drotrecogin.

After the results of a study on the treatment of septic shock (PROWESS-SHOCK study) in 2011 failed to meet the endpoints, the positive risk-benefit ratio for drotrecogin was again questioned. The manufacturer Eli Lilly announced in October 2011 that it would cease sales of the drug worldwide.

Individual evidence

  1. ^ Marianne Abele-Horn: Antimicrobial Therapy. Decision support for the treatment and prophylaxis of infectious diseases. With the collaboration of Werner Heinz, Hartwig Klinker, Johann Schurz and August Stich, 2nd, revised and expanded edition. Peter Wiehl, Marburg 2009, ISBN 978-3-927219-14-4 , p. 37.
  2. ^ EPAR - Scientific Discussion. November 17, 2005 (PDF; 411 kB).
  3. ↑ EMA press release: Xigris (drotrecogin alfa (activated)) to be withdrawn due to lack of efficacy. PROWESS-SHOCK study shows no gain in 28-day survival of septic shock patients , from October 25, 2011.
  4. ^ AJ Marti-Carvajal, I. Sola, D. Lathyris, AF Cardona: Human recombinant activated protein C for severe sepsis. In: Cochrane reviews. 2011, doi: 10.1002 / 14651858.CD004388.pub4
  5. ↑ Eli Lilly's press release of October 25, 2001, available online as html ; last accessed on October 25, 2011.
  6. ↑ Rote-Hand-Brief from Eli Lilly on October 28, 2011. (PDF; 209 kB) Accessed on October 28, 2011 .

literature

  • V. Costa, JM Brophy: Drotrecogin alfa (activated) in severe sepsis: a systematic review and new cost-effectiveness analysis. In: BMC Anesthesiol. 7, 2007 Jun 25, p. 5. PMID 17592639 ; PMC 1929064 (free full text)