Men with severe hemophilia in the United States: birth cohort analysis of a large national database

Mazepa, Marshall A.; Monahan, Paul E.; Baker, Jean H.; Riske, Brenda; Soucie, J. Michael

doi:10.1182/blood-2015-10-675140

Cited by 102 publications

(139 citation statements)

References 30 publications

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“…33 The long-term outcomes regarding sustained, stable factor IX coagulant activity on joint health and quality of life are not yet known. Recent preclinical work has shown that factor IX products with an extended half-life improved synovial and osteochondral healing after hemarthrosis in mice with hemophilia B, whereas short-term factor IX replacement for hemostasis did not prevent arthropathy.…”

Section: Discussionmentioning

confidence: 99%

Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant

Sullivan²,

et al. 2017

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BACKGROUND The prevention of bleeding with adequately sustained levels of clotting factor, after a single therapeutic intervention and without the need for further medical intervention, represents an important goal in the treatment of hemophilia. METHODS We infused a single-stranded adeno-associated viral (AAV) vector consisting of a bioengineered capsid, liver-specific promoter and factor IX Padua (factor IX–R338L) transgene at a dose of 5×1011 vector genomes per kilogram of body weight in 10 men with hemophilia B who had factor IX coagulant activity of 2% or less of the normal value. Laboratory values, bleeding frequency, and consumption of factor IX concentrate were prospectively evaluated after vector infusion and were compared with baseline values. RESULTS No serious adverse events occurred during or after vector infusion. Vector-derived factor IX coagulant activity was sustained in all the participants, with a mean (±SD) steady-state factor IX coagulant activity of 33.7±18.5% (range, 14 to 81). On cumulative follow-up of 492 weeks among all the participants (range of follow-up in individual participants, 28 to 78 weeks), the annualized bleeding rate was significantly reduced (mean rate, 11.1 events per year [range, 0 to 48] before vector administration vs. 0.4 events per year [range, 0 to 4] after administration; P = 0.02), as was factor use (mean dose, 2908 IU per kilogram [range, 0 to 8090] before vector administration vs. 49.3 IU per kilogram [range, 0 to 376] after administration; P = 0.004). A total of 8 of 10 participants did not use factor, and 9 of 10 did not have bleeds after vector administration. An asymptomatic increase in liver-enzyme levels developed in 2 participants and resolved with short-term prednisone treatment. One participant, who had substantial, advanced arthropathy at baseline, administered factor for bleeding but overall used 91% less factor than before vector infusion. CONCLUSIONS We found sustained therapeutic expression of factor IX coagulant activity after gene transfer in 10 participants with hemophilia who received the same vector dose. Transgene-derived factor IX coagulant activity enabled the termination of baseline prophylaxis and the near elimination of bleeding and factor use. (Funded by Spark Therapeutics and Pfizer; ClinicalTrials.gov number, NCT02484092.)

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Section: Discussionmentioning

confidence: 99%

Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant

Sullivan²,

et al. 2017

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“…[1][2][3] In this context, more and more of them are becoming confronted with a new challenge: ageing. Ageing influences their well-being, because older PWH carry the burden of the physical and psychological consequences of the inadequate treatment received in the early periods of their lives.…”

Section: Introductionmentioning

confidence: 99%

Ageing successfully with haemophilia: A multidisciplinary programme

et al. 2017

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Introduction Persons with haemophilia (PWH) born before the middle 1970s have spent a substantial part of their lives without the benefits of replacement therapy, that became available on a relative large scale only during the 1970s. As a consequence, this group of PWH, although still relatively young, suffers from musculoskeletal and functional problems that are typical of old people. Methods We report herewith the short‐term results of a project based upon a multidisciplinary training programme led by a physiotherapist and an occupational therapist, that was implemented over a period of 12 months in 40 patients with severe or moderate hemophilia A or B born before the middle 1970s and regularly followed‐up at a comprehensive haemophilia treatment centre in Italy. The project was aimed to provide information and skills in order to empower the older PWH carrying physical handicaps and functional limitations that had resulted from the inadequate management in their early ages, and to enable them to cope more efficiently with their crippling disease and prevent further disabilities. Results and Conclusions The comparison of the data obtained before and after the 12‐month programme found marginal improvements, but the purpose of this programme was indeed to offer a blueprint for the future. In this respect, the level of satisfaction for the programme was very high and we expect that it will be implemented long‐term by our older PWH.

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“…4,16 Presence of target joints has been associated with fatigue, loss of enjoyment, reduced leisure pursuits and particularly pain, with more than eight times as many patients reporting extreme pain or discomfort in the presence of a target joint. 4,16 Presence of target joints has been associated with fatigue, loss of enjoyment, reduced leisure pursuits and particularly pain, with more than eight times as many patients reporting extreme pain or discomfort in the presence of a target joint.…”

Section: Milestone 2 Minimal Joint Impairment/ Improved Quality Ofmentioning

confidence: 99%

Achieving the unimaginable: Health equity in haemophilia

et al. 2019

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Haemophilia. 2020;26:17-24.wileyonlinelibrary.com/journal/hae | 17 | INTRODUC TI ONCurrent prophylaxis protocols for haemophilia A are designed conservatively, with a minimal goal of achieving factor VIII (FVIII) trough levels of ≥1%. This threshold was originally selected based on generally favourable outcomes from early cryoprecipitate studies that targeted trough FVIII levels of 1%-3%, supportive evidence that moderate haemophilia was associated with fewer bleeds and better preserved joint function than severe haemophilia, and limitations in plasma resources at the time. 1-3 However, persons with haemophilia (PwH) who are maintained at 1% FVIII continue to experience spontaneous bleeding and remain at higher risk for injury with daily activities. 4 Furthermore, current prophylaxis regimens do not prevent haemophilic arthropathy over a PwH's lifetime. 5 With the growing availability of current therapies, the validity of the 1% threshold has come under scrutiny, accompanied by the proposal to target higher thresholds ≥15%. 6 Recent success in clinical development of haemophilia therapies opens an era of new possibilities and holds great promise for people Abstract Historically, treatment based on the availability of clotting factor replacement has resulted in an arcane guideline for the correction of factor deficiencies in people with haemophilia (PwH). While all other disease entities seek to restore function to a normal level, PwH are restricted to factor nadirs still equivalent to mild or moderate disease, resulting in continued risk of bleeding. A new treatment paradigm is needed based on the defined needs of PwH. A treatment model was developed by a panel of haemophilia providers, patient advocates and health economists to establish specific treatment milestones and targeted outcomes. The panel defined a series of treatment milestones to characterize the activity and outcomes linked to level of factor deficiency correction. All agreed that the ultimate goal should be 'functional cure' and 'health equity'. Seven levels to achieving a functional cure were identified, (a) Sustain life; (b) Minimal joint impairment; (c) Freedom from any spontaneous bleeds;(d) Attainment of 'normal' mobility; (e) Able to sustain minor trauma without additional intervention; (f) Ability to sustain major surgery or trauma; and (g) Normal haemostasis. A parallel set of patient-reported outcomes to achieve health equity was identified. These guidelines are now comparable with other disorders where the goal is to replace missing proteins to attain normal activity levels. As we are no longer limited by plasma supply due to the manufacture of recombinant factors, mimetics, and the early success of gene therapy, health equity is now achievable. K E Y W O R D Shaemophilia, outcomes, prophylaxis, replacement factor How to cite this article: Skinner MW, Nugent D, Wilton P, et al.Achieving the unimaginable: Health equity in haemophilia.

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Men with severe hemophilia in the United States: birth cohort analysis of a large national database

Abstract: Key Points Prospectively collected data on demographics, complications, and mortality are described for 4899 US men with severe hemophilia. Analyzing multiple birth cohorts of US men with severe and mild hemophilia demonstrates ongoing morbidity in need of surveillance.

Cited by 102 publications

References 30 publications

Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant

Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant

Ageing successfully with haemophilia: A multidisciplinary programme

Achieving the unimaginable: Health equity in haemophilia

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