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. 2024 Feb 27;2(2):CD014544.
doi: 10.1002/14651858.CD014544.pub2.

Non-clotting factor therapies for preventing bleeds in people with congenital hemophilia A or B

Omotola O Olasupo  1 , Noella Noronha  1 , Megan S Lowe  2 , Derek Ansel  3 , Mihir Bhatt  4 , Davide Matino  5
Affiliations

Non-clotting factor therapies for preventing bleeds in people with congenital hemophilia A or B

Omotola O Olasupo et al. Cochrane Database Syst Rev. .

Abstract

Background: Management of congenital hemophilia A and B is by prophylactic or on-demand replacement therapy with clotting factor concentrates. The effects of newer non-clotting factor therapies such as emicizumab, concizumab, marstacimab, and fitusiran compared with existing standards of care are yet to be systematically reviewed.

Objectives: To assess the effects (clinical, economic, patient-reported, and adverse outcomes) of non-clotting factor therapies for preventing bleeding and bleeding-related complications in people with congenital hemophilia A or B compared with prophylaxis with clotting factor therapies, bypassing agents, placebo, or no prophylaxis.

Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, electronic databases, conference proceedings, and reference lists of relevant articles and reviews. The date of the last search was 16 August 2023.

Selection criteria: Randomized controlled trials (RCTs) evaluating people with congenital hemophilia A or B with and without inhibitors, who were treated with non-clotting factor therapies to prevent bleeds.

Data collection and analysis: Two review authors independently reviewed studies for eligibility, assessed risk of bias, and extracted data for the primary outcomes (bleeding rates, health-related quality of life (HRQoL), adverse events) and secondary outcomes (joint health, pain scores, and economic outcomes). We assessed the mean difference (MD), risk ratio (RR), 95% confidence interval (CI) of effect estimates, and evaluated the certainty of the evidence using GRADE.

Main results: Six RCTs (including 397 males aged 12 to 75 years) were eligible for inclusion. Prophylaxis versus on-demand therapy in people with inhibitors Four trials (189 participants) compared emicizumab, fitusiran, and concizumab with on-demand therapy in people with inhibitors. Prophylaxis using emicizumab likely reduced annualized bleeding rates (ABR) for all bleeds (MD -22.80, 95% CI -37.39 to -8.21), treated bleeds (MD -20.40, 95% CI -35.19 to -5.61), and annualized spontaneous bleeds (MD -15.50, 95% CI -24.06 to -6.94), but did not significantly reduce annualized joint and target joint bleeding rates (AjBR and AtjBR) (1 trial; 53 participants; moderate-certainty evidence). Fitusiran also likely reduced ABR for all bleeds (MD -28.80, 95% CI -40.07 to -17.53), treated bleeds (MD -16.80, 95% CI -25.80 to -7.80), joint bleeds (MD -12.50, 95% CI -19.91 to -5.09), and spontaneous bleeds (MD -14.80, 95% CI -24.90 to -4.71; 1 trial; 57 participants; moderate-certainty evidence). No evidence was available on the effect of bleed prophylaxis using fitusiran versus on-demand therapy on AtjBR. Concizumab may reduce ABR for all bleeds (MD -12.31, 95% CI -19.17 to -5.45), treated bleeds (MD -10.10, 95% CI -17.74 to -2.46), joint bleeds (MD -9.55, 95% CI -13.55 to -5.55), and spontaneous bleeds (MD -11.96, 95% CI -19.89 to -4.03; 2 trials; 78 participants; very low-certainty evidence), but not target joint bleeds (MD -1.00, 95% CI -3.26 to 1.26). Emicizumab prophylaxis resulted in an 11.31-fold increase, fitusiran in a 12.5-fold increase, and concizumab in a 1.59-fold increase in the proportion of participants with no bleeds. HRQoL measured using the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) physical and total health scores was improved with emicizumab, fitusiran, and concizumab prophylaxis (low-certainty evidence). Non-serious adverse events were higher with non-clotting factor therapies versus on-demand therapy, with injection site reactions being the most frequently reported adverse events. Transient antidrug antibodies were reported for fitusiran and concizumab. Prophylaxis versus on-demand therapy in people without inhibitors Two trials (208 participants) compared emicizumab and fitusiran with on-demand therapy in people without inhibitors. One trial assessed two doses of emicizumab (1.5 mg/kg weekly and 3.0 mg/kg bi-weekly). Fitusiran 80 mg monthly, emicizumab 1.5 mg/kg/week, and emicizumab 3.0 mg/kg bi-weekly all likely resulted in a large reduction in ABR for all bleeds, all treated bleeds, and joint bleeds. AtjBR was not reduced with either of the emicizumab dosing regimens. The effect of fitusiran prophylaxis on target joint bleeds was not assessed. Spontaneous bleeds were likely reduced with fitusiran (MD -20.21, 95% CI -32.12 to -8.30) and emicizumab 3.0 mg/kg bi-weekly (MD -15.30, 95% CI -30.46 to -0.14), but not with emicizumab 1.5 mg/kg/week (MD -14.60, 95% CI -29.78 to 0.58). The percentage of participants with zero bleeds was higher following emicizumab 1.5 mg/kg/week (50% versus 0%), emicizumab 3.0 mg/kg bi-weekly (40% versus 0%), and fitusiran prophylaxis (40% versus 5%) compared with on-demand therapy. Emicizumab 1.5 mg/kg/week did not improve Haem-A-QoL physical and total health scores, EQ-5D-5L VAS, or utility index scores (low-certainty evidence) when compared with on-demand therapy at 25 weeks. Emicizumab 3.0 mg/kg bi-weekly may improve HRQoL measured by the Haem-A-QoL physical health score (MD -15.97, 95% CI -29.14 to -2.80) and EQ-5D-5L VAS (MD 9.15, 95% CI 2.05 to 16.25; 1 trial; 43 participants; low-certainty evidence). Fitusiran may result in improved HRQoL shown as a reduction in Haem-A-QoL total score (MD -7.06, 95% CI -11.50 to -2.62) and physical health score (MD -19.75, 95% CI -25.76 to -11.94; 1 trial; 103 participants; low-certainty evidence). The risk of serious adverse events in participants without inhibitors also likely did not differ following prophylaxis with either emicizumab or fitusiran versus on-demand therapy (moderate-certainty evidence). Transient antidrug antibodies were reported in 4% (3/80) participants to fitusiran, with no observed effect on antithrombin lowering. A comparison of the different dosing regimens of emicizumab identified no differences in bleeding, safety, or patient-reported outcomes. No case of treatment-related cancer or mortality was reported in any study group. None of the included studies assessed our secondary outcomes of joint health, clinical joint function, and economic outcomes. None of the included studies evaluated marstacimab.

Authors' conclusions: Evidence from RCTs shows that prophylaxis using non-clotting factor therapies compared with on-demand treatment may reduce bleeding events, increase the percentage of individuals with zero bleeds, increase the incidence of non-serious adverse events, and improve HRQoL. Comparative assessments with other prophylaxis regimens, assessment of long-term joint outcomes, and assessment of economic outcomes will improve evidence-based decision-making for the use of these therapies in bleed prevention.

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Conflict of interest statement

Omotola Olasupo: no relevant conflict of interest.

Noella Noronha: no relevant conflict of interest.

Megan Lowe: no relevant conflict of interest.

Derek Ansel: no relevant conflict of interest.

Mihir Bhatt: no relevant conflict of interest.

Davide Matino: reports research grants paid directly to the Institution from Bayer, Pfizer, Novo Nordisk, Sanofi, Spark, Octapharma; personal fees outside the submitted work from Sanofi, Sobi, Novo Nordisk, Bayer, Pfizer, Octapharma for participation in advisory boards, lectures, and preparation of educational material.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgments about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Emicizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 1: Annualized Bleeding Rates (ABR)
1.2
1.2. Analysis
Comparison 1: Emicizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 2: Proportion with zero bleeds (risk ratio)
1.3
1.3. Analysis
Comparison 1: Emicizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 3: HRQoL—Haem‐A‐QoL
1.4
1.4. Analysis
Comparison 1: Emicizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 4: HRQoL—EQ‐5D‐5L VAS
1.5
1.5. Analysis
Comparison 1: Emicizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 5: HRQoL—EQ‐5D‐5L Utility Index Score
1.6
1.6. Analysis
Comparison 1: Emicizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 6: Adverse events
2.1
2.1. Analysis
Comparison 2: Fitusiran prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 1: Bleeding rates
2.2
2.2. Analysis
Comparison 2: Fitusiran prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 2: Proportion with zero bleeds (risk ratio)
2.3
2.3. Analysis
Comparison 2: Fitusiran prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 3: HRQoL—Haem‐A‐QoL
2.4
2.4. Analysis
Comparison 2: Fitusiran prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 4: Adverse events
3.1
3.1. Analysis
Comparison 3: Concizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 1: Bleeding rates
3.2
3.2. Analysis
Comparison 3: Concizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 2: Proportion with zero bleeds (risk ratio)
3.3
3.3. Analysis
Comparison 3: Concizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 3: HRQoL—SF‐36v2
3.4
3.4. Analysis
Comparison 3: Concizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 4: Adverse events
3.5
3.5. Analysis
Comparison 3: Concizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 5: Bleeding rates (fixed effects model)
4.1
4.1. Analysis
Comparison 4: Emicizumab 1.5 mg/kg/week prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 1: Bleeding rates
4.2
4.2. Analysis
Comparison 4: Emicizumab 1.5 mg/kg/week prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 2: Proportion of participants with zero bleeds (risk ratio)
4.3
4.3. Analysis
Comparison 4: Emicizumab 1.5 mg/kg/week prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 3: HRQoL—Haem‐A‐QoL
4.4
4.4. Analysis
Comparison 4: Emicizumab 1.5 mg/kg/week prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 4: HRQoL—EQ‐5D‐5L VAS
4.5
4.5. Analysis
Comparison 4: Emicizumab 1.5 mg/kg/week prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 5: HRQoL—EQ‐5D‐5L Utility Index Score
4.6
4.6. Analysis
Comparison 4: Emicizumab 1.5 mg/kg/week prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 6: Adverse events
5.1
5.1. Analysis
Comparison 5: Emicizumab 3.0 mg/kg bi‐weekly prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 1: Bleeding rates
5.2
5.2. Analysis
Comparison 5: Emicizumab 3.0 mg/kg bi‐weekly prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 2: Proportion of participants with zero bleeds
5.3
5.3. Analysis
Comparison 5: Emicizumab 3.0 mg/kg bi‐weekly prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 3: HRQoL—Haem‐A‐QoL
5.4
5.4. Analysis
Comparison 5: Emicizumab 3.0 mg/kg bi‐weekly prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 4: HRQoL—EQ‐5D‐5L VAS
5.5
5.5. Analysis
Comparison 5: Emicizumab 3.0 mg/kg bi‐weekly prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 5: HRQoL—EQ‐5D‐5L Utility Index Score
5.6
5.6. Analysis
Comparison 5: Emicizumab 3.0 mg/kg bi‐weekly prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 6: Adverse events
6.1
6.1. Analysis
Comparison 6: Emicuzimab 1.5 mg/kg/week versus 3.0 mg/kg bi‐weekly in people without inhibitors, Outcome 1: Bleeding rates
6.2
6.2. Analysis
Comparison 6: Emicuzimab 1.5 mg/kg/week versus 3.0 mg/kg bi‐weekly in people without inhibitors, Outcome 2: Proportion of participants with zero bleeds
6.3
6.3. Analysis
Comparison 6: Emicuzimab 1.5 mg/kg/week versus 3.0 mg/kg bi‐weekly in people without inhibitors, Outcome 3: HRQoL—Haem‐A‐QoL
6.4
6.4. Analysis
Comparison 6: Emicuzimab 1.5 mg/kg/week versus 3.0 mg/kg bi‐weekly in people without inhibitors, Outcome 4: HRQoL—EQ‐5D‐5L VAS
6.5
6.5. Analysis
Comparison 6: Emicuzimab 1.5 mg/kg/week versus 3.0 mg/kg bi‐weekly in people without inhibitors, Outcome 5: HRQoL—EQ‐5D‐5L Utility Index Score
6.6
6.6. Analysis
Comparison 6: Emicuzimab 1.5 mg/kg/week versus 3.0 mg/kg bi‐weekly in people without inhibitors, Outcome 6: Adverse events
7.1
7.1. Analysis
Comparison 7: Fitusiran prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 1: Bleeding rates
7.2
7.2. Analysis
Comparison 7: Fitusiran prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 2: Proportion of participants with zero bleeds (risk ratio)
7.3
7.3. Analysis
Comparison 7: Fitusiran prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 3: Change in HRQoL—Haem‐A‐QoL
7.4
7.4. Analysis
Comparison 7: Fitusiran prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 4: Adverse events
See this image and copyright information in PMC

Update of

References

References to studies included in this review

ATLAS ‐ A/B {published data only}
    1. CTRI/2018/07/014698. A phase 3 study to evaluate the efficacy and safety of fitusiran in patients with hemophilia A or B, without inhibitory antibodies to factor VIII or IX [ATLAS-A/B: A Phase 3 Study to Evaluate the Efficacy and Safety of Fitusiran in Patients With Hemophilia A or B, Without Inhibitory Antibodies to Factor VIII or IX]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2018/07/014698 (first received 2 Jul 2018).
    1. EUCTR2016-001464-11-IE. A study of fitusiran (ALN-AT3SC) in hemophilia A and B patients without inhibitors. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2016-001464-11-IE (first received 5 Jul 2017). [CFGD REGISTER: HG135c]
    1. EUCTR2016-001464-11-NL. A study of fitusiran (ALN-AT3SC) in hemophilia A and B patients without inhibitors. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2016-001464-11-NL (first received 6 Jun 2018). [CFGD REGISTER: HG135b]
    1. NCT03417245. A study of fitusiran (ALN-AT3SC) in severe hemophilia a and b patients without inhibitors. clinicaltrials.gov/show/NCT03417245 (first received 31 Jan 2018). [CFGD REGISTER: HG135a]
    1. Srivastava A, Rangarajan S, Kavakli K, Klamroth R, Kenet G, Khoo L, et al. Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial. Lancet Haematology 2023;10(5):e322-e332. [DOI: 10.1016/S2352-3026(23)00037-6] [PMID: ] - DOI - PubMed
ATLAS ‐ INH {published data only}
    1. CTRI/2018/06/014682. A Phase 3 study to Evaluate the Efficacy and Safety of Fitusiran in Patients with Hemophilia A or B, with Inhibitory Antibodies to Factor VIII or IX [ATLAS-INH: A Phase 3 Study to Evaluate the Efficacy and Safety of Fitusiran in Patients with Hemophilia A or B, with Inhibitory Antibodies to Factor VIII or IX]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2018/06/014682 (first received 29 Jun 2018).
    1. EUCTR2016-001463-36-BG. A Study of fitusiran (ALN-AT3SC) in hemophilia A and B patients with inhibitors. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2016-001463-36-BG (first received 6 Jul 2017). [CFGD REGISTER: HG136b]
    1. NCT03417102. A study of fitusiran (ALN-AT3SC) in severe hemophilia a and b patients with inhibitors. clinicaltrials.gov/ct2/show/NCT03417102 (first received 31 Jan 2018). [CFGD REGISTER: HG136a]
    1. Young G, Srivastava A, Kavakli K, Ross C, Sathar J, You CW, et al. Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial. Lancet 2023;401(10386):1427-1437. [DOI: 10.1016/S0140-6736(23)00284-2] [PMID: ] - DOI - PubMed
EXPLORER 4 {published data only}
    1. Astermark J, Angchaisuksiri P, Benson G, Castaman G, Chowdary P, Eichler H, et al. Longer-term efficacy and safety of concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: Results from the main and extension parts of concizumab phase 2 trials. In: Research and Practice in Thrombosis and Haemostasis. Vol. 5. 2021. [DOI: ]
    1. Astermark J, Angchaisuksiri P, Benson G, Castaman G, Chowdary P, Eichler H, et al. Subcutaneous prophylaxis with the anti-TFPI monoclonal antibody concizumab in hemophilia A and hemophilia A/B with inhibitors: Phase 2 trial results. Research and Practice in Thrombosis and Haemostasis 2019;3(Supplement 2):1. [DOI: ]
    1. Astermark J, Angchaisuksiri P, Benson G, Castaman G, Chowdary P, Eichler H, et al. Subcutaneous prophylaxis with the anti-TFPI monoclonal antibody concizumab in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. Research and Practice in Thrombosis and Haemostasis 2019;3(Suppl 2):1. [CFGD REGISTER: HG119c]
    1. EUCTR2016-000510-30-ES. A trial evaluating the efficacy and safety of prophylactic administration of concizumab in haemophilia a and b patients with inhibitors. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2016-000510-30-ES (first received 4 Jul 2017). [CFGD REGISTER: HG119b]
    1. Faller M, Toonder SM, Porstmann T. Improvement in health-related quality of life measures after long-term, daily, subcutaneous concizumab prophylaxis in patients with hemophilia a/b with and without inhibitors: Results from the main and extension parts of phase 2 clinical trials. Blood 2021;138(Suppl 1):1041. [DOI: 10.1182/blood-2021-152257] - DOI
EXPLORER 7 {published data only}
    1. Hampton K, Knoebl P, Neergaard JS, Odgaard-Jensen J, Stasyshyn O, Thaung Zaw JJ, et al. Treatment burden and patient preference in patients with haemophilia A or B with inhibitors on concizumab prophylaxis: results from the phase 3 EXPLORER 7 study. Haemophilia 2023;29(Supplement 1):77-78. [DOI: ]
    1. Kaushik C, Jimenez-Yuste V, Angchaisuksiri P, Castaman G, Cepo K, Haaning J, et al. Concizumab Prophylaxis in Patients with Haemophilia A or B with Inhibitors: Efficacy and Safety Results from the Primary Analysis of the Phase 3 EXPLORER7 Trial. Indian Journal of Hematology and Blood Transfusion 2022;38(Supplement 1):S3. [DOI: ]
    1. Linari S, Shapiro A, Neergaard JS, Odgaard-Jensen J, Thaung Zaw JJ, Tran H. Health-related quality of life in patients with haemophilia A or B with inhibitors on concizumab prophylaxis: results from the phase 3 EXPLORER 7 study. Haemophilia 2023;29(Supplement 1):94-95. [DOI: ]
    1. Mathias M, Cepo K, D'Oiron R, Frei-Jones M, Goh A-S, Odgaard-Jensen J. Subcutaneous concizumab prophylaxis in patients with haemophilia A or B with inhibitors: efficacy and safety results by haemophilia subtype from the EXPLORER t trial. Haemophilia 2023;29(Supplement 1):17. [DOI: ]
    1. Matsushita T, Shapiro A, Abraham A, Angchaisuksiri P, Castaman G, Cepo K, et al, Explorer7 Investigators. Phase 3 Trial of Concizumab in Hemophilia with Inhibitors. New England Journal of Medicine 2023;389(9):783-794. [DOI: 10.1056/NEJMoa2216455] [PMID: ] - DOI - PubMed
HAVEN 1 {published data only}
    1. Adamkewicz JI, Schmitt C, Asikanius E, Xu J, Levy G, Kim B, et al. Factor VIII (FVIII) inhibitor testing using a validated chromogenic bethesda assay (CBA) in HAVEN 1 (BH29884), a Phase 3 trial of emicizumab in persons with hemophilia a (PwHA) with inhibitors. Research and Practice in Thrombosis and Haemostasis 2017;1(Supplement 1):724-5. [CFGD REGISTER: HA149l]
    1. Callaghan M, Negrier C, Young G, Khoo L, Mahlangu J, Windyga J, et al. Use of bypassing agents prior to and post bypassing agent dosing guidance during emicizumab prophylaxis: Analyses from the haven 1 study. British Journal of Haematology 2018;181(Supplement 1):129. [CFGD REGISTER: HA149d]
    1. Callaghan M, Negrier C, Young G, Khoo L, Mahlangu J, Windyga J, et al. Use of bypassing agents prior to and post bypassing agent dosing guidance during emicizumab prophylaxis: analyses from the haven 1 study. British Journal of Haematology 2018;181:129. [DOI: 10.1111/bjh.15226] - DOI
    1. Callaghan MU, Negrier C, Paz-Priel I, Chang T, Chebon S, Lehle M, et al. Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. Blood 2021;137(16):2231-42. [CFGD REGISTER: HA149s // HA150m] [DOI: 10.1182/blood.2020009217] - DOI - PMC - PubMed
    1. Callaghan MU, Negrier C, Paz-Priel I, Chang T, Chebon S, Lehle M, et al. Safety and efficacy of emicizumab in persons with haemophilia a with/without FVIII inhibitors: pooled data from four phase III studies (Haven 1-4). Haemophilia 2021;27(Suppl 2):126-7. [CFGD REGISTER: HA149r // HA150l]
HAVEN 3 {published data only}
    1. Callaghan M, Trzaskoma B, Ko RH, Lee L, Patel AM, Tzeng E, et al. Factor VIII use in the treatment of breakthrough bleeds in hemophilia A patients without inhibitors on emicizumab prophylaxis: the phase 3 haven 3 study experience. Blood 2019;134(Suppl 1):2395. [CFGD REGISTER: HA150j]
    1. Callaghan MU, Negrier C, Paz-Priel I, Chang T, Chebon S, Lehle M, et al. Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. Blood 2021;137(16):2231-42. [CFGD REGISTER: HA149s // HA150m] - PMC - PubMed
    1. Callaghan MU, Negrier C, Paz-Priel I, Chang T, Chebon S, Lehle M, et al. Safety and efficacy of emicizumab in persons with haemophilia a with/without FVIII inhibitors: pooled data from four phase III studies (Haven 1-4). Haemophilia 2021;27(Suppl 2):126-7. [CFGD REGISTER: HA149r // HA150l]
    1. Callaghan MU, Negrier C, Paz-Priel I, Chang T, Chebon S, Lehle M, et al. Safety and efficacy of emicizumab in persons with hemophilia a with or without fviii inhibitors: pooled data from four phase iii studies (haven 1-4). Blood 2020;136(SUPPL 1):3-5. [CFGD REGISTER: HA149q // HA150k]
    1. EUCTR2016-000072-17-ES. A Study to Evaluate the Effectiveness and Safety of Prophylactic Emicizumab Versus no Prophylaxis in Haemophilia A Patients Without Inhibitors. EUCTR 2016.

References to studies excluded from this review

Agers 2014 {published data only}
    1. Agersø H, Overgaard RV, Petersen MB, Hansen L, Hermit MB, Sørensen MH, et al. Pharmacokinetics of an anti-TFPI monoclonal antibody (concizumab) blocking the TFPI interaction with the active site of FXa in Cynomolgus monkeys after iv and sc administration. European Journal of Pharmaceutical Sciences 2014;56:65-9. [DOI: 10.1016/j.ejps.2014.02.009] - DOI - PubMed
AKATSUKI {published data only}
    1. JPRN-jRCTs041200037. AKATSUKI Study [A prospective, multicenter study to evaluate the safety of emicizumab under and after immune tolerance induction in patients with congenital hemophilia A with FVIII inhibitors]. trialsearch.who.int/Trial2.aspx?TrialID=JPRN-jRCTs041200037 (registered 3 Aug 2020).
Aledort 2017 {published data only}
    1. Aledort LM, Ewenstein BM. Emicizumab prophylaxis in hemophilia A with inhibitors. New England Journal of Medicine 2017;377(22):2193. [DOI: 10.1056/NEJMc1712683] [PMID: ] - DOI - PubMed
Aledort 2019 {published data only}
    1. Aledort LM. Deaths associated with emicizumab in patients with hemophilia A. New England Journal of Medicine 2019;381(19):1878-9. [DOI: 10.1056/NEJMc1909742] - DOI - PubMed
Aledort 2020 {published data only}
    1. Aledort LM. Emicizumab prophylaxis in hemophilia A with inhibitors. New England Journal of Medicine 2020;382(8):786. [DOI: ] - PubMed
A‐LONG 2011 {published data only}
    1. CTRI/2011/11/002103. Study to evaluate the safety, pharmacokinetics and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with severe hemophilia A [An open-label, multicenter evaluation of the safety, pharmacokinetics, and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in the prevention and treatment of bleeding in previously treated subjects with severe hemophilia A - A LONG]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2011/11/002103 (registered 2 Nov 2011).
    1. Klamroth R, Wojciechowski P, Aballéa S, Diamand F, Hakimi Z, Nazir J, et al. Efficacy of rFVIIIFc versus emicizumab for the treatment of patients with Hemophilia A without Inhibitors: matching-adjusted indirect comparison of A-LONG and HAVEN trials. Journal of Blood Medicine 2021;12:115-22. [DOI: 10.2147/jbm.S288283] - DOI - PMC - PubMed
ATLAS ‐ PPX {published data only}
    1. NCT03549871. A study of fitusiran in severe hemophilia A and B patients previously receiving factor or bypassing agent prophylaxis (ATLAS-PPX). clinicaltrials.gov/ct2/show/NCT03549871 (first posted 18 Jun 2018).
Barg 2019 {published data only}
    1. Barg AA, Avishai E, Budnik I, Levy-Mendelovich S, Barazani TB, Kenet G, et al. Emicizumab prophylaxis among infants and toddlers with severe hemophilia A and inhibitors-a single-center cohort. Pediatric Blood and Cancer 2019;1(11):e27886. [DOI: 10.1002/pbc.27886] - DOI - PubMed
Barg 2020 {published data only}
    1. Barg AA, Livnat T, Budnik I, Avishai E, Brutman-Barazani T, Tamarin I, et al. Emicizumab treatment and monitoring in a paediatric cohort: real-world data. British Journal of Haematology 2020;1(2):282-90. [DOI: 10.1111/bjh.16964] - DOI - PubMed
Barg 2021 {published data only}
    1. Barg AA, Budnik I, Avishai E, Brutman-Barazani T, Bashari D, Misgav M, et al. Emicizumab prophylaxis: Prospective longitudinal real-world follow-up and monitoring. Haemophilia 2021;27(3):383-91. [DOI: 10.1111/hae.14318] - DOI - PubMed
Batsuli 2019 {published data only}
    1. Batsuli G, Zimowski KL, Tickle K, Meeks SL, Sidonio RF Jr. Immune tolerance induction in paediatric patients with haemophilia A and inhibitors receiving emicizumab prophylaxis. Haemophilia 2019;25(5):789-96. [DOI: 10.1111/hae.13819] - DOI - PubMed
Benton 2019 {published data only}
    1. Benton M, Shi L, Patel AM, Monnette A, Hong D, Thielmann H, et al. Evaluating patient and caregiver treatment preferences in hemophilia A using a discrete choice experiment. RPTH 2019;3:270-271. [DOI: 10.1002/rth2.12229] - DOI
Bertolet 2020a {published data only}
    1. Bertolet M, Brooks MM, Ragni MV. The design of a Bayesian platform trial to prevent and eradicate inhibitors in patients with hemophilia. Blood Advances 2020;4(21):5433-41. [CFGD REGISTER: HA160b // HA161b] - PMC - PubMed
    1. NCT04303559. The hemophilia inhibitor prevention trial. www.clinicaltrials.gov/show/NCT04303559 (first posted 11 Mar 2020). [CFGD REGISTER: HA160a]
Bertolet 2020b {published data only}
    1. Bertolet M, Brooks MM, Ragni MV. The design of a Bayesian platform trial to prevent and eradicate inhibitors in patients with hemophilia. Blood Advances 2020;4(21):5433-41. [CFGD REGISTER: HA160b // HA161b] - PMC - PubMed
    1. NCT04303572. The hemophilia inhibitor eradication trial. www.clinicaltrials.gov/show/NCT04303572 (first posted 11 Mar 2020).
Beyond ABR {published data only}
    1. NCT05181618. A study to evaluate overall health, physical activity, and joint outcomes in participants with severe or moderate hemophilia A without Factor VIII inhibitors on emicizumab prophylaxis (Beyond ABR). clinicaltrials.gov/study/NCT05181618 (first received 6 December 2021).
Biron‐Andreani 2020 {published data only}
    1. Biron-Andreani C, Diaz-Cau I, Ranc A, Navarro R, Leonardi C, Dischino M, et al. Major surgery management in patients with haemophilia A and inhibitors on emicizumab prophylaxis without global coagulation monitoring. British Journal of Haematology 2020;1(3):e100-e103. [DOI: 10.1111/bjh.16512] - DOI - PubMed
Blair 2019 {published data only}
    1. Blair HA. Emicizumab: a review in haemophilia A. Drugs 2019;79(15):1697-1707. [DOI: 10.1007/s40265-019-01200-2] [PMID: ] - DOI - PubMed
Brophy 2019 {published data only}
    1. Brophy DF, Martin EJ, Kuhn J. Use of global assays to monitor emicizumab prophylactic therapy in patients with haemophilia A with inhibitors. Haemophilia 2019 Mar;25(2):e121-e123. [DOI: 10.1111/hae.13689] [PMID: ] - DOI - PubMed
Brown 2020 {published data only}
    1. Brown LJ, La HA, Li J, Brunner M, Snoke M, Kerr AM. The societal burden of haemophilia A. III - The potential impact of emicizumab on costs of haemophilia A in Australia. Haemophilia 2020;26 Suppl 5:21-9. [DOI: 10.1111/hae.14082] - DOI - PubMed
Buckner 2020 {published data only}
    1. Buckner TW, Watson C, Recht M. Emicizumab in hemophilia A. New England Journal of Medicine 2020;382(8):785-786. [DOI: 10.1056/NEJMc1916299] [PMID: ] - DOI - PubMed
Bukkems 2021 {published data only}
    1. Bukkems LH, Fischer K, Kremer-Hovinga I, Donners AA, Fijnvandraat K, Schutgens RE, et al. Emicizumab dosing in children and adults with hemophilia A: simulating a user-friendly and cost-efficient regimen. Thrombosis and Haemostasis 2022;122(2):208-15. [DOI: 10.1055/a-1499-0030] - DOI - PubMed
B‐YOND {published data only}
    1. CTRI/2012/05/002708. To study the long-term safety and efficacy of recombinant human coagulation factor IX fusion protein (rFIXFc) in haemophilia B patients [An open-label, multicenter evaluation of the long-term safety and efficacy of recombinant human coagulation factor IX fusion protein (rFIXFc) in the prevention and treatment of bleeding episodes in previously treated subjects with haemophilia B - B-YOND]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2012/05/002708 (registered 30 May 2012).
Cafuir 2019 {published data only}
    1. Cafuir L, Kruse-Jarres R, Mancuso ME, Kempton CL. Emicizumab for hemophilia A without inhibitors. Expert Review of Hematology 2019;12(7):515-524. [DOI: 10.1080/17474086.2019.1624519] [PMID: ] - DOI - PubMed
Callaghan 2018 {published data only}
    1. Callaghan MU, Kuebler PJ, Gao L, Ko RH, Devenport J, Liberman M. Characterization of the impact of prior ITI on patient outcomes in HAVEN1. American Journal of Hematology 2018;93(9):E10‐E11. [DOI: 10.1002/ajh.25268] - DOI
Cardinal 2018 {published data only}
    1. Cardinal M, Kantaridis C, Zhu T, Sun P, Pittman DD, Murphy JE, et al. A first-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-06741086, an anti-tissue factor pathway inhibitor mAb, in healthy volunteers. Journal of Thrombosis and Haemostasis 2018;16(9):1722-31. [DOI: 10.1111/jth.14207] - DOI - PubMed
Chowdary 2015 {published data only}
    1. Chowdary P, Friedrich U, Lethagen S, Angchaisuksiri P. A new treatment concept for haemophilia: safety, pharmacokinetics and pharmacodynamics of single i.v. and s.c. doses of a monoclonal anti-TFPI antibody in healthy males and haemophilia subjects. Journal of Thrombosis and Haemostasis 2013;11 Suppl 2:460. [ABSTRACT NO.: PA4.07-5] [CFGD REGISTER: HG86b]
    1. Chowdary P, Lethagen S, Friedrich U, Brand B, Hay C, Karim FA, et al. Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial. Journal of Thrombosis and Haemostasis 2015;13(5):743-54. [CFGD REGISTER: HG86a] - PubMed
Cortesi 2020 {published data only}
    1. Cortesi PA, Castaman G, Trifirò G, Creazzola SS, Improta G, Mazzaglia G, et al. Cost-effectiveness and budget impact of emicizumab prophylaxis in haemophilia A patients with inhibitors. Thrombosis and Haemostasis 2020;1(2):216-28. [DOI: 10.1055/s-0039-3401822] - DOI - PubMed
CTRI201106001832 {published data only}
    1. CTRI/2011/06/001832. A clinical trial to study the effects of IB1001 in previously treated patients children with hemophilia B [Study of recombinant factor IX product, IB1001, in previously treated pediatric subject with hemophilia BÂ - NIL]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2011/06/001832 (registered 24 Jun 2011).
CTRI201204002596 {published data only}
    1. CTRI/2012/04/002596. A clinical trial to see the effect of EMOCLOT drug (Kedrion factor VIII concentrate) in 50 previously treated haemophilia A children [Open label, phase III, multicenter study on pharmacokinetic, efficacy and safety evaluation of Kedrion Factor VIII concentrate (EMOCLOT) in 50 previously treated haemophilia A children]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2012/04/002596 (first registered 24 Apr 2012).
CTRI201307003823 {published data only}
    1. CTRI/2013/07/003823. A clinical trial to study the effect of an unregistered drug in hemophilia B patients [BAX326 (Recombinant Factor IX): evaluation of safety, immunogenicity, and hemostatic efficacy in previously treated patients with severe (FIX level 1%) or moderately severe (FIX level â?¤ 2%) hemophilia B â?? A continuation study]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2013/07/003823 (registered 19 Jul 2013).
CTRI201807014754 {published data only}
    1. CTRI/2018/07/014754. A post-marketing study receiving RIXUBIS as on-demand or prophylaxis under standard clinical practice in patients with Hemophilia B [Phase IV Multi-center, Prospective, Interventional, Post-marketing study in Hemophilia B Patients in India receiving RIXUBIS as on-demand or Prophylaxis under standard clinical practice - None]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2018/07/014754 (registered 5 Jul 2018).
Donners 2021 {published data only}
    1. Donners AA, Rademaker CM, Bevers LA, Huitema AD, Schutgens RE, Egberts TC, et al. Pharmacokinetics and associated efficacy of emicizumab in humans: a systematic review. Clinical Pharmacokinetics 2021;60(11):1395-406. [DOI: 10.1007/s40262-021-01042-w] - DOI - PMC - PubMed
Ebbert 2020 {published data only}
    1. Ebbert PT, Xavier F, Seaman CD, Ragni MV. Emicizumab prophylaxis in patients with haemophilia A with and without inhibitors. Haemophilia 2020;26(1):41-6. [DOI: 10.1111/hae.13877] - DOI - PubMed
Eichler 2018 {published data only}
    1. Eichler H, Angchaisuksiri P, Kavakli K, Knoebl P, Windyga J, Jimenez-Yuste V, et al. A randomized trial of safety, pharmacokinetics and pharmacodynamics of concizumab in people with hemophilia A. Journal of Thrombosis and Haemostasis 2018;16(11):2184-95. [HG120b] - PubMed
    1. Eichler H, Angchaisuksiri P, Kavakli K, Knoebl P, Windyga J, Jimenez-Yuste V, et al. Evaluation of safety and establishment of a PK/PD relationship of concizumab in hemophilia a patients. Research and Practice in Thrombosis and Haemostasis 2017;1(Suppl 2):1-2. [CFGD REGISTER: HG120c]
    1. NCT02490787. Trial investigating safety, pharmacokinetics and pharmacodynamics of concizumab administered subcutaneously to haemophilia a subjects. www.clinicaltrials.gov/show/NCT02490787 (first posted 7 Jul 2015). [CFGD REGISTER: HG120a]
Explorer 5 {published data only}
    1. TCTR20170512002. A multi-centre trial evaluating efficacy and safety of prophylactic administration of concizumab in patients with severe haemophilia A without inhibitors [Explorer 5]. trialsearch.who.int/Trial2.aspx?TrialID=TCTR20170512002 (registered 12 May 2017).
Fontana 2020 {published data only}
    1. Fontana P, Alberio L, Albisetti M, Angelillo-Scherrer A, Asmis LM, Casini A, et al. Management of bleeding events and invasive procedures in patients with haemophilia A without inhibitors treated with emicizumab. Swiss Medical Weekly 2020;150:w20422. [DOI: 10.4414/smw.2020.20422] - DOI - PubMed
Franchini 2018 {published data only}
    1. Franchini M, Mannucci PM. Non-factor replacement therapy for haemophilia: a current update. Trasfusione del sangue [Blood Transfusion] 2018;16(5):457-461. [DOI: 10.2450/2018.0272-17] - DOI - PMC - PubMed
Franchini 2019 {published data only}
    1. Franchini M, Marano G, Pati I, Candura F, Profili S, Veropalumbo E, et al. Emicizumab for the treatment of haemophilia A: a narrative review. Trasfusione del sangue [Blood Transfusion] 2019;17(3):223-228. [DOI: 10.2450/2019.0026-19] - DOI - PMC - PubMed
Franchini 2020 {published data only}
    1. Franchini M, Marano G, Pati I, Veropalumbo E, Vaglio S, Pupella S, et al. Investigational drugs to treat hemophilia. Expert Opinion on Investigational Drugs 2020;29(3):295-301. [DOI: 10.1080/13543784.2020.1722999] - DOI - PubMed
FRONTIER1 {published data only}
    1. EUCTR2019-000465-20-ES. A research study of how a new medicine NNC0365-3769 (Mim8) works in the body of healthy people and patients with bleeding disorder. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2019-000465-20-ES (registered 28 Feb 2020). [CFGD REGISTER: HA140b]
    1. NCT04204408. A research study investigating mim8 in people with haemophilia a. www.clinicaltrials.gov/show/NCT04204408 (first posted 19 Dec 2019). [CFGD REGISTER: HA140a]
Hassan 2021 {published data only}
    1. Hassan E, Motwani J. Management and outcomes of paediatric patients on emicizumab prophylaxis undergoing surgical procedures: experience from a large haemophilia centre in the UK. Haemophilia 2021;27(5):e620-3. [DOI: 10.1111/hae.14358] - DOI - PubMed
HAVEN 2 {published data only}
    1. Mancuso ME, Mahlangu J, Sidonio R Jr, Trask P, Uguen M, Chang T, et al. Health-related quality of life and caregiver burden of emicizumab in children with haemophilia A and factor VIII inhibitors - results from the HAVEN 2 study. Haemophilia 2020;1(6):1009-18. - PMC - PubMed
    1. NCT02795767. A study of emicizumab administered subcutaneously (SC) in pediatric participants with hemophilia A and Factor VIII (FVIII) inhibitors. clinicaltrials.gov/study/NCT02795767 (first received 7 June 2016).
    1. Young G, Callaghan M, Dunn A, Kruse-Jarres R, Pipe S. Emicizumab for hemophilia A with factor VIII inhibitors. Expert Review of Hematology 2018 Nov;11(11):835-846. [DOI: 10.1080/17474086.2018.1531701] [PMID: ] - DOI - PubMed
    1. Young G, Liesner R, Chang T, Sidonio R, Oldenburg J, Jiménez-Yuste V, et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood 2019;1(24):2127-38. [DOI: 10.1182/blood.2019001869] - DOI - PMC - PubMed
HAVEN 4 {published data only}
    1. JapicCTI-163391. Phase III clinical study of emicizumab given every 4 weeks (Q4W) in patients with hemophilia A. trialsearch.who.int/Trial2.aspx?TrialID=JPRN-JapicCTI-163391 (registered 30 Sep 2016). [CFGD REGISTER: HA167]
    1. Jimenez-Yuste V, Shima M, Paz-Priel I, Parnes A, Lehle M, Giermasz A, et al. Preference for emicizumab over prior factor treatments: results from the HAVEN 3 and HAVEN 4 studies. Blood 2018;132(Suppl 1):1187.
    1. Klamroth R, Wojciechowski P, Aballéa S, Diamand F, Hakimi Z, Nazir J, et al. Efficacy of rFVIIIFc versus emicizumab for the treatment of patients with hemophilia A without inhibitors: matching-adjusted indirect comparison of A-LONG and HAVEN trials. Journal of Blood Medicine 2021;12:115-22. [DOI: 10.2147/jbm.S288283] - DOI - PMC - PubMed
    1. Pipe SW, Shima M, Lehle M, Shapiro A, Chebon S, Fukutake K, et al. 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. Lancet Haematology 2019;1(6):e295-e305. [DOI: 10.1016/S2352-3026(19)30054-7] - DOI - PubMed
    1. Skinner M, Negrier C, Paz-Priel I, Chebon S, Jimenez-Yuste V, Callaghan M, et al. Emicizumab prophylaxis improves long-term physical health scores in persons with haemophilia A (PWHA) with and without inhibitors: update from the haven 3 and haven 4 studies. Research and Practice in Thrombosis and Haemostasis 2019;3:328-9.
HAVEN 6 {published data only}
    1. Negrier C, Mahlangu J, Lehle M, Chowdary P, Catalani O, Bernardi RJ, et al. Emicizumab in people with moderate or mild haemophilia A (HAVEN 6): a multicentre, open-label, single-arm, phase 3 study. The Lancet Haematology 2023;10(3):e168-e177. [DOI: 10.1016/S2352-3026(22)00377-5] - DOI - PubMed
    1. Negrier C, Mahlangu J, Lehle M, Chowdary P, Catalani O, Jimenez-Yuste V, et al. Emicizumab prophylaxis in persons with mild or moderate hemophilia A: results from the interim analysis of the HAVEN 6 study. Blood 2021;138(Suppl 1):343. [DOI: 10.1182/blood-2021-146009] - DOI
Hilden 2012 {published data only}
    1. Hilden I, Lauritzen B, Sørensen BB, Clausen JT, Jespersgaard C, Krogh BO, et al. Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model. Blood 2012;119(24):5871-8. [DOI: 10.1182/blood-2012-01-401620] - DOI - PubMed
ISRCTN57549638 {published data only}
    1. ISRCTN57549638. Prevention of bleeding in haemophilia A by prophylactic treatment with Nuwiq® [Prevention of bleeding in haemophilia A by prophylactic treatment with Nuwiq®: a prospective, multi-national, non-interventional study to evaluate routine practice prophylactic treatment schedules – NIS-Previq]. trialsearch.who.int/Trial2.aspx?TrialID=ISRCTN57549638 (registered 23 Mar 2015).
JapicCTI‐173710 {published data only}
    1. JPRN-JapicCTI-173710. Phase III clinical trial of emicizumab given every 2 weeks and 4 weeks in hemophilia A pediatric patients without inhibitors (HOHOEMI). https://jrct.niph.go.jp/latest-detail/jRCT2080223654 (first received September 12, 2017).
Klamroth 2021 {published data only}
    1. Klamroth R, Wojciechowski P, Aballéa S, Diamand F, Hakimi Z, Nazir J, et al. Efficacy of rFVIIIFc versus emicizumab for the treatment of patients with Hemophilia A without Inhibitors: matching-adjusted indirect comparison of A-LONG and HAVEN trials. Journal of Blood Medicine 2021;12:115-22. [DOI: 10.2147/jbm.S288283] - DOI - PMC - PubMed
Krumb 2021 {published data only}
    1. Krumb E, Fijnvandraat K, Makris M, Peyvandi F, Ryan A, Athanasopoulos A, et al. Adoption of emicizumab (Hemlibra®) for hemophilia A in Europe: Data from the 2020 European Association for Haemophilia and Allied Disorders survey. Haemophilia 2021;27(5):736-43. [DOI: 10.1111/hae.14372] - DOI - PubMed
Kruse‐Jarres 2020 {published data only}
    1. Kruse-Jarres R, Hay CRM. Emicizumab in hemophilia A. New England Journal of Medicine 2020;382(8):785. [DOI: 10.1056/NEJMc1916299] - DOI - PubMed
Kruse‐Jarres 2022 {published data only}
    1. Kruse-Jarres R, Peyvandi F, Oldenburg J, Chang T, Chebon S, Doral MY, et al. Surgical outcomes in people with hemophilia A taking emicizumab prophylaxis: experience from the HAVEN 1-4 studies. Blood Advances 2022;6(24):6140-6150. [DOI: 10.1182/bloodadvances.2022007458] - DOI - PMC - PubMed
Lee 2021 {published data only}
    1. Lee H, Cho H, Han JW, Kim AY, Park S, Lee M, et al. Cost-utility analysis of emicizumab prophylaxis in haemophilia A patients with factor VIII inhibitors in Korea. Haemophilia 2021;27(1):e12-e21. [DOI: 10.1111/hae.14143] - DOI - PubMed
Le Quellec 2020 {published data only}
    1. Le Quellec S. Clinical evidence and safety profile of emicizumab for the management of children with hemophilia A. Drug Design, Development and Therapy 2020 Feb;3(14):469-481. [DOI: 10.2147/DDDT.S167731] [PMID: ] - DOI - PMC - PubMed
Levy‐Mendelovich 2020 {published data only}
    1. Levy-Mendelovich S. Emicizumab for infants and children with haemophilia A. British Journal of Haematology 2020;191(2):145-6. [DOI: 10.1111/bjh.16965] - DOI - PubMed
Lewandowska 2021 {published data only}
    1. Lewandowska M, Randall N, Bakeer N, Maahs J, Sagar J, Greist A, et al. Management of people with haemophilia A undergoing surgery while receiving emicizumab prophylaxis: Real-world experience from a large comprehensive treatment centre in the US. Haemophilia 2021;27(1):90-9. [DOI: 10.1111/hae.14212] - DOI - PMC - PubMed
Machin 2018 {published data only}
    1. Machin N, Ragni MV. An investigational RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B. Journal of Blood Medicine 2018;9:135-40. [DOI: 10.2147/jbm.S159297] - DOI - PMC - PubMed
Mahlangu 2019 {published data only}
    1. Mahlangu J. Emicizumab for the prevention of bleeds in hemophilia A. Expert Opinion on Biological Therapy 2019;19(8):753-761. [DOI: 10.1080/14712598.2019.1626370] - DOI - PubMed
Mahlangu 2023 {published data only}
    1. Mahlangu J, Luis Lamas J, Cristobal Morales J, Malan DR, Teeter J, Charnigo RJ, et al. Long-term safety and efficacy of the anti-tissue factor pathway inhibitor marstacimab in participants with severe haemophilia: Phase II study results. British Journal of Haematology 2023;200(2):1470-1477. [DOI: 10.1111/jth.14491] - DOI - PMC - PubMed
McCary 2020 {published data only}
    1. McCary I, Guelcher C, Kuhn J, Butler R, Massey G, Guerrera MF, et al. Real-world use of emicizumab in patients with haemophilia A: bleeding outcomes and surgical procedures. Haemophilia 2020;26(4):631-6. - PubMed
Misgav 2021 {published data only}
    1. Misgav M, Brutman-Barazani T, Budnik I, Avishai E, Schapiro J, Bashari D, et al. Emicizumab prophylaxis in haemophilia patients older than 50 years with cardiovascular risk factors: real-world data. Haemophilia 2021;27(2):253-60. [DOI: 10.1111/hae.14261] - DOI - PubMed
NCT04030052 {published data only}
    1. NCT04030052. Emicizumab PUPs and Nuwiq ITI Study. https://clinicaltrials.gov/study/NCT04030052 (first received 23 July 2019).
NCT05935358 {published data only}
    1. NCT05935358. Nuwiq for Perioperative Management Of Patients With Haemophilia A on Emicizumab Regular Prophylaxis Study (NuPOWER). https://clinicaltrials.gov/study/NCT05935358 (first received 7 July 2023).
Nogami 2016 {published data only}
    1. Nogami K, Hanabusa H, Taki M, Matsushita T, Sato T, Fukutake K, et al. Updated results of an ongoing long-term phase 1/2 study of emicizumab (ACE910) in hemophilia A patients with or without inhibitors. Haemophilia 2016;22(Suppl 4):76. [DOI: 10.1111/hae.12980] [PMID: ] - DOI - PubMed
Nogami 2017 {published data only}
    1. Nogami, K, Taki, M, Matsushita, T, Sato, T, Fukutake, K, Kasai, R, Yoneyama, K, Yoshida, H, Shima, M. Updated results of a long-term phase 1/2 study of emicizumab (ACE910) in haemophilia A patients. British Journal of Haematology 2017;176(Suppl 1):112. [DOI: 10.1111/bjh.14613] [PMID: ] - DOI - PubMed
Nogami 2019 {published data only}
    1. Nogami K. A bispecific antibody mimicking factor VIII in hemophilia A therapy. Rinsho Ketsueki 2016;1(6):709-14. - PubMed
    1. Nogami K. Emicizumab, a bispecific antibody mimicking factor VIII: a novel alternative therapy for hemophilia A with inhibitors. Rinsho Ketsueki 2019;1(5):475-9. - PubMed
Pasi 2021 {published data only}
    1. Chowdary P, Georgiev P, Mant T, Creagh MD, Lissitchkov T, Bevan D, et al. Phase 1 and phase 1/2 extension study of fitusiran, an investigational RNAi therapeutic targeting antithrombin for the treatment of hemophilia: updated results in patients without inhibitors. Haemophilia 2017;23(Suppl 2):118-9. [CFGD REGISTER: HG103a]
    1. NCT02035605. A phase 1 study of an investigational drug, ALN-AT3SC, in healthy volunteers and hemophilia a or b patients. www.clinicaltrials.gov/show/NCT02035605 (first posted 14 Jan 2014). [CFGD REGISTER: HG103e]
    1. Pasi KJ, Georgiev P, Mant T, Creagh MD, Issitchkov TL, Bevan D, et al. A subcutaneously administered investigational RNAi therapeutic, fitusiran (ALN-AT3), targeting antithrombin for treatment of hemophilia: interim results in patients with hemophilia a or b. Haemophilia 2016;22:76. [CFGD REGISTER: HG103c]
    1. Pasi KJ, Georgiev P, Mant T, Creagh MD, Lissitchkov T, Bevan D, et al. A subcutaneously administered investigational RNAi therapeutic (ALN-AT3) targeting antithrombin for treatment of hemophilia: interim weekly and monthly dosing results in patients with hemophilia a or b. Blood 2015;126(23):551. [CFGD REGISTER: HG103h]
    1. Pasi KJ, Georgiev P, Mant T, Creagh MD, Lissitchkov T, Bevan D, et al. Phase 1 and phase 1/2 extension study of fitusiran, an investigational RNAi therapeutic targeting antithrombin for the treatment of hemophilia: updated results in patients with inhibitors. Haemophilia 2017;23 Suppl 2:88-9. [CFGD REGISTER: HG103b]
Patel 2019 {published data only}
    1. Patel A, Corman S, Chaplin S, Raimundo K, Sidonio R. Economic impact model of delayed factor viii inhibitor development in persons with hemophilia a receiving emicizumab for the prevention of bleeding events. Journal of Managed Care & Specialty Pharmacy 2018 ;24:10-a Suppl:S1-S112. [DOI: 10.18553/jmcp.2018.24.10-a.s1] - DOI
    1. Patel AM, Corman SL, Chaplin S, Raimundo K, Sidonio RF. Economic impact model of delayed inhibitor development in patients with hemophilia a receiving emicizumab for the prevention of bleeding events. Journal of Medical Economics 2019;1(12):1328-37. - PubMed
Pierce 2019 {published data only}
    1. Pierce GF, Hart DP, Kaczmarek R. Safety and efficacy of emicizumab and other novel agents in newborns and infants. Haemophilia 2019;25(5):e334-5. [DOI: 10.1111/hae.13822] - DOI - PubMed
Polack 2021 {published data only}
    1. Polack B, Trossaërt M, Cousin M, Baffert S, Pruvot A, Godard C. Cost-effectiveness of emicizumab vs bypassing agents in the prevention of bleeding episodes in haemophilia A patients with anti-FVIII inhibitors in France. Haemophilia 2021;27(1):e1-e11. [DOI: 10.1111/hae.14129] - DOI - PubMed
PRIORITY {published data only}
    1. NCT04621916. Preventing inhibitor recurrence indefinitely (PRIORITY). www.clinicaltrials.gov/show/NCT04621916 (first posted 9 Nov 2020).
RBR 8z787r 2018 {published data only}
    1. RBR-8z787r. A study without drug intervention to observe bleeding episodes, factor VIII infusions, and patient-reported outcomes in individuals with severe hemophilia A [A prospective non-interventional study of bleeding episodes, factor VIII infusions, and patient-Reported outcomes in individuals with severe hemophilia A]. trialsearch.who.int/Trial2.aspx?TrialID=RBR-8z787r (registered 6 Nov 2018).
Recht 2021 {published data only}
    1. Recht M. Safety first: tracking adverse events associated with new therapies for people with hemophilia. Journal of Thrombosis and Haemostasis 2021;19 Suppl 1:3-5. [DOI: 10.1111/jth.15188] - DOI - PubMed
Shima 2017 {published data only}
    1. JapicCTI-121934. Phase 1 study of ACE910. trialsearch.who.int/Trial2.aspx?TrialID=JPRN-JapicCTI-121934 (registered 17 Aug 2012).
    1. Shima M, Hanabusa H, Taki M, Matsushita T, Sato T, Fukutake K, et al. Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors. Blood Advances 2017;1(22):1891-9. [DOI: 10.1182/bloodadvances.2017006684] - DOI - PMC - PubMed
Shima 2019 {published data only}
    1. Shima M, Nogami K, Nagami S, Yoshida S, Yoneyama K, Ishiguro A, et al. A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors. Haemophilia 2019;25(6):979-87. [DOI: 10.1111/hae.13848] - DOI - PMC - PubMed
Stonebraker 2021 {published data only}
    1. Stonebraker JS, O'Mahony B, Noone D, Iorio A. Converting factor and nonfactor usage into a single metric to facilitate benchmarking the resources consumed for haemophilia care across jurisdictions and over time. Haemophilia 2021;27(5):e596-e608. [DOI: 10.1111/hae.14364] - DOI - PubMed
Stonebraker 2021a {published data only}
    1. Stonebraker JS, Ducore JM. Modelling future usage and cost of factor and emicizumab to treat haemophilia A for the US Western States Region IX haemophilia treatment centres. Haemophilia 2021;27(1):e22-e29. [DOI: 10.1111/hae.14159] - DOI - PubMed
Teeter 2022 {published data only}
    1. Teeter J, Charnigo R, Cossons N, Raje S, Hwang E, Le Duigou T. Safety and efficacy of marstacimab for prevention of bleeding episodes in paediatric patients with severe haemophilia A or moderately severe to severe haemophilia A with or without inhibitors. Haemophilia 2022;28(SUPPL 1):88-89. [DOI: 10.1111/hae.14479] - DOI
Wada 2017 {published data only}
    1. Wada H, Matsumoto T, Katayama N. Emicizumab prophylaxis in hemophilia A with inhibitors. New England Journal of Medicine 2017;377(22):2193-4. [DOI: 10.1056/NEJMc1712683] - DOI - PubMed
Warren 2021 {published data only}
    1. Warren BB, Chan A, Manco-Johnson M, Branchford BR, Buckner TW, Moyer G, et al. Emicizumab initiation and bleeding outcomes in people with hemophilia A with and without inhibitors: A single-center report. Research and Practice in Thrombosis and Haemostasis 2021;5(5):e12571. [DOI: 10.1002/rth2.12571] - DOI - PMC - PubMed
Yuan 2019 {published data only}
    1. Yuan D, Rode F, Cao Y. A systems pharmacokinetic/pharmacodynamic model for concizumab to explore the potential of anti-TFPI recycling antibodies. European Journal of Pharmceutical Sciences 2019;138:105032. [DOI: 10.1016/j.ejps.2019.105032] - DOI - PMC - PubMed
Zhou 2020 {published data only}
    1. Zhou ZY, Raimundo K, Patel AM, Han S, Ji Y, Fang H, et al. Model of short- and long-term outcomes of emicizumab prophylaxis treatment for persons with hemophilia A. Journal of Managed Care & Specialty Pharmacy 2020;1(9):1109-20. - PMC - PubMed

References to ongoing studies

EXPLORER 8 {published data only}
    1. NCT04082429. Research study to look at how well the drug concizumab works in your body if you have haemophilia without inhibitors. www.clinicaltrials.gov/show/NCT04082429 (first posted 9 Sep 2019).
HAVEN 5 {published data only}
    1. NCT03315455. Efficacy, safety, and pharmacokinetic study of prophylactic emicizumab versus no prophylaxis in hemophilia a participants. www.clinicaltrials.gov/show/NCT03315455 (first posted 20 Oct 2017). [CFGD REGISTER: HA159a]
    1. Wang S, Zhao X, Wang X, Sun J, Chuansumrit A, Zhou J, et al. A randomized, multicenter, open-label, phase III clinical trial to evaluate the efficacy, safety, and pharmacokinetics of prophylactic emicizumab versus no prophylaxis in persons with hemophilia A in the Asia-Pacific region (HAVEN 5). Research and Practice in Thrombosis and Haemostasis 2020;4(Suppl 1):480. [CFGD REGISTER: HA159b]
NCT05053139 {published data only}
    1. EUCTR2020-001048-24-IE. A research study investigating Mim8 in adults and adolescents with haemophilia A with or without inhibitors. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2020-001048-24-IE (registered 26 Nov 2020). [CFGD REGISTER: HA139a]
    1. NCT05053139. A research study investigating mim8 in adults and adolescents with haemophilia a with or without inhibitors. www.clinicaltrials.gov/show/NCT05053139 (first posted 22 Sep 2021). [CFGD REGISTER: HA139b]

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References to other published versions of this review

Olasupo 2021a
    1. Olasupo OO, Noronha N, Lowe MS, Ansel D, Bhatt M, Matino D. Non‐clotting factor therapies for preventing bleeds in people with hemophilia. Cochrane Database of Systematic Reviews 2021, Issue 8. Art. No: CD014544. [DOI: 10.1002/14651858.CD014544] [PMID: ] - DOI - PMC - PubMed

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