Conestat alfa

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Conestat alfa
Conestat alfa
Mass / length primary structure 478 amino acids (67 kDa)
Identifier
Gene name (s) SERPING1
External IDs
Drug information
ATC code B06 AC04
Drug class C1 esterase inhibitor (C1INH)

Conestat alfa is a recombinant , human C1-esterase inhibitor (rhC1-INH), which for the treatment of acute attacks of hereditary angioedema (HAE) is used due to a C1-inhibitor deficiency in adults.

Conestat alfa (trade name Ruconest ) received European market approval in October 2010 and is currently approved in all 27 EU countries as well as Norway, Iceland and Liechtenstein.

application areas

Conestat alfa is used to treat acute hereditary angioedema attacks in adults who have a deficiency in working C1-INH. Adults up to 84 kg body weight receive an intravenous injection of 50 units per kilogram body weight (50 U / kg), adults with a body weight of more than 84 kg body weight receive an intravenous injection of 4,200 units.

Chemical and pharmaceutical information

Conestat alfa is produced by recombinant DNA technology and isolated from the milk of transgenic rabbits . This means that larger quantities of C1-INH can also be produced without any problems, depending on medical requirements. A product purity of over 99% can be guaranteed through a total of eight purification steps including nanofiltration. Recombinant production eliminates the risk of infection with pathogenic human pathogens (e.g. hepatitis A , hepatitis B , human parvoviruses , prions, etc.), which could be transmitted by preparations obtained from human blood plasma.

rhC1-INH has an identical amino acid sequence as human C1-INH. It consists of 478 amino acids and has a mass of 67 kDa . It has N-glycosylation in six places and O-glycosylation in at least seven places .

Mechanism of action

Conestat alfa increases the plasma concentration of functional C1-INH in a dose-dependent manner . The administration of 50 units per kilogram of body weight was able to restore normal levels of C1-INH in almost all HAE patients. C1-INH has an inhibitory effect on various proteases (target proteases) of the contact and complement systems . The effect of conestat alfa on the following target proteases was examined in vitro : activated C1s, kallikrein , factor XIIa and factor XIa . The inhibition kinetics were comparable to those of human C1-INH obtained from plasma.

Absorption and distribution in the body

There is no excretion, as conestat alfa in the liver by receptor-mediated endocytosis followed by complete hydrolytic degradation in the bloodstream eliminated is. The plasma half-life is approximately 2 hours.

Studies

In a randomized controlled study , all patients treated with 50 U / kg conestat alfa onset of symptom relief within four hours. The effectiveness of Ruconest in the treatment of acute angioedema attacks has been demonstrated by a significantly shorter time to onset of symptom relief and minimal symptoms, as well as few cases of treatment failure. The results of the open studies were in agreement with the above findings and support the repeated use of conestat alfa for the treatment of consecutive angioedema attacks. Relapses were not observed. Another study with a total of 75 patients confirms the significant effectiveness. No clinically relevant antibodies against C1-INH or host-related contaminants were detected.

unwanted effects

Headache was observed as a common side effect (in 1% to 10% of patients treated) in clinical studies.

Individual evidence

  1. ^ Gene Symbol Report
  2. ↑ a b c d e f g h Summary of the characteristics of Ruconest (in German) (PDF; 200 kB), European Medicines Agency (EMA)
  3. ↑ European Public Assessment Report (EPAR) European Medicines Agency (EMA)
  4. ↑ Pharming's Ruconest ™ For HAE Granted European Marketing Authorization (in English) ( Memento of the original from October 29, 2011 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. Sobi press release dated October 28, 2010 @1@ 2Template: Webachiv / IABot / www.sobi.com
  5. ^ Van Veen HA u. a .: Characterization of recombinant human C1 inhibitor secreted in milk of transgenic rabbits. In: Journal of Biotechnology . September 17, 2012, p. pii: S0168-1656 (12) 00638-4 , doi : 10.1016 / j.jbiotec.2012.09.005 . [Epub ahead of print]
  6. ↑ Smaal E u. a .: Recombinant human C1 inhibitor: production in the milk of transgenic rabbits. Poster presented at: XIX International Complement Workshop, Palermo 2002
  7. ↑ van Doorn MB and a .: A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema. In: J Allergy Clin Immunol . 2005, p. 876-883 , doi : 10.1016 / j.jaci.2005.05.019 .
  8. ↑ Zuraw B u. a .: Recombinant human C1 inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema . In: Journal of Allergy and Clinical Immunology . tape 126 , no. 4 , October 2010, p. 821–827.e14 , doi : 10.1016 / j.jaci.2010.07.021 .
  9. ↑ Bernstein J u. a .: Conestat alfa for the treatment of angioedema attacks . In: Therapeutics and Clinical Risk Management . July 2011, p. 265 , doi : 10.2147 / TCRM.S15544 , PMC 3132097 (free full text).
  10. ↑ Moldovan D u. a .: Efficacy and safety of recombinant human C1-inhibitor for the treatment of attacks of hereditary angioedema: European open-label extension study. In: Clinical Allergy . 2012, p. 929-935 , doi : 10.1111 / j.1365-2222.2012.03984.x .
  11. ↑ Statistically significant results for primary endpoint of time to beginning of symptom relief Pharming press release of November 7, 2012
  12. ↑ Hack CE u. a .: Immunogenicity assessment of recombinant human c1 inhibitor: an integrated analysis of clinical studies . In: BioDrugs . October 2012, p. 303-13 , doi : 10.2165 / 11634370-000000000-00000 , PMID 22928662 .

Trade names

  • Ruconest

Web links