• HAVEN 2 assessed Hemlibra prophylaxis given QW, Q2W, and Q4W in children <12 years of age with HA with FVIII inhibitors.
• At the primary analysis, 65 patients had enrolled in the QW cohort with a median efficacy period of 58 (range, 17.9-92.6) weeks. 77% of patients had zero treated bleeds and ABR for treated bleeds was 0.3 (95% CI, 0.17-0.5).
• Safety was generally consistent with previous studies. No TMAs or TEs were reported.
• HAVEN 7, is assessing Hemlibra prophylaxis in previously untreated and minimally treated infants with severe HA without FVIII inhibitors.
• Interim analysis of 54 patients who received Hemlibra for a median of 42.1 (range, 1-60) weeks reported zero treated bleeds in 77.8% of patients and a treated bleed ABR of 0.4 (95% CI, 0.23-0.65).
• No new safety signals were identified. No reports of TEs, TMAs, ICH, or fatality were reported.
• HOHOEMI assessed Hemlibra prophylaxis administered Q2W and Q4W in Japanese children <12 years of age with severe HA without FVIII inhibitors.
• At the primary analysis, 13 patients had completed ≥24 weeks on Hemlibra prophylaxis.
• Hemlibra prophylaxis resulted in ABRs of 1.3 (95% CI, 0.59-2.92) and 0.7 (95% CI, 0.18-2.65) for treated bleeds in the Q2W and Q4W cohorts, respectively.
• No new safety signals were identified and all 13 patients tested negative for ADA.
• AOZORA is assessing the long-term safety and effects on joint health of Hemlibra in paediatric patients with HA without inhibitors.
• An interim analysis of 3-year joint health analysis that joint health was improved or maintained based on MRI assessments and HJHS evaluations.
• Among the 10 patients, all experienced ≥1 AE. Other than one ISR, no AE or SAE was considered related to Hemlibra. No TEs or TMAs were observed.

ABRs=annualized bleed rates

ADAs=antidrug antibodies

AE(s)=adverse event(s)

aPTT=activated partial partial thromboplastin time

BPA(s)=bypassing agent(s)

BTB=breakthrough bleeding

FVIII=factor VIII

HA= hemophilia A

HJHS=Hemophilia Joint Health Scores

ISR=injection-site reaction

NIS=non-interventional study

PK= pharmacokinetics

PUP(s)=previously untreated patient(s)

PD=pharmacodynamics

QW=once weekly

Q2W=every 2 weeks

Q4W=every 4 weeks

SAE(s)=serious adverse event(s)

TE(s)=thromboembolic event(s)

TMA=thrombotic microangiopathy

Study description

HAVEN 2, a non-randomized, open-label, multicenter, Phase 3 clinical trial, evaluated the efficacy, safety, and PK of Hemlibra prophylaxis in children <12 years of age with HA and FVIII inhibitors.[1]

Patient population

The key criteria for enrollment in the study were

• children with congenital HA
• aged <12 years or 12 to 17 years if patient weighed < 40kg
• with presence of FVIII inhibitors, and
• received previous treatment with BPAs.[1]

A total of 88 eligible patients were enrolled of which 18 came from a previous NIS and received BPAs either as prophylaxis (n=15) or on-demand (n=3). Those NIS patients were included to enable direct intra-patient comparison of outcomes with prior BPAs versus Hemlibra prophylaxis.[1]

Hemlibra treatment

Patients were enrolled in three cohorts based on the Hemlibra dosing regimen: [1]

• Cohort A — 3 mg/kg QW for 4 weeks, followed by 1.5 mg/kg QW (n=65)
• Cohort B — 3 mg/kg QW for 4 weeks, followed by 3 mg/kg Q2W (n=10)
• Cohort C — 3 mg/kg QW for 4 weeks, followed by 6 mg/kg Q4W (n=10)

The NIS patients were enrolled in cohort A.[1]

As Cohort B and C were added later to the study, at the 52-weeks primary analysis of Cohort A, the median efficacy periods were

• 57.6 (range, 17.9-92.6) weeks for Cohort A
• 21.3 (range, 18.6-24.1) weeks for Cohort B, and
• 19.9 (range, 8.9-24.1) weeks for Cohort C.[1]

Main efficacy results in primary analysis

Across all 3 dosing regimens, Hemlibra prophylaxis resulted in clinically meaningful efficacy on treated bleed rate: [1]

• In Cohort A, 76.9% (95% CI: 64.8; 86.5) experienced zero treated bleeds and ABR was 0.3 (95% CI; 0.17-0.50).
• In Cohort B, 90% (95% CI: 55.5; 99.7) experienced zero treated bleeds and ABR was 0.2 (95% CI, 0.03-1.72).
• In Cohort C, 60% (95% CI: 26.2; 87.8) experienced zero treated bleeds and ABR was 2.2 (95% CI, 0.69-6.81).

In the intra-patient comparison in NIS patients, Hemlibra QW prophylaxis reduced treated bleeds by 99% (95% CI: 97.7; 99.4) compared to prior prophylaxis with BPAs (n=15).[1]

Main safety results in primary analysis

The most frequent AEs were nasopharyngitis and ISRs. No TE, TMA, or fatalities occurred.[1]

Two of 88 participants developed ADAs with neutralizing potential, that is, associated with decreased emicizumab plasma concentrations: [1]

• 1 experienced loss of efficacy, and
• in the other, ADAs disappeared over time without intervention or BTB.

All other participants achieved effective emicizumab plasma concentrations, regardless of the treatment regimen.[1]

Main PK results in primary analysis

Mean trough plasma concentrations maintained at therapeutic levels across all dosing regimens and PK profiles were consistent across age groups and body weights.[1]

Additional follow-up results

A final 52-week efficacy and safety analysis was done for the Q2W and Q4W cohorts.[2]

Efficacy

Median efficacy periods were

• 67.1 (range, 54.7-129.4) weeks for Cohort B, and
• 66.6 (range, 8.1-140.4) weeks for Cohort C.[2]

Effect of Hemlibra prophylaxis on treated bleed rate: [2]

• In Cohort B, 70% experienced zero treated bleeds and ABRs were 0.2 (95% CI, 0.06-0.54).
• In Cohort C, 60% experienced zero treated bleeds and ABRs were 1.8 (95% CI, 0.32-10.59).

Safety

No new safety signals were identified with either dosing regimen and the frequency of AEs within each arm was consistent with the safety of the overall study population. No TEs, TMAs, or deaths were reported.[2]

Study description

HAVEN 7 is an ongoing non-randomized, open-label, multicenter Phase 3 study designed to evaluate the efficacy, safety, PK, and PD of Hemlibra prophylaxis in infants with HA.[3]

Patient population

Infants aged from birth to 12 months with severe HA without FVIII inhibitors and previously untreated or minimally treated.[3]

A total of 54 eligible patients were enrolled at the time of interim analysis.[3]

Hemlibra treatment 

Patients received Hemlibra 3mg/kg weekly for 4 weeks, then 3mg/kg every 2 weeks for a total of 52 weeks.[3] 

At week 53, participants could continue with this regimen or switch to 1.5mg/kg weekly or 6mg/kg every 4 weeks for the 7-year long-term follow-up period.

At the time of interim analysis, participants were exposed to Hemlibra for a median duration of 42.1 (range,1-60) weeks.[3]

Main efficacy results at interim analysis

77 bleeds were reported in 31 participants (57.4%) of which

• 88.3% were traumatic
• 5.2% were procedural or surgical, and
• 6.5% were spontaneous.[3]

77.8% of participants experienced zero treated bleeds, no participant experienced more than two treated bleeds, and ABR for treated bleeds was 0.4 (95% CI: 0.23; 0.65).[3]

All participants had zero treated spontaneous bleeds; all treated bleeds were traumatic.[3]

Main safety results at interim analysis

No new safety signals were identified. No AEs led to withdrawal or dose modification or interruption. All related AEs were ISRs; no SAEs were considered related to treatment. No TEs, TMAs, intracranial hemorrhage, or fatalities reported. No ADAs were reported.[3]

Main PK and PD results at interim analysis

PK

The steady-state trough concentrations of approximately 60-65 mcg/mL were maintained through the study and were above those reported in previous HAVEN studies.[3]

PD

Mean steady-state trough concentrations increased slightly with age until approximately 6 months of age, at which time they reached approximately 65 mcg/mL.[3]

The mean factor IX and factor X concentrations were not impacted by Hemlibra and aPTT was normalized in most patients by week 3.[3]

Study description

HOHOEMI was a non-randomized, open-label, multicenter, Phase 3 study that assessed the efficacy, safety, and PK of Hemlibra prophylaxis in Japanese children <12 years of age.[4]

Patient population

Japanese paediatric patients aged <12 years, weighing over 3 kg, with severe HA without FVIII inhibitors.[4]

All patients were previously treated with FVIII prophylaxis, with the exception of one PUP.

A total of 13 eligible patients were enrolled in this study at the time of primary analysis.

Hemlibra treatment

Patients received Hemlibra for ≥24 weeks and were enrolled in two cohorts based on the Hemlibra dosing regimen: [4]

• Cohort Q2W — 3 mg/kg QW for 4 weeks, followed by 3 mg/kg Q2W (n=6), or
• Cohort Q4W — 3 mg/kg QW for 4 weeks, followed by 6 mg/kg Q4W (n=7).

At the time of primary analysis, participants were exposed to Hemlibra for a median duration of

• 39.9 (range, 37.9-41.4) weeks in the Q2W cohort, and
• 34.1 (range, 24.1-37.1) weeks in the Q4W cohort.[4]

Main efficacy results

Across both dosing regimens, Hemlibra prophylaxis resulted in clinically meaningful efficacy on treated bleed rate: [4]

• In Cohort Q2W, two patients experienced zero treated bleeds and ABR was 1.3 (95% CI, 0.59-2.92).
• In Cohort Q4W, five patients experienced zero treated bleeds and ABR was 0.7 (95% CI: 0.2;2.6).

In the intra-patient comparison based on historical bleeding records collected retrospectively, Hemlibra prophylaxis resulted in zero bleeds or a decrease in ABR from the pre-treatment period in 

• 4 out of 6 patients in the Q2W cohort, and
• all 7 patients in the Q4W cohort.[4]

All caregivers preferred Hemlibra to the patient's previous treatment.[4]

Main safety results

No new safety signals were identified.[4] There was only one AE, an ISR, that was related AE to Hemlibra. There were no TEs, TMAs, or fatalities. All 13 patients tested negative for ADAs.[4]

Main PK results

Individual trough plasma concentrations of emicizumab were within the variability observed in preceding adult and adolescent studies.[4]

Study description

AOZORA is ongoing non-randomized, open-label, multicenter phase 4 study that is assessing the long-term safety and effects on joint health of Hemlibra over a period of 6 years in paediatric patients with HA without inhibitors.[5]

Patient population

Paediatric patients <12 years old, weighing >3 kg, and diagnosed with severe HA without FVIII inhibitors. A total of 30 patients have enroled in AOZORA study. They entered in the study as Hemlibra-naïve or following the Phase 3 HOHOEMI study (n=10).[5]

Hemlibra treatment 

Treatment-naïve patients received Hemlibra 3 mg/kg QW for 4 weeks followed by Hemlibra 1.5 mg/kg QW, 3 mg/kg Q2W, or 6 mg/kg Q4W.[5]

Patients from HOHOEMI study continued their regimen of Hemlibra 1.5 mg/kg QW, 3 mg/kg Q2W, or 6 mg/kg Q4W.[5]

Main efficacy results at interim analysis

The pre-defined interim analysis presents 3-year joint evaluation results of the 10 participants who continued from HOHOEMI. Data cut-off was the last day of week 145 for each participant.[5]

3-year joint health

MRI assessments and HJSH evaluations at 3 years showed that joint health was maintained or improved: [5]

MRI findings were confirmed in 13 joints in 5 patients at week 1. Three of the 5 patients had joint health improvement with no MRI findings in any joint at Week 145. MRI findings show

• at week 1 mild effusion or hemarthrosis in 6 knee joints and 6 ankle joints, and both mild synovial hypertrophy and mild hemosiderin in 1 ankle joint, and
• at week 145 mild effusion or hemarthrosis in 1 knee joint and ankle joints, and no synovial hypertrophy or hemosiderin.[5]

No osteochondral changes were observed upon MRI.[5]

In the HJHS evaluations of the 10 patients, 5 maintained an HJHS of zero from weeks 1-145; including the patient with synovial hypertrophy and hemosiderin of the ankle joint at Week 1. Of the 5 patients with an HJHS ≥1 between weeks 1-145, 3 had a zero score after week 97.[5]

Annualized bleed rates

ABR was reduced following treatment with Hemlibra as described in table 1.[5]

Table 1. ABR for treated joint bleeds in AOZORA

Notes: * Interim analysis of 10 patients who were enrolled from HOHOEMI.

Abbreviations: IQR=interquartile range.

Main safety results at interim analysis

Among the 10 patients, all experienced ≥1 AE. One ISR was considered related to Hemlibra. Four SAEs were observed in 3 patients but none were considered related to Hemlibra. No TEs or TMAs were observed.[5]

Clinicians interested in information regarding ongoing clinical research may find the following websites useful:

www.clinicaltrials.gov (National Institutes of Health)

www.clinicaltrialsregister.eu (European Union Clinical Trials Register)

www.cancer.gov (National Cancer Institute)

For more information on specific Roche trials in your country location, please contact the local Roche affiliate nearest you.

Go on the URL link http://www.roche.com and click on the Roche Worldwide tab on the top of the page to locate the country nearest you for contact information.

For US trials or global trials with US sites only, please contact the Trial Information Support Line

1-888-662-6728 Monday to Friday

1. Young G, Liesner R, Chang T, et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood 2019;134:2127-2138. https://www.ncbi.nlm.nih.gov/pubmed/31697801
2. Young G, Sidonio JR, Oldenburg, J, et al. Efficacy/safety in children on 2/4-weekly emicizumab prophylaxis: 52-week outcomes in HAVEN 2. Presented at the American Society of Pediatric Hematology/Oncology Conference in Pittsburgh, Pennsylvania; May 4-7, 2022. ASPHO Poster #P010.
3. Pipe S, Collins P, Dhalluin C, et al. 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. Presented at the American Society of Pediatric Hematology/Oncology Conference in New Orleans, LA; December 10-13, 2022. ASH Oral presentation. https://doi.org/10.1182/blood-2022-157264
4. Shima M, Nogami K, Nagami S, et al. A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors. Haemophilia 2019;25:979-987. https://www.ncbi.nlm.nih.gov/pubmed/31515851
5. Shima M, Takedani H, Kitsukawa K, et al. AOZORA study: interim analysis of joint health in children with hemophilia A, without FVIII inhibitors, 3 years after initiating emicizumab. Presented at the American Society of Hematology Annual Meeting and Exposition in New Orleans, LA; December 10-13, 2022. ASH Poster #1161. https://ashpublications.org/blood/article/140/Supplement%201/2742/491199/AOZORA-Study-Interim-Analysis-of-Joint-Health-in