Improvement in Health-Related Quality of Life Measures after Long-Term, Daily, Subcutaneous Concizumab Prophylaxis in Patients with Hemophilia A/B with and without Inhibitors: Results from the Main and Extension Parts of Phase 2 Clinical Trials

Relative to the general population, health-related quality of life (HRQoL) is impaired in patients with hemophilia, who report increased pain and reduced physical activity. It is therefore of interest to assess the change in HRQoL after long-term prophylactic treatment. Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody in clinical development for a subcutaneous, prophylactic treatment of patients with hemophilia. Here, we present results from exploratory analyses assessing changes in HRQoL after long-term concizumab treatment (≤126 treatment weeks), which includes data from the main and extension parts of explorer4 (NCT03196284) and explorer5 (NCT03196297) phase 2 trials.

Both trials comprised a main part (≤24 weeks), and an extension part (explorer4: ≤94 weeks; explorer5: ≤102 weeks). In explorer4, patients with hemophilia A and B with inhibitors (HAwI/HBwI) were recruited and randomized 2:1 to concizumab prophylaxis (n=17) or recombinant activated factor VII on-demand treatment (n=9). Patients in the on-demand arm switched to concizumab prophylaxis in the extension part. Twenty-six patients were recruited for explorer4, 25 patients were exposed to concizumab in the extension part, and 22 patients completed the trial. In explorer5, 36 patients with severe hemophilia A (HA) were recruited, 32 patients entered the extension part, and 30 patients completed the trial. Patients were asked to complete the 36-item Short Form Health Survey (SF-36v2) at baseline (for this analysis, baseline was defined as the last assessment before first treatment with concizumab), and throughout the main and extension parts. Scoring was conducted according to the SF-36v2 scoring software (version 5.0). Only patients who completed the entire trial were included for analysis.

T score points of SF-36v2 domains were used to determine clinically meaningful differences at group level from baseline to the end of the extension part, based on minimally important difference criteria (MID; SF-36v2 manual 3rd edition, 2013). At an individual level, a responder analysis was conducted to identify the proportion of patients who had improved scores in the physical component summary (PCS), physical function (PF) and bodily pain (BP) domains, based on the recommended individual-level response threshold of 3.4, 4.3 and 6.2, respectively (based on 2009 United States general population norms; SF-36v2 manual). The results presented here demonstrate the change in HRQoL before and after long-term concizumab use in the main and extension parts of explorer4 and explorer5.

For explorer4, 22 patients (14 HAwI; 8 HBwI) were included in the current exploratory analysis, which showed that the difference in improvement from baseline to end of extension part exceeded the MID thresholds for PCS score (Table 1), at group level. Additionally, the MID thresholds were also met for PF, BP, role-physical, general health, vitality, social functioning, and mental health domains in explorer4 (Table 1). At an individual level, the responder analysis revealed that 63.6%, 54.5% and 50.0% of 22 patients had an improvement that met or exceeded the response threshold for PCS, PF and BP scores. In the 30 patients with severe HA included in the explorer5 analysis, PCS score met the MID threshold for difference in improvement from baseline to end of extension, although large standard deviations were observed (Table 1). At an individual level, the responder analysis revealed that 43.3%, 33.3% and 33.3% of 30 patients had an improvement that met or exceeded the response threshold for PCS, PF and BP scores.

While these analyses are exploratory and should be interpreted with caution, they illustrated that patients with HAwI/HBwI reported improved HRQoL after long-term, subcutaneous concizumab prophylaxis, particularly in clinically relevant domains such as PF and BP, suggesting a potential positive effect of concizumab prophylaxis on physical functioning and reduced pain. Interestingly, PCS improvement was observed across all hemophilia subgroups, suggesting better functional health, albeit the large standard deviation reported. The potential beneficial effect of concizumab prophylaxis on HRQoL in hemophilia patients is being investigated further in the ongoing phase 3 trials.

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