HEMLIBRA was evaluated in HAVEN – an extensive clinical trial programme in patients with congenital haemophilia A^1–5

Males with severe congenital haemophilia A (endogenous FVIII activity, <1%) without inhibitors, ≥12 years; treated with episodic FVIII or FVIII prophylaxis* in the prior 24 weeks (N=152).^2,6

*At least five bleeding events in the prior 24 weeks required for episodic FVIII. No bleed requirements with prior prophylaxis.⁶

Patients in Arm C received no prophylaxis; after completing ≥24 weeks in the trial they could receive HEMLIBRA prophylaxis Q2W (and remain in Arm C). For all participants, additional FVIII was administered at investigator-determined doses for breakthrough bleeding.

Primary efficacy endpoint: treated bleeds at ≥24 weeks in Arm A vs. C and Arm B vs. C.²

Two patients (one in Arm A and one in Arm C) were lost to follow-up and not treated. These patients were included in the primary efficacy analysis, but not in the surgery analysis.^2,7

The non-interventional study (NIS) followed patients receiving FVIII prophylaxis (n=48) and prospectively collected data on bleeds and FVIII administration. The availability of granular data enabled paired analyses, using identical definitions and methodologies to HAVEN 3. Each patient received adequate prophylaxis, as determined by investigators. The NIS resulted in an intra-individual comparison analysis – part of HAVEN 3, Arm D, which was controlled for inter-individual variability (e.g. bleeding characteristics, risk factors for bleeds and patient recognition of bleeds).^2,8

Data cut-off: 15 September 2017.

*All values based on electronic case-report forms. Does not include data from the non-interventional study.⁶

^†In Arm B, one patient reported ‘Other’ as the product used. Therefore, percentages based on 34 participants in Arm B and 151 participants in the Total column.⁶

Males with congenital haemophilia A with FVIII inhibitors, ≥12 years, ≥40 kg; treated with episodic BPAs or BPA prophylaxis in the prior 24 weeks (N=109).^3,9

Primary efficacy endpoint: treated bleeds at ≥24 weeks in Arm A vs. B.

Patients in Arm B received no prophylaxis and no subcutaneous control injections; after completing ≥24 weeks in the trial they could receive HEMLIBRA prophylaxis QW (and remain in Arm B). All participants receiving HEMLIBRA could receive episodic treatment with BPAs for breakthrough bleeding, as needed.

One patient in Arm A discontinued prior to treatment; this patient was included in the primary efficacy analysis and the surgical analysis. Since the data cut-off for the primary analysis, an additional four patients were enrolled and included in the surgery analysis.^7,9

Arm C included patients from the intra-individual comparison from the non-interventional study (NIS, n=24). This prospective NIS evaluated real-world bleeding and safety data. Eligible patients were subsequently able to participate in HAVEN 1. Arm D included NIS participants enrolled after randomisation deadline and included in the safety analysis (n=7 at cut-off).³ Data from Arms C and D are not presented here; for details, please refer to the HAVEN 1 publication

Data cut-off: 25 October 2016.

*All values based on electronic case-report forms and not on data from the NIS.³

^†All participants had a FVIII inhibitor titre of ≥5.0 Bethesda units/ml.³

Males with congenital haemophilia A with FVIII inhibitors, <12 years*; treated with episodic BPAs or BPA prophylaxis in the prior 24 weeks (N=88).⁴

*Participants aged <2 years were enrolled after results of the interim analysis if they had a high medical need (n=8). Participants aged 12–17 years and <40 kg were included in Arm A, but not in the efficacy analysis (n=3).⁴

HAVEN 2 was designed as a descriptive study with no defined primary or secondary endpoints. Efficacy endpoints included the rate of treated bleeding events.⁴

The Q2W and Q4W cohorts (Arms B and C) were added later for characterisation of PK, to support extrapolation. No patients <2 years old or 12–17 years old could enrol in these cohorts.⁴

Data cut-off: 30 April 2018.

Males with congenital haemophilia A, classified as severe or with FVIII inhibitors, ≥12 years; treated with BPAs or FVIII in the prior 24 weeks (N=48).⁵

Patients in the initial run-in cohort (n=7) received HEMLIBRA 6.0 mg/kg/Q4W for ≥24 weeks to assess safety and establish pharmacokinetics of the regimen.

Patients in the expansion cohort (n=41) were included in the efficacy analysis: treated annualised bleed rate (ABR). At the time of analysis all patients had received ≥24 weeks treatment.

Data cut-off: 15 December 2017.

 *Includes one patient with mild haemophilia, inhibitors (32 Bethesda units/ml) and <1% FVIII activity at study entry.⁵