Emicizumab

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Emicizumab
Mass / length primary structure 145.6 kDa
Identifier
External IDs
Drug information
ATC code B02 BX06
Drug class Monoclonal antibody resp. Bispecific antibody

Emicizumab (trade name Hemlibra ; manufacturer Roche ) is a humanized monoclonal antibody and drug for the treatment of hemophilia A ( with and without inhibitors ). Emicizumab is one of the so-called bispecific antibodies and binds to both coagulation factor IXa and factor X and mediates their activation. This is usually the function of coagulation factor VIII, which is absent in haemophilia A patients. Emicizumab thus mimics the coagulation factor and thus acts as a factor VIII mimetic .

Hemophilia A.

Haemophilia A, also known as hemophilia, is a hereditary disease in which blood clotting is impaired. After injuries, the blood does not coagulate or only coagulates slowly. Frequently there is also spontaneous bleeding, which occurs without visible wounds and can be life-threatening under certain circumstances. B. Cerebral haemorrhage. Hemophilia A occurs almost exclusively in men. Affected people are colloquially referred to as hemophiliacs. Hemophilia A is caused by a deficiency in factor VIII (antihemophilic globulin, FVIII). So far, the missing factor VIII has been "replaced" by intravenous injection 2–3 times a week - prophylactically or as required. The antibody emicizumab has recently become available for prophylactic long-term therapy in haemophilia A patients with or without inhibitors. It is injected subcutaneously with an interval of up to four weeks.

The main complication in hemophilia A therapy with FVIII is the formation of neutralizing antibodies against factor VIII, the so-called inhibitors. The inhibitors reduce the effect of the intravenously injected FVIII very strongly, so that the necessary increase in the factor level is not achieved and bleeding occurs again as a result. This complication is also known as inhibitor hemophilia . Worldwide studies show that about 30% of treated patients develop inhibitors. It is also discussed whether the inhibition takes place solely through the blocking of the FVIII activity or whether there is an increased clearance of the FVIII through the recognition of the inhibitors.

Clinical information

Application areas (indications)

Hemlibra is used as routine prophylaxis against bleeding events in patients with

  • Hemophilia A with factor VIII inhibitors
  • severe haemophilia A without factor VIII inhibitors.

It can be used in all age groups.

Type and duration of application

Emicizumab is administered subcutaneously once a week in adults, adolescents and children with haemophilia A - with or without inhibitors - as a prophylactic dose to prevent bleeding . After a four-week initial dose - depending on the preferences of the doctor and the patient - due to the constant plasma level, the interval with the maintenance dose of 1, 2 or 4 weeks can be selected, which best supports therapy adherence.

Mechanism of action (pharmacodynamics)

Emicizumab is a bispecific monoclonal antibody . One "arm" of emicizumab binds to factor IXa and the other "arm" to factor X. In doing so, emicizumab brings these two factors together in a manner similar to how activated factor VIII would. After the injection, factor Xa is released, which restores normal blood clotting. Emicizumab thus acts as a factor VIIIa mimetic.

Approval aspects

Chemical and pharmaceutical information

Emicizumab is a humanized, monoclonal modified immunoglobulin G4 (IgG4) antibody with a bispecific antibody structure-binding factor IXa and factor X. Emicizumab has an approximate molecular weight of 145.6 kDa and is produced by genetically modified mammalian cells (Chinese hamster ovary). Emicizumab has no structural relationship or sequence homology to FVIII and, as such, does not induce or potentiate the development of direct inhibitors to FVIII. Emicizumab also works in their presence.

history

Japanese researchers originally succeeded in developing the antibody emicizumab. In a small dose-finding study with 18 patients over 12 weeks, an effect of the treatment could also be shown in antibody-producing patients. Emicizumab was initially developed by the Japanese company Chugai Pharmaceutical Co., Ltd. developed. The Swiss pharmaceutical company Roche then further developed emicizumab together with its two subsidiaries Chugai and the American company Genentech and clinically tested it in the extensive HAVEN study program.

Admission overview

In November 2017, emicizumab was approved for use in hemophilia A patients with inhibitors by the US FDA . The approval was preceded by a classification as Breakthrough Therapy (English for 'breakthrough in therapy'), which significantly accelerated the approval process. The data submitted for the EU approval were also checked using the accelerated procedure . The approval for Europe was granted in February 2018. In October 2018, emicizumab was granted approval for the USA and March 2019 for Europe for patients of all ages with severe hemophilia A, even without inhibitors.

Admission Studies

The approval of Hemlibra is based on two Phase III studies in patients with haemophilia A and inhibitors aged ≥ 12 years (HAVEN 1) and <12 years (HAVEN 2). In the HAVEN 1 study, the annualized bleeding rate (ABR) in adult and adolescent haemophilia A patients with inhibitors (n = 109) was significantly reduced by 87% (p <0.0001) compared to the comparison group. In children under 12 years of age with haemophilia A and inhibitors against factor VIII (n = 60), the results in HAVEN 2 were even more favorable: In the currently evaluated observation period of around 40 weeks, 94.7% of the children under Hemlibra prophylaxis were not treated Bleeding recorded.

Web links

See also

Individual evidence

  1. ↑ New ATC (Deadline for objection to temporary code; September 1, 2017; Implementation in the ATC / DDD index: 2018) WHO Collaborating Center for Drug Statistics Methodology, accessed November 26, 2017
  2. ↑ a b c Hemlibra technical information. Retrieved March 26, 2019 .
  3. ↑ a b European Commission approves Roche's Hemlibra for people with severe haemophilia A without factor VIII inhibitors , PM Roche (Engl.) Of 14 March 2019. Retrieved on March 16, 2019
  4. ↑ a b European Commission grants approval extension for Roche substance , PM Roche (German / only for experts) from March 14, 2019, accessed on March 16, 2019
  5. ↑ a b c Emicizumab Prophylaxis in Hemophilia A with Inhibitors . In: New England Journal of Medicine . 377, No. 377, 2017, pp. 809-818. doi : 10.1056 / NEJMoa1703068 .
  6. ↑ Positive phase III results for Roche's emicizumab in haemophilia A published in The New England Journal of Medicine , PM Roche, July 10, 2017, accessed November 26, 2017
  7. ↑ Roche's Hemlibra significantly reduced bleeds in phase III study in haemophilia A , PM Roche, November 20, 2017, accessed on November 26, 2017
  8. ↑ FDA grants Priority Review to Roche's Hemlibra for people with haemophilia A without factor VIII inhibitors , Roche PM, June 5, 2018, accessed June 6, 2018
  9. ↑ Superiority of a Roche substance also compared to factor VIII preparations in the prophylaxis of haemophilia A , PM Roche (German / only for experts) from May 22, 2018, accessed on March 16, 2019
  10. ↑ a b c FDA grants accelerated review for Roche emicizumab for the treatment of hemophilia A with inhibitors , Roche PM dated August 24, 2017, accessed November 26, 2017
  11. ↑ Factor VIII mimetic function of Humanized Bispecific Antibody in Hemophilia A . In: New England Journal of Medicine . 374, No. 21, 2016, pp. 2044-53. doi : 10.1056 / NEJMoa1511769 . PMID 27223146 .
  12. ↑ Roche's Hemlibra significantly reduced bleeds in phase III study in haemophilia A , PM Roche, November 20, 2017, accessed on November 26, 2017
  13. ↑ Factor VIIIa-mimetic cofactor activity of a bispecific antibody to factors IX / IXa and X / Xa, emicizumab, depends on its ability to bridge the antigens . In: Thrombosis and Haemostasis . No. 7, 2017, pp. 1348–1357. doi : 10.1160 / TH17-01-0030 . PMID 28451690 .
  14. ↑ HIGHLIGHTS OF PRESCRIBING INFORMATION , Genentech website, accessed November 26, 2017
  15. ↑ Midori Shima, Hideji Hanabusa, Masashi Taki, Tadashi Matsushita, Tetsuji Sato et alia: Factor VIII – Mimetic Function of Humanized Bispecific Antibody in Hemophilia A N Engl J Med 2016; 374: 2044-2053May 26, 2016, doi : 10.1056 / NEJMoa1511769
  16. ↑ FDA approves new treatment to prevent bleeding in certain patients with hemophilia A , PM FDA dated November 16, 2017, accessed on November 26, 2017
  17. ↑ FDA approves Roche's Hemlibra (emicizumab-kxwh) for haemophilia A with inhibitors , PM Roche, November 16, 2017, accessed November 26, 2017
  18. ↑ Hemlibra® (emicizumab) receives EU approval for routine prophylaxis of haemophilia A with inhibitors against coagulation factor VIII , Roche PM dated February 28, 2018, accessed on February 28, 2018
  19. ↑ Young G: Oral Communication Session, OC 24.1 Hemorrhagic Disorders: Pediatric Aspects, July 10, 2017, ISTH 2017, doi: 10.1002 / rth2.12012
  20. ↑ Young G: Disorders of Coagulation or Fibrinolysis: Novel Therapies and Clinical Trials in Bleeding Disorders, Oral Communication Session 322, December 9, 2017, ASH 2017