Participants with hemophilia A received B-domain–deleted factor VIII gene therapy delivered in an AAV5 vector. A decrease in annualized bleeding rates was maintained for 2 years despite declining ...factor VIII levels.
Patients with severe hemophilia A were treated with an adenoviral construct containing coagulation factor VIII cDNA and followed for 1 to 3 years. Median factor VIII activity at 49 to 52 weeks was 24 ...IU per deciliter, and annualized bleeding rates decreased after treatment. Elevations in alanine aminotransferase were the most common toxic effect and were mainly controlled with glucocorticoids.
Hemophilia A (factor VIII FVIII deficiency) and hemophilia B (factor IX FIX deficiency) are the X-linked recessive bleeding disorders that clinically manifest with recurrent bleeding, predominantly ...into muscles and joints. In its severe presentation, when factor activity is less than 1% of normal, hemophilia presents with spontaneous musculoskeletal bleeds and may progress to debilitating chronic arthropathy. Management of hemophilia has changed profoundly in the past decades. From on-demand to prophylactic factor concentrate replacement, the treatment goal shifted from controlling bleeds to preventing bleeds and improving quality of life. In this new scenario, gene therapy has arisen as a paradigm-changing therapeutic option, a one-time treatment with the potential to achieve sustained coagulation FVIII or FIX expression even within the normal range. This review discusses the critical impact of adeno-associated virus (AAV) gene transfer in hemophilia care, including the recent clinical outcomes, changes in disease perceptions, and its treatment burden. We also discuss the challenging scenario of the AAV-directed immune response in the clinical setting and potential strategies to improve the long-lasting efficacy of hemophilia gene therapy efficacy.
Current and emerging gene therapies for haemophilia A and B Kaczmarek, Radoslaw; Miesbach, Wolfgang; Ozelo, Margareth C. ...
Haemophilia : the official journal of the World Federation of Hemophilia,
April 2024, Letnik:
30, Številka:
S3
Journal Article
Recenzirano
Odprti dostop
Introduction
After decades of stumbling clinical development, the first gene therapies for haemophilia A and B have been commercialized and have normalized factor (F)VIII and factor (F)IX levels in ...some individuals in the long term. Several other clinical programs testing adeno‐associated viral (AAV) vector gene therapy are at various stages of clinical testing.
Discussion
Multiyear follow‐up in phase 1/2 and 3 studies showed long‐term and sometimes curative but widely variable and unpredictable efficacy. Liver toxicities, mostly low‐grade, occur in the 1st year in at least some individuals in all haemophilia A and B trials and are poorly understood. Wide variability and unpredictability of outcome and slow decline of FVIII levels are a major disadvantage because immune responses to AAV vectors preclude repeat dosing, which otherwise could improve suboptimal or restore declining expression, while overexpression may predispose to thrombosis. Long‐term safety outcomes will need lifelong monitoring because AAV vectors infused at high doses integrate into chromosomes at rates that raise questions about potential oncogenicity and necessitate vigilance. Alternative gene transfer systems employing gene editing and/or non‐viral vectors are under development and promise to overcome some limitations of the current state of the art for both haemophilia A and B.
Conclusions
AAV gene therapies for haemophilia have now become new treatment options but not universal cures. AAV is a powerful but imperfect gene transfer platform. Biobetter FVIII transgenes may help solve some problems plaguing gene therapy for haemophilia A. Addressing variability and unpredictability of efficacy, and delivery of gene therapy to ineligible patient subgroups may require different gene transfer systems, most of which are not ready for clinical translation yet but bring innovations needed to overcome the current limitations of gene therapy.
Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA). However, pre-existing immunity ...against AAV may limit transduction efficiency and hence treatment success. Global data on the prevalence of AAV serotypes are limited. In this global, prospective, noninterventional study, we determined the prevalence of pre-existing immunity against AAV2, AAV5, AAV6, AAV8, and AAVrh10 among people ≥12 years of age with HA and residual FVIII levels ≤2 IU/dL. Antibodies against each serotype were detected using validated, electrochemiluminescent-based enzyme-linked immunosorbent assays. To evaluate changes in antibody titers over time, 20% of participants were retested at 3 and 6 months. In total, 546 participants with HA were enrolled at 19 sites in 9 countries. Mean (standard deviation) age at enrollment was 36.0 (14.87) years, including 12.5% younger than 18 years, and 20.0% 50 years of age and older. On day 1, global seroprevalence was 58.5% for AAV2, 34.8% for AAV5, 48.7% for AAV6, 45.6% for AAV8, and 46.0% for AAVrh10. Considerable geographic variability was observed in the prevalence of pre-existing antibodies against each serotype, but AAV5 consistently had the lowest seroprevalence across the countries studied. AAV5 seropositivity rates were 51.8% in South Africa (
= 56), 46.2% in Russia (
= 91), 40% in Italy (
= 20), 37.2% in France (
= 86), 26.8% in the United States (
= 71), 26.9% in Brazil (
= 26), 28.1% in Germany (
= 89), 29.8% in Japan (
= 84), and 5.9% in the United Kingdom (
= 17). For all serotypes, seropositivity tended to increase with age. Serostatus and antibody titer were generally stable over the 6-month sampling period. As clinical trials of AAV-mediated gene therapies progress, data on the natural prevalence of antibodies against various AAV serotypes may become increasingly important.
PUPs A-LONG evaluated safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously untreated patients (PUPs) with hemophilia A. This open-label, Phase 3 study enrolled ...male PUPs (<6 years) with severe hemophilia A to receive rFVIIIFc. The primary endpoint was occurrence of inhibitor development. Secondary endpoints included annualized bleed rate (ABR). Of 103 subjects receiving ≥1 dose of rFVIIIFc, 80 (78%) were aged <1 year at study start, 20 (19%) had family history of inhibitors, and 82 (80%) had high-risk F8 mutations. Twenty subjects began on prophylaxis, while 81 began an on-demand regimen (69 later switched to prophylaxis). Eighty-seven (81%) subjects completed the study. Inhibitor incidence was 31.1% (95% confidence interval CI: 21.8%–41.7%) in subjects with ≥10 exposure days (or inhibitor); high-titer inhibitor incidence was 15.6% (95% CI: 8.8%–24.7%). The median (range) time to high-titer inhibitor development was 9 (4–14) exposure days. Twenty-eight (27%) subjects experienced 32 rFVIIIFc treatment-related adverse events; most were inhibitor development. There was 1 non–treatment-related death due to intracranial hemorrhage (onset prior to first rFVIIIFc dose). The overall median (interquartile range) ABR was 1.49 (0.00–4.40) for subjects on variable prophylaxis dosing regimens. In this study of rFVIIIFc in pediatric PUPs with severe hemophilia A, overall inhibitor development was within expected range, although high-titer inhibitor development was on the low end of the range reported in literature. rFVIIIFc was well-tolerated and effective as prophylaxis and for treatment of bleeds. This trial is registered at www.clinicaltrials.gov (NCT02234323).
Haemophilia gene therapy—Update on new country initiatives Reiss, Ulrike M.; Mahlangu, Johnny; Ohmori, Tsukasa ...
Haemophilia : the official journal of the World Federation of Hemophilia,
20/May , Letnik:
28, Številka:
S4
Journal Article
Recenzirano
Introduction
Gene therapy is emerging as a potential cure for haemophilia. Gene therapy is a one‐time treatment that can elevate factor levels for many years and minimize or eliminate the need for ...clotting factor concentrate (CFC) replacement therapy. However, there is a paucity of reports on gene therapy efforts in countries outside of North America or Europe, especially in low‐and‐middle‐income countries (LMIC). All indications are that gene therapy will be one of standard care treatments for haemophilia in the future. Still, it may not be accessible to many countries due to various barriers and challenges. At the same time, each country may formulate solutions that may be used globally.
Aim
To summarize the approaches taken to establish haemophilia gene therapy in Japan, China, India, South Africa, and Brazil, and to describe the US‐initiated multi‐LMIC haemophilia gene therapy development program to include Peru, Vietnam, Thailand, Nepal, and Sri Lanka.
Methods
A review of related published information or as accessible by each country's author.
Results
Different starting conditions, differing input and level of support from the multitude of stakeholders, and strong leadership have led to various approaches for facilitating research and developing needed infrastructure and regulatory and financing models. Gene therapy programs are at various stages of development and include both adeno‐associated viral and lentiviral vectors.
Conclusion
Global partnerships and collaboration, exchange of knowledge and experience, and alignment of processes across borders will promote further progress towards global access to gene therapy for haemophilia.
Hemophilia A and B are hereditary bleeding disorders, characterized by factor VIII or IX deficiencies, respectively. For many decades, prophylaxis with coagulation factor concentrates (replacement ...therapy) was the standard‐of‐care approach in hemophilia. Since the 1950s, when prophylaxis started, factor concentrates have been improved with virus inactivation and molecule modification to extend its half‐life. The past years have brought an intense revolution in hemophilia care, with the development of nonfactor therapy and gene therapy. Emicizumab is the first and only nonreplacement agent to be licensed for prophylaxis in people with hemophilia A, and real‐world data show similar efficacy and safety from the pivotal studies. Other nonreplacement agents and gene therapy have ongoing studies with promising results. Innovative approaches, like subcutaneous factor VIII and lipid nanoparticles, are in the preclinical phase. These novel agents, such as extended half‐life concentrates and emicizumab, have been available in resource‐constrained countries through the constant efforts of the World Federation of Haemophilia Humanitarian Aid Program. Despite the wide range of new approaches and therapies, the main challenge remains the same: to guarantee treatment for all. In this article, we discuss the evolution of hemophilia care, global access to hemophilia treatment, and the current and future strategies that are now under development. Finally, we summarize relevant new data on this topic presented at the ISTH 2021 virtual congress.
