Safety and Efficacy of Recombinant Factor VIIa (rFVIIa) in Congenital Hemophilia with Inhibitors (CHwI) in the Home Treatment Setting: Systematic Review of Clinical Studies and Registries

Background: The FDA approved rFVIIa (NovoSeven®RT) in 1999 for treatment of CHwI patients (pts) and it has been studied in compassionate/emergency use programs, clinical trials, and registries for nearly 30 years in this indication. US prescribing information directs that initially, treatment should be instituted under supervision of a physician. While home treatment is common in hemophilia including patients with inhibitors in clinical studies, scientific publications often omit the treatment location. Recent information requests in relation to policy decisions by payers around home use of rFVIIa prompted systematic analysis of clinical studies and registries where predominant use was in the home setting.

Aim: To analyze rFVIIa safety and efficacy data in home treatment in clinical trials and registries.

Methods: A systematic review focusing on the efficacy and safety of rFVIIa for the management of congenital hemophilia A and B patients with inhibitors in the home setting was performed. Studies included in the review consisted of clinical trials (phase I-IV) and prospective and retrospective registries evaluating bleed management and prophylaxis.

Results: A detailed review identified 14 studies for treatment of bleeding (3 phase II, 2 phase III, 9 phase IV) in the home setting including studies reporting on standard doses (90 mcg/kg), high single doses (270 mcg/kg), and observational studies (dosing per physician direction). These studies captured 865 patients treated for 9,024 bleeding episodes (see Table 1), including 640 patients with 6,999 episodes in studies where efficacy was evaluable. Efficacy was consistently high across studies. The 10-year Japanese post-marketing study (F7HAEM-1947) required all adverse events to be reported irrespective of causality; one patient had visual field defect and suspected cerebral infarction, one central venous occlusion, and two others had events that are not clearly thrombotic (hemolytic uremic syndrome, acute renal failure). The only thromboembolic event (TE) reported in phase II-III studies was in 1 patient in the phase II adept™2 trial, which compared vatreptacog alpha with rFVIIa. Apart from the Japanese study, thrombotic rate was 1/7306 bleeds (0.014%).

Table 1. On demand treatment of bleeding with rFVIIa

Trial ID	Phase	Number of Patients	Number of  Bleeds	Efficacy	Safety
F7HAEM-1510	II	22	42	88%	No TE
F7HAEM-2068	II	24	45	91-92%	No TE
NN7128-1907 (Pioneer 1)	II	23	359	84%	No TE
F7HT/USA/1/USA (US Home Trx )	III	56	877	92%	No TE
NN1731-3562 (adept™2)	III	57	227	93%	1 TE
HRS/HTRS Registry (2000-2003)	IV	42	793	87%	No TE
HTRS Registry (2004-2008)	IV	129	2,041	89-93%	No TE
F7HAEM-1965 (DOSE)	IV	35	158	Not assessed (diary)	No TE
F7HAEM-3507 (ONE)	IV	102	496	85-96%	No TE
NN7025-3601 (SMART-7)	IV	51	511	Not reported (interim)	No TE
F7HAEM-3537 (UKHCDO Registry)	IV	139	1,356	Not reported (diaries)	No TE
F7HAEM-1947	IV	144*	1,718*	88%	2TE†
F7AHEM-1921 (WIRK Registry)	IV	14	269	90%	No TE
F7HAEM-3850	IV	27	132	81%-92%	No TE
Total		865	9,024

* Patients with evaluable efficacy.

† One visual field defect with suspected cerebral infarction, one central venous occlusion.

Two studies evaluated rFVIIa for secondary prophylaxis (1 phase II, 1 phase IV) (see Table 2). The phase II study captured 22 patients treated with 90 or 270 mcg/kg daily. The phase IV retrospective study captured 86 patients with varied rFVIIa doses that often changed over time. Effective reduction in bleeding was seen in both studies. Across 108 patients treated with prophylaxis at home over 42,861 days, there were no thrombotic events reported.

Table 2. Secondary Prophylaxis with rFVIIa

Trial ID	Phase	Number of Patients	Number of   Prophylaxis Days	Efficacy	Safety
F7HAEM-1505	II	22	1,885	45-59% reduction	No TE
F7HAEM-3695 (PRO-PACT)	IV	86	40,976	46-52%	No TE
Total		108	42,861

Conclusions: Analysis of data from clinical studies of rFVIIa in home treatment of bleeding and secondary prophylaxis of bleeding demonstrates consistent efficacy for treatment and prevention of bleeding. Thrombotic events were uncommon across ~9,000 bleeding episodes and not reported in ~43,000 prophylaxis days. These data support the safety and efficacy of rFVIIa in the home treatment setting and sufficient evidence for payers to continue its approval in the home management of hemophilia patients.