Opportunities for Improvement: The Lot of the Inhibitor Patient Is Not a Happy One
Authors: Booth Frank V. McL. , Mahlangu Johnny , Levy Howard 
Published: October 2019

Abstract
INTRODUCTION: Hemophilia A or B carries significant morbidity - progressive throughout life. The mainstay of treatment is regular factor replacement to treat or prevent bleeding episodes. Up to 30% of Hemophilia A and up to 5% of Hemophilia B develop neutralizing antibodies (inhibitors) rendering factor replacement therapy ineffective. Hemophilia patients with inhibitors are managed with bypassing agents for treatment or prevention of bleeds.
Prophylaxis is not adequate in inhibitor patients using currently available bypassing products due to their very short half-life (2-3 hours for rFVIIa; 5-6 hours for aPCC) so they are treated on an episodic basis for bleeds. On-demand treatment results in poor quality of life, significantly higher mortality and inferior musculoskeletal outcomes in inhibitor patients when compared to patients without inhibitors. The quality of life of hemophilia has been evaluated using EQ-5D and Haem-A-QOL and impaired activity has been measured with Haemophilia Activity List (HAL). The EQ-5D is a widely used internationally validated general-purpose quality of life instrument however it lacks granularity and is not specific to Hemophilia. Haem A-QOL (Mackensen et al 2004) and Hemophilia Activities List (HAL) (Van Genderen FR et al 2006.) were developed and validated specifically to address the typical disabilities and life issues faced by patients with Hemophilia.
Marzeptacog alfa (activated) (MarzAA) was created using a structure-based rational protein design and has 4 amino acid substitutions to enhance the biological properties of FVIIa. This variant molecule has substantially (6-7x) greater potency than wild-type FVIIa, a greater half-life and sufficient bioavailability when given subcutaneously (SQ).
There is currently a paucity of data on quality of life (QoL) of inhibitor patients. We evaluated the baseline QoL and functional activity of inhibitor patients enrolled in the MAA-201 study using the EQ-5D , Haem-A-QoL and HAL compared the results to those of reference hemophilia patients without inhibitors.
METHODS A phase 2 / 3 open-label study evaluating safety and efficacy of MarzAA in hemophilia patients with inhibitors is underway MAA-201, (NCT03407651)
Subject eligibility required an annualized bleeding rate of >12 and documented inhibitor to replacement factor. The primary aim of the trial was the complete prevention of breakthrough bleeding for 50 days by the daily administration of a fixed SQ dose of MarzAA. If breakthrough bleeding occurred, up to three dose escalations were permitted. At baseline and study conclusion, each subject completed quality of life assessment tools the EQ-5D, Haem-A-QOL and the Hemophilia Activities List
Haem-A-QOL assesses subjects across ten domains and provides a summarized score. Subjects in the present trial (MARZAAPOP) were compared to baseline values for subjects with severe hemophilia but without inhibitors recruited into a long-term prophylaxis trial (The A-LONG trial - ALONGREFPOP).
Mean baseline Haem-A-QOL summed score in the A-LONG trial was 29.3 ±15.7 contrasting sharply with a mean baseline summed score of 42 ±15.2 for subjects in the present trial (Table 1)
HAL is more motor function oriented and assesses patients across ten domains of which seven assess basic functionality and three are composites intended to assess disability in performing complex tasks. HAL provides both raw and normalized scores. Normalized scores provide meaningful output in the case of missing data elements. For each domain and for the sum score, a raw score of 0 and a normalized score of 100 indicates no functional deficit. Figure 1 provides a visual comparison between recruited subjects (MARZAAPOP) in the present trial and the population used to validate the HAL tool. (HALREFPOP).
CONCLUSION: In examining recruits into the present trial, it is clear that inhibitor patients have generally worse functional scores than either of two reference groups. Effective long-term prophylaxis is expected to produce measurable improvement in QOL scores in this hard-to-treat population.

Disclosures
Booth: Catalyst Biosciences: Consultancy. Mahlangu:Sanofi: Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy; Catalyst Biosciences: Consultancy, Research Funding; Biomarin: Research Funding, Speakers Bureau; Biogen: Research Funding, Speakers Bureau; Bayer: Research Funding; Amgen: Consultancy; Alnylam: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding. Levy:Catalyst Biosciences: Employment, Equity Ownership.