HEMLIBRA Efficacy for Pediatric Patients

HEMLIBRA was studied in pediatric hemophilia A patients with and without factor VIII inhibitors.5,16

Children with inhibitors8

  • 1.5 mg/kg QW, 3 mg/kg Q2W, or 6 mg/kg Q4W 

“The decision to prescribe HEMLIBRA was made together with the patient’s family. They were excited about a subcutaneous option and the potential for better efficacy and less bleeding.”1
—Michael Callaghan, MD, Children’s Hospital of Michigan

Starting early

Starting prophylaxis at a young age helps prevent breakthrough bleeds17

Breakthrough bleeds impact patients in several ways.17-19

  • Clinical bleeds and subclinical bleeds can both result in increased joint damage over time
  • Repeated bleeds can cause irreversible damage, leading to chronic pain and arthropathy, even in early childhood
  • A single serious bleed can cause new bleeds to occur in a damaging cycle

Prophylactic FVIII in young boys (≤6 years of age) with severe hemophilia A reduced the risk of joint damage by 83% vs on-demand treatment*20

Percentage of patients observed at 6 years of age with normal ankle, knee, and elbow joints 

Information about prophylaxis in boys under 6 years of age with hemophilia A.

 

Based on a randomized trial (N=65) with a mean observation period of 49 months.

*Results from a multicenter, randomized, open-label trial of young boys (<30 months old) with severe hemophilia A without inhibitors randomized to regular prophylactic recombinant FVIII infusions or to an enhanced episodic infusion schedule. Clinical assessments of index joints were performed with plain-film x-rays or magnetic resonance imaging at age 6.20

The MASAC guidelines discuss using HEMLIBRA early on in hemophilia A patients experiencing bleeds21

  • MASAC recommends that prophylaxis be considered optimal therapy for individuals with severe hemophilia A and should be instituted early (prior to the onset of frequent bleeding)
  • MASAC further recommends that infants should be considered for prophylaxis with HEMLIBRA at any time after birth, given the increased risk of intracranial hemorrhage prior to initiation of FVIII prophylaxis
    • There are no data on HEMLIBRA in the context of intracranial hemorrhage
  • There are limited data on the use of HEMLIBRA in infants under 6 months of age, and the pharmacokinetic exposure is likely to be lower compared with older infants and children
    • In pediatric patients less than 6 months old, the predicted concentrations of HEMLIBRA were 19% to 33% lower than in the older patients, especially with the 3 mg/kg Q2W or 6 mg/kg Q4W maintenance doses
Patients with inhibitors
Zero treated bleeds data for HAVEN 2.

Additional HEMLIBRA data for pediatric patients with FVIII inhibitors (interim analysis)8:

  • 90% of patients receiving HEMLIBRA Q2W (3 mg/kg) had zero treated bleeds (95% CI: 55.5; 99.7)
  • 60% of patients receiving HEMLIBRA Q4W (6 mg/kg) had zero treated bleeds (95% CI: 26.2; 87.8)
  • The primary endpoint for the Q2W and Q4W cohorts was descriptive
  • The median efficacy periods for the Q2W and Q4W were 21 weeks and 20 weeks, respectively
    • Patients in these cohorts will receive 52 weeks of treatment before the final analysis

HEMLIBRA prophylaxis showed improvement at 25 weeks from baseline in physical health score.5

The HAVEN 2 study evaluated patient-reported hemophilia-related symptoms (painful swellings and presence of joint pain) and physical functioning (pain with movement) using the Physical Health Score of the Hemophilia-specific Quality of Life Short Form (Haemo-QoL-SF) questionnaire for patients ≥8 to <12 years of age.

Intra-patient data for pediatric patients with FVIII inhibitors taking HEMLIBRA

67% of pediatric patients receiving HEMLIBRA had zero treated bleeds vs 6% on prior BPAs.8

INTRA-individual
Comparison

HAVEN 2: Individual patient ABR at a median study duration of 89 weeks in QW cohort (N=15)1

Intrapatient data for pediatric patients with FVIII inhibitors taking HEMLIBRA® (emicizumab-kxhw).
  • HAVEN 2 intra-patient comparison was not prespecified to show superiority in ABR vs prior BPAs1

Based on HAVEN 2: Non-randomized, multicenter, open-label clinical trial in pediatric patients (age <12 years, or 12–17 years who weigh <40 kg) with hemophilia A with FVIII inhibitors. All patients received HEMLIBRA prophylaxis at 3 mg/kg QW for the first 4 weeks. Sixty-eight patients received 1.5 mg/kg QW, 10 patients received 3 mg/kg Q2W, and 10 patients received 6 mg/kg Q4W thereafter.
A comparison of data from HAVEN 2 vs data in the NIS prior to enrollment.

Intraindividual comparison of 15 participants who previously took BPA prophylaxis showed that emicizumab prophylaxis reduced the ABR by 99% (95% CI: 97.4; 99.4).§8

§ABR was calculated with a negative binomial regression model, accounting for different follow-up times.

Patients without inhibitors

The majority of patients on HEMLIBRA experienced zero treated bleeds16

  • HAVEN 2: 77% of pediatric patients with FVIII inhibitors taking HEMLIBRA QW (n=65) had zero treated bleeds
  • HAVEN 4: 56% of adults and adolescents with or without FVIII inhibitors taking HEMLIBRA Q4W (n=41) had zero treated bleeds5

As observed over at least 52 weeks (HAVEN 2) and at least 24 weeks (HAVEN 4).16
Based on HAVEN 4: A single-arm, multicenter, open-label trial in 41 adult and adolescent males with hemophilia A with or without FVIII inhibitors who previously received either on-demand or prophylactic treatment with FVIII or BPAs. All patients received HEMLIBRA prophylaxis at 3 mg/kg QW for the first 4 weeks followed by 6 mg/kg Q4W thereafter.5

HOHOEMI: A multicenter, open-label study of pediatric patients without FVIII inhibitors12

  • Patients were <12 years old
  • One patient in the Q4W cohort who was 4 months old had never been treated with FVIII
  • This trial had a limited sample size (N=13) and was conducted in Japan
  • HOHOEMI was a descriptive study with no formal hypothesis testing
Hohoemi study data for pediatric patients without FVIII inhibitors taking HEMLIBRA® (emicizumab-kxhw).
Hohoemi study data for pediatric patients without FVIII inhibitors taking HEMLIBRA® (emicizumab-kxhw).

In a safety analysis of the HOHOEMI study:

  • The most common adverse reactions were contusion (n=10), nasopharyngitis (n=5), excoriation (n=4), and falls (n=4)
  • Two serious adverse events were reported, which consisted of bleeding from soft tissue surrounding a right knee and pain from bruised lower leg, both of which were unrelated to HEMLIBRA

§ABR was calculated with a negative binomial regression model, accounting for the different follow-up times.
HOHOEMI was a non-randomized study in pediatric patients (Japanese children <12 years) with hemophilia A without FVIII inhibitors. All patients received HEMLIBRA prophylaxis at 3 mg/kg once weekly for the first 4 weeks. Six patients received 3 mg/kg Q2W and 7 patients received 6 mg/kg Q4W thereafter.12

Frequently Asked Questions
Get your questions about HEMLIBRA answered

ABR=annualized bleed rate. ABR calculated with a negative binomial regression model, which accounts for different follow-up times15; BPA=bypassing agent; CI=confidence interval; FVIII=factor VIII; MASAC=Medical and Scientific Advisory Council; NIS=non-interventional study; QW=once weekly; Q2W=once every 2 weeks; Q4W=once every 4 weeks.

Indication & Important Safety Information

Indication
HEMLIBRA is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients ages newborn and older with hemophilia A with or without factor VIII inhibitors.

Important Safety Information
Boxed WARNING: THROMBOTIC MICROANGIOPATHY and THROMBOEMBOLISM
Cases of thrombotic microangiopathy and thrombotic events were reported when on average a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving HEMLIBRA prophylaxis. Monitor for the development of thrombotic microangiopathy and thrombotic events if aPCC is administered. Discontinue aPCC and suspend dosing of HEMLIBRA if symptoms occur. 

Warnings and Precautions
Thrombotic Microangiopathy (TMA) and Thromboembolism Associated With HEMLIBRA and aPCC
In clinical trials, TMA was reported in 0.8% of patients (3/391) and thrombotic events were reported in 0.5% of patients (2/391). In patients who received at least one dose of aPCC, TMA was reported in 8.1% of patients (3/37) and thrombotic events were reported in 5.4% of patients (2/37). Patients with TMA presented with thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, without severe deficiencies in ADAMTS13.

Consider the benefits and risks if aPCC must be used in a patient receiving HEMLIBRA prophylaxis. Due to the long half-life of HEMLIBRA, the potential for an interaction with aPCC may persist for up to 6 months after the last dose. Monitor for the development of TMA and/or thromboembolism when administering aPCC. Immediately discontinue aPCC and interrupt HEMLIBRA prophylaxis if clinical symptoms, imaging, or laboratory findings consistent with TMA and/or thromboembolism occur, and manage as clinically indicated. Consider the benefits and risks of resuming HEMLIBRA prophylaxis following complete resolution of TMA and/or thrombotic events on a case-by-case basis.

Laboratory Coagulation Test Interference
HEMLIBRA affects intrinsic pathway clotting-based laboratory tests, including activated clotting time (ACT); activated partial thromboplastin time (aPTT); and all assays based on aPTT, such as one-stage, factor VIII (FVIII) activity. Therefore, intrinsic pathway clotting-based coagulation laboratory test results in patients who have been treated with HEMLIBRA prophylaxis should not be used to monitor HEMLIBRA activity, determine dosing for factor replacement or anti-coagulation, or measure FVIII inhibitor titers.

Results affected by HEMLIBRA: aPTT; Bethesda assays (clotting-based) for FVIII inhibitor titers; one-stage, aPTT-based single-factor assays; aPTT-based Activated Protein C Resistance (APC-R); ACT.

Results unaffected by HEMLIBRA: Bethesda assays (bovine chromogenic) for FVIII inhibitor titers; thrombin time (TT); one-stage, prothrombin time (PT)-based single-factor assays; chromogenic-based single-factor assays other than FVIII (see Drug Interactions for FVIII chromogenic activity assay considerations); immuno-based assays (ie, ELISA, turbidimetric methods); genetic tests of coagulation factors (eg, Factor V Leiden, Prothrombin 20210).

Most Common Adverse Reactions
The most common adverse reactions (incidence ≥10%) are injection site reactions, headache, and arthralgia.

Adverse Reactions
Characterization of aPCC Treatment in Pooled Clinical Trials
There were 130 instances of aPCC treatment in 37 patients, of which 13 instances (10%) consisted of on average a cumulative amount of >100 U/kg/24 hours of aPCC for 24 hours or more; 2 of the 13 were associated with thrombotic events and 3 of the 13 were associated with TMA. No TMA or thrombotic events were associated with the remaining instances of aPCC treatment.

Injection Site Reactions
In total, 85 patients (22%) reported injection site reactions (ISRs). All ISRs observed in HEMLIBRA clinical trials were reported as mild to moderate intensity and 93% resolved without treatment. The commonly reported ISR symptoms were injection site erythema (11%), injection site pruritus (4%), and injection site pain (4%).

Other Less Common (<1%) Reactions
Rhabdomyolysis was reported in 2 adult patients with asymptomatic elevations in serum creatine kinase without associated renal or musculoskeletal symptoms. In both instances, the event occurred following an increase in physical activity.

Drug Interactions
Clinical experience suggests that a drug interaction exists with HEMLIBRA and aPCC.

Pregnancy, Lactation, Females and Males of Reproductive Potential
Women of childbearing potential should use contraception while receiving HEMLIBRA. It is not known whether HEMLIBRA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. HEMLIBRA should be used during pregnancy only if the potential benefit for the mother outweighs the risk to the fetus. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HEMLIBRA and any potential adverse effects on the breastfed child from HEMLIBRA or from the underlying maternal condition.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.

Please see the HEMLIBRA full Prescribing Information for additional Important Safety Information, including Boxed WARNING.

    • Data on file. Genentech, Inc.

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