• Sign Up

Use coupon code EXTENDEDHOLIDAY2020 at checkout for 20% off

Emicizumab


Emicizumab

Article Author:
Kate Parisi
Article Editor:
Abhishek Kumar
Updated:
6/2/2020 1:35:54 PM
For CME on this topic:
Emicizumab CME
PubMed Link:
Emicizumab

Indications

Inherited and acquired hemophilia A (HA) causes significant morbidity resulting from deficiency of factor VIII (FVIII), which is critical to normal coagulation. The management of patients with HA is complex, and requires replacement of FVIII for bleeding prophylaxis and to treat acute bleeding episodes.[1] The short plasma half-life of FVIII necessitates frequent dosing. Hemophilia A patients receiving FVIII replacement endure intravenous FVIII administration at least three times weekly. Acquired hemophilia A (AHA), resulting from autoantibodies against endogenous FVIII, can also be challenging to manage. In addition to supplementing FVIII levels, therapies for Acquired Hemophilia A incorporate immune suppression to eradicate inhibitors.[2][3] To obtain long-term results, patients with hemophilia A must have a comprehensive approach arranged with a multidisciplinary group of specialists.[1] Emicizumab was created to circumvent challenges associated with frequent intravenous administration of FVIII and to offer a standardized treatment option for Hemophilia A patients with and without inhibitors.[4]

Mechanism of Action

The drug emicizumab is a bispecific monoclonal antibody that restores the function of missing activated FVIII by bridging FIXa and FX, basically mimicking activated Factor VIIIa independently of Factor VIII levels. Thereby promotes effective hemostasis in patients with hemophilia A.[5][6] Emicizumab is manufactured by inserting specific genetic material into a Chinese hamster ovary (CHO) cell line, which then multiplies and produces the target antibody. The antibody is subsequently separated from the cellular component and tested for purity and potency. Neither human plasma nor blood products are used in the manufacturing of emicizumab.[7] 

Administration

In many countries, subcutaneous emicizumab has been cleared to be used in the prophylaxis of bleeding episodes in individuals diagnosed with hemophilia A, regardless of FVIII inhibitor status.[8] In phase III clinical trials, emicizumab prophylaxis significantly reduced annualized bleeding rates in adolescents and adults with hemophilia A including those with FVIII inhibitors. It also prevented or significantly decreased bleeding in children in the same medical situation.[9][10][11] Because of the drug's convenient subcutaneous route of administration and relatively infrequent dosing ability (dose every 1, 2, or 4 weeks), emicizumab provides an effective alternative to conventional FVIII replacement products, which tend to be more frequent.[12][13][14] The drug has a longer elimination half-life when compared to other current treatments, and on average stays in the body approximately 4 to 5 weeks.[15]

Adverse Effects

The most commonly reported adverse reactions after emicizumab administration were injection site reactions, headache, and arthralgia.[16] A less common adverse reaction, which occurred in less than 1% of patients taking emicizumab, including rhabdomyolysis. Although significantly less frequent, unprovoked or traumatic bleeding may occur in patients taking emicizumab necessitating treatment with other hemostatic agents such as recombinant FVIIa (rFVIIa) and activated prothrombin complex concentrates (aPCC). It is especially important for treating clinicians to note whether the emicizumab effect is present to anticipate consequences of concurrent administration of hemostatic agents (see Contraindications) and to understand the impact on coagulation assays (see Monitoring).

Similar to FVIII replacement therapy, emicizumab has the potential for immunogenicity. Per the emicizumab prescribing information, 3.5% of patients in the HAVEN clinical trials tested positive for anti-emicizumab antibodies, though less than 1% of patients developed antibodies with neutralizing potential.[9]

Contraindications

A boxed warning cautions that thrombotic microangiopathy (TMA) and other thrombotic complications have been reported with concurrent administration of aPCC greater than 100 U/kg within 24 hours in patients taking emicizumab.[17] Per the important safety information emicizumab, TMA occurred in 8.1% of the patients, as well as thrombotic events in 5.4% of patients who received at least one dose of aPCC. Patients with TMA often would present with either: microangiopathic hemolytic anemia, low platelet levels, and/or acute kidney injury, without severe ADAMTS13 deficiency. Other thrombotic events included: thrombotic microangiopathy, cavernous sinus thrombosis, as well as thrombophlebitis.[16] 

In emergent cases of bleeding, when the benefit of aPCC exceeds the risk of inducing a pro-coagulable state, clinicians should monitor patients for thrombotic microangiopathy and thromboembolism and discontinue aPCC if symptoms occur. Using both rFVIIa and emicizumab theoretically should have an increased risk for thrombotic complications. However, several pharmaceutical manufacturers have analyzed the data from the HAVEN study, which concluded that rFVIIa use in the context of emicizumab prophylaxis did not change the rFVIIa safety profile as described in the product information.[18] 

Monitoring

Measuring plasma emicizumab level is not required for therapy. However, in specific medical incidences, such as confirmation of compliance, a drug level may be helpful. Monitoring can also be beneficial in situations of breakthrough bleeding, situations that require an on-demand coagulation factor, or antibody monitoring.[19] At present, the only accurate method of detection is a sandwich enzyme-linked immunosorbent (ELISA) assay that employs an anti-emicizumab antibody. The test is highly precise and reproducible in current trials and literature. 

A noteworthy consideration while treating patients on emicizumab is the drug’s effect on laboratory testing.[19] Coagulation tests based on the intrinsic pathway (i.e., aPTT) measure total clotting time, which includes the time needed for activation of FVIII to FVIIIa by thrombin. Emicizumab, which mimics FVIIIa cofactor activity by bridging FIXa and FX, obviates thrombin activation and results in overly shortened clotting times. Adamkewicz et al. showed that emicizumab has a strong interference effect on numerous assays that are aPTT based. The drug also will affect assays for FVIII, protein C and S activity. There is a weak disturbance on tests for prothrombin time as well as derived fibrinogen assays. Lupus anticoagulant testing in patients taking emicizumab poses a significant problem because it utilizes both an aPTT based assay, which may result in false-negative results, and a DRVVT based assay, which may result in false-positive results.[20] [Level 1]

Clinicians need to be aware of assay interference when ordering FVIII activity, or inhibitor titers in a patient taking emicizumab[21] [Level 5] Clotting based assays may overestimate FVIII activity and place patients at risk for bleeding. Bethesda assays show a significant impact from emicizumab and may result in undetectable anti-FVIII titer in patients with clinically significant inhibitors.[22] Ultimately, clinicians must discuss testing modalities with laboratory directors and request FVIII activity and FVIII inhibitor testing via chromogenic assays with a bovine reagent that is insensitive to emicizumab.[23] Lastly, it is imperative clinicians understand that due to its extended half-life, emicizumab may affect coagulation assays for up to 6 months after it the last administration.

Toxicity

Using previous trials like HAVEN, an efficacious range for emicizumab is 30 to 70 microgram/milliliter.[19] Per the emicizumab prescribing information, females of childbearing age should consider the use of contraception while receiving emicizumab. There is no current data for fetal safety in a pregnant woman, nor the effect on reproduction ability. In pregnancy, emicizumab is only recommended for the potential benefit of the mother, and the risks to the fetus are less. Currently, there is no information regarding the presence of emicizumab in human milk, effects on breastfed children, or the effects on milk production.

Enhancing Healthcare Team Outcomes

Researchers performed the HAVEN 2 trial on children with hemophilia with inhibitor development. Typically they develop inhibitor within 50 days of Factor VIII therapy. Because children need high-volume infusions, they will most likely need a central venous access device (CVAD), which can lead to increased infection/thrombosis.[9] The study revealed that once a week, subcutaneous injection decreased annual bleeding rates in children with hemophilia A with Factor VIII inhibitor by 99%rs.[9] [Level 1]

An open study on giving emicizumab to children with hemophilia A and no inhibitors was also conducted. Results supported a decrease in bleeding events throughout the year. It also supported decreased worry associated with possible bleed causes, including activity levels. Subjects reported increased physical activity during the trial. Patients received either 2-week dosing or 4-week dosing. Both of which showed an appropriate decrease in bleeding and disruption in daily living.[10] [Level 2] 

With regards to adults with hemophilia A and no inhibitors, dosing of once every four weeks is adequate for bleeding control as well as being well tolerated by patients. [Level 3] This is a clinical trial and is still ongoing.[24]

Overall, emicizumab is generally well-tolerated and has versatile dosing options, including once every 1, 2, or 4 weeks. This novel drug allows an alternative to conventional Factor VIII replacement products in patients with hemophilia A, with or without the presence of inhibitors.[12] [Level 5]


References

[1] Bauer KA, Current challenges in the management of hemophilia. The American journal of managed care. 2015 Mar;     [PubMed PMID: 26168206]
[2] Kruse-Jarres R,Kempton CL,Baudo F,Collins PW,Knoebl P,Leissinger CA,Tiede A,Kessler CM, Acquired hemophilia A: Updated review of evidence and treatment guidance. American journal of hematology. 2017 Jul;     [PubMed PMID: 28470674]
[3] Haya S, Prophylactic treatment in hemophilic patients with inhibitors. Blood coagulation     [PubMed PMID: 31517711]
[4] Oldenburg J,Mahlangu JN,Bujan W,Trask P,Callaghan MU,Young G,Asikanius E,Peyvandi F,Santagostino E,Kruse-Jarres R,Negrier C,Kessler C,Xu J,Windyga J,Shima M,von Mackensen S, The effect of emicizumab prophylaxis on health-related outcomes in persons with haemophilia A with inhibitors: HAVEN 1 Study. Haemophilia : the official journal of the World Federation of Hemophilia. 2019 Jan;     [PubMed PMID: 30427582]
[5] Emicizumab 2012;     [PubMed PMID: 31643959]
[6] Barg AA,Avishai E,Budnik I,Levy-Mendelovich S,Barazani TB,Kenet G,Livnat T, Emicizumab prophylaxis among infants and toddlers with severe hemophilia A and inhibitors-a single-center cohort. Pediatric blood     [PubMed PMID: 31348595]
[7] Lenting PJ,Denis CV,Christophe OD, Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: how does it actually compare to factor VIII? Blood. 2017 Dec 7;     [PubMed PMID: 29042366]
[8] Shima M, [Congenital hemophilia: a new treatment paradigm]. [Rinsho ketsueki] The Japanese journal of clinical hematology. 2019;     [PubMed PMID: 31281158]
[9] Young G,Liesner R,Chang T,Sidonio R,Oldenburg J,Jiménez-Yuste V,Mahlangu J,Kruse-Jarres R,Wang M,Uguen M,Doral MY,Wright LY,Schmitt C,Levy GG,Shima M,Mancuso ME, A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood. 2019 Dec 12;     [PubMed PMID: 31697801]
[10] Shima M,Nogami K,Nagami S,Yoshida S,Yoneyama K,Ishiguro A,Suzuki T,Taki M, A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors. Haemophilia : the official journal of the World Federation of Hemophilia. 2019 Nov;     [PubMed PMID: 31515851]
[11] Franchini M,Marano G,Pati I,Candura F,Profili S,Veropalumbo E,Masiello F,Catalano L,Piccinini V,Vaglio S,Pupella S,Liumbruno GM, Emicizumab for the treatment of haemophilia A: a narrative review. Blood transfusion = Trasfusione del sangue. 2019 May;     [PubMed PMID: 31246563]
[12] Blair HA, Emicizumab: A Review in Haemophilia A. Drugs. 2019 Oct;     [PubMed PMID: 31542880]
[13] Al-Banaa K,Alhillan A,Hawa F,Mahmood R,Zaki A,El Abdallah M,Zimmerman J,Musa F, Emicizumab Use in Treatment of Acquired Hemophilia A: A Case Report. The American journal of case reports. 2019 Jul 18;     [PubMed PMID: 31318850]
[14] Rodriguez-Merchan EC,Valentino LA, Emicizumab: Review of the literature and critical appraisal. Haemophilia : the official journal of the World Federation of Hemophilia. 2019 Jan;     [PubMed PMID: 30431213]
[15] Yoneyama K,Schmitt C,Kotani N,Levy GG,Kasai R,Iida S,Shima M,Kawanishi T, A Pharmacometric Approach to Substitute for a Conventional Dose-Finding Study in Rare Diseases: Example of Phase III Dose Selection for Emicizumab in Hemophilia A. Clinical pharmacokinetics. 2018 Sep;     [PubMed PMID: 29214439]
[16] Emicizumab for haemophilia A. Australian prescriber. 2019 Feb;     [PubMed PMID: 30765913]
[17] Castaman G,Santoro C,Coppola A,Mancuso ME,Santoro RC,Bernardini S,Pugliese FR,Lubrano R,Golato M,Tripodi A,Rocino A,Santagostino E, Emergency management in patients with haemophilia A and inhibitors on prophylaxis with emicizumab: AICE practical guidance in collaboration with SIBioC, SIMEU, SIMEUP, SIPMeL and SISET. Blood transfusion = Trasfusione del sangue. 2019 Oct 18;     [PubMed PMID: 31657709]
[18] Levy GG,Asikanius E,Kuebler P,Benchikh El Fegoun S,Esbjerg S,Seremetis S, Safety analysis of rFVIIa with emicizumab dosing in congenital hemophilia A with inhibitors: Experience from the HAVEN clinical program. Journal of thrombosis and haemostasis : JTH. 2019 Sep;     [PubMed PMID: 31124272]
[19] Müller J,Pekrul I,Pötzsch B,Berning B,Oldenburg J,Spannagl M, Laboratory Monitoring in Emicizumab-Treated Persons with Hemophilia A. Thrombosis and haemostasis. 2019 Sep;     [PubMed PMID: 31203578]
[20] Adamkewicz JI,Kiialainen A,Paz-Priel I, Effects and interferences of emicizumab, a humanized bispecific antibody mimicking activated factor VIII cofactor function, on lupus anticoagulant assays. International journal of laboratory hematology. 2019 Oct 31;     [PubMed PMID: 31670901]
[21] Jenkins PV,Bowyer A,Burgess C,Gray E,Kitchen S,Murphy P,Platton S,Riddell A,Chowdary P,Lester W, Laboratory coagulation tests and emicizumab treatment A United Kingdom Haemophilia Centre Doctors' Organisation guideline. Haemophilia : the official journal of the World Federation of Hemophilia. 2019 Dec 20;     [PubMed PMID: 31859415]
[22] Nogami K,Soeda T,Matsumoto T,Kawabe Y,Kitazawa T,Shima M, Routine measurements of factor VIII activity and inhibitor titer in the presence of emicizumab utilizing anti-idiotype monoclonal antibodies. Journal of thrombosis and haemostasis : JTH. 2018 Jul;     [PubMed PMID: 29734520]
[23] Adamkewicz JI,Chen DC,Paz-Priel I, Effects and Interferences of Emicizumab, a Humanised Bispecific Antibody Mimicking Activated Factor VIII Cofactor Function, on Coagulation Assays. Thrombosis and haemostasis. 2019 Jul;     [PubMed PMID: 31064025]
[24] Pipe SW,Shima M,Lehle M,Shapiro A,Chebon S,Fukutake K,Key NS,Portron A,Schmitt C,Podolak-Dawidziak M,Selak Bienz N,Hermans C,Campinha-Bacote A,Kiialainen A,Peerlinck K,Levy GG,Jiménez-Yuste V, Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study. The Lancet. Haematology. 2019 Jun;     [PubMed PMID: 31003963]