• Bleeding Data across Baseline FIX Expression Levels in People with Hemophilia B: An Analysis Using the 'Factor Expression Study'

      Burke, Tom; Shaikh, Anum; Ali, Talaha; Li, Nanxin; Konkle, Barbara A; Noone, Declan; O'Mahony, Brian; Pipe, Steven W; O'Hara, Jamie (American Society of Hematology, 2021-11-05)
      Abstract Introduction Complications such as spontaneous and trauma-related bleeding events typically experienced by people with hemophilia B (PWHB) are associated with long-term joint damage and chronic pain, and burdensome treatment with intravenous factor IX administration. Gene therapy, designed to enable the endogenous production of the missing clotting factor, has potential for curative benefit in PWHB (Dolan et al, 2018). Due to its link to risk for bleeding episodes, factor expression level (FEL) is commonly used as an endpoint in hemophilia gene therapy trials. However, little data currently exist linking FEL to bleeding risk in PWHB, most notably within the mild range. As such, the aim of this analysis was to examine the relationship between annual bleed rate (ABR) data across baseline FEL in PWHB. Methods Data from adult non-inhibitor PWHB, across Europe and the United States (US) who received clotting factor on-demand (OD), were drawn from the 'Cost of HaEmophilia in adults: a Socioeconomic Survey' (CHESS) studies. The CHESS studies are retrospective, burden-of-illness studies in people with hemophilia A or B, capturing the economic and humanistic burden associated with living with hemophilia. Additional data were collected to supplement the existing CHESS studies, particularly in people with exogenous FEL in the mild and moderate range. ABR was defined as the physician-reported number of bleed events experienced by the patient in the 12 months to study capture. A generalized linear model (GLM) was used to analyze variation in ABR data across FEL, adjusting for covariates age, body mass index (BMI), and blood-borne viruses. Following this, a multivariable restricted cubic spline (RCS) GLM regression was performed to create, model, and test for the potential non-linear relationship between FEL and ABR. The RCS regression employed 3 knots, located at baseline FEL values of 1, 5, and 10, and controlled once again for age, BMI, and blood-borne viruses. Results A total of 407 adult non-inhibitor PWHB, receiving an OD therapy regimen and with information on ABR, were profiled. The GLM provided adequate fit for the modeling of bleed data; the average marginal effect at the mean was computed from the GLM regression outputs. After controlling for the effects of all other model covariates, the regression analysis showed a significant association between FEL and ABR; for every 1% increase in FEL, the average ABR decreased by 0.08 units (p<0.001). The results of the RCS regression found a significant non-linear relationship between FEL and ABR, ceteris paribus (p<0.001). Conclusions The results of this analysis found baseline FEL to be significantly associated with ABR in PWHB; as baseline FEL increased, ABR reduced. This highlights the clinical importance of new hemophilia gene therapies potentially increasing FEL to that of the mild or non-hemophilic range in terms of reducing patient burden through the better prevention of bleeding events in PWHB. Disclosures Ali: UniQure: Current Employment. Li: UniQure: Current Employment. Konkle: Pfizer, Sangamo, Sanofi, Sigilon, Spark, Takeda and Uniqure: Research Funding; BioMarin, Pfizer and Sigilon: Consultancy. O'Mahony: BioMarin Pharmaceutical Inc.: Consultancy; Freeline: Consultancy; Uniqure: Speakers Bureau. Pipe: Apcintex: Consultancy; ASC Therapeutics: Consultancy; Bayer: Consultancy; Biomarin: Consultancy, Other: Clinical trial investigator; Catalyst Biosciences: Consultancy; CSL Behring: Consultancy; HEMA Biologics: Consultancy; Freeline: Consultancy, Other: Clinical trial investigator; Novo Nordisk: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy, Other; Sangamo Therapeutics: Consultancy; Sanofi: Consultancy, Other; Takeda: Consultancy; Spark Therapeutics: Consultancy; uniQure: Consultancy, Other; Regeneron/ Intellia: Consultancy; Genventiv: Consultancy; Grifols: Consultancy; Octapharma: Consultancy; Shire: Consultancy.
    • Bleeding Data across Baseline FIX Expression Levels in People with Hemophilia B: An Analysis Using the 'Factor Expression Study'

      Burke, Tom; Shaikh, Anum; Ali, Talaha; Li, Nanxin; Konkle, Barbara A; Noone, Declan; O'Mahony, Brian; Pipe, Steven W; O'Hara, Jamie (Elsevier, 2021-12-24)
      Introduction Complications such as spontaneous and trauma-related bleeding events typically experienced by people with hemophilia B (PWHB) are associated with long-term joint damage and chronic pain, and burdensome treatment with intravenous factor IX administration. Gene therapy, designed to enable the endogenous production of the missing clotting factor, has potential for curative benefit in PWHB (Dolan et al, 2018). Due to its link to risk for bleeding episodes, factor expression level (FEL) is commonly used as an endpoint in hemophilia gene therapy trials. However, little data currently exist linking FEL to bleeding risk in PWHB, most notably within the mild range. As such, the aim of this analysis was to examine the relationship between annual bleed rate (ABR) data across baseline FEL in PWHB. Methods Data from adult non-inhibitor PWHB, across Europe and the United States (US) who received clotting factor on-demand (OD), were drawn from the 'Cost of HaEmophilia in adults: a Socioeconomic Survey' (CHESS) studies. The CHESS studies are retrospective, burden-of-illness studies in people with hemophilia A or B, capturing the economic and humanistic burden associated with living with hemophilia. Additional data were collected to supplement the existing CHESS studies, particularly in people with exogenous FEL in the mild and moderate range. ABR was defined as the physician-reported number of bleed events experienced by the patient in the 12 months to study capture. A generalized linear model (GLM) was used to analyze variation in ABR data across FEL, adjusting for covariates age, body mass index (BMI), and blood-borne viruses. Following this, a multivariable restricted cubic spline (RCS) GLM regression was performed to create, model, and test for the potential non-linear relationship between FEL and ABR. The RCS regression employed 3 knots, located at baseline FEL values of 1, 5, and 10, and controlled once again for age, BMI, and blood-borne viruses. Results A total of 407 adult non-inhibitor PWHB, receiving an OD therapy regimen and with information on ABR, were profiled. The GLM provided adequate fit for the modeling of bleed data; the average marginal effect at the mean was computed from the GLM regression outputs. After controlling for the effects of all other model covariates, the regression analysis showed a significant association between FEL and ABR; for every 1% increase in FEL, the average ABR decreased by 0.08 units (p<0.001). The results of the RCS regression found a significant non-linear relationship between FEL and ABR, ceteris paribus (p<0.001). Conclusions The results of this analysis found baseline FEL to be significantly associated with ABR in PWHB; as baseline FEL increased, ABR reduced. This highlights the clinical importance of new hemophilia gene therapies potentially increasing FEL to that of the mild or non-hemophilic range in terms of reducing patient burden through the better prevention of bleeding events in PWHB. Disclosures Ali:  UniQure: Current Employment. Li:  UniQure: Current Employment. Konkle:  Pfizer, Sangamo, Sanofi, Sigilon, Spark, Takeda and Uniqure: Research Funding; BioMarin, Pfizer and Sigilon: Consultancy. O'Mahony:  BioMarin Pharmaceutical Inc.: Consultancy; Freeline: Consultancy; Uniqure: Speakers Bureau. Pipe:  Apcintex: Consultancy; ASC Therapeutics: Consultancy; Bayer: Consultancy; Biomarin: Consultancy, Other: Clinical trial investigator; Catalyst Biosciences: Consultancy; CSL Behring: Consultancy; HEMA Biologics: Consultancy; Freeline: Consultancy, Other: Clinical trial investigator; Novo Nordisk: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy, Other; Sangamo Therapeutics: Consultancy; Sanofi: Consultancy, Other; Takeda: Consultancy; Spark Therapeutics: Consultancy; uniQure: Consultancy, Other; Regeneron/ Intellia: Consultancy; Genventiv: Consultancy; Grifols: Consultancy; Octapharma: Consultancy; Shire: Consultancy.
    • Evidence of a disability paradox in patient-reported outcomes in haemophilia.

      O'Hara, Jamie; Martin, Antony P; Nugent, Diane; Witkop, Michelle; orcid: 0000-0003-0758-286X; Buckner, Tyler W; Skinner, Mark W; orcid: 0000-0002-0934-0680; O'Mahony, Brian; Mulhern, Brendan; Morgan, George; orcid: 0000-0003-2014-3415; Li, Nanxin; et al. (2021-02-17)
      People with inherited and long-term conditions such as haemophilia have been shown to adapt to their levels of disability, often reporting better quality of life (QoL) than expected from the general population (the disability paradox). To investigate the disability paradox in people with haemophilia in the United States by examining preference differences in health state valuations versus the general population. We conducted a discrete choice experiment including duration to capture valuations of health states based on patient-reported preferences. Participants indicated their preferences for hypothetical health states using the EQ-5D-5L, where each participant completed 15 of the 120 choice tasks. Response inconsistencies were evaluated with dominated and repeated scenarios. Conditional-logit regressions with random sampling of the general population responses were used to match the sample of patients with haemophilia. We compared model estimates and derived preferences associated with EQ-5D-5L health states. After removing respondents with response inconsistencies, 1327/2138 (62%) participants remained (177/283 haemophilia; 1150/1900 general population). Patients with haemophilia indicated higher preference value for 99% of EQ-5D-5L health states compared to the general population (when matched on age and gender). The mean health state valuation difference of 0.17 indicated a meaningful difference compared to a minimal clinically important difference threshold of 0.07. Results were consistent by haemophilia type and severity. Our findings indicated the presence of a disability paradox among patients with haemophilia, who reported higher health states than the general population, suggesting the impact of haemophilia may be underestimated if general population value sets are used. [Abstract copyright: © 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.]
    • Examination and Validation of a Patient-Centric Joint Metric: “Problem Joint”; Empirical Evidence from the CHESS US Dataset

      Burke, Tom; Rodriguez Santana, Idaira; Chowdary, Pratima; Curtis, Randall; Khair, Kate; Laffan, Michael; McLaughlin, Paul; Noone, Declan; O'Mahony, Brian; Pasi, John; et al. (Elsevier, 2021-08-03)
      Introduction Severe hemophilia (FVIII/FIX level <1%) is characterized by spontaneous hemarthrosis leading to progressive joint deterioration and chronic pain in the affected individual. Unless these recurrent hemarthroses can be prevented, e.g. with the use of prophylactic factor replacement therapy, these patients will develop chronic synovitis, pain, and eventually destruction of the joint. Current metrics such as ’Target joint’ and other clinical measures of joint morbidity are prevalent and widely accepted. Measures focused solely on bleeding activity, such as the ’Target joint’ metric, are arguably becoming less sensitive as current treatment strategies look to significantly reduce or eradicate joint bleeds, though they maintain clinically relevant and complementary to delivery of comprehensive hemophilia care. Key opinion leaders in the haemophilia field have debated the need for a more patient relevant measure of haemophilia-related joint morbidity. ‘Problem Joint’ (PJ), which is defined as having chronic joint pain and/or limited range of movement due to compromised joint integrity (chronic synovitis and/or haemophilic arthropathy), with or without persistent bleeding was derived through consensus. The objectives of this working group are to examine the usefulness and validity of the PJ metric. Initial research presented here was used to test the sensitivity of PJ as a patient relevant metric with respect to key outcomes for US haemophilia patients. Methods Data on PJs, as well as demographic, clinical and socio-economic variables was captured within the ‘Cost of Haemophilia Across Europe: A Socioeconomic Survey’ datasets (CHESS: I, II, Paediatric, and US studies). These data contain a total of 992 paediatric (age 1-17) and 2,437 adults (age 18+) with haemophilia from eight European countries and the US. Statistical analysis explored the association of PJ count and location with respect to two key outcomes: quality of life, as measured by an EQ-5D score, and overall work impairment, measured by the Work Productivity and Activity Impairment Questionnaire (WPAI). Those with current inhibitors were excluded from the analysis, and the US cohort comprised the focus of this initial research into the topic. Results The US cohort contained information on 345 people with haemophilia (PwH) and captured adults only, with a mean age of 35 years. Approximately, 43% of PwH had one or more PJs. Lower body PJs were more prevalent than upper body: 40% had one or more lower body PJs vs. 27% upper body. The majority of PJs were located in the ankles, knees and elbows. The relationship between EQ-5D and number of PJs showed a negative trend (see Figure 1): the average EQ-5D score was: 0.81 for those with zero PJs (N=197); 0.79 for those with one PJ (N=24); 0.70 for two PJs (N=29); 0.68 for three PJs (N=24) and 0.49 for those patients with four of more PJs (N=59). Similarly, an increase in number of PJs meant greater work productivity impairment versus no PJs recorded: 30.08% (N=102) vs. 19.51% (N=137), respectively. Discussion Results from the US cohort found that an increase in the number of PJs was associated with an increasing humanistic burden in PwH. The proposed Problem Joint definition takes a holistic viewpoint and provides a patient relevant perspective. Further work is planned to evaluate the appropriateness of the measure, and test the sensitivity in European and pediatric cohorts. Disclosures Burke: HCD Economics: Current Employment; University of Chester: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Rodriguez Santana: HCD Economics: Current Employment. Chowdary: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Shire (Baxalta): Membership on an entity's Board of Directors or advisory committees; Spark: Membership on an entity's Board of Directors or advisory committees; BioMarin: Honoraria; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Freeline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Curtis: Bayer: Consultancy; Novo Nordisk: Consultancy; Patient Reported Outcomes, Burdens and Experiences: Consultancy; USC Hemophilia Utilization Group Study (HUGS): Consultancy. Khair: Haemnet: Membership on an entity's Board of Directors or advisory committees; Biomarin: Consultancy; HCD Economics: Consultancy; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medikhair: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau. Laffan: Shire: Consultancy; LFB: Consultancy; Roche: Consultancy; Sobi: Consultancy; Pfizer: Consultancy; CSL: Consultancy; Pfizer: Speakers Bureau; Bayer: Speakers Bureau; Roche-Chugai: Speakers Bureau; Takeda: Speakers Bureau; Leo-Pharma: Speakers Bureau; Octapharma: Consultancy. McLaughlin: BioMarin: Consultancy; Novo Nordisk: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Roche/Chugai: Speakers Bureau; Takeda: Speakers Bureau. Noone: European Haemophilia Consortium: Membership on an entity's Board of Directors or advisory committees; Research Investigator PROBE: Research Funding; Healthcare Decision Consultants: Membership on an entity's Board of Directors or advisory committees. O'Mahony: Biomarin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Freeline: Honoraria; UniQure: Honoraria. Pasi: BioMarin: Consultancy, Honoraria, Other: Grants, personal fees, and nonfinancial support; honoraria as member of scientific advisory boards and symposia; uniQure: Other: Grants and nonfinancial support , Research Funding; ApcinteX: Consultancy, Other: Personal fees ; Octapharma: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia , Speakers Bureau; Novo Nordisk: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia ; Catalyst Biosciences: Consultancy, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Biotest: Consultancy, Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Alnylam (Sanofi): Other: Personal fees and nonfinancial support ; Takeda: Consultancy, Honoraria, Other: Personal fees; honoraria as member of scientific advisory boards and symposia ; Sanofi: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia, Research Funding; Sigilon: Research Funding; Tremeau: Research Funding; Sobi: Consultancy, Honoraria, Other; Roche: Honoraria, Other; Pfizer: Other. Skinner: Genentech: Consultancy, Honoraria; Spark Therapeutics: Other, Speakers Bureau; Pfizer: Other, Speakers Bureau; Takeda: Honoraria, Research Funding; uniQure: Research Funding; Biomarin: Consultancy, Research Funding; CSL Behring: Research Funding; Freeline Therapeutics: Research Funding; Novo Nordisk: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Sobi: Research Funding; Bayer: Consultancy, Research Funding. O'Hara: HCD Economics: Current Employment, Current equity holder in private company; F. Hoffmann-La Roche Ltd: Consultancy.
    • Patient‐relevant health outcomes for hemophilia care: Development of an international standard outcomes set

      Balen, Erna C.; orcid: 0000-0002-3678-6581; O'Mahony, Brian; Cnossen, Marjon H.; Dolan, Gerard; Blanchette, Victor S.; Fischer, Kathelijn; Gue, Deborah; O'Hara, Jamie; Iorio, Alfonso; orcid: 0000-0002-3331-8766; Jackson, Shannon; et al. (Wiley, 2021-03-06)
    • Patient‐relevant health outcomes for hemophilia care: Development of an international standard outcomes set

      van Balen, Erna C.; orcid: 0000-0002-3678-6581; O'Mahony, Brian; Cnossen, Marjon H.; Dolan, Gerard; Blanchette, Victor S.; Fischer, Kathelijn; Gue, Deborah; O'Hara, Jamie; Iorio, Alfonso; orcid: 0000-0002-3331-8766; Jackson, Shannon; et al. (2021-03-06)
      Abstract: Background: Patient‐relevant health outcomes for persons with hemophilia should be identified and prioritized to optimize and individualize care for persons with hemophilia. Therefore, an international group of persons with hemophilia and multidisciplinary health care providers set out to identify a globally applicable standard set of health outcomes relevant to all individuals with hemophilia. Methods: A systematic literature search was performed to identify possible health outcomes and risk adjustment variables. Persons with hemophilia and multidisciplinary health care providers were involved in an iterative nominal consensus process to select the most important health outcomes and risk adjustment variables for persons with hemophilia. Recommendations were made for outcome measurement instruments. Results: Persons with hemophilia were defined as all men and women with an X‐linked inherited bleeding disorder caused by a deficiency of coagulation factor VIII or IX with plasma activity levels <40 IU/dL. We recommend collecting the following 10 health outcomes at least annually, if applicable: (i) cure, (ii) impact of disease on life expectancy, (iii) ability to engage in normal daily activities, (iv) severe bleeding episodes, (v) number of days lost from school or work, (vi) chronic pain, (vii) disease and treatment complications, (viii) sustainability of physical functioning, (ix) social functioning, and (x) mental health. Validated clinical as well as patient‐reported outcome measurement instruments were endorsed. Demographic factors, baseline clinical factors, and treatment factors were identified as risk‐adjustment variables. Conclusion: A consensus‐based international set of health outcomes relevant to all persons with hemophilia, and corresponding measurement instruments, was identified for use in clinical care to facilitate harmonized longitudinal monitoring and comparison of outcomes.
    • Patient‐relevant health outcomes for hemophilia care: Development of an international standard outcomes set

      Balen, Erna C.; orcid: 0000-0002-3678-6581; O'Mahony, Brian; Cnossen, Marjon H.; Dolan, Gerard; Blanchette, Victor S.; Fischer, Kathelijn; Gue, Deborah; O'Hara, Jamie; Iorio, Alfonso; orcid: 0000-0002-3331-8766; Jackson, Shannon; et al. (Wiley, 2021-03-06)