Concizumab Subcutaneous Prophylaxis Improves Health-Related Quality-of-Life Measures in Patients with Congenital Hemophilia with Inhibitors: Phase 2 Trial Results
Authors: Lee Xin Ying , Cepo Katarina , Porstmann Thomas 
Published: November 2019

Introduction Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in clinical development for the subcutaneous prophylactic treatment of hemophilia patients. We present exploratory analyses assessing the impact of concizumab prophylaxis on health-related quality-of-life (HRQoL) in hemophilia A and B with inhibitor (HAwI/HBwI) patients compared with recombinant activated factor VII (rFVIIa) on-demand treatment in a phase 2 trial (NCT03196284; explorer4). HRQoL is impaired in patients with hemophilia relative to the general population and this impairment is more pronounced among patients with inhibitors, including HBwI patients for whom treatment options are particularly limited.
Methods HAwI and HBwI patients were randomized 2:1 to concizumab prophylaxis (n=17) or rFVIIa on demand (recombinant activated factor VII; n=9). Patients completed the 36-item Short Form Health Survey (SF-36v2; 4-week recall) questionnaire at baseline and at the end of the main phase of the trial (24 weeks). Scoring was conducted according to the SF-36v2 scoring software (version 5.0). The change in SF-36v2 scores after treatment onset from baseline to Week 24 was analyzed with an analysis of covariance (ANCOVA model) with regimen as factor and baseline score as a covariate. Improvement in SF-36v2 scores was assessed at both group and individual patient level. At group level, SF-36v2 score improvement was assessed based on minimally important difference (MID) criteria as recommended by the SF-36v2 manual (3rd edition; 2013) (Table 1). A responder analysis was also conducted to identify the proportion of patients who had an improvement in the Physical Component Summary (PCS) in terms of meeting the recommended individual level response threshold of 3.4 points (established based on the 2009 United States general population norms; SF-36v2 manual).
Results Overall, improved HRQoL was observed in patients receiving concizumab prophylaxis as reflected by improvements (higher scores) in all SF-36v2 domain scores. At a group level, the difference in improvement from baseline for concizumab prophylaxis vs rFVIIa on-demand for the PCS score met the MID criterion (Table 1), as did the difference in improvement from baseline for the following SF-36v2 domains: Social Functioning, Vitality Score, Health Perception, Bodily Pain and Physical Functioning (Table 2). This difference in improvement between the two groups was not statistically significant, as the study was not powered to show significance for this endpoint. In addition, a larger percentage of patients on concizumab prophylaxis achieved an improvement that met or exceeded the response threshold on the PCS score scale compared with patients receiving rFVIIa on-demand treatment.
Conclusions Hemophilia patients have been reported to have a worse HRQoL than members of the general population, particularly in relation to physical activity and pain. In results from the concizumab phase 2 explorer4 trial presented here, HAwI and HBwI patients on concizumab prophylaxis reported higher values for change from baseline in all SF-36v2 domain scores compared with patients receiving rFVIIa on demand after 24 weeks of treatment, indicating better functional health and well-being. A reduction in bleeding rate in these patients is likely to have a positive effect on physical function and reduce pain. In explorer4, there was a 78% reduction in the estimated annualized bleeding rate (ABR) among patients on concizumab prophylaxis vs those on rFVIIa on-demand treatment (Shapiro et al., ASH 2019; abstract submitted). The larger reduction in ABR observed with concizumab subcutaneous prophylaxis may have contributed to the larger improvement in HRQoL relative to the rFVIIa on-demand treatment arm. The potential beneficial effect of concizumab prophylaxis on HRQoL in all hemophilia patients will be investigated further in the phase 3 trials.

Disclosures
Lee: Novo Nordisk A/S: Employment. Cepo:Novo Nordisk A/S: Employment. Porstmann:Novo Nordisk Health Care AG: Employment, Honoraria.