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Pharmacokinetics and Pharmacodynamics of Emicizumab in Hemophilia A

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May 5, 2026

Pharmacokinetics/pharmacodynamics of emicizumab in hemophilia A

Emicizumab exhibits predictable, dose-proportional pharmacokinetics with sustained plasma concentrations that produce FVIII-equivalent hemostatic activity and reduce bleeding rates by 94% through an exposure-response relationship plateauing above 30 µg/mL.

Abstract

Emicizumab demonstrates dose-proportional, predictable pharmacokinetics across diverse hemophilia A populations, with subcutaneous administration achieving sustained trough concentrations of 42-66 µg/mL during maintenance dosing across weekly (1.5 mg/kg), every-2-weeks (3 mg/kg), and every-4-weeks (6 mg/kg) regimens. The median elimination half-life is 23-30 days, with time to steady-state of 12 weeks with loading doses and 24 weeks without. Interindividual variability in trough concentrations is moderate (32%), influenced primarily by body weight, age, albumin levels, and rarely by neutralizing antibodies. Infants achieve higher concentrations (60-65 µg/mL) than older individuals with identical dosing, while bioavailability decreases after age 65. Pharmacodynamically, emicizumab maintains FVIII-equivalent activity of 17-25 IU/dL, thrombin generation >100 nM, and normalized aPTT without affecting FIX, FX, or coagulation activation markers.

Exposure-response modeling establishes that bleeding control plateaus above emicizumab concentrations of 30 µg/mL (IC50 3.58 µg/mL), explaining equivalent efficacy across dosing regimens that achieve mean concentrations of 53.5 µg/mL and produce a 94% reduction in annualized bleeding rates. Clinical studies demonstrate annualized bleeding rates for treated bleeds of 0.4-2.4, with 54-78% of patients achieving zero treated bleeds. The safety profile is favorable, with injection site reactions as the most common adverse event (16-22%), no thromboembolic events when used alone, and minimal immunogenicity. These pharmacokinetic and pharmacodynamic characteristics support body weight-based dosing without routine therapeutic drug monitoring, with potential for individualized dosing in patients maintaining concentrations substantially above the 30 µg/mL efficacy threshold.

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 - Hemophilia A, Intervention - Emicizumab, Outcome - PK/PD Data, Study Population - Human Subjects, Study Design, Intervention Specificity, Population Specificity, Data Relevance

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: “Pharmacokinetics/pharmacodynamics of emicizumab in hemophilia A”

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:

• Population - Hemophilia A: Does the study include patients diagnosed with hemophilia A?
• Intervention - Emicizumab: Does the study investigate emicizumab as the primary intervention?
• Outcome - PK/PD Data: Does the study report pharmacokinetic data (e.g., plasma concentrations, clearance, half-life, bioavailability) and/or pharmacodynamic data (e.g., factor VIII mimetic activity, bleeding rates, coagulation parameters)?
• Study Population - Human Subjects: Is the study conducted in human subjects (not animal or in vitro studies)?
• Study Design: Is the study a clinical trial (Phase I, II, III, IV), observational study, case series, case report, systematic review, or meta-analysis?
• Intervention Specificity: Does the study include emicizumab as an intervention (not focusing solely on other hemophilia treatments without emicizumab)?
• Population Specificity: Does the study include hemophilia A participants (not exclusively patients with hemophilia B or other bleeding disorders without any hemophilia A participants)?
• Data Relevance: Does the study report pharmacokinetic and/or pharmacodynamic data (not only clinical efficacy or safety outcomes without PK/PD data)?

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.

• Study Population:

Extract patient demographics and clinical characteristics relevant to emicizumab pharmacokinetics/pharmacodynamics in hemophilia A, including:

• Age range and median/mean age

• Body weight/BMI characteristics

• Hemophilia A severity (mild, moderate, severe)

• FVIII inhibitor status (presence/absence, titer levels if available)

• Prior treatment history (treatment-naive, previously treated)

• Geographic/ethnic population

• Sample size for PK/PD analyses

• Any other patient factors mentioned as potentially affecting emicizumab PK/PD

• Dosing Regimen:

Extract all details about emicizumab dosing and administration for PK/PD assessment, including:

• Dose level(s) tested (mg/kg)

• Dosing frequency (weekly, every 2 weeks, every 4 weeks)

• Loading dose regimen if applicable

• Maintenance dose regimen

• Route of administration

• Duration of treatment/observation

• Any dose adjustments or individualization strategies

• Sampling timepoints for PK/PD measurements

• PK Parameters:

Extract pharmacokinetic parameters and characteristics of emicizumab in hemophilia A patients, including:

• Plasma/serum emicizumab concentrations (steady-state, peak, trough)

• Clearance (CL/F)

• Volume of distribution (V/F or Vss/F)

• Half-life (t½)

• Time to steady-state

• Bioavailability or relative bioavailability

• Dose-proportionality findings

• PK variability (inter-patient, intra-patient)

• Any population PK modeling results

• Comparison across different dosing regimens if applicable

• PD Outcomes:

Extract pharmacodynamic outcomes and biomarkers for emicizumab in hemophilia A, including:

• FVIII-equivalent activity levels (IU/dL or %)

• Coagulation parameters (aPTT, thrombin generation, etc.)

• Annualized bleeding rates (ABR) for treated bleeds, spontaneous bleeds, joint bleeds

• Proportion of patients with zero bleeds

• Time to first bleeding episode

• Bleeding severity and location

• Need for additional hemostatic treatment

• Any other hemostatic efficacy measures

• Methods used to assess each PD outcome

• PK/PD Relationships:

Extract any analyses of exposure-response or concentration-effect relationships for emicizumab in hemophilia A, including:

• Correlations between emicizumab concentration and FVIII-equivalent activity

• Exposure-efficacy relationships (concentration vs. bleeding rates)

• Exposure-safety relationships

• Population PK/PD modeling results

• Threshold concentrations for efficacy

• Model parameters (EC50, Emax, slope factors)

• Goodness-of-fit assessments

• Predictions or simulations of different dosing scenarios

• Safety Profile:

Extract safety and immunogenicity data relevant to emicizumab PK/PD in hemophilia A, including:

• Injection site reactions

• Thrombotic/thromboembolic events

• Anti-drug antibodies (ADA) development and impact on PK/PD

• Neutralizing antibodies

• Other treatment-related adverse events

• Laboratory safety parameters

• Any safety findings that could affect dosing or PK/PD interpretation

• Discontinuations due to safety concerns

• Covariates:

Extract factors identified as affecting emicizumab pharmacokinetics or pharmacodynamics in hemophilia A patients, including:

• Age effects on PK/PD parameters

• Body weight/size effects

• Inhibitor status effects on efficacy

• Prior treatment history effects

• Genetic factors or ethnic differences

• Concomitant medications effects

• Disease-related factors affecting drug disposition

• Any other identified sources of PK/PD variability

• Magnitude and clinical significance of covariate effects

• Study Methods:

Extract methodological details relevant to PK/PD assessment of emicizumab in hemophilia A, including:

• Study design and phase
• PK sampling strategy and timepoints
• Bioanalytical methods for emicizumab concentration measurement
• Methods for measuring FVIII-equivalent activity and coagulation parameters
• PK analysis methods (non-compartmental, population modeling software)
• Statistical approaches for PK/PD analysis
• Validation of bioanalytical and PD assays
• Any limitations affecting PK/PD interpretation

Results

Characteristics of Included Studies

The review included 10 sources examining emicizumab pharmacokinetics and pharmacodynamics in hemophilia A, comprising clinical trial reports, a systematic review, and an exposure-response modeling study. The studies varied in design from Phase I dose-escalation trials to Phase III pivotal studies and represented diverse patient populations.

Study

Full text retrieved?

Study Type

Population

Sample Size (PK/PD)

Study Design

C. Schmitt et al., 2020

Yes

Primary study (Phase III)

Adults/adolescents (12-75 years) with severe HA and FVIII inhibitors; multicenter (14 countries)

112

Open-label, multicenter, randomized

A. Kiialainen et al., 2023

No (abstract only)

Pooled analysis

HAVEN 1-4 participants

Not specified

Phase III trials

M. Shima et al., 2016

No (abstract only)

Primary study (Phase I)

Japanese adults with severe HA with/without inhibitors

18

Open-label, non-randomized, dose-escalation

M. Shima et al., 2017

Yes

Primary study (Phase I/II extension)

Japanese adults (12-58 years) with severe HA with/without inhibitors

18

Open-label, long-term extension

S. Pipe et al., 2022

No (abstract only)

Primary study (Phase IIIb interim)

Infants ≤12 months with severe HA without inhibitors

52

Multi-center, open-label (HAVEN 7)

Qianqian Mao et al., 2025

No (abstract only)

Primary study (retrospective)

Chinese pediatric patients (0.93-16.25 years) with HA

46

Retrospective single-center

S. Pipe et al., 2023

No (abstract only)

Primary study (Phase IIIb primary)

Infants ≤12 months with severe HA without inhibitors

55

Multi-center, open-label (HAVEN 7)

A. Donners et al., 2021

Yes

Systematic review

Adults and children (0 to ≥12 years) with HA with/without inhibitors

469 PwHA, 140 volunteers

Systematic review of 15 studies

S. Pipe et al., 2019

No (abstract only)

Primary study (Phase III)

Adults/adolescents (≥12 years) with severe HA with/without inhibitors from 6 countries

41 (expansion cohort)

Multi-center, open-label, two-stage (HAVEN 4)

F. Jonsson et al., 2021

Yes

Modeling study

445 PwHA with/without inhibitors (age 1-77 years)

385 emicizumab-treated

Exposure-response modeling of pooled Phase III data

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The populations spanned a wide age range from infants (9 days old) to adults (up to 77 years), including specialized studies in infants ≤12 months and Chinese pediatric patients. Most studies included patients with severe hemophilia A, with variable inhibitor status across studies. Prior treatment history varied, with several studies including previously untreated or minimally treated patients.

Dosing Regimens and Administration

Emicizumab was administered subcutaneously across all studies, with various loading and maintenance regimens tested to optimize pharmacokinetic profiles.

Study

Loading Dose

Maintenance Dose

Dosing Frequency

Duration

C. Schmitt et al., 2020

3 mg/kg weekly for 4 weeks

1.5 mg/kg

Once weekly

Median 60.5 weeks (range 3.3-94.2)

A. Kiialainen et al., 2023

3 mg/kg weekly for 4 weeks

1.5 mg/kg, 3 mg/kg, or 6 mg/kg

Weekly, Q2W, or Q4W

Not specified

M. Shima et al., 2016

None mentioned

0.3, 1.0, or 3.0 mg/kg

Weekly

12 weeks

M. Shima et al., 2017

1 mg/kg (cohort 1), 3 mg/kg (cohort 2)

0.3, 1.0, or 3.0 mg/kg

Once weekly

Up to 33.3 months

S. Pipe et al., 2022

3 mg/kg weekly for 4 weeks

3 mg/kg

Every 2 weeks for 52 weeks

≥52 weeks with 7-year follow-up

Qianqian Mao et al., 2025

Median 2.85 mg/kg per week (range 2.14-3.90)

Median 5.21 mg/kg (range 2.54-6.46)

Loading: weekly; Maintenance: every 28 days

December 2023-July 2025

S. Pipe et al., 2023

3 mg/kg weekly for 4 weeks

3 mg/kg, 1.5 mg/kg, or 6 mg/kg

Q2W for 52 weeks; then weekly or Q4W options

≥52 weeks with 7-year follow-up

A. Donners et al., 2021

Not mentioned

1.5 mg/kg, 3 mg/kg, or 6 mg/kg

Weekly (75%), Q2W (11%), Q4W (14%)

≥16 weeks

S. Pipe et al., 2019

3 mg/kg weekly for 4 weeks

6 mg/kg

Every 4 weeks

≥24 weeks

F. Jonsson et al., 2021

3 mg/kg weekly for 4 weeks

1.5 mg/kg, 3 mg/kg, or 6 mg/kg

Once weekly, Q2W, or Q4W

365.25 days for ABR calculation

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The standard loading regimen across recent studies was 3 mg/kg weekly for 4 weeks, designed to rapidly achieve therapeutic concentrations. Maintenance dosing flexibility allowed for once-weekly (1.5 mg/kg), every-2-weeks (3 mg/kg), or every-4-weeks (6 mg/kg) administration. Dose adjustments were permitted in some studies, with up-titration to 3 mg/kg weekly allowed for suboptimal efficacy after 6 months and individualized dose modifications implemented based on efficacy and safety committee review. In the HAVEN 7 study, one participant required dose up-titration from biweekly to weekly due to decreasing emicizumab levels.

Pharmacokinetic Parameters

Emicizumab demonstrated predictable, dose-proportional pharmacokinetics across diverse patient populations.

Plasma Concentrations

Study

Steady-State Trough Concentrations

Peak/Loading Concentrations

Time to Steady-State

C. Schmitt et al., 2020

≥50 µg/mL maintained; mean 54.1 µg/mL after loading, sustained >50 µg/mL

Not specified

Not specified

A. Kiialainen et al., 2023

42.1-52.3 µg/mL with maintenance dosing

Mean 52.9 µg/mL (SD 13.6) at week 5

Not specified

M. Shima et al., 2016

Increased in dose-dependent manner

Not specified

Not specified

M. Shima et al., 2017

10.3 mg/mL (cohort 1), 29.9 mg/mL (cohort 2), 120 mg/mL (cohort 3)

Not specified

~12 weeks with loading, 24 weeks without

S. Pipe et al., 2022

60-65 µg/mL maintained

Mean 63.2 µg/mL (95% CI: 59.5-66.8) at Week 5

Not specified

Qianqian Mao et al., 2025

Maintenance: median 50.6 µg/mL (range 17.3-81.7)

Loading: median 57.7 µg/mL (range 31.8-79.9)

Not specified

S. Pipe et al., 2023

Sustained at 57-66 µg/mL

Mean 62.0 µg/mL (95% CI: 58.3-65.6) at Week 5

Not specified

A. Donners et al., 2021

Moderate interindividual variability (32%)

Not specified

Not specified

S. Pipe et al., 2019

Not specified

Not specified

Not specified

F. Jonsson et al., 2021

~50 µg/mL across regimens; trough: 28.4 (QW), 24.9 (Q2W), 17.7 (Q4W) µg/mL

Not specified

Not specified

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Trough concentrations increased during the loading phase, reaching mean values of 52.9-63.2 µg/mL by week 5, and were sustained at 42.1-66 µg/mL with maintenance dosing. The Chinese pediatric study reported somewhat lower median trough concentrations during maintenance (50.6 µg/mL). Dose-proportional increases in steady-state trough levels were observed across dose cohorts in the Phase I/II extension, with levels of 10.3, 29.9, and 120 mg/mL for 0.3, 1.0, and 3.0 mg/kg weekly dosing, respectively. Plasma concentrations increased in a dose-dependent manner across all dose escalation studies.

A notable finding was higher emicizumab concentrations in infants compared to older populations. In HAVEN 7, infant concentrations (60-65 µg/mL) were higher than those observed with the same dosing regimen in HAVEN 1-4 studies of older patients (46.7 ± 14.9 µg/mL) and HAVEN 2-3 studies (46-48 µg/mL).

Pharmacokinetic Model Parameters

The Chinese pediatric study provided detailed estimates using the published population PK model. Median clearance (CL/F) was 0.0637 L/day (range 0.0421-0.1578), volume of distribution (V/F) was 2.1543 L (range 1.2629-6.2103), and elimination half-life was 23.44 days (range 20.79-27.28). The earlier Phase I study reported a longer half-life of 4-5 weeks, while another source cited approximately 30 days. The systematic review noted that clearance was comparable to other therapeutic IgG4-based monoclonal antibodies (0.2-0.5 L/day), but emicizumab demonstrated increased distribution volumes (10 vs. 6 L) and a longer half-life. Time to steady-state was approximately 12 weeks with a loading dose and 24 weeks without loading.

Pharmacokinetic Variability

Interindividual variability in trough concentrations was moderate at 32% and remained consistent across various subgroups including FVIII inhibitor status, age group, and dosing interval. Total PK interindividual variability was approximately 60%, influenced by body weight, neutralizing antidrug antibodies, age, and albumin levels. Children showed slightly less variability than adults and adolescents. The long half-life was expected to result in minimal variation in peak/trough plasma concentrations, supporting stable pharmacokinetics with minimal peak-trough fluctuation.

Emicizumab demonstrated high subcutaneous bioavailability, with bioavailability decreasing with age, particularly after 65 years. The dose-linear pharmacokinetics supported body weight-based dosing, although individualized monitoring may allow for more cost-effective dosing.

Pharmacodynamic Outcomes

FVIII-Equivalent Activity and Coagulation Parameters

Study

FVIII-Equivalent Activity (IU/dL)

aPTT Response

Thrombin Generation (nM)

Other Coagulation Parameters

C. Schmitt et al., 2020

Remained above 20 U/dL

Normalized at subtherapeutic concentrations

Peak height above 100 nM

FIX, FX, fibrinogen, PT, D-dimer, PF1.2 not significantly affected

A. Kiialainen et al., 2023

25.2 IU/dL at week 5, sustained 17-23 IU/dL

Shortened following first dose

115.2 nM at week 5, sustained >116 nM

Not mentioned

M. Shima et al., 2016

Not mentioned

Remained short throughout

Not mentioned

No clinically relevant coagulation abnormalities

M. Shima et al., 2017

Not mentioned

Remained short, within or shorter than reference range

Promotion of FXIa-triggered thrombin generation

Not mentioned

S. Pipe et al., 2022

21 U/dL during loading, sustained

Normalized by Week 3

Increased to 100 nM from Week 17 onwards

FIX and FX unaffected

Qianqian Mao et al., 2025

Loading: 14.6 IU/dL (range 7.4-39.2); Maintenance: 20.2 IU/dL (range 8.9-39.6)

Not mentioned

Not mentioned

Not mentioned

S. Pipe et al., 2023

Not mentioned

Not mentioned

Not mentioned

Not mentioned

A. Donners et al., 2021

Not mentioned

Not mentioned

Not mentioned

Not mentioned

S. Pipe et al., 2019

Not mentioned

Not mentioned

Not mentioned

Not mentioned

F. Jonsson et al., 2021

Not mentioned

Not mentioned

Not mentioned

Not mentioned

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FVIII-like activity increased during the loading period to 21-25.2 IU/dL and was sustained at 17-23 IU/dL with maintenance dosing, remaining consistently above 20 U/dL. The Chinese pediatric study reported median FVIII-equivalent activity of 14.6 IU/dL during loading and 20.2 IU/dL during maintenance. These levels theoretically convert patients with severe hemophilia A to a mild disease phenotype.

Thrombin generation peak height increased during loading, reaching 100-115.2 nM by week 5-17, and was sustained above 100-116 nM thereafter. Activated partial thromboplastin time (aPTT) was normalized at subtherapeutic concentrations of emicizumab, shortened following the first dose, normalized by Week 3 in most participants, and remained short throughout studies.

Importantly, emicizumab did not significantly affect plasma concentrations of target antigens FIX and FX, nor did it affect fibrinogen, prothrombin time (international normalized ratio), D-dimer, or prothrombin fragment 1.2 levels, indicating no induction of consumptive coagulopathy or coagulation activation.

Bleeding Outcomes

Study

Treated Bleeds ABR (95% CI)

All Bleeds ABR (95% CI)

Treated Joint Bleeds ABR (95% CI)

Zero Treated Bleeds (%)

C. Schmitt et al., 2020

87% reduction vs. no prophylaxis

Not specified

Not specified

62.9%

M. Shima et al., 2016

Cohort 1: 32.5→4.4; Cohort 2: 18.3→0.0; Cohort 3: 15.2→0.0

Not specified

Not specified

73% (with inhibitors), 71% (without)

M. Shima et al., 2017

Median: Cohort 1: 1.4; Cohort 2: 0.2; Cohort 3: 0

Not specified

Not specified

8/18 patients (44%)

S. Pipe et al., 2022

0.4 (0.23-0.65)

1.9 (1.35-2.68)

0.1 (0.01-0.22)

77.8%

Qianqian Mao et al., 2025

Median ABR: 0

Not specified

Not specified

Not specified

S. Pipe et al., 2023

0.4 (0.30-0.63)

2.0 (1.49-2.66)

0.0 (0.01-0.09)

54.5%

A. Donners et al., 2021

At 30 µg/mL: 2.4; At 50 µg/mL: 1.9

Not specified

At 30 µg/mL: 1.1; At 50 µg/mL: 1.0

70.8%→80.2% after 1 year

S. Pipe et al., 2019

2.4 (1.4-4.3)

4.5 (3.1-6.6)

1.7 (0.8-3.7)

56.1% (39.7-71.5)

F. Jonsson et al., 2021

Predicted mean: 1.28 at 53.5 µg/mL (94% reduction from baseline)

Not specified

Not specified

Not specified

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Emicizumab prophylaxis demonstrated substantial efficacy in reducing bleeding rates across all studies. In the infant population (HAVEN 7), the model-based ABR for treated bleeds was 0.4 (95% CI: 0.23-0.65 in interim analysis and 0.30-0.63 in primary analysis), with ABR for all bleeds of 1.9-2.0 and treated joint bleeds of 0.0-0.1. No intracranial hemorrhage occurred in this vulnerable population. The proportion of patients achieving zero treated bleeds ranged from 54.5% to 77.8% in the HAVEN 7 analyses.

In the Phase I dose-escalation study, median ABRs decreased from baseline values of 18.3-32.5 to 0.0-4.4 across cohorts receiving 0.3-3.0 mg/kg weekly, with 71-73% of patients experiencing no bleeding. The long-term extension showed median ABRs remaining low at 0.0-1.4.

The HAVEN 4 study examining every-4-weeks dosing reported an ABR of 2.4 (95% CI: 1.4-4.3) for treated bleeds, with 56.1% of patients reporting no treated bleeds. The Chinese pediatric study achieved a median ABR of 0. Overall, the systematic review found that 70.8% of patients had no treated bleeds initially, increasing to 80.2% after 1 year of treatment.

The majority of bleeds were traumatic (87.9% in HAVEN 7), with breakthrough bleeding episodes successfully treated with episodic FVIII or bypassing agents when needed. The episodic use of clotting factors to control bleeding was reduced.

Exposure-Response Relationships

Several studies characterized the relationship between emicizumab concentrations and clinical outcomes, demonstrating clear concentration-dependent effects on both pharmacodynamic biomarkers and bleeding control.

Concentration-Biomarker Correlations

FVIII-like activity and thrombin generation peak height correlated with emicizumab concentrations. The Chinese pediatric study quantified this relationship, finding a positive correlation between emicizumab concentration and FVIII-equivalent activity by linear regression (Y = 0.9569·X + 33.24, R² = 0.37, p < 0.01) and Spearman correlation (ρ = 0.56, p < 0.01). The relationship between emicizumab plasma concentration and aPTT was well described by an inhibitory Emax model.

In the infant population, sustained FVIII-like activity and normalization of aPTT suggested a concentration-effect relationship, with higher emicizumab concentrations in infants compared to older individuals contributing to excellent bleeding control.

Concentration-Efficacy Relationships

The systematic review by Donners et al. performed detailed exposure-response modeling using an Emax model relating trough plasma concentrations to annualized bleeding rates. The EC50 for treated bleeds was 1.47 µg/mL with an Emax of 0.96, while for treated joint bleeds the EC50 was 1.09 µg/mL with an Emax of 0.98. Critically, the control of bleeds did not improve above emicizumab concentrations of 30 µg/mL, establishing an effectiveness plateau. At 30 µg/mL, the expected ABR was 2.4 for treated bleeds and 1.1 for treated joint bleeds, while at 50 µg/mL these values were 1.9 and 1.0, respectively.

The comprehensive exposure-response analysis by Jonsson et al. using a generalized Poisson distribution and inhibitory Emax relationship found that emicizumab concentrations were inversely related to bleeding rates, with higher concentrations leading to reduced bleeding. The IC50 was estimated at 3.58 µg/mL, indicating the concentration required for half-maximal effect. Importantly, concentrations above 30 µg/mL provided clinically meaningful control of bleeding. At the average steady-state concentration across all regimens (53.5 µg/mL), the predicted mean annualized bleeding rate was 1.28, corresponding to a 94.0% reduction from baseline. Simulations demonstrated that the three dosing regimens (1.5 mg/kg QW, 3 mg/kg Q2W, 6 mg/kg Q4W) maintain concentrations near the plateau of effect.

Visual predictive checks from the exposure-response model showed adequate prediction of bleeding onset over time, supporting the model’s validity. The PK profile of once-weekly emicizumab provided sustained therapeutic plasma levels consistent with population PK models.

Factors Affecting Pharmacokinetics and Pharmacodynamics

Body Weight and Size Effects

Body weight was a significant covariate affecting emicizumab pharmacokinetics across multiple studies. Dosing regimens were universally based on body weight (mg/kg), and including body weight in population PK models significantly reduced interindividual variability in both clearance (CL/F) and volume of distribution (V/F). Body weight also affected apparent clearance and distribution volume in the exposure-response model. The Chinese pediatric study documented body size characteristics, with median weight of 14.5 kg (range 8.5-41.8 kg) and median BMI of 16.8 kg/m² (range 13.8-21.5 kg/m²).

Plasma concentrations of emicizumab increased in a dose-dependent manner, and steady-state trough levels increased in a dose-proportional manner, supporting body weight-based dosing strategies. However, the systematic review suggested that individualized monitoring of emicizumab concentrations may allow for more cost-effective dosing.

Age Effects

Age emerged as an important covariate affecting emicizumab pharmacokinetics and potentially pharmacodynamics. Bioavailability decreased with age, particularly after 65 years. Conversely, infants demonstrated higher emicizumab concentrations compared to older individuals with the same dosing regimen, with concentrations of 60-65 µg/mL in HAVEN 7 versus 46.7 ± 14.9 µg/mL in older HAVEN 1-4 participants and 46-48 µg/mL in HAVEN 2-3.

The Chinese pediatric study population had a median age at enrollment of 3.52 years (range 0.93-16.25 years) and a median age at emicizumab initiation of 1.40 years, with height (median 92.0 cm) also documented. The HAVEN 7 studies focused specifically on infants ≤12 months of age, demonstrating feasibility and efficacy in this youngest population. Studies in adults included participants from age 12 to 75 years.

Inhibitor Status and Prior Treatment History

FVIII inhibitor status did not significantly affect emicizumab PK variability or efficacy. Emicizumab was effective in patients with FVIII inhibitors as well as those without, with no significant difference in bleeding control between the two groups.

Prior treatment history varied across studies and was considered as a potential covariate. Several studies included previously untreated or minimally treated patients (PUPs/MTPs). The Chinese pediatric study reported that 15 patients were previously untreated or minimally treated, and 9 had a history of inhibitors. In the exposure-response analysis, prior prophylaxis with FVIII significantly reduced bleeding hazard by 44.7%, representing the most clinically significant covariate effect identified.

Other Covariates

Albumin levels affected pharmacokinetics, with low albumin levels associated with decreased exposure and albumin affecting apparent clearance. The Chinese pediatric study documented median albumin levels of 46.1 g/L (range 41.4-49.6 g/L).

Ethnic differences were observed, with African race mentioned as a factor affecting PK variability and ethnicity affecting distribution volume in population PK models. The Chinese pediatric study specifically noted that ethnic and developmental factors—such as body size, nutritional status, and earlier treatment initiation—may influence drug exposure and clinical response.

Neutralizing antidrug antibodies represented a primary source of interindividual PK variability, though their actual occurrence was rare (discussed in safety section below). Age >30 years was also identified as a factor affecting PK variability.

Safety and Immunogenicity

Emicizumab demonstrated a favorable safety profile across all studies, with most adverse events being mild and not leading to treatment discontinuation.

Injection Site Reactions and General Tolerability

Injection site reactions were the most frequent treatment-related adverse event. In the Phase I/II extension, mild injection site reactions occurred in 38.9% of patients (7/18). In the infant studies, 16.4-16.7% of participants experienced emicizumab-related injection site reactions, all Grade 1. The HAVEN 4 study reported injection site reactions in 22% of patients.

Most participants in infant studies experienced at least one adverse event (92.6-100%), but importantly, no adverse events led to treatment withdrawal, modification, or interruption. The long-term Phase I/II extension reported no discontinuations due to safety concerns, and the treatment was generally well tolerated with limited toxicity.

Thrombotic Events

Notably, no thromboembolic events or thrombotic microangiopathies occurred in the infant studies or the long-term Phase I/II extension. The HAVEN 4 study also observed no thrombotic events. In the HAVEN 1 study, two participants experienced thrombotic microangiopathy and thromboembolism, but these were associated with the use of bypassing agents (activated prothrombin complex concentrate) rather than emicizumab itself. The systematic review noted an increased thrombotic risk when emicizumab was used with high doses of activated prothrombin complex concentrate.

Immunogenicity

Emicizumab demonstrated minimal immunogenicity across studies. None of the participants in the HAVEN 7 studies tested positive for anti-drug antibodies (ADAs) at any timepoint (baseline, Week 5, or 12-weekly thereafter). The early Phase I study reported no development of antibodies to emicizumab.

In the Phase I/II extension, 4 patients tested positive for ADAs, but these were nonneutralizing and did not affect PK/PD parameters. Similarly, the systematic review noted that neutralizing antidrug antibodies affected PK variability but their actual development was rare. The HAVEN 4 study observed no development of de-novo antidrug antibodies with neutralizing potential.

Regarding development of FVIII inhibitors in previously untreated patients, one PUP in HAVEN 7 was confirmed positive for FVIII inhibitors on Day 603 after three FVIII exposure days (for traumatic bleed treatment), and another PUP tested positive on Day 428 after 10 FVIII exposure days (for post-tonsillectomy bleed management), with confirmatory titer pending at the analysis cut-off.

Laboratory Safety Parameters

Emicizumab did not significantly affect key laboratory safety parameters. Platelet count, fibrinogen, D-dimer, and prothrombin fragment 1.2 (PF1.2) levels were not significantly affected. FIX and FX plasma antigen levels, prothrombin time, and concentrations of exploratory safety markers of coagulation activation (D-dimer, prothrombin fragment 1 + 2, and fibrinogen) were not notably affected. In the infant study, aPTT was normalized by Week 3 and mean FIX and FX concentrations were unaffected by emicizumab.

Serious Adverse Events

Serious adverse events were infrequent and not attributed to emicizumab. In HAVEN 7, 29.1% of participants (16/55) reported 30 serious adverse events, all considered serious due to hospitalization, but none were considered emicizumab-related. The Phase I/II extension reported that 4 patients experienced serious adverse events, but none were related to emicizumab treatment. One participant in HAVEN 7 experienced an anaphylactic reaction following food allergy, not considered emicizumab-related. The systematic review noted joint pain episodes at high concentrations (90 µg/mL).

Five participants were withdrawn from emicizumab treatment in HAVEN 1 due to adverse events or physician/patient decision, though specific details were not provided.

Study Methodologies

The studies employed diverse methodological approaches to assess emicizumab pharmacokinetics and pharmacodynamics, ranging from Phase I dose-escalation studies to large Phase III randomized trials and sophisticated modeling analyses.

Study Designs

The evidence base included open-label, non-randomized, dose-escalation Phase I studies, Phase III multicenter, open-label, randomized studies, Phase IIIb multi-center, open-label studies, and a two-stage Phase III study with run-in and expansion cohorts. The systematic review pooled data from 15 studies including 469 patients with hemophilia A and 140 volunteers. The exposure-response modeling study analyzed pooled Phase III trial data. One real-world study employed a retrospective single-center design.

Pharmacokinetic Assessment Methods

PK sampling strategies varied by study. The HAVEN 1 study collected blood samples before the first dose, weekly for the first month, every 2 weeks for the second month, every 4 weeks from the third to sixth month, every 8 weeks from the seventh to twelfth month, and every 12 weeks thereafter. HAVEN 7 measured plasma trough emicizumab concentrations at Week 5 and thereafter. The Chinese pediatric study collected peripheral blood samples during both loading and maintenance phases.

Bioanalytical methods for emicizumab concentration measurement included validated enzyme-linked immunosorbent assay (ELISA) in Phase I-III studies and a modified one-stage clotting assay (OSA) in Phase IV studies. The HAVEN 1 study used a validated ELISA, while the Chinese pediatric study employed a modified one-stage assay.

PK analysis approaches included graphical exploratory analyses and linear regressions, population pharmacokinetic modeling using NONMEM software, and application of published population PK models. The systematic review employed non-linear least squares regression using a maximum effect (Emax) model. Statistical approaches included descriptive analysis, negative binomial regression for calculating ABRs, generalized Poisson distribution and inhibitory Emax relationship for exposure-response modeling, and linear regression and Spearman correlation for PK/PD relationships.

Pharmacodynamic Assessment Methods

FVIII-equivalent activity was measured using chromogenic assays, including the Hyphen Biophen FVIII:C assay containing human factors and the HYPHEN chromogenic FVIII assay. Thrombin generation was assessed using the Calibrated Automated Thrombogram method. Efficacy endpoints in the infant studies were estimated using a negative binomial regression model for annualized bleeding rates.

Assay precision and accuracy for emicizumab concentration measurement were validated in key studies, though detailed validation information for pharmacodynamic assays was not consistently reported across all studies.

Study Limitations

Several methodological limitations were noted. The Phase I/II extension was not randomized or controlled and had small patient numbers in each dose cohort. Sample sizes in some studies were based on clinical considerations rather than statistical power calculations. The systematic review cited limitations including a limited number of available studies, heterogeneous study populations, and lack of blinded, placebo-controlled studies. The exposure-response modeling study noted a limited range of exposure concentrations at the lower end of the dose-response curve.

Synthesis

The pharmacokinetic and pharmacodynamic characteristics of emicizumab demonstrate remarkable consistency across diverse populations and study designs, supporting its use as a prophylactic treatment for hemophilia A. Several key findings emerge from synthesis of the evidence.

Dose-Concentration-Response Relationships

The evidence establishes a clear hierarchy of dose-proportional pharmacokinetics leading to sustained therapeutic concentrations, which in turn correlate with pharmacodynamic biomarkers and translate to clinically meaningful bleeding control. The convergence of findings from mechanistic studies, clinical trials, and sophisticated modeling analyses provides robust evidence for a threshold effect, with bleeding control plateauing above concentrations of 30 µg/mL. This plateau has important implications: it explains why all three approved maintenance regimens (1.5 mg/kg weekly, 3 mg/kg every 2 weeks, 6 mg/kg every 4 weeks) achieve similar efficacy despite different trough concentrations, and it suggests that therapeutic drug monitoring could enable dose reduction in patients maintaining concentrations substantially above this threshold.

Age-Related Pharmacokinetic Differences

The consistently higher emicizumab concentrations observed in infants compared to older populations receiving identical dosing regimens represents a genuine population-specific difference rather than measurement artifact, as it was replicated across studies and correlates with known developmental changes in antibody pharmacokinetics. Infants have lower total body weight but proportionally higher body surface area and different tissue composition compared to adults, which may reduce volume of distribution relative to body weight. Additionally, the neonatal Fc receptor (FcRn), which protects IgG antibodies from catabolism, may function differently in infants, potentially reducing clearance and increasing bioavailability. These age-related differences in exposure did not translate to safety concerns, as thrombotic events remained absent in the infant population despite higher concentrations. This suggests the concentration-safety relationship may also plateau, or that young children have different thrombotic risk profiles. The decrease in bioavailability with age, particularly after 65 years, suggests older patients may require adjusted dosing to maintain therapeutic concentrations.

Clinical Implications of PK/PD Variability

The moderate 32% interindividual variability in trough concentrations remains consistent across FVIII inhibitor status, age groups, and dosing intervals, supporting body weight-based dosing without routine therapeutic drug monitoring. However, specific subpopulations may benefit from concentration monitoring: patients with low albumin or those who develop neutralizing antibodies, patients over 65 years with reduced bioavailability, and potentially African patients given ethnic effects on distribution volume. The finding that prior FVIII prophylaxis reduces bleeding hazard by 44.7%—the single largest covariate effect identified—suggests that the benefits of emicizumab may be partially additive to those of prior prophylaxis, possibly through prevention of joint damage that would otherwise increase bleeding risk.

Reconciling Safety Findings

The favorable safety profile, particularly the absence of thromboembolic events in most studies, requires reconciliation with the two thrombotic events in HAVEN 1. These events occurred specifically with concomitant use of high-dose activated prothrombin complex concentrate (aPCC), representing a drug-drug interaction rather than an inherent property of emicizumab. The mechanism likely involves emicizumab providing baseline hemostatic activity that, when combined with high doses of bypassing agents, creates excessive thrombin generation exceeding physiologic regulatory capacity. This context-specific risk led to modifications in clinical practice guidelines recommending caution with bypassing agents in emicizumab-treated patients. The very low immunogenicity likely reflects the humanized antibody design and subcutaneous route of administration, which promotes tolerance compared to intravenous dosing.

References

C. Schmitt, J. Adamkewicz, Jin Xu, Claire Petry, O. Catalani, and 4 more\ (2020).Pharmacokinetics and Pharmacodynamics of Emicizumab in Persons with Hemophilia A with Factor VIII Inhibitors: HAVEN 1 Study. Thrombosis and Haemostasis

A. Kiialainen, J. Adamkewicz, Claire Petry, J. Oldenburg, S. Pipe, and 9 more\ (2023).Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks. Research and Practice in Thrombosis and Haemostasis

A. Donners, C. Rademaker, Lisanne A H Bevers, A. Huitema, R. Schutgens, and 2 more\ (2021).Pharmacokinetics and Associated Efficacy of Emicizumab in Humans: A Systematic Review. Clinical Pharmacokinetics

S. Pipe, M. Shima, M. Lehle, A. Shapiro, S. Chebon, and 12 more\ (2019).Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study. The Lancet Haematology

F. Jonsson, C. Schmitt, Claire Petry, F. Mercier, N. Frey, and 1 more\ (2021).Exposure–Bleeding Count Modeling of Emicizumab for the Prophylaxis of Bleeding in Persons with Hemophilia A with/Without Inhibitors Against Factor VIII. Clinical Pharmacokinetics

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

M. Shima, H. Hanabusa, M. Taki, T. Matsushita, Tetsuji Sato, and 5 more\ (2017).Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors. Blood Advances

S. Pipe, P. Collins, C. Dhalluin, G. Kenet, C. Schmitt, and 10 more\ (2022).Emicizumab Prophylaxis for the Treatment of Infants with Severe Hemophilia A without Factor VIII Inhibitors: Results from the Interim Analysis of the HAVEN 7 Study. Blood

Qianqian Mao, Zhengping Li, Zhenping Chen, Runhui Wu\ (2025).Pharmacokinetic and pharmacodynamic characteristics of emicizumab in Chinese pediatric patients with hemophilia A: A retrospective single-center study. Blood

S. Pipe, P. Collins, C. Dhalluin, G. Kenet, C. Schmitt, and 12 more\ (2023).Emicizumab Prophylaxis in Infants with Severe Hemophilia A without Factor VIII Inhibitors: Results from the Primary Analysis of the HAVEN 7 Study. Blood

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Pharmacokinetics and Pharmacodynamics of Emicizumab in Persons with Hemophilia A with Factor VIII Inhibitors: HAVEN 1 Study

C. Schmitt, J. Adamkewicz, Jin Xu, Claire Petry, O. Catalani, G. Young, C. Négrier, M. Callaghan, G. Levy

Thrombosis and Haemostasis·

2020·

77 citations

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Study Population

- Age range: 12-75 years - Median age: 29 years - Hemophilia A severity: Severe (93.8%) - FVIII inhibitor status: Present, titer range 5-5,000 BU/mL - Prior treatment history: Previously treated with BPAs - Geographic/ethnic population: Multicenter study across 14 countries - Sample size for PK/PD analyses: 112 participants

Dosing Regimen

- Dose level(s) tested: 1.5 mg/kg once weekly for maintenance; 3 mg/kg once weekly for loading dose - Dosing frequency: Once weekly - Loading dose regimen: 3 mg/kg once weekly for 4 weeks - Maintenance dose regimen: 1.5 mg/kg once weekly - Route of administration: Subcutaneous - Duration of treatment/observation: Median exposure of 60.5 weeks (range: 3.3-94.2 weeks) - Dose adjustments: Uptitration to 3 mg/kg once weekly allowed for suboptimal efficacy after 6 months - Sampling timepoints: Before first dose, weekly for first month, every 2 weeks for second month, then less frequently

PK Parameters

- Plasma/serum emicizumab concentrations: Steady-state trough concentrations ≥50 µg/mL; mean trough concentration after loading dose: 54.1 µg/mL; sustained slightly above 50 µg/mL during maintenance. - Half-life (t½): Approximately 30 days. - Bioavailability: High subcutaneous bioavailability. - Population PK modeling results: Dosing regimen selected based on population PK/efficacy modeling to achieve and maintain therapeutic trough levels.

PD Outcomes

- FVIII-equivalent activity levels: FVIII-like activity above 20 U/dL - Coagulation parameters: aPTT normalized at subtherapeutic concentrations; TG peak height above 100 nM - Annualized bleeding rates (ABR): 87% reduction in treated bleed ABR compared to no prophylaxis - Proportion of patients with zero bleeds: 62.9% - Methods used: Chromogenic FVIII activity assays; thrombin generation tests

PK/PD Relationships

- Correlations between emicizumab concentration and FVIII-equivalent activity: FVIII-like activity and TG peak height correlated with emicizumab concentrations. - Exposure-efficacy relationships: FVIII-like activity and TG peak height remained above 20 U/dL and 100 nM, respectively, with a weekly maintenance dose. - Exposure-safety relationships: aPTT was normalized at subtherapeutic concentrations of emicizumab. - Population PK/PD modeling results: The PK profile was consistent with population PK models. - Threshold concentrations for efficacy: Emicizumab trough concentrations ≥ 50 µg/mL were maintained throughout the study. - Model parameters: The relationships between emicizumab plasma concentration and aPTT were well described by an inhibitory Emax model. - Goodness-of-fit assessments: Not mentioned. - Predictions or simulations of different dosing scenarios: Not mentioned.

Safety Profile

- Injection site reactions: Not mentioned - Thrombotic/thromboembolic events: Two participants experienced thrombotic microangiopathy and thromboembolism associated with bypassing agents, not emicizumab. - Anti-drug antibodies (ADA) development and impact on PK/PD: Not mentioned - Neutralizing antibodies: Not mentioned - Other treatment-related adverse events: Five participants withdrawn due to adverse events or physician/patient decision; specific details not provided. - Laboratory safety parameters: No significant effects on platelet count, fibrinogen, D-dimer, or PF1.2 levels. - Safety findings affecting dosing or PK/PD interpretation: None mentioned - Discontinuations due to safety concerns: Five participants withdrawn due to adverse events or physician/patient decision.

Covariates

- Age effects on PK/PD parameters: Not mentioned - Body weight/size effects: Dosing based on body weight (1.5 mg/kg), but no specific effects on PK/PD mentioned - Inhibitor status effects on efficacy: Emicizumab is effective in patients with FVIII inhibitors - Prior treatment history effects: Participants previously treated with BPAs, but no specific effects on PK/PD mentioned - Genetic factors or ethnic differences: Not mentioned - Concomitant medications effects: Not mentioned - Disease-related factors affecting drug disposition: Presence of FVIII inhibitors is a significant factor - Magnitude and clinical significance of covariate effects: Not detailed

Study Methods

- Study design and phase: Phase III, open-label, multicenter, randomized study - PK sampling strategy and timepoints: Blood samples collected before first dose, weekly for the first month, every 2 weeks for the second month, every 4 weeks from the third to the sixth month, every 8 weeks from the seventh to the twelfth month, and every 12 weeks thereafter - Bioanalytical methods for emicizumab concentration measurement: Validated enzyme-linked immunosorbent assay - Methods for measuring FVIII-equivalent activity and coagulation parameters: Chromogenic assay for FVIII activity, Calibrated Automated Thrombogram method for thrombin generation - PK analysis methods: Graphical exploratory analyses, linear regressions - Statistical approaches for PK/PD analysis: Descriptive analysis - Validation of bioanalytical and PD assays: Assay precision and accuracy for emicizumab concentration measurement were validated - Limitations affecting PK/PD interpretation: Sample size based on clinical considerations rather than statistical power

Abstract Emicizumab, a bispecific monoclonal antibody, bridges activated factor IX (FIXa) and FX, replacing the function of missing FVIIIa to restore effective hemostasis in persons with hemophilia A (PwHA). Here we assess pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers in PwHA with FVIII inhibitors in the Phase III HAVEN 1 study (NCT02622321). Blood samples from 112 PwHA receiving 1.5 mg/kg once-weekly subcutaneous emicizumab were analyzed at central laboratories. Emicizumab concentrations for PK analysis were measured via validated immunoassay. PD effects were assessed using FVIII chromogenic activity assay containing human factors (Hyphen Biophen FVIII:C), and by FXIa-triggered thrombin generation (TG). Activated partial thromboplastin time (aPTT), prothrombin time (PT), antigen levels of FIX and FX, fibrinogen, D-dimer, and prothrombin fragment 1.2 (PF1.2) levels were determined. Emicizumab trough concentrations ≥ 50 µg/mL were maintained throughout the study. FVIII-like activity and TG (peak height) correlated with emicizumab concentrations and remained above 20 U/dL and 100 nM, respectively, with a weekly maintenance dose, theoretically converting persons with severe hemophilia A to a mild disease phenotype. aPTT was normalized at subtherapeutic concentrations of emicizumab. Plasma concentrations of target antigens FIX and FX were not significantly affected by emicizumab treatment; nor were fibrinogen, PT (international normalized ratio), D-dimer, or PF1.2. The PK profile of once-weekly emicizumab in HAVEN 1 provides sustained therapeutic plasma levels, consistent with population PK models. Both the PK profile and the PD and safety biomarkers are consistent with the established efficacy of emicizumab prophylaxis in PwHA with FVIII inhibitors.

Introduction

Hemophilia A results from congenital deficiency of coagulation factor (F) VIII. 1 Persons with hemophilia A (PwHA) can experience frequent clinical bleeding-related symptoms including easy bruising, prolonged bleeding after trauma or surgery, and spontaneous bleeding into joints, muscles, or soft tissues.

The current standard of care for PwHA with a frequent bleeding phenotype (mostly severe hemophilia) is regular prophylactic intravenous infusions of FVIII, 1,2 the goal being to maintain target trough FVIII activity levels of ! 1 U/dL to prevent bleeds and mitigate long-term secondary complications. Approximately 30% of PwHA develop neutralizing alloantibodies (FVIII inhibitors), which render FVIII replacement therapy ineffective. 1 Prior to the availability of emicizumab, hemostatic treatments for PwHA with FVIII inhibitors were prothrombotic coagulation factors that bypass FVIII. However, bypassing agents (BPAs) such as activated prothrombin complex concentrate (aPCC) and recombinant-activated human FVII (rFVIIa) have suboptimal hemostatic effects and a high treatment burden associated with significant limitations (short half-life, slow intravenous infusion rate). 3,4 micizumab (HEMLIBRA ® ; F. Hoffmann-La Roche Ltd, Basel, Switzerland) is a bispecific, humanized, monoclonal antibody that bridges activated FIX (FIXa) and FX, mimicking the cofactor function of missing activated FVIII (FVIIIa), to restore effective hemostasis in PwHA. 5,6 It has no sequence homology with FVIII, and is therefore unlikely to induce FVIII inhibitors and is unaffected by their presence. 5,7 Emicizumab has high subcutaneous bioavailability 8 and a half-life of approximately 30 days, 9 enabling treatment with once weekly, 10 every 2 week, 11 or every 4 week 12 subcutaneous dosing regimens, thus avoiding the need for frequent intravenous administration.

Following the results of HAVEN 1 10 and HAVEN 2, 13,14 1.5 mg/kg subcutaneous once-weekly emicizumab was approved as a prophylactic treatment for PwHA with FVIII inhibitors of all age groups in several countries (including European Union member states). The original indication and dosing of emicizumab has now been expanded in many countries based on the results of HAVEN 3 11 and HAVEN 4 12 to include 1.5 mg/kg once weekly, 3.0 mg/kg every 2 week, or 6.0 mg/kg every 4 week prophylaxis for PwHA regardless of their inhibitor status. The European Medicines Agency has approved emicizumab for use in patients without FVIII inhibitors only for those with severe (< 1 U/dL FVIII activity) hemophilia A. 15,16 HAVEN 1 10 was a pivotal Phase III study designed to evaluate the efficacy, safety, and pharmacokinetics (PK) of subcutaneous once-weekly emicizumab prophylaxis versus no prophylaxis in adult and adolescent (aged ! 12 years) PwHA with FVIII inhibitors. Emicizumab was well tolerated and demonstrated an 87% reduction in treated bleed annualized bleeding rate (ABR) versus no prophylaxis (ABR [95% confidence interval [CI]] 2.9 [1.69-5.02] vs. 23.3 [12.33-43.89]). Of those treated with emicizumab, 62.9% experienced zero treated bleeds. Emicizumab improves upon current treatment options and fulfills a previously unmet medical need. 11,12,17,18 hile emicizumab mimics FVIII cofactor activity, it has fundamental differences from FVIII in terms of PK and biochemical and pharmacological properties. 19 This article presents the secondary objectives assessing PK, pharmacodynamic (PD), and safety biomarkers from HAVEN 1.

Patients

Adult and adolescent (! 12 years old) PwHA with FVIII inhibitors previously treated with BPAs with suboptimal success were enrolled based on a comprehensive list of inclusion and exclusion criteria. 10 articipants (n ¼ 113) were enrolled between November 18, 2015 and September 28, 2016; the clinical cut-off date for this analysis was September 8, 2017. All participants provided written informed consent prior to study entry. The study protocol was approved by the relevant independent ethics committee/institutional review board at each participating institution and was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice.

Study Design

HAVEN 1, a Phase III, open-label, multicenter, randomized study in PwHA with FVIII inhibitors, took place at 43 centers across 14 countries. Full methods of the HAVEN 1 study have been published previously. 10 Briefly, participants receiving episodic BPA treatment before study entry were randomized 2:1 to receive either emicizumab prophylaxis (arm A) or no prophylaxis (arm B). Participants previously treated with prophylactic BPAs were assigned to arm C to receive emicizumab prophylaxis. Participants from a noninterventional study (NCT02476942) 20 who were unable to enroll in arms A, B, or C before enrollment was closed were eligible for arm D.

PwHA in arms A, C, and D were given a loading dose of subcutaneous emicizumab 3 mg/kg once weekly for 4 weeks, followed by 1.5 mg/kg subcutaneous once weekly maintenance thereafter; PwHA in arm B received no prophylaxis. After completing ! 24 weeks in the study, arm B participants emicizumab. Plasma concentrations of target antigens FIX and FX were not significantly affected by emicizumab treatment; nor were fibrinogen, PT (international normalized ratio), D-dimer, or PF1.2. The PK profile of once-weekly emicizumab in HAVEN 1 provides sustained therapeutic plasma levels, consistent with population PK models. Both the PK profile and the PD and safety biomarkers are consistent with the established efficacy of emicizumab prophylaxis in PwHA with FVIII inhibitors. could receive emicizumab prophylaxis as described (i.e., 3 mg/kg once weekly for 4 weeks, 1.5 mg/kg once weekly thereafter). All participants could receive episodic BPAs for the treatment of breakthrough bleeding, as needed. In case of suboptimal efficacy after ! 6 months of emicizumab prophylaxis, uptitration to 3 mg/kg once weekly was permitted. 10 pproved subcutaneous administration sites were the abdomen, upper arm, and thigh.

Blood Sampling and Analyses

Blood samples for PK and PD analyses were taken from all participants at the following scheduled time points: before first emicizumab dose; immediately prior to emicizumab injection (at trough) every week for the first month; every 2 weeks for the second month; every 4 weeks from the third to the sixth month; every 8 weeks from the seventh to the twelfth month; and every 12 weeks thereafter. Following thrombotic microangiopathy and thromboembolism in two participants treated with an average cumulative aPCC dose of ! 100 U/kg/ 24 hours while receiving emicizumab prophylaxis, the HAVEN 1 protocol was amended to recommend the optional collection of additional samples for platelet count, D-dimer, prothrombin fragment 1.2 (PF1.2), and fibrinogen analysis within 24 hours of BPA use from October 2016 onwards.

Blood samples (2 mL) for emicizumab measurement were collected using ethylenediaminetetraacetic acid-containing plastic tubes. Samples were centrifuged (1,500 Â g, 4°C) for 15 minutes to collect plasma and were stored below -70°C prior to analysis.

Blood samples (5.4-18.9 mL depending on body weight) were collected in plastic tubes containing 3.2% sodium citrate for analysis of: FVIII activity, thrombin generation (TG), activated partial thromboplastin time (aPTT), prothrombin time (PT), FIX and FX antigens, D-dimer, PF1.2, fibrinogen, and von Willebrand factor antigen (VWF:Ag). Samples were centrifuged (3,000 Â g, room temperature) for 20 minutes to obtain plasma and samples were stored below -70°C prior to analysis.

Emicizumab plasma concentrations were determined using a validated enzyme-linked immunosorbent assay, performed by QPS Netherlands B.V. (Groningen, The Netherlands). The lower limit of quantitation was 100 ng/mL in human plasma. Assay precision and accuracy were 9.5 to 13.3% and 97.6 to 103%, respectively.

All biomarkers (except platelet count) were analyzed at Medpace Reference Laboratories (Cincinnati, Ohio, United States). FVIII activity of emicizumab was measured using a validated chromogenic assay containing human FIXa and FX (Hyphen Biomed, Neuville-sur-Oise, France) with two different calibration curves: high, for samples with ! 10 U/dL FVIII activity; and low, for samples with < 10 U/dL FVIII activity. Human-derived factors were used in the chromogenic assays as bovine-derived components are insensitive to emicizumab, and therefore cannot be used to measure emicizumab activity. 21 Of note, FVIII activity reported for PwHA treated with emicizumab with this assay cannot be compared with, or interpreted as equivalent to, FVIII activity reported in participants treated with FVIII; it will, therefore, be called FVIII-like activity throughout the rest of the article. TG was measured with the Calibrated Automated Thrombogram method (Diagnostica Stago, Asnièressur-Seine, France), which used a triggering reagent containing FXIa, as this has been shown to be more robust and sensitive than tissue factor, especially for those with low apparent FVIII activities, as would be expected in HAVEN 1 participants (0-30 U/dL FVIII). 22 TG (peak height) was derived from the thrombogram. Clotting times (aPTT and PT), D-dimer, PF1.2, fibrinogen, and VWF:Ag were analyzed using commercial test kits approved for in vitro diagnostic use according to the manufacturers' kit inserts (see Supplementary Material, available in the online version). Protein levels of both FIX and FX were measured using validated immunoassays (Assaypro, St. Charles, Missouri, United States). Platelet count was measured at the local clinical sites as part of regular safety monitoring and was recommended to be measured within 24 hours of BPA administration.

Pharmacokinetics/Pharmacodynamics Analysis

Exploratory graphical analyses were performed to investigate the PK/PD relationship between emicizumab concentration and FVIII-like activity, TG, or aPTT. The data from all participants were pooled for analysis. With only trough samples, hysteresis could not be checked in the present study. However, as indicated in previous studies in healthy subjects 23 and in PwHA, 6 PD markers (e.g., aPTT or TG) are directly linked to emicizumab concentration without time delay (i.e., no hysteresis). Therefore, a direct relationship between PK and PD effect was considered.

The PK/PD relationships for TG and FVIII-like activity could not be appropriately described by a maximum effect (E max ) model due to the limited range of emicizumab concentrations achieved in the HAVEN 1 study. Linear regressions were, therefore, performed on the "linear" portion of the E max model (i.e., for concentrations up to 80 µg/mL).

For aPTT, different inhibitory E max models were tested for best fit, and an appropriate model was selected on the basis of the Akaike information criterion. Model diagnosis was also performed by visual analysis of the weighted residual plots and by observation of the relative standard error of the estimated variables. The estimates and associated relative standard error were reported. The relationships between emicizumab plasma concentration and aPTT were well described by an inhibitory E max model:

Here, E is the aPTT, E 0 is the aPTT at baseline (seconds), I max is the maximum inhibition at infinite emicizumab concentration, C is the emicizumab plasma concentration (µg/mL), and IC 50 is the emicizumab concentration causing half of the maximum effect (µg/mL) (►Supplementary Table S1 , available in the online version).

Graphical investigations of the potential effects of average FIX and FX concentrations (emicizumab target antigens) on the PK/PD relationships were also performed.

Of note, investigation of the relationship between emicizumab exposure and bleeding events is the subject of dedicated publications. 9,24, 25

Statistical Analysis

The total HAVEN 1 sample size was based on clinical rather than statistical considerations, taking into account the limited number of PwHA with FVIII inhibitors available for participation, and to collect sufficient data to assess the safety and efficacy of emicizumab as previously described. 10 ll participants initially received the same emicizumab dosing regimen. Consequently, PK and PD data are presented as a single-dose group. Since participants in arm B switched to emicizumab prophylaxis after completing 24 weeks on study, their scheduled time relative to first emicizumab dose was used for graphical displays. PK and PD data were subject to descriptive analysis. Data from participants who uptitrated to 3 mg/kg once-weekly emicizumab were included in the descriptive statistics until uptitration, and continued to be included in the PK/PD relationship plots after uptitration. PD data in the form of aPTT and TG from participants who had their blood samples drawn via ports and for whom contamination with heparin was suspected were excluded from the summary statistics calculations.

Study Population

A full description of participants enrolled in the HAVEN 1 study, together with baseline demographics and clinical characteristics of each treatment arm, has been published previously. 10 Briefly, 113 male participants with a median age of 29 years (range: 12-75 years) were enrolled in HAVEN 1; all participants had a historic FVIII inhibitor titer ! 5 Bethesda Units per mL (BU/mL) (range: 5-5,000 BU/mL), 106 (93.8%) had a diagnosis of severe congenital hemophilia A, and 69.6% (78 of 112) had target joints. The median duration of exposure to emicizumab was 60.5 weeks (range: 3.3-94.2 weeks). For this analysis, since the primary analysis clinical cut-off date (October 25, 2016) 10 the five outstanding participants in arm B were switched to emicizumab prophylaxis and are now included in the analysis population, and four additional participants have enrolled in arm D. One participant withdrew from the study without receiving any emicizumab treatment, and five participants were withdrawn from emicizumab treatment; three due to adverse events and two following physician or patient decision (►Supplementary Fig. S1 , available in the online version).

Pharmacokinetics

At clinical data cut-off, 112 PwHA who had received at least one emicizumab dose and had at least one postdose emicizumab concentration sample were included in the PK analysis. Mean emicizumab trough concentration (C trough ) increased with once weekly subcutaneous doses of 3 mg/kg emicizumab (loading dose); by the end of the loading dose period (week 5), a mean C trough of 54.1 µg/mL (median [interquartile range [IQR, 25th and 75th percentiles]]: 52.7 [44.5-62.8] µg/mL) was achieved (►Fig. 1) . During the maintenance dose phase, C trough was sustained slightly above 50 µg/mL with 1.5 mg/kg once weekly subcutaneous emicizumab. The data variability was moderate, with an IQR of 41.6 to 61.6 1 µg/mL.

FVIII-Like Chromogenic Activity

As expected in participants with FVIII deficiency, there was no detectable FVIII activity in PwHA at baseline (►Fig. 2A), except for one participant with mild hemophilia who presented with 15 U/dL FVIII-like activity at baseline. The participant, who had a highest historical FVIII inhibitor titer of 18 BU/mL, presented with a baseline FVIII inhibitor titer of 17 BU/mL and lacked documented coagulation factor use immediately prior to sampling. This participant, who has a missense mutation of the F8 gene (Arg2150His), may have developed alloantibodies against exogenous (wild-type) FVIII, but not against his own mutated, dysfunctional, endogenous FVIII, as previously reported with this mutation. 26 s measured using a validated chromogenic assay containing human FIXa and FX, mean FVIII-like activity increased to 29.8 U/dL (95% CI, 15.2-44.3) among the study population (n ¼ 112) at the end of the emicizumab loading dose period, and stabilized above 20 U/dL thereafter; at week 72, mean FVIII-like activity was 20.3 U/dL (95% CI, 12.3-28.4).

Thrombin Generation

As expected for PwHA with high FVIII inhibitor titers, there was no detectable TG at baseline (►Fig. 2B), except for one participant in whom a peak height of 165 nM was reported (the same participant with a history of mild hemophilia who exhibited 15 U/dL FVIII-like activity at baseline).

Following the emicizumab loading dose phase, mean TG peak height increased on average among the study population to 108.8 nM (95% CI, 29.7-187.9) and was sustained thereafter; at week 72, mean TG peak height was 108.7 nM (95% CI, 46.3-171.1).

Of note, six participants had no detectable TG at some or all time points despite treatment with emicizumab. In these participants, blood samples were drawn via a port, and contamination with heparin was later confirmed. These blood samples did exhibit chromogenic FVIII-like activity consistent with the patients' emicizumab concentration and the overall population PD data.

Activated Partial Thromboplastin Time

aPTT was prolonged in all participants at baseline, but was normalized below 30 seconds after the first dose of emicizumab and remained largely within normal limits (laboratory-determined reference range, 23.9-40 seconds) for the entire duration of treatment (►Fig. 2C); at week 72, mean (standard deviation) aPTT was 23.6 seconds (2.0). A few participants consistently had values just under the lower limit of the normal range. Six participants presented with some prolonged aPTT values despite treatment with emicizumab. These participants (who also had undetectable TG) had their blood samples drawn via a port, and contamination with heparin was suspected.

Prothrombin Time

Overall, treatment with emicizumab had no effect on PT (international normalized ratio [INR]); the majority of participants had PT between 13 and 14 seconds at baseline (corresponding to INR of 0.9-1.1) and at all subsequent visits while receiving emicizumab once weekly subcutaneously (►Fig. 2D). A minor increase of 0.6 seconds, however, could be seen after the first dose of emicizumab.

Exploratory Safety Biomarkers

Treatment with emicizumab had no clinically significant effects on plasma concentrations of the target antigens of emicizumab, FIX (►Fig. 3A) and FX (►Fig. 3B). A few elevated values of both FIX and FX plasma concentrations were observed at baseline; these were mainly observed in participants in arm C, who had used prophylactic aPCC before entering the study. Likewise, emicizumab treatment had no clinically significant effects on D-dimer (►Fig. 3C) or PF1.2 (►Fig. 3D). Highly elevated D-dimer concentrations were observed on single visits in two participants who had used aPCC for the treatment of breakthrough bleeding in the 24 to 48 hours before sample collection. Isolated instances of elevated PF1.2 concentrations were also noted in a few participants, most of whom had used aPCC for treating breakthrough bleeds in the days before sample collection.

Other safety markers that were measured included platelet count (►Supplementary Fig. S2A , available in the online version), fibrinogen (►Supplementary Fig. S2B , available in the online version), and VWF:Ag (►Supplementary Fig. S2C , available in the online version), all of which remained constant within expected limits from screening through to the clinical cut-off. Further safety results have been reported previously.

Pharmacokinetic/Pharmacodynamic Relationships

Chromogenic FVIII-like activity (measured using a FVIII chromogenic assay with human FIXa and FX) was well correlated with emicizumab plasma concentration (►Fig. 4A). It increased linearly up to approximately 80 to 100 µg/mL and seemed to flatten thereafter, although the scarcity of data values above 100 µg/mL emicizumab prevented complete characterization in this range. Similar to FVIII-like activity, TG (peak height) also correlated well with emicizumab levels in an apparently linear fashion up to emicizumab concentrations of approximately 80 to 100 µg/mL (►Fig. 4B). Of note, the concentration of FIX or FX did not appear to impact the PK/PD relationships of either FVIII-like activity or TG (►Supplementary Figs. S3 and S4 , available in the online version). A concentration-dependent normalization of aPTT (< 40 seconds) was observed starting at plasma emicizumab concentrations of ! 5 µg/mL, with a maximal effect achieved at concentrations ! 30 µg/mL (►Fig. 4C).

Discussion

Emicizumab is a novel and recently approved therapy for PwHA. Its biochemical and pharmacological properties enable it to address challenges faced by PwHA. Emicizumab allows for subcutaneous rather than intravenous dosing, a more convenient once weekly, every 2 week, or every 4 week administration schedule, functionality as a FVIIIa-mimicking cofactor without being affected by the presence of FVIII inhibitors (providing effective bleed control in PwHA both with/without FVIII inhibitors), and lack of induction of FVIII inhibitors. 11,23 he HAVEN 1 dosing regimen of 3 mg/kg once weekly emicizumab for 4 weeks followed by 1.5 mg/kg once weekly emicizumab thereafter was selected by population PK/efficacy modeling 9 to rapidly achieve and to maintain thereafter therapeutic emicizumab C trough . At the end of the loading dose period, mean C trough levels slightly above 50 µg/mL were achieved on average among the study population, and were maintained thereafter with 1.5 mg/kg once weekly dosing for the entire study duration (> 16 months). Owing to its long elimination half-life of approximately 1 month, 23 minimal peak-trough fluctuation is expected with emicizumab. 9 his provided sustained therapeutic exposure to emicizumab for the majority of participants. Based on an estimated potential conversion factor of 0.3 U/dL of FVIII activity per µg/mL of emicizumab, 6 a mean steady-state C trough of ! 50 µg/mL is expected to continuously provide an equivalent FVIII activity of ! 15 U/dL. This sustained level of protection, which is considered sufficient to reduce the risk of joint bleeding, 27 was confirmed by the substantial reduction in individual ABRs for most participants in HAVEN 1. 10 Activation of FX by emicizumab/FIXa and the subsequent downstream effects on the coagulation cascade were monitored in HAVEN 1 via various PD markers. Unlike FVIII, emicizumab does not require a rate-limiting activation step but instead directly mimics the cofactor activity of FVIIIa. 5 Therefore, the shortening effect of emicizumab on aPTT is considerably greater than that of FVIII. Consequently, conventional aPTT-based assays (1-stage) that measure FVIII activity are significantly affected by emicizumab and report artificially elevated FVIII activity. 28 In the present study, the FVIII-like activity of emicizumab was monitored with a chromogenic FVIII activity assay using human FIXa and FX. FVIII-like activity increased with emicizumab loading doses, achieving activity levels of approximately 30 U/dL at the end of the loading dose period (week 5). With the administration of maintenance emicizumab doses, FVIII-like activity stabilized at approximately 20 U/dL on average among the study population, corresponding to approximately 20% of the FVIII-like activity seen in healthy subjects. 29 he slight apparent decline in FVIII-like activity over time is thought to be the result of a signal drift in the assay (i.e., a change in signal level [FVIII activity] at a given emicizumab concentration with time), likely due to a change in the manufacture of multiple assay kits. This explanation for the artifact in the chromogenic FVIII activity assay was further supported by the absence of a similar decline or difference between groups in either emicizumab plasma concentration or TG.

Chromogenic FVIII-like activity and emicizumab concentration levels were well correlated, with a linear increase in FVIIIlike activity with emicizumab plasma concentration up to 80 µg/mL (►Supplementary Fig. S5 , available in the online version). Of note, reported FVIII-like activity for PwHA treated with emicizumab should not be interpreted as equivalent to FVIII activity reported in participants treated with FVIII. Due to the different enzymatic cofactor properties of the two molecules, FVIII-like activity can only be used as an approximation of hemostatic emicizumab activity in vivo. 5,19 Nevertheless, the increase and steady maintenance of FVIII-like activity provides a relative indication of the procoagulant activity of emicizumab.

Similarly, TG (peak height) increased following the initiation of treatment with emicizumab. By the end of the loading dose period, TG peak height of approximately 110 nM, equivalent to 20 to 30% of that in healthy people (316-488 nM), 23 was observed and sustained thereafter with emicizumab 1.5 mg/kg once weekly maintenance doses. TG was well correlated with emicizumab plasma concentration (►Supplementary Fig. S6 , available in the online version). 1][32] These TG peak height results confirmed the procoagulant effect of emicizumab and demonstrated the ability of TG assays to provide an indication of emicizumab procoagulant activity. Although availability of TG assays is limited to specialized laboratories, this usage was evidenced by a recently published case in which TG was used to guide the management of breakthrough bleeds with BPAs in a participant receiving emicizumab. 33 omparison of the measured values of FVIII-like activity and TG peak height in this study with available reference data suggests that the procoagulant activity achieved in HAVEN 1 corresponded to approximately 15 to 30% of that seen in healthy normo-coagulative people. 23,29 This suggests that persons with severe hemophilia A treated with emicizumab prophylaxis at a maintenance dose of 1.5 mg/kg/week could theoretically be converted to a mild hemophilia disease phenotype. Of note, similar findings have recently been obtained with human chromogenic FVIII and TG assays from direct comparisons between healthy adults, PwHA and FVIII inhibitors receiving emicizumab, and persons with mild hemophilia A without FVIII inhibitors receiving no therapy. 34 IX and FX, the target antigens of emicizumab, have the potential to impact its procoagulant activity. 31 However, in the range of concentrations seen in this study (FIX, 6-12 ng/mL; FX, 11-32 ng/mL), FIX and FX concentrations did not affect the PK/PD relationships between emicizumab and FVIII-like activity (►Supplementary Fig. S3 , available in the online version) or TG (►Supplementary Fig. S4 , available in the online version).

As reported in previous studies, emicizumab had a strong effect on aPTT. 6,26 aPTT was shortened to within normal limits after the first dose of emicizumab and remained largely within these limits thereafter. The normalization of aPTT at low emicizumab concentrations (! 5 µg/mL), with an estimated IC 50 of 1.1 µg/mL, is thought to be a direct consequence of the mechanism of action of emicizumab (as discussed above) and its resulting interference with clotting time-based assay methods. 6 Normalization of aPTT occurs at subtherapeutic emicizumab concentrations. 9,35,36 Consequently, aPTT is not an accurate marker of hemostasis in the presence of emicizumab and should not be used to monitor emicizumab efficacy. However, in the presence of unanticipated bleeding event together with low values of FVIII-like activity, marked increase of aPTT could be an indicator of the presence of anti-emicizumab antibody or noncompliance.

Emicizumab is not expected to affect the extrinsic pathway of the coagulation cascade. However, emicizumab has potential for a modest interference effect on the activation of FX by the FVIIa-TF complex due to the binding of emicizumab to FX and subsequent steric hindrance. 37 De facto, a tiny increase of PT was noticed after the first dose of emicizumab. This corresponded to approximately 0.05 INR units and was not considered clinically relevant. PT remained stable thereafter throughout the duration of the study.

Owing to its low target-antigen affinity, emicizumab had no effect on FIX or FX concentrations, confirming previous findings. 6 Slightly elevated FIX and FX concentrations were observed, mainly at baseline (i.e., in the absence of emicizumab); these are believed to reflect previous use of aPCC containing both FIX and FX 38 before study entry.

In terms of the safety markers, emicizumab had no effect on D-dimer or PF1.2 levels. Overall, this is consistent with the inability of emicizumab to activate coagulation in the absence of an initiating signal. There were isolated instances in which changes in these markers were observed; however, these appeared to be related to the use of BPAs (aPCC and rFVIIa) either before study entry or for treatment of breakthrough bleeding (►Supplementary Fig. S7 , available in the online version). Furthermore, emicizumab had no effect on platelet count, fibrinogen, or VWF:Ag (►Supplementary Fig. S2 , available in the online version). The absence of PT prolongation, platelet count decrease, or fibrinogen decrease in participants treated with emicizumab confirms that emicizumab alone does not induce consumptive coagulopathy. ][12][13] In conclusion, the PK profile of 1.5 mg/kg subcutaneously once weekly emicizumab in HAVEN 1 was consistent with population PK models and provides prophylactic bleed control in a majority of PwHA with FVIII inhibitors. 9 With regard to PD, both chromogenic FVIII-like activity and TG correlated with emicizumab concentrations and demonstrated stable activity throughout the maintenance-dosing period. Due to the differing biochemical characteristics of FVIII and emicizumab, the chromogenic FVIII assay may only be used to approximate PD effects of emicizumab in PwHA. TG, which provides a global assessment of coagulation, may have potential to confirm the pharmacological effect of emicizumab and guide BPA use in emicizumabtreated PwHA in case of surgeries or breakthrough bleeding. In addition to standardization of the TG assay, further investigations are needed to confirm this conclusion. FIX and FX levels and a panel of coagulation assays and markers including D-dimer were unaffected by emicizumab. aPTT, which is normalized at subtherapeutic emicizumab levels, should not be used to guide clinical decisions regarding PwHA receiving emicizumab. Studies are underway to determine the effects of emicizumab on different assay classes not examined here, to inform appropriate changes in clinical laboratory practice to better accommodate emicizumab. 28 at is known about this topic?

• Emicizumab, a humanized, bispecific antibody, mimics missing activated factor VIII (FVIII) function in persons with hemophilia A (PwHA). • In the HAVEN 1 study, emicizumab administered subcutaneously once a week resulted in a decrease in the annualized bleed rate of PwHA with FVIII inhibitors when compared with on-demand and prophylactic treatment with bypassing agents.

What does this paper add?

• During HAVEN 1, emicizumab administration provided sustained therapeutic trough plasma concentrations. • FVIII chromogenic activity and thrombin generation assay provided an indication of emicizumab procoagulant activity. • Based on these biomarkers, emicizumab may theoretically convert persons with severe hemophilia A to a mild disease phenotype.

annex

Authors' Contributions C.S., J.I.A., C.N., M.U.C., and G.G.L. contributed to the development of the HAVEN 1 study design. C.P. and O.C. contributed to the acquisition of data for these analyses. C.S., J.I.A., J.X., C.P., O.C., G.Y., C.N., M.U.C., and G.G.L. contributed to data analysis and interpretation. All authors critically reviewed this manuscript and approved the final version for submission.

Conflict of Interest

C.S., J.I.A., C.P., and G.G.L. are employees of F. Hoffmann-La Roche Ltd/Genentech, Inc. and hold stocks in F. Hoffmann-La Roche Ltd. J.X. is an employee of Gilead Sciences, and previous employee of F. Hoffmann-La Roche Ltd/Genentech, Inc. with stocks in F. Hoffmann-La Roche Ltd. O.C. is an employee of F. Hoffmann-La Roche Ltd. G.Y. has received grants and personal fees from Genentech, Inc./F. Hoffmann-La Roche Ltd, Takeda, and Grifols and personal fees from Novo Nordisk, UniQure, Sanofi, Spark Therapeutics, and BioMarin. C.N. has received personal fees from Bayer, CSL Behring, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Sanofi, Shire, and Spark Therapeutics; and personal fees and other from Sobi and F. Hoffmann-La Roche Ltd. M.U.C. has received personal fees from F. Hoffmann-La Roche Ltd, Genentech, Inc., Bayer, Shire/ Takeda, Pfizer, Novo Nordisk, Bioverative/Sanofi, Global Blood Therapeutics, Spark Therapeutics, BioMarin, Kedrion, Octapharma, Grifols; and has equity in Alnylam.

Acknowledgements

AcknowledgmentsMedical writing assistance for this manuscript was provided by Sophie Nobes, BSc, of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.

Funding

FundingThis study was sponsored by F. Hoffmann-La Roche Ltd.

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