Elicit: Emicizumab in Hemophilia A Outcomes

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Emicizumab in Hemophilia A Outcomes

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May 6, 2026

Clinical outcomes of emicizumab prophylaxis in hemophilia A with FVIII inhibitors

Emicizumab prophylaxis in hemophilia A patients with FVIII inhibitors achieves 79-99% reductions in bleeding rates, zero bleeds in 63-88% of patients, and improved quality of life with generally favorable safety characterized mainly by injection site reactions.

Abstract

Emicizumab prophylaxis demonstrates substantial efficacy in reducing bleeding episodes in hemophilia A patients with FVIII inhibitors across diverse patient populations. Ten studies encompassing randomized trials, observational cohorts, and registry data show annualized bleeding rates ranging from 0.0 to 4.4 events per year on emicizumab, representing 79-99% reductions compared to previous bypassing agent prophylaxis or episodic treatment. Between 63-88% of patients achieved zero treated bleeding episodes, with particularly marked improvements in joint bleeding. Standard dosing consists of 3 mg/kg weekly for 4 weeks followed by 1.5 mg/kg weekly maintenance, though weekly and every-2-week regimens show comparable efficacy. Safety is favorable, with injection site reactions being most common (3.6-15% incidence) and thrombotic events rare but serious, particularly when combined with high-dose activated prothrombin complex concentrate. Antidrug antibodies developed in 2 of 88 pediatric patients, with one experiencing loss of efficacy. Quality of life improved significantly across multiple domains including physical health, daily functioning, and school attendance. These outcomes appear consistent across age groups from infants to elderly adults and are maintained over follow-up periods extending to 42 months.

Methods

We analyzed 10 sources from an initial pool of 200, using 8 screening criteria. Each paper was reviewed for 8 key aspects that mattered most to the research question. More on methods

Records from Elicit search

n = 200

Papers screened using: Population, Intervention, Clinical Outcomes, Study Design, Data Extractability, Study Type, Publication Type, Study Duration

n = 200

Papers screened out

n = 190

Papers included for extraction

n = 10

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Paper search

We performed a semantic search across over 138 million academic papers from the Elicit search engine, which includes all of Semantic Scholar and OpenAlex.

We ran this query: “Clinical outcomes of emicizumab prophylaxis in hemophilia A with FVIII inhibitors”

The search returned 200 total results from Elicit.

We retrieved 200 papers most relevant to the query for screening.

Screening

We screened in sources based on their abstracts that met these criteria:

We considered all screening questions together and made a holistic judgement about whether to screen in each paper.

Data extraction

We asked a large language model to extract each data column below from each paper. We gave the model the extraction instructions shown below for each column.

Extract study design and basic study characteristics, including:

Extract characteristics of hemophilia A patients with FVIII inhibitors enrolled in the study, including:

Extract all details about emicizumab prophylaxis regimen used in hemophilia A patients with inhibitors, including:

Extract details about treatments used before emicizumab in hemophilia A patients with inhibitors, including:

Extract all bleeding-related efficacy outcomes for hemophilia A patients with inhibitors on emicizumab prophylaxis, including:

Extract all safety and adverse event data for emicizumab use in hemophilia A patients with inhibitors, including:

Extract patient-reported outcomes and quality of life measures for hemophilia A patients with inhibitors receiving emicizumab, including:

Extract study timeline and follow-up information for emicizumab treatment in hemophilia A patients with inhibitors, including:

Results

Characteristics of included studies

The review included 10 studies evaluating emicizumab prophylaxis in hemophilia A patients with FVIII inhibitors, comprising randomized controlled trials, observational studies, registries, and systematic reviews.

Study

Full text retrieved?

Study Type

Setting

Sample Size (inhibitor patients)

Median/Mean Follow-up

Patient Age

Hemophilia Severity

J. Oldenburg et al., 2017

Yes

Randomized controlled trial

Multicenter

109

24.0 weeks

Median 28 years (range 12-75)

Most severe

Sheikh Bilal Ahmad et al., 2025

No

Retrospective observational

Single center

17

Not mentioned

Median 14 years

Severe

G. Young et al., 2019

Yes

Phase 3 nonrandomized open-label

Multicenter

85

Median 57.6 weeks

<12 years (pediatric)

97% severe

R. Muniz et al., 2023

No

Systematic review and meta-analysis

N/A

Not mentioned

Not mentioned

Not mentioned

Not mentioned

M. Shima et al., 2016

Yes

Open-label nonrandomized dose-escalation

Multicenter

At least 2 per cohort

12 weeks

12-59 years

Severe

Caroline Wall et al., 1971

No

Observational registry

Multicenter

117

Median 42 months

Not mentioned

Not mentioned

G. Giuffrida et al., 2021

No

Observational

Single center

5

Median 12 months

Median 26.8 years

Severe

Tiago Paiva Prudente et al., 2024

No

Systematic review and meta-analysis

N/A

56

Not mentioned

Not mentioned

Not mentioned

M. Borhany et al., 2024

Yes

Prospective observational

Single center

19

~18 months

Mean 19.7 years

Severe

Sarina Levy-Mendelovich et al., 2023

Yes

Prospective observational

Single center

51

Median 3.3 years

1 month to 80 years

Not explicitly mentioned

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The studies varied substantially in design, ranging from large multicenter randomized trials to small single-center observational studies. Follow-up duration ranged from 12 weeks to a median of 42 months, with the longest individual follow-up extending to 3.3 years. Patient populations spanned all age groups, from pediatric patients under 12 years to adults up to 80 years. Most studies enrolled patients with severe hemophilia A.

Prior to emicizumab, patients were predominantly treated with bypassing agents including recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (aPCC), administered either episodically or prophylactically. The UK registry study included patients previously on immune tolerance induction (ITI), with varying ITI outcomes including successful ITI, failed ITI, and deferred ITI.

Emicizumab dosing regimens

Emicizumab dosing varied across studies, with most employing a loading dose followed by maintenance therapy.

Study

Loading Dose

Maintenance Dose

Frequency

Route

J. Oldenburg et al., 2017

3.0 mg/kg weekly for 4 weeks

1.5 mg/kg

Weekly

Subcutaneous

Sheikh Bilal Ahmad et al., 2025

Not mentioned

Not mentioned

Not mentioned

Not mentioned

G. Young et al., 2019

3 mg/kg weekly for 4 weeks

Group A: 1.5 mg/kg
Group B: 3 mg/kg
Group C: 6 mg/kg

Group A: Weekly
Group B: Every 2 weeks
Group C: Every 4 weeks

Subcutaneous

R. Muniz et al., 2023

Not mentioned

Not mentioned

Not mentioned

Not mentioned

M. Shima et al., 2016

Cohort 1: 1.0 mg/kg
Cohorts 2-3: 3.0 mg/kg

Cohort 1: 0.3 mg/kg
Cohorts 2-3: 1.0-3.0 mg/kg

Weekly

Subcutaneous

Caroline Wall et al., 1971

Not mentioned

Not mentioned

Not mentioned

Not mentioned

G. Giuffrida et al., 2021

3 mg/kg weekly for 4 weeks

1.5 mg/kg

Weekly or every 2 weeks

Subcutaneous

Tiago Paiva Prudente et al., 2024

Not mentioned

Not mentioned

Not mentioned

Not mentioned

M. Borhany et al., 2024

3 mg/kg over first 4 weeks

6 mg/kg/month

Monthly

Subcutaneous

Sarina Levy-Mendelovich et al., 2023

Not mentioned

Not mentioned

Not mentioned

Not mentioned

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The most commonly reported regimen consisted of a loading dose of 3 mg/kg weekly for 4 weeks, followed by maintenance doses of 1.5 mg/kg weekly. The HAVEN 2 pediatric trial explored flexible dosing with weekly, every-2-week, and every-4-week maintenance regimens. All regimens were administered subcutaneously. One study allowed dose escalation to 3.0 mg/kg weekly for patients with suboptimal bleeding control.

Effects on bleeding outcomes

Emicizumab prophylaxis demonstrated substantial reductions in bleeding across all studies reporting quantitative outcomes.

Study

Annualized Bleeding Rate (ABR) on Emicizumab

ABR Before Emicizumab

Reduction

Zero Bleeds

Joint Bleeding

J. Oldenburg et al., 2017

2.9 events (95% CI 1.7-5.0)

23.3 events (95% CI 12.3-43.9) no prophylaxis

87%

63%

Significant differences observed

Sheikh Bilal Ahmad et al., 2025

0.0

20.7

100%

Not mentioned

Significantly reduced

G. Young et al., 2019

Group A: 0.3 (95% CI 0.17-0.50)
Group B: 0.2 (95% CI 0.03-1.72)
Group C: 2.2 (95% CI 0.69-6.81)

BPA prophylaxis (intraindividual)

99% vs BPA prophylaxis

77% (Group A)

Mean ABR in target joints decreased from 3.3 to 0

R. Muniz et al., 2023

Standard mean difference: -1.7 (95% CI -2.4 to -0.9)

N/A

N/A

Not mentioned

Not mentioned

M. Shima et al., 2016

Cohort 1: 4.4
Cohort 2: 0.0
Cohort 3: 0.0

Cohort 1: 32.5
Cohort 2: 18.3
Cohort 3: 15.2

Significant reduction across cohorts

73%

Cohort 1: 27.4 to 4.3
Cohort 2: 15.2 to 0.0
Cohort 3: 9.1 to 0.0

Caroline Wall et al., 1971

0.32 (95% CI 0.18-0.39)

N/A

89% reduction

88% (increased from 45%)

Not mentioned

G. Giuffrida et al., 2021

0.4

1.8

From 1.8 to 0.4

Not mentioned

Not mentioned

Tiago Paiva Prudente et al., 2024

Standard mean difference: -1.58 (95% CI -2.50 to -0.66)

N/A

N/A

Not mentioned

Not mentioned

M. Borhany et al., 2024

2.4%

53.6%

From 53.6% to 2.4%

Not mentioned

90% reduced to 2.4%

Sarina Levy-Mendelovich et al., 2023

Decrease observed

N/A

Not specified

Not mentioned

Not mentioned

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The magnitude of bleeding reduction was remarkably consistent across studies. The HAVEN 1 trial demonstrated an 87% reduction in bleeding rate with emicizumab prophylaxis compared to no prophylaxis (2.9 vs 23.3 events per year). When compared to previous bypassing agent prophylaxis, reductions were even more pronounced: 79% lower in HAVEN 1 group C, 99% lower in the HAVEN 2 pediatric trial, and 89% lower in the UK registry study.

Zero bleeding episodes were achieved by 63% of patients in HAVEN 1, 77% in HAVEN 2 group A, 73% in the Shima dose-escalation study, and 88% in the UK registry (increased from 45% pre-emicizumab). The percentage achieving zero bleeds increased substantially when comparing pre- and post-emicizumab periods.

Joint bleeding showed particularly marked improvement. Target joint bleeding decreased from a mean ABR of 3.3 to 0 in the pediatric HAVEN 2 trial. In the Shima study, joint bleeding rates fell from 27.4 to 4.3 in the low-dose cohort, and from 15.2 and 9.1 to 0.0 in the higher-dose cohorts. More than 90% of patients in the Borhany study experienced reduced joint bleeding to 2.4%.

Both systematic reviews quantified the treatment effect across multiple studies. Muniz et al. found a standard mean difference of -1.7 (95% CI -2.4 to -0.9, p<0.00001) for ABR in patients with inhibitors, while Prudente et al. reported a standard mean difference of -1.58 (95% CI -2.50 to -0.66, p=0.0008), though both noted moderate to substantial heterogeneity.

Breakthrough bleeding episodes occurred but were infrequent. In HAVEN 2, breakthrough bleeds were mostly traumatic. The Levy-Mendelovich study documented 31 breakthrough bleeding episodes across 22 of 51 participants over a median 3.3-year follow-up. The HAVEN 1 trial noted that breakthrough bleeding episodes were associated with high cumulative doses of activated prothrombin complex concentrate.

Safety and tolerability

Emicizumab demonstrated a favorable safety profile across studies, with most adverse events being mild and non-serious.

Study

Most Frequent Adverse Events

Serious Adverse Events

Thrombotic Events

Injection Site Reactions

Antidrug Antibodies

J. Oldenburg et al., 2017

Injection-site reactions (15%)

Thrombotic microangiopathy (2 participants)
Thrombosis (2 participants)

Associated with high-dose aPCC

15%

Not detected (but 2 had declining concentrations)

Sheikh Bilal Ahmad et al., 2025

One non-significant AE

Not mentioned

Not mentioned

Not mentioned

Not mentioned

G. Young et al., 2019

Nasopharyngitis
Injection-site reactions

None mentioned

No thrombotic events occurred

Common

4 developed ADAs (2 with neutralizing potential)

R. Muniz et al., 2023

Injection site reaction

Not mentioned

Not mentioned

Most frequent

Not mentioned

M. Shima et al., 2016

Nasopharyngitis (≥15%)

None reported

None reported

Mild (erythema, rash, pruritus, discomfort)

None developed

Caroline Wall et al., 1971

Cutaneous reactions (3.6%)
Headaches (1.4%)
Nausea (2.8%)
Arthralgia (1.4%)

3 arterial thrombotic events (2 possibly drug-related)

3 arterial thrombotic events

Not mentioned

Not mentioned

G. Giuffrida et al., 2021

None occurred

None occurred

None occurred

Not mentioned

Not mentioned

Tiago Paiva Prudente et al., 2024

Not mentioned

Not mentioned

Not mentioned

Not mentioned

Not mentioned

M. Borhany et al., 2024

Well tolerated

Not mentioned

Not mentioned

Not mentioned

Not mentioned

Sarina Levy-Mendelovich et al., 2023

Not mentioned

Not mentioned

Not mentioned

Not mentioned

Not mentioned

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Injection site reactions were the most consistently reported adverse event, occurring in 15% of participants in HAVEN 1, as a common event in HAVEN 2, and as the most frequent adverse event in the Muniz systematic review. These reactions were generally mild, consisting of erythema, rash, pruritus, and discomfort. Only one patient in the Shima study discontinued treatment due to injection-site erythema. The UK registry reported cutaneous reactions in 3.6% of patients.

Other common non-serious adverse events included nasopharyngitis, reported in at least 15% of patients in the Shima study and as a frequent event in HAVEN 2. The UK registry also reported headaches (1.4%), nausea (2.8%), and arthralgia (1.4%), which were generally non-severe and limited to early treatment.

Thrombotic events were rare but serious. HAVEN 1 reported thrombotic microangiopathy and thrombosis in 2 participants each, associated with multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding. The UK registry documented 3 arterial thrombotic events, with 2 possibly drug-related. No thrombotic events occurred in HAVEN 2, the Shima study, or the Giuffrida single-center experience.

Antidrug antibody (ADA) development was uncommon. HAVEN 1 detected no ADAs, though 2 participants showed declining emicizumab concentrations suggesting potential antibodies. In HAVEN 2, 4 participants developed ADAs, with 2 having neutralizing potential. One of these participants experienced loss of efficacy and discontinued treatment, while another had decreased plasma concentrations but remained on study without breakthrough bleeding. ADAs without neutralizing potential did not affect efficacy. No ADAs developed during the Shima study.

Treatment discontinuation rates were low. In HAVEN 2, 87% of participants completed 52 weeks of treatment, with discontinuations due to switching to commercial emicizumab or lack of efficacy. No participants discontinued due to adverse events in the Borhany study, and the Giuffrida study reported no adverse events requiring discontinuation.

Quality of life outcomes

Quality of life improved substantially with emicizumab prophylaxis in studies that measured patient-reported outcomes.

Study

Instruments Used

Key Findings

J. Oldenburg et al., 2017

Haem-A-QoL
EQ-5D-5L

Significant improvements in Haem-A-QoL and EQ-5D-5L scores at week 25

Sheikh Bilal Ahmad et al., 2025

Not mentioned

Not mentioned

G. Young et al., 2019

Haemo-QoL-SF
Inhib-QoL

Week 25 physical health domain score change from baseline: 21.1
Reduced days missed from school/daycare: baseline 0.41 to 0.25 at week 13
Improved caregiver-reported quality of life

R. Muniz et al., 2023

Not mentioned

Not mentioned

M. Shima et al., 2016

Not mentioned

Not mentioned

Caroline Wall et al., 1971

Haemtrack patient-reported data

Not mentioned

G. Giuffrida et al., 2021

HAL v 2.0
pedHAL v 2.0

Significant improvement in quality of life scores after 6 months

Tiago Paiva Prudente et al., 2024

Not mentioned

Not mentioned

M. Borhany et al., 2024

EQ-5D-5L

52.6% reduction in pain/discomfort
66.6% improvement in self-care
58.6% improvement in anxiety/depression
Enhanced independence in daily activities

Sarina Levy-Mendelovich et al., 2023

Not mentioned

Not mentioned

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HAVEN 1 demonstrated significant improvements in both disease-specific (Haem-A-QoL) and generic (EQ-5D-5L) quality of life measures at week 25. The pediatric HAVEN 2 trial showed near-maximal improvements in the Haemophilia-Quality of Life Short Form, with a clinically meaningful change of 21.1 points in the physical health domain at week 25. The trial also documented improved caregiver-reported quality of life using the Adapted Health-Related Quality of Life in Haemophilia Patients with Inhibitors questionnaire.

Impact on daily functioning was substantial. School and daycare attendance improved in HAVEN 2, with the proportion of days missed decreasing from a baseline mean of 0.41 to 0.25 at week 13. The Borhany study reported comprehensive improvements across multiple EQ-5D-5L domains: 52.6% reduction in pain/discomfort, 66.6% improvement in self-care, 58.6% improvement in anxiety/depression, and enhanced independence in daily activities. The Giuffrida single-center study found significant improvement in HAL scores after 6 months of emicizumab prophylaxis.

Joint health assessments complemented quality of life measures. The UK registry study reported that in a subgroup of 37 patients, total Haemophilia Joint Health Score (HJHS) improved in 36%, remained stable in 46%, and deteriorated in 18%, with a median within-person change of -2.0 (IQR -9 to 1.5, p=0.04). The Borhany study showed improvement in FISH scores from a baseline mean of 16 to 9, and HJHS scores from 10 to 4.

Synthesis

The evidence converges on emicizumab’s substantial efficacy in reducing bleeding in hemophilia A patients with FVIII inhibitors, though apparent heterogeneity in bleeding rates requires careful interpretation.

Explaining Heterogeneity in Bleeding Outcomes

Annualized bleeding rates on emicizumab ranged from 0.0 to 4.4 events per year across studies. This variation reflects predictable differences in study populations and treatment intensity rather than inconsistent drug efficacy. Studies with the lowest bleeding rates (0.0-0.4 events/year) enrolled patients who had previously received prophylactic bypassing agents or had longer observation periods allowing regression to stable state. In contrast, the HAVEN 1 trial’s higher rate of 2.9 events/year included patients transitioning from episodic treatment (group A) or no prophylaxis (group B), representing a more bleeding-prone baseline population.

Dose-response relationships were evident in the Shima dose-escalation study, where higher doses (1.0-3.0 mg/kg weekly) achieved zero joint bleeding, while the lowest dose (0.3 mg/kg) reduced but did not eliminate bleeding (ABR 4.4). The HAVEN 2 trial’s exploration of dosing frequency showed weekly and every-2-week regimens achieved similarly low bleeding rates (0.3 and 0.2 events/year), while the every-4-week regimen had modestly higher rates (2.2 events/year), suggesting diminishing efficacy at extended dosing intervals.

Population-Specific Contexts

Age did not substantially affect efficacy. The pediatric HAVEN 2 trial (patients <12 years) achieved a 99% reduction in bleeding versus bypassing agent prophylaxis, comparable to the 79-89% reductions seen in predominantly adult populations. However, the pediatric population showed particularly marked improvement in school attendance, reflecting the unique burden of hemophilia in this developmental stage.

Prior immune tolerance induction (ITI) status created distinct patient subgroups in the Levy-Mendelovich study. Among patients with successful ITI who were then exposed to FVIII during emicizumab prophylaxis, inhibitor levels remained zero, indicating successful tolerance maintenance. In contrast, patients who had failed ITI showed transient anamnestic responses following FVIII exposures, demonstrating that emicizumab does not restore immune tolerance but provides effective prophylaxis independent of tolerance status.

Methodological Quality Considerations

The systematic reviews by Muniz et al. and Prudente et al. reported moderate to substantial heterogeneity (I²=68.4%), which they attributed to differences in study populations and previous treatments. Both reviews weighted the large multicenter HAVEN trials most heavily, showing standard mean differences of -1.58 to -1.7 favoring emicizumab. Smaller observational studies contributed to heterogeneity but consistently showed bleeding reductions, supporting the robustness of the effect across settings.

The two thrombotic microangiopathy events in HAVEN 1 occurred specifically in patients receiving high cumulative doses of activated prothrombin complex concentrate for breakthrough bleeding, not in patients receiving emicizumab alone. The UK registry’s three arterial thrombotic events occurred in a real-world cohort with longer follow-up (median 42 months) and potentially more comorbidities than controlled trials, illustrating how safety profiles differ between efficacy trials and effectiveness studies.

Conclusions for Specific Contexts

For hemophilia A patients with FVIII inhibitors receiving emicizumab at standard doses (1.5 mg/kg weekly or equivalent every-2-week dosing), bleeding reductions of 79-99% can be expected compared to previous prophylaxis or episodic treatment, with 63-88% achieving zero treated bleeds. Joint bleeding shows particularly marked improvement, translating to improved joint health scores and quality of life.

In patients requiring concurrent bypassing agents for breakthrough bleeds, activated prothrombin complex concentrate should be used cautiously given the thrombotic risk, while recombinant FVIIa appears safer. For patients who have achieved successful ITI, occasional FVIII exposure during emicizumab prophylaxis does not appear to disrupt tolerance, whereas those with failed or deferred ITI may develop transient anamnestic responses.

The development of neutralizing antidrug antibodies, though rare (2 of 88 patients in HAVEN 2), can result in loss of efficacy, warranting monitoring in patients with breakthrough bleeding patterns. Extended dosing intervals beyond 2 weeks may result in higher bleeding rates, though individual variation suggests some patients may tolerate less frequent dosing.

References

J. Oldenburg, J. Mahlangu, Benjamin Kim, C. Schmitt, M. Callaghan, and 10 more\ (2017).Emicizumab Prophylaxis in Hemophilia A with Inhibitors. New England Journal of Medicine

Sheikh Bilal Ahmad, Asifa Amin, Malik Rohi, Sarwat Muzaffar, Sheikh Fahad\ (2025).A retrospective single-center study on the effectiveness and tolerability of emicizumab in patients with hemophilia a with and without inhibitors. Expert Review of Hematology

G. Young, R. Liesner, Tiffany Y. Chang, R. Sidonio, J. Oldenburg, and 11 more\ (2019).A multicenter, open-label, phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood

R. Muniz, R. M. Camelo, M. S. Araújo, M. M. Barbosa, A. Guerra, and 2 more\ (2023).Efficacy/effectiveness and safety of emicizumab prophylaxis of people with hemophilia A: a systematic review and meta-analysis. Expert Review of Hematology

M. Shima, H. Hanabusa, M. Taki, T. Matsushita, Tetsuji Sato, and 5 more\ (2016).Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. New England Journal of Medicine

Caroline Wall, H. Xiang, B. Palmer, Elizabeth Chalmers, P. Chowdary, and 10 more\ (1971).Prophylaxis in haemophilia. The Lancet

G. Giuffrida, D. Nicolosi, A. Condorelli, U. Markovic, F. Di Raimondo\ (2021).Use of Emicizumab in Patients with Hemophilia a with and without Inhibitors: A Single Center Experience. Blood

Tiago Paiva Prudente, R. M. Camelo, Rafael Alves Guimarães, M. Roberti\ (2024).Emicizumab prophylaxis in people with hemophilia A and inhibitors: a systematic review and meta-analysis. Sao Paulo medical journal = Revista paulista de medicina

M. Borhany, Aisha Arshad, H. Qureshi, Rukhshanda Nadeem, A. Jamal, and 1 more\ (2024).Emicizumab Prophylaxis in Patients with Severe Hemophilia A: Insights from A Resource Limited Country. Clinical and applied thrombosis/hemostasis

Sarina Levy-Mendelovich, Nitzan Atia, I. Budnik, A. Barg, E. Avishai, and 4 more\ (2023).Factor VIII inhibitors in hemophilia A treated with emicizumab: longitudinal follow-up of outcomes. Research and Practice in Thrombosis and Haemostasis

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A multicenter, open-label, phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors.

G. Young, R. Liesner, Tiffany Y. Chang, R. Sidonio, J. Oldenburg, V. Jiménez‐Yuste, J. Mahlangu, R. Kruse-Jarres, Michael Wang, Marianne Uguen, M. Doral, Lilyan Y. Wright, C. Schmitt, G. Levy, M. Shima, M. Mancuso

Blood·

2019·

319 citations

SourceDOI

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Study Design

- Study type: Phase 3, multicenter, nonrandomized, open-label trial - Single center vs multicenter: Multicenter - Sample size of hemophilia A patients with FVIII inhibitors: 85 participants aged <12 years - Study objectives related to emicizumab outcomes: Evaluate efficacy in terms of bleeding rates and HRQoL, and safety outcomes such as adverse events and antidrug antibodies

Patient Characteristics

- Age distribution: Pediatric (85 participants <12 years, 3 participants ≥12 years) - Hemophilia A severity: Severe (97%) - FVIII inhibitor status: High-titer inhibitors (>5 Bethesda units/mL) - Previous inhibitor history: 72% previously underwent ITI - Baseline joint damage: 39% had target joints

Emicizumab Dosing

- Loading dose schedule: 4 once-weekly doses of 3 mg/kg - Maintenance dose amount: - Group A: 1.5 mg/kg weekly - Group B: 3 mg/kg every 2 weeks - Group C: 6 mg/kg every 4 weeks - Dosing frequency: - Group A: weekly - Group B: every 2 weeks - Group C: every 4 weeks - Route of administration: subcutaneous - Any dose adjustments or modifications: Protocol amended to avoid using aPCC with emicizumab

Previous Treatment

- Type of bypassing agents used: aPCC for 13 participants, rFVIIa for 2 participants - Dosing regimen of previous treatment: Both episodic and prophylactic - Duration of previous treatment: Not explicitly mentioned - Reason for switching to emicizumab: Inferred as potential for more effective prophylaxis with reduced bleeding rates - Concurrent treatments allowed during emicizumab therapy: Episodic treatment with BPAs as needed; avoidance of aPCC due to safety concerns

Efficacy Outcomes

- Annualized bleeding rate (ABR) for all bleeds and treated bleeds: - Group A: 0.3 (95% CI, 0.17-0.50) - Group B: 0.2 (95% CI, 0.03-1.72) - Group C: 2.2 (95% CI, 0.69-6.81) - Percentage of patients with zero treated bleeding episodes: 77% (Group A) - Breakthrough bleeding episodes: Mostly traumatic; specific locations in supplemental Table 1 - Reduction in bleeding rate compared to previous treatment: 99% reduction in ABR compared to BPA prophylaxis - Joint bleeding rates specifically: Mean ABR in target joints decreased from 3.3 to 0 over time - Time to first bleeding episode: Not explicitly mentioned

Safety Outcomes

- Most frequent adverse events: Nasopharyngitis and injection-site reactions - Serious adverse events related to emicizumab: None mentioned - Thrombotic events: No thrombotic events (arterial or venous) occurred - Injection site reactions: Common adverse event - Development of antidrug antibodies (ADAs) and neutralizing antibodies: Four participants developed ADAs; two had neutralizing potential - Impact of ADAs on efficacy: One participant experienced loss of efficacy and discontinued treatment; another had decreased plasma concentrations but no breakthrough bleeding - Treatment discontinuations due to adverse events: One participant discontinued due to ADAs with neutralizing potential and lack of efficacy

Quality of Life

- Specific quality of life instruments used: Haemophilia-Quality of Life-Short Form (Haemo-QoL-SF), Adapted Health-Related Quality of Life in Haemophilia Patients with Inhibitors (Inhib-QoL) - Baseline and follow-up scores: Near-maximal improvements observed; week 25 physical health domain score change from baseline of 21.1 - Clinically meaningful changes in quality of life: Improvements across multiple domains; clinically meaningful differences defined as 10 points on physical health subscale - Patient satisfaction with treatment: Indirectly indicated by improved quality of life scores and reduced days missed from school/daycare - Impact on daily activities, work, or school attendance: Reduced days missed from school/daycare; baseline mean proportion of days missed was 0.41, decreased to 0.25 at week 13 - Caregiver burden assessments: Improved caregiver-reported quality of life using Inhib-QoL

Follow-up Duration

- Total study duration: Approximately 52 weeks - Median follow-up time on emicizumab: 57.6 weeks (range: 17.9-92.6 weeks) - Patient retention rates: 87% completed 52 weeks of treatment - Reasons for discontinuation: Switching to commercial emicizumab, lack of efficacy - Duration of efficacy and safety data collection: Up to 52 weeks - Long-term follow-up plans: Additional studies underway to characterize use in pediatric patients <1 year of age

Emicizumab, a bispecific humanized monoclonal antibody, bridges activated factor (F) IX and FX to restore the function of missing activated FVIII in hemophilia A. Emicizumab prophylaxis in children with hemophilia A and FVIII inhibitors was investigated in a phase 3 trial (HAVEN 2; NCT02795767). Participants, previously receiving episodic/prophylactic bypassing agents (BPAs), were treated with subcutaneous emicizumab: 1.5 mg/kg weekly (group A), 3 mg/kg every 2 weeks (group B), or 6 mg/kg every 4 weeks (group C). Pharmacokinetics, safety, and efficacy (including an intraindividual comparison of participants from a noninterventional study) were evaluated. Eighty-five participants aged <12 years were enrolled. In group A (n=65), the annualized rate of treated bleeding events (ABR) was 0.3 (95% CI, 0.17-0.50), and 77% had no treated bleeding events. Intraindividual comparison of 15 participants who previously took BPA prophylaxis showed that emicizumab prophylaxis reduced the ABR by 99% (95% CI, 97.4-99.4). In groups B (n=10) and C (n=10), ABRs were 0.2 (95% CI, 0.03-1.72) and 2.2 (95% CI, 0.69-6.81), respectively. The most frequent adverse events were nasopharyngitis and injection-site reactions; no thrombotic events occurred. Two of 88 participants developed antidrug antibodies (ADAs) with neutralizing potential, ie, associated with decreased emicizumab plasma concentrations; 1 experienced loss of efficacy; in the other, ADAs disappeared over time without intervention or breakthrough bleeding. All other participants achieved effective emicizumab plasma concentrations, regardless of the treatment regimen. Emicizumab prophylaxis has been shown to be a highly effective novel medication for children with hemophilia A and inhibitors.

Introduction

Congenital hemophilia A results from mutations in the factor VIII (FVIII) gene (F8) with consequent deficiency of coagulation FVIII, which leads to a lifelong bleeding tendency. Frequent and recurrent bleeding into joints, muscles, and potentially life-threatening locations (central nervous system) can result in significant long-term sequelae. 1 3][4][5][6] However, up to 30% of previously untreated persons with hemophilia A develop neutralizing anti-FVIII antibodies (inhibitors), which render replacement therapy ineffective. This leads to significant medical complications, increased morbidity and mortality, and decreased health-related quality of life. 7,8 Inhibitors typically develop within the first 50 exposure days to FVIII therapy and therefore early in life (median age, 1.7-3.3 3][14][15][16] Furthermore, because children with inhibitors frequently require high-volume infusions, they are more likely to require central venous access devices (CVADs) and as a result are prone to catheter-related complications, including infection and/or thrombosis. 17,18 More effective prophylactic options with reduced treatment burden are needed for pediatric persons with hemophilia A with inhibitors.

3][24] In a phase 3 trial, we assessed the efficacy, safety, and pharmacokinetics of emicizumab prophylaxis in pediatric persons with hemophilia A with FVIII inhibitors.

Study design and participants

This is an ongoing phase 3, multicenter, nonrandomized, openlabel trial, investigating emicizumab prophylaxis in children with hemophilia A with inhibitors. To enable direct comparisons of outcomes with prior BPAs vs emicizumab prophylaxis, all participants from a noninterventional study (NIS; clinicaltrials.gov #NCT02476942) who met the eligibility criteria for this study were permitted to enroll in HAVEN 2 (group A) and were included in an intrapatient comparison. These patients were selected by site investigators based on their availability and eligibility. Individuals aged 2 to 11 years with congenital hemophilia A and a history of high-titer FVIII inhibitors ($5 Bethesda units/mL), and who were receiving episodic or prophylactic treatment with BPAs, were eligible to participate. Adolescents aged 12 to 17 years weighing ,40 kg were also permitted to enroll, provided they met the other eligibility criteria. Infants/toddlers aged ,2 years and determined by the investigator to have a high unmet medical need could potentially be enrolled, depending on results of an interim analysis (further information on the interim analysis can be found later in this section). Participants were required to have adequate hematological, hepatic, and renal function. Patients were ineligible for the study if they had ongoing/ planned ITI therapy. Comprehensive eligibility criteria are listed in the supplemental Methods (available on the Blood Web site).

Participants received emicizumab prophylaxis subcutaneously with 4 once-weekly loading doses of 3 mg/kg body weight followed by a maintenance regimen of 1.5 mg/kg weekly (group A; Figure 1 ). Patients were provided with exact weight-based doses, without rounding for either loading or maintenance dosing; emicizumab was discarded if need be.

As this was a first-in-child study, a joint monitoring committee (JMC) comprising external experts and sponsor members was established to review interim analysis results after the first 10 participants had completed $12 weeks of treatment. This review was performed to determine whether the maintenance dose was appropriate in children, and whether participants aged ,2 years could be recruited. Both were considered appropriate. To investigate the possibility of flexible dosing frequencies, maintenance regimens of 3 mg/kg every 2 weeks (group B) and 6 mg/kg every 4 weeks (group C) were subsequently added to the study (Figure 1 ). Recruitment to groups B and C occurred in parallel after group A was fully enrolled. Alternate group allocation was performed via an interactive voice/web response system (S-Clinica Sprl, Brussels, Belgium).

Participants could receive episodic treatment with BPAs as needed (eg, for management of breakthrough bleeds; see supplemental Methods for details). Following identification of thrombotic events (TEs) and thrombotic microangiopathy (TMA) cases in participants enrolled in the HAVEN 1 study who received multiple doses of aPCC while receiving emicizumab, the HAVEN 2 protocol was amended to recommend avoiding the use of aPCC in combination with emicizumab in participants who had the option of using other BPAs to treat bleeds. If aPCC was the only available BPA, the lowest dose expected to achieve hemostasis was to be prescribed, with #50 U/kg administered as an initial dose. Study treatment was administered for $52 weeks; participants could then continue in this study or switch to commercial emicizumab if available.

Using an electronic handheld device, the primary caregivers of participants recorded all bleeding events and information about these events as soon as they occurred, in addition to administration of hemophilia-related medications and emicizumab. Definitions of bleeding events and collection of records via a Bleed and Medication Questionnaire were as described previously. 23 ata on health-related quality of life (HRQoL) were collected during clinic visits prior to emicizumab dosing at week 1 and every 12 weeks thereafter. Participants aged $8 years used the Haemophilia-Quality of Life-Short Form (Haemo-QoL-SF) questionnaire. 25 Caregivers reported their perception of their child's HRQoL, and on aspects of caregiver burden via the Adapted Health-Related Quality of Life in Haemophilia Patients with Inhibitors (Inhib-QoL) questionnaire; the Inhib-QoL tool was field tested and validated in a group of caregivers of children with inhibitors. 26 Numbers of days missed by participants from daycare/school due to hemophilia-related problems were also collected.

With the exception of minor surgeries such as CVAD removals and tooth extractions, planned surgeries were prohibited during the study. However, unplanned surgeries did occur. Perioperative management was determined by the treating physician.

The trial was initiated in July 2016 and conducted at 27 centers in 10 countries across North America, Central America, Europe, Africa, and Asia (supplemental Methods) in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki. The protocol was approved by the relevant independent ethics committee/institutional review board at each center. Written informed consent was obtained from parents or legally acceptable representatives, and assent was obtained from children (aged 8-11 years) and adolescents (aged 12-17 years).

End points

HAVEN 2 was designed to be a descriptive study; as such, no primary or secondary end points were defined. Efficacy end points were (1) the rate of treated bleeding events (hereafter referred to as the bleeding rate), all bleeding events (treated and untreated), and spontaneous, joint, and target joint bleeding events; (2) intraindividual comparisons of bleeding rates in participants aged ,12 years with well-documented BPA prophylaxis from participation in the NIS; and (3) HRQoL of children aged 8 to 17 years and caregiver-reported HRQoL and aspects of caregiver burden.

The presence of target joints was recorded at trial entry. Target joints were defined as major joints (eg, hip, elbow, shoulder, knee, ankle) in which $3 bleeding events occurred over a 24-week period. Target joint resolution was defined as #2 bleeding events in a 52-week period in a joint previously defined as a target joint 27 (supplemental Methods). Safety end points were adverse events, serious adverse events, thrombotic events, injection-site reactions, abnormal laboratory values (hematology and serum chemistries), and the development of antidrug antibodies (ADAs). In the absence of a neutralizing ADA assay, pharmacokinetic and pharmacodynamic profiles were used to identify ADAs with neutralizing potential (see supplemental Methods). Laboratory abnormalities were assessed at screening, every 2 weeks during weeks 2 to 4, every 4 weeks during weeks 7 to 49, and every 12 weeks from week 57 onwards. Antiemicizumab antibodies were assessed predose at weeks 1, 5, 17, 33, and 49, and every 12 weeks from week 57 onward. The pharmacokinetic objective was to characterize emicizumab exposure over time to confirm the appropriate pediatric dose. Pharmacokinetic sampling was performed prior to drug administration on day 1, every week during weeks 1 to 4, every 2 weeks during weeks 5 to 9, every 4 weeks during weeks 13 to 37, every 8 weeks during weeks 41 to 57, and every 12 weeks thereafter.

Statistical analysis

Depending on recruitment feasibility and clinical considerations, ;60 eligible participants were to be enrolled in group A. Participants aged ,2 years were enrolled in group A following the interim analysis and JMC review; recruitment remained open for participants aged ,2 years after the group was fully accrued. Ten participants each were enrolled in groups B and C to support pharmacokinetic characterization; the study was not designed for efficacy comparisons across regimens. No formal statistical hypothesis testing was planned. All analyses are descriptive. The primary analysis for all arms was performed 52 weeks after all participants in the primary population of group A (aged $2 years) had enrolled or withdrawn prematurely, whichever occurred first. At the primary analysis, 59 participants had completed .52 weeks of the study. The clinical cutoff date for this analysis was 30 April 2018.

Efficacy and HRQoL analyses were performed in treated participants aged ,12 years; all participants aged ,12 years who had been followed in the NIS and subsequently enrolled into group A were involved in the intraindividual analysis; results are presented for those previously treated with prophylactic BPAs. A negative binomial regression model, accounting for different follow-up times, was used to characterize bleed-related end points and compare bleed rates in the intraindividual comparison. The efficacy period was defined by the number of days between the first dose of emicizumab and the clinical cutoff date or the participant's withdrawal from the study (whichever occurred earlier). The mean proportion of days missed of school/ daycare was calculated by dividing the number of patients who missed any day at school/daycare by the number of respondents to the questionnaire. Safety was analyzed in all participants who received $1 dose of emicizumab. Trough emicizumab plasma concentrations (mean and 95% confidence intervals [CI]) were calculated and presented by regimen.

Data analysis was conducted by the trial statistician and a pharmacologist (employed by the sponsor) who vouched for the completeness and accuracy of the data and analyses. Data were available to all authors, who confirm adherence to the protocol and the statistical analysis plan.

Participant demographics

Overall, 88 male participants were enrolled (n 5 68 in group A; n 5 10 in group B; n 5 10 in group C) with a median age of 7 years (range, 1-15 years). Eighty-five participants were aged ,12 years, and 3 were aged $12 years. The majority of participants had severe hemophilia A (97%), had previously undergone ITI (72%), and were receiving treatment with prophylactic BPAs (75%). Thirty-four of 88 participants (39%) had target joints at baseline (Table 1 ). Among the 19 who participated in the NIS, 18 participants were ,12 years; of those 15 were managed with prior BPA prophylaxis and 3 with prior BPA ondemand.

At data cutoff, 59 participants (87%) enrolled in group A had completed 52 weeks of treatment. Three participants discontinued from study treatment due to switching to commercial emicizumab (n 5 2, group A) or lack of efficacy (n 5 1, group C; Figure 2 ).

Efficacy

The median duration (range) of the efficacy period in participants receiving the once-weekly regimen (group A) was 57.6 weeks (17.9-92.6 weeks). In the 65 participants aged ,12 years in this group, the annualized bleed rate (ABR) was 0.3 (95% CI, 0.17-0.50), and 77% of participants had zero treated bleeding events. The rates of other bleed-related end points (all bleeding events, and treated spontaneous, joint, or target joint bleeds) were low (Table 2 ). Overall, 22 treated bleeding episodes were reported in 15 of 65 group A participants aged ,12 years, 91% of which were traumatic; the locations of these bleeds are reported in supplemental Table 1. In the subset of patients in cohort A with target joints, who had completed at least 48 weeks on study, the mean ABR in the first 24 weeks was 3.3 (95% CI, 0.7-9.2) whereas in the second 24 weeks, the mean ABR was 0 (not applicable to 3.7), suggesting that even in patients with a more severe phenotype, bleed rates continued to decrease with ongoing emicizumab treatment.

Among the 15 participants aged ,12 years receiving BPA prophylaxis who had participated in the NIS, intraindividual comparisons showed a substantially lower bleeding rate with once-weekly emicizumab compared with prior standard prophylaxis, which included aPCC for 13 participants and rFVIIa for 2 (see Figure 3 for individual patient treatment duration). The ABR with emicizumab was 0.3 (95% CI, 0.12-0.56) vs 21.1 (95% CI, 15.99-27.82) with prior BPA, representing a 99% (95% CI, 97.4-99.4) reduced risk of bleeding with emicizumab (Figure 3 ). The median duration (range) of the efficacy period among these 15 participants was 89.1 weeks (56.0-92.6 weeks).

The median duration (range) of the efficacy period in participants receiving emicizumab every 2 weeks (group B) or every 4 weeks (group C) was 21.3 weeks (18.6-24.1 weeks) and 19.9 weeks (8.9-24.1 weeks), respectively. ABRs in these groups were 0.2 (95% CI, 0.03-1.72) and 2.2 (95% CI, 0.69-6.81), with 90% and 60% of participants having reported zero treated bleeding events, respectively ( participant developed ADAs with neutralizing potential resulting in undetectable levels of emicizumab within the first 8 weeks of treatment. No participant from groups A, B, or C reported .3 treated bleeding events during the efficacy period (Tables 2 and 3 ).

In 23 participants receiving emicizumab prophylaxis for $52 weeks who had target joints at baseline, 45 of 45 target joints (100%) were resolved. Twenty of 23 participants (87%) had no target joint bleeding events while on emicizumab, including 2 participants who had 3 and 5 target joints, respectively, at baseline.

Of 43 participants who started the study with a CVAD, 21 (49%) underwent CVAD removals while on study (supplemental Figure 1 ). Seventeen (81%) of these procedures were performed without the administration of BPA prophylaxis; only 1 resulted in a postoperative treated bleeding event. Information on surgical procedures performed in phase 3 studies of emicizumab, including HAVEN 2, will be presented in a future report.

HRQoL

Near-maximal improvements were observed and sustained across multiple domains of the Haemo-QoL-SF and Adapted Inhib-QoL questionnaires, whose scores range from 0 to 100, with lower scores reflecting better HRQoL. Clinically meaningful differences are 10 points for the score on the physical health subscale. In patients receiving emicizumab prophylaxis, the week 25 physical health domain score reflected a change from baseline of 211. A loading dose of 3 mg/kg emicizumab was given for 4 weeks followed by 1.5 mg/kg per week.

NA, not applicable. See Table 1 for expansion of other abbreviations.

*Model-based annualized rates were estimated using negative binomial regression.

that their child had not missed any days at daycare/school during the 4 weeks prior to the questionnaire completion; this increased to 61% by week 13 of emicizumab treatment.

At baseline, the mean proportion of days missed of daycare/ school was 0.41 (95% CI, 0.29-0.53); following emicizumab treatment, this decreased to 0.25 (95% CI, 0.01-0.49) at week 13 and remained low at all subsequent time points.

Safety

Overall, 712 adverse events were reported in 82 of 88 participants (Table 4 ). The most common adverse events were nasopharyngitis (33

Pharmacokinetics and immunogenicity

Mean trough plasma concentrations of emicizumab slightly above 50 mg/mL were observed at week 5 following 4 loading doses for all groups (Figure 4 ). Mean steady-state trough concentrations were maintained at effective levels across all dosing regimens until the time of analysis: ;50, 48, and 38 mg/mL in groups A, B, and C, respectively. Emicizumab concentrations above 30 mg/mL are predicted to provide clinically meaningful control of bleeding. 28 Pharmacokinetic profiles were consistent across age groups and body weights (supplemental Figures 3 and 4 ).

Four participants tested positive for ADAs, 2 of whom had ADAs with neutralizing potential based on pharmacokinetics, decreased reported FVIII activity, and prolongation of activated partial thromboplastin time (aPTT). ADAs were detected at week 5 (at the end of the loading dose period) in 1 of these participants; subsequently, emicizumab plasma concentrations rapidly declined to undetectable levels within 4 weeks of ADA positivity, reported FVIII activity using a human reagent-based chromogenic assay dropped to ;1%, and aPTT was prolonged. This participant discontinued emicizumab due to lack of efficacy. The other participant experienced a gradual decrease in emicizumab plasma concentrations to low but detectable levels; ADA positivity was detected at week 32 with a corresponding reduction in reported human reagent-based chromogenic FVIII activity, however, aPTT remained within normal values. This participant remained on study without modifying the treatment regimen and did not experience any bleeding events. Data collected after the clinical cutoff date (48 weeks after initial detection of ADAs) showed that he had become ADA-negative, with restoration of anticipated emicizumab plasma concentrations. No clear risk factors for developing ADAs were identified, though 1 patient had a history of high-titer FVIII inhibitor at time of inhibitor diagnosis. ADAs without neutralizing potential did not impact efficacy, and no ADA was associated with hypersensitivity or anaphylaxis. Further details are provided in the supplemental Results.

Discussion

In the HAVEN 2 study, once-weekly subcutaneous emicizumab prophylaxis resulted in a very low bleeding rate in children with hemophilia A and FVIII inhibitors, with 77% of participants having no treated bleeding events. Furthermore, 100% of all evaluable target joints resolved during the study period. Intraindividual comparison demonstrated a 99% reduction in bleeding rate with emicizumab vs BPA prophylaxis in a preceding NIS, Comparison of ABR for treated bleeds in individual participants receiving emicizumab 1.5 mg/kg once weekly during HAVEN 2 vs BPA prophylaxis in the NIS. The efficacy periods within NIS and HAVEN 2 for individual patients are described below the x-axis. Participants exposed to emicizumab started with loading dose 3 mg/kg per week for 4 weeks followed by 1.5 mg/kg per week. Treated bleed is defined as a bleed followed by treatment of bleed. Bleeds due to surgery/procedure are excluded.

which provided a robust standard-of-care comparator that controlled for participant-related confounders in this otherwise descriptive study.

Efficacy was maintained with less frequent emicizumab dosing; all participants experienced 3 or fewer treated bleeding events, regardless of dosing schedule received. 3][24] The numerically higher ABR in group C compared with groups A or B was primarily driven by 2 participants in this small sample. One participant had multiple active target joints at baseline and experienced 3 bleeding events into these joints over ;20 weeks of emicizumab treatment (ABR of 7.9). The second participant developed ADAs with neutralizing potential following the loading period, and experienced 2 bleeding events within the first 8 weeks of treatment when emicizumab plasma concentration was near minimal (ABR of 11.8). As the ABRs in children dosed every 4 weeks were numerically higher in this small sample with a short follow-up, health care professionals may consider following patients on this regimen more closely.

One of the most frequent minor surgeries in children with hemophilia is CVAD procedures, 29 either to secure access for lifesaving coagulation factor, or due to complications with the CVAD itself (eg, infection, dysfunction). By far the most common procedure that occurred on HAVEN 2 was a CVAD removal, with nearly one-half of patients who started the study with a CVAD removing it by the end. Notably, 17 of 21 CVAD removals (81%) were performed without the administration of BPA prophylaxis, and resulted in just 1 treated bleed.

HAVEN 2 represents the largest prospective bleed prevention study in pediatric persons with hemophilia A and inhibitors A loading dose of 3 mg/kg emicizumab was given for 4 weeks followed by the maintenance dose listed.

See Tables 1 and 2 for expansion of abbreviations.

*Model-based annualized rates were estimated using negative binomial regression.

to date, demonstrating lower bleeding rates compared with those previously reported in this population with BPA prophylaxis 14,15,30 Indeed, bleeding rates reported here are more in range of those achieved in pivotal studies of FVIII prophylaxis in children with hemophilia A without inhibitors (supplemental Table 3 ). Notably, this is the first report of a treatment resolving target joints in an inhibitor population, which until now has only been reported when using FVIII products in patients without inhibitors. 31,32 These findings translated into improvements in participants' HRQoL, particularly in the physical health domain scores. Young children stand to benefit most, as they are less likely to have developed permanent joint damage compared with adolescents or adults; preventing bleeding or resolving target joints may yield lifelong benefit by maintaining joint health until adulthood.

Emicizumab had a favorable safety profile in children, with no TE or TMA events. This may be related to low bleed rate and low concomitant aPCC exposure (use of concomitant aPCC treatment was low, with only 2 patients treated with a single dose of ,50 U/kg each). 23 As expected for a humanized monoclonal antibody, ADAs were observed; the frequency was low and consistent with rates observed across 3 other HAVEN studies. 33 th participants who reported ADAs with neutralizing potential exhibited distinctive clinical courses, 1 experiencing loss of efficacy, and the other spontaneous resolution of ADA with recovery of expected pharmacokinetic exposure. Importantly, ADAs without neutralizing potential were not associated with higher bleeding rates, and the safety profile in participants testing positive for ADAs was similar to those without ADAs.

Effective trough concentrations of emicizumab were sustained with all maintenance regimens throughout the study, consistent across a wide range of ages and body weights. Slightly lower trough concentrations with maintenance dosing every 4 weeks were as expected based on pharmacokinetic simulations, 34 and efficacy was comparable with adolescent/adult participants as predicted by pharmacokinetic-efficacy simulations. 34,35 Following the approved prescribing information (eg, regarding a strict weightbased dosing regimen) is recommended for clinical practice.

Limitations of this study are characteristic of pediatric hemophilia trials, which are often descriptive in nature and constrained by recruitment challenges. The later addition of groups B and C resulted in smaller numbers and shorter follow-up in those groups, although overall this study enrolled a relatively large Thromboembolic event 0 0 0 0 TMA 0 0 0 0

Multiple occurrences of the same adverse event in 1 individual are counted only once except for in the "Total adverse events" row, in which multiple occurrences of the same adverse event are counted separately.

*Seventeen participants experienced 21 events: device-related infection (n 5 2), muscle hemorrhage (n 5 2), hemorrhage (n 5 2), asthma (n 5 2), mouth hemorrhage (n 5 1), appendicitis (n 5 1), bronchiolitis (n 5 1), catheter site infection (n 5 1), epididymitis (n 5 1), clavicle fracture (n 5 1), fall (n 5 1), head injury (n 5 1), ligament sprain (n 5 1), mouth injury (n 5 1), positive for ADAs with neutralizing potential (n 5 1), ketoacidosis (n 5 1), and headache (n 5 1). †One participant withdrew from emicizumab treatment due to ADAs with neutralizing potential and subsequent lack of efficacy. ‡Fifteen participants experienced 19 events: asthma (n 5 3), hemorrhage (n 5 2), appendicitis (n 5 1), catheter site infection (n 5 1), device-related infection (n 5 1), epididymitis (n 5 1), sinusitis (n 5 1), sleep apnea syndrome (n 5 1), mouth hemorrhage (n 5 1), chest pain (n 5 1), clavicle fracture (n 5 1), positivity for ADAs with neutralizing potential (n 5 1), diabetes mellitus (n 5 1), ketoacidosis (n 5 1), pain in extremity (n 5 1), and headache (n 5 1). §Thirty participants experienced 67 events: injection-site reaction (n 5 57), indeterminable ABO blood type (n 5 3), eosinophil count increased (n 5 1), positive for ADAs with neutralizing potential (n 5 1), ecchymosis (n 5 1), erythema (n 5 1), urticaria (n 5 1), nausea (n 5 1), and cough (n 5 1).

‖All but 2 of the injection-site reactions were grade 1 in intensity and resolved within 1 to 5 days without treatment. No participant discontinued due to injection-site reactions. ¶The numbers for systemic hypersensitivity/anaphylactic/anaphylactoid reaction using the Sampson criteria include all participants who experienced indicative symptoms. One participant experienced symptoms of abdominal pain and cough that were identified as a potential systemic hypersensitivity/anaphylactic/anaphylactoid reaction using the protocoldefined search criteria; however, medical review of the case confirmed that this was not indicative of a systemic hypersensitivity, anaphylactic, or anaphylactoid reaction.

number of participants worldwide, representative of pediatric inhibitor patients reported in prior studies. 15,30 Furthermore, additional studies are under way or are required to characterize the use of emicizumab in pediatric patients ,1 year of age, including previously untreated patients, as well as those on ITI therapy. In conclusion, emicizumab prophylaxis is well tolerated, and can prevent or substantially reduce bleeds in children with hemophilia A with FVIII inhibitors. Clinically meaningful efficacy and pharmacokinetic results were achieved with all 3 dosing regimens assessed, suggesting the potential for reduced treatment burden. Despite a rapidly evolving treatment landscape in hemophilia, children have been largely excluded from recent trials of novel agents; thus, emicizumab stands to become the next-generation standard of care for pediatric persons with hemophilia A with FVIII inhibitors.

Authorship

Contribution: G.Y., T.C., J.O., J.M., R.K.-J., M.U., C.S., G.G.L., and M.S. contributed to the study design; G.Y., R.L., R.S., J.O., V.J.-Y., J.M., R.K.-J., M.W., M.S., and M.E.M. collected data for the study; G.Y., R.L., T.C., R.S., V.J.-Y., M.U., M.Y.D., L.Y.W., C.S., G.G.L., and M.E.M. participated in the analysis and interpretation of the data; and all authors critically reviewed the manuscript, approved the final version, and support this publication.

Conflict-of-interest disclosure: G.Y. has received honoraria and consulting fees from Alnylam, Bayer, Bioverativ, CSL Behring, Genentech/ Roche, Grifols, Kedrion, Novo Nordisk, Shire, Spark, and uniQure, and an investigator-initiated grant award from Genentech. R.L. has consulted for CSL Behring, Novo Nordisk, Roche, Octapharma, Sobi/Biogen, Baxalta/ Shire, Grifols, and Bayer. T.C. and L.Y.W. are employed by Genentech. R.S. has consulted for Bayer, Pfizer, UniQure, BioMarin, Novo Nordisk, Shire, Genentech/Roche, Spark, Octapharma, Grifols, Kedrion, and Bioverativ, and has investigator-initiated grant funding from Bioverativ, Kedrion/Grifols, Genentech, and Octapharma. J.O. has received honoraria and consulting fees from Chugai, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, and Shire, and grants from CSL Behring, Novo Nordisk, Octapharma, Pfizer, and Shire. V.J-Y. has received grants and personal fees from Novo Nordisk, Shire, Bayer, Pfizer, Grifols, Sobi, and Octapharma, and personal fees from CSL Behring and Roche. J.M. has received research grant support from Bayer, Biogen, Biomarin, CSL Behring, Novo Nordisk, Sobi, Roche, and uniQure; personal fees from Amgen, Bayer, Biotest, Biogen, Baxalta, CSL Behring, Catalyst Biosciences, Chugai, Freeline, LFB, Novo Nordisk, Roche, and Spark; and has been a member of a speaker's bureau for Alnylam, Bayer, Biotest, Biogen, Novo Nordisk, Pfizer, Sobi, Shire, Roche, the International Society on Thrombosis and Haemostasis, and the World Federation of Hemophilia. R.K.-J. has consulted for CSL Behring, Genentech/Roche, Grifols, and Pfizer, and has received research funding from CSL Behring, Genentech/ Roche, and Pfizer. M.W. has consulted for Bayer Healthcare, Bioverativ, CSL Behring, Novo Nordisk, Octapharma, Roche/Genentech, and HEMA Biologics. M.U. is employed by Roche. M.Y.D. and C.S. are employed by and hold stock with Roche. G.G.L. is employed by Genentech and holds stock with Roche. M.S. has received grants and personal fees from Shire, Bioverativ, Chugai, Novo Nordisk, and Bayer; grants from Roche, CSL Behring, and Pfizer; and personal fees from Sysmex. M.E.M. has received personal fees from Bayer, CSL Behring, Novo Nordisk, Roche, Octapharma, Pfizer, Sobi/Biogen, Bioverativ, Baxalta/Shire, Biotest, and Grifols. ORCID profiles: J.O., 0000-0002-1585-4100; V.J.-Y., 0000-0003-3937-3499; M.W., 0000-0001-9289-4862. The online version of this article contains a data supplement.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734.

Acknowledgements

AcknowledgmentsEditorial assistance for the development of this manuscript, under the direction of the authors, was provided by Maria Alfaradhi and Rebecca A. Bachmann of Gardiner-Caldwell Communications.Sylvia Von Mackensen is the developer of the Haemo-QoL-SF and Adapted Inhib-QoL questionnaires.This work was supported by F. Hoffmann-La Roche Ltd and Chugai Pharmaceutical Co, Ltd.Editorial assistance was funded by F. Hoffmann-La Roche Ltd.

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