Emicizumab in Hemophilia A Buckner, Tyler W; Watson, Crystal; Recht, Michael
The New England journal of medicine,
02/2020, Letnik:
382, Številka:
8
Journal Article
Introduction
Estimates of the size and characteristics of the US haemophilia population are needed for healthcare planning and resource needs assessment. A network of comprehensive haemophilia ...treatment centres (HTCs) located throughout the United States receives federal support for diagnosis and management of haemophilia and other rare bleeding disorders.
Aim
Estimate the incidence and prevalence of haemophilia among US males using the HTC network.
Methods
During the period 2012‐2018, de‐identified surveillance data were collected on all males who visited an HTC that included year of birth, gender, race, Hispanic ethnicity, residence zip code, haemophilia type and severity. Data from all patients were used to calculate period prevalence by haemophilia type, severity and state of residence. Data from a subset of patients born 1995‐2014 were used to estimate incidence rates over the 20‐year period.
Results
During the period, 21 748 males with haemophilia visited the HTCs resulting in an age‐adjusted prevalence of 15.7 cases per 100 000 males (12 for haemophilia A and 3.7 for haemophilia B). Prevalence was higher among whites (15.1) than blacks (12.4) or Hispanics of either race (12.4). State‐specific prevalence varied from 1.6 to 23.3 cases per 100 000. Based on 9587 males born during the index period, the average haemophilia incidence was 1 case per 4334 live male births.
Conclusion
Based on these data, we estimate that there are between 29 761 and 32 985 males with haemophilia living in the United States today, the majority of whom receive comprehensive care in specialized clinical centres.
Introduction
In chronic diseases, disease‐related distress can impact disease outcomes. Distress and haemophilia‐related distress has been demonstrated in people with haemophilia (PwH). The ...association of haemophilia‐related distress on disease outcomes among PwH is unknown.
Aim
To study the association of haemophilia‐related distress with haemophilia specific outcomes, including adherence to prophylactic therapy, the presence of a target joint, healthcare utilization and work‐impairment.
Methods
In a cross‐sectional study, adults with haemophilia A or B were enrolled in a study to validate the haemophilia‐related distress questionnaire (HRDq). In this planned analysis, univariate and multivariate associations between the HRDq total score and disease outcomes were explored.
Results
The 114 participants in this analysis were male, mostly with haemophilia A (92%) and severe disease (52%) with a median age of 31.9 years. On univariate analysis, HRDq total score (5‐point change) was associated with the presence of a target joint (P = .002), high healthcare utilization (P = .011), poor adherence (P = .033) and work‐impairment (P ≤ .001). After adjustment for age, race, severity and other potential confounders, adherence (aβ 0.33, 95% CI .17, .49) and work‐impairment (aβ 4.69, 95% CI 3.27‐6.1) remained statistically significantly associated with HRDq total score.
Conclusion
Haemophilia‐related distress is associated with poor adherence to factor prophylaxis and work‐impairment. The direction of the association (causation) is yet to be determined and requires future study.
For people with haemophilia B (PwHB), bleeding may occur despite prophylaxis, negatively affecting health-related quality of life (HRQoL). The pivotal phase 3 HOPE-B trial investigating the ...adeno-associated virus gene transfer product, etranacogene dezaparvovec (EDZ), demonstrated sustained factor IX (FIX) activity and bleed protection in PwHB with baseline FIX levels ≤2%.
Assess how EDZ affects HRQoL in HOPE-B trial participants.
HRQoL was evaluated using generic and disease-specific patient reported outcomes (PROs) including the EQ-5D-5L and the Hem-A-QoL questionnaires. Mean domain and total scores were compared 6 months pre- and the first 2 years post-EDZ administration using repeated measures linear mixed models. The percentage of participants with minimal clinically important improvements in HRQoL was also evaluated.
Two years post-EDZ, there were nominally significant increases in the least squares (LS) mean score for the EQ-5D-5L Index Value (.04; p = .0129), reflecting better HRQoL. Nominally significant decreases in the LS mean scores, reflecting better HRQoL, were also found for the Hem-A-QoL total score (-6.0; p < .0001) and the Treatment (-13.94; p < .0001), Feelings (-9.01; p < .0001), Future (-6.45; p = .0004) and Work/School (-5.21; p = .0098) domains. The percentage of participants with ≥15-point improvement ranged from 45.83% (95% CI: 31.37%, 60.83%) for Treatment to 13.89% (95% CI: 4.67%, 29.50%) for Family Planning. Results were similar for Year 1.
In conclusion, gene therapy with EDZ improved HRQoL in the first and second years in several Hem-A-QoL domains, including Treatment, Feelings, Work/School and Future domains, whereas improvement in other aspects of HRQoL were not demonstrated.
PURPOSE OF REVIEWNonsevere hemophilia A (NSHA) patients have received relatively little clinical and research attention as compared with their severe counterparts. There is increasing recognition ...that despite their milder bleeding phenotype, the management of NSHA can be a challenge, with most management decisions largely inferred from severe hemophilia A data. This review focuses on some of the more recent developments in the field of NSHA.
RECENT FINDINGSEpidemiologic studies suggest that NSHA remain under-recognized and under-diagnosed globally. As the NSHA population ages, they are susceptible to age-related comorbidities. Large cohort studies of NSHA report that the most common primary cause of death is malignancy. NSHA patients have a lifetime risk of inhibitor development with increasing exposure to factor VIII concentrate. Even so, not all patients with inhibitors will require eradication treatment, irrespective of bleeding phenotype at time of inhibitor development.
SUMMARYAs there are currently no evidence-based strategies for inhibitor eradication in NSHA patients, preventive strategies are critical to mitigate inhibitor risk in NSHA. There is a need for active surveillance of NSHA patients by hemophilia treatment centers to address hemophilia-related issues and other age-related comorbidities, in collaboration with primary care physicians and other subspecialists.
Options for management of haemophilia are increasing rapidly with completely novel therapeutic approaches that cannot be compared using traditional factor assays. In addition, as prophylaxis regimens ...have improved, bleeding rates have decreased, and consequently, it is difficult to show an impact of novel therapies on rates of spontaneous bleeding. There is currently an urgent need for a panel of outcome measures to compare therapies that are dissimilar in many essential ways. Conventional objective outcome measures including joint physical examination and joint imaging continue to hold a central importance. Factor assays are essential for evaluation of products derived from native factor genes, but are not applicable to some extended half‐life factors or non‐factor bypassing agents. Global assays including thrombin generation and chromogenic assays of factor X activation are under investigation for their usefulness in haemophilia assessment. Bleeding rate is a conventional subjective patient‐reported outcome that, while decreasing in frequency, is indispensable as an outcome given that the primary manifestation of haemophilia is bleeding. Other patient‐reported outcomes such as pain intensity and interference, health‐related quality of life and activities and participation are increasingly important to distinguish superior outcomes in comparative trials. This review of outcome measures for haemophilia presents examples of existing outcome measures with an emphasis on their strengths and limitations.
Introduction
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).
Aim
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.
Methods
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.
Results
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.
Conclusion
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.
Introduction
Head‐to‐head evaluation of valoctocogene roxaparvovec, the first gene therapy approved for haemophilia A, with emicizumab is not available. Therefore, phase 3 trial data were indirectly ...compared.
Aim
To compare bleeding rates in trials evaluating 6 × 1013 vg/kg valoctocogene roxaparvovec (GENEr8‐1; NCT03370913), 1.5 mg/kg emicizumab dosed every week (HAVEN 3; NCT02847637), and FVIII prophylaxis (270–902) in participants with severe haemophilia A (FVIII ≤1 IU/dL).
Methods
Valoctocogene roxaparvovec versus emicizumab and FVIII prophylaxis as used in 270–902 versus emicizumab cross‐trial comparisons were performed using matching‐adjusted indirect comparison (MAIC). Individual participant data from GENEr8‐1 and 270–902 were weighted to equalise aggregate participant baseline characteristics from HAVEN 3. After MAIC weighting, annualised bleeding rates (ABR) and proportions of participants without bleeds were compared for treated bleeds, all bleeds, treated joint bleeds, and treated spontaneous bleeds.
Results
After MAIC weighting, ABR for all bleeds was statistically significantly lower with valoctocogene roxaparvovec than emicizumab (rate ratio 95% CI, .55 .33–.93). Additionally, significantly higher proportions of participants had no treated joint bleeds (odds ratio 95% CI, 2.75 1.20–6.31) and no treated bleeds (3.25 1.53–6.90) with valoctocogene roxaparvovec versus emicizumab. When compared with the mainly standard half‐life FVIII prophylaxis regimens in 270–902, mean ABRs (except for all bleeds) were significantly lower, and significantly higher proportions reported 0 bleeds for all outcomes with emicizumab.
Conclusion
Valoctocogene roxaparvovec provided generally lower bleeding rates and higher probability of no bleeds, including treated joint bleeds, than emicizumab. Emicizumab was more effective than FVIII prophylaxis regimens used in 270–902.
Relative treatment effect on proportion of participants with no treated bleeds after matching participants receiving emicizumab prophylaxis (HAVEN 3 Group D) and participants who received valoctocogene roxaparvovec (GENEr8‐1)
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