Valoctocogene roxaparvovec delivers a B-domain-deleted factor VIII coding sequence with an adeno-associated virus vector to prevent bleeding in persons with severe hemophilia A. The findings of a ...phase 3 study of the efficacy and safety of valoctocogene roxaparvovec therapy evaluated after 52 weeks in men with severe hemophilia A have been published previously.
We conducted an open-label, single-group, multicenter, phase 3 trial in which 134 men with severe hemophilia A who were receiving factor VIII prophylaxis received a single infusion of 6×10
vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in the annualized rate of treated bleeding events at week 104 after receipt of the infusion. The pharmacokinetics of valoctocogene roxaparvovec were modeled to estimate the bleeding risk relative to the activity of transgene-derived factor VIII.
At week 104, a total of 132 participants, including 112 with data that were prospectively collected at baseline, remained in the study. The mean annualized treated bleeding rate decreased by 84.5% from baseline (P<0.001) among the participants. From week 76 onward, the trajectory of the transgene-derived factor VIII activity showed first-order elimination kinetics; the model-estimated typical half-life of the transgene-derived factor VIII production system was 123 weeks (95% confidence interval, 84 to 232). The risk of joint bleeding was estimated among the trial participants; at a transgene-derived factor VIII level of 5 IU per deciliter measured with chromogenic assay, we expected that participants would have 1.0 episode of joint bleeding per year. At 2 years postinfusion, no new safety signals had emerged and no new serious adverse events related to treatment had occurred.
The study data show the durability of factor VIII activity and bleeding reduction and the safety profile of valoctocogene roxaparvovec at least 2 years after the gene transfer. Models of the risk of joint bleeding suggest that the relationship between transgene-derived factor VIII activity and bleeding episodes is similar to that reported with the use of epidemiologic data for persons with mild-to-moderate hemophilia A. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.).
Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus 5 (AAV5)-based gene-therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-selective ...promoter. The efficacy and safety of the therapy were previously evaluated in men with severe hemophilia A in a phase 1-2 dose-escalation study.
We conducted an open-label, single-group, multicenter, phase 3 study to evaluate the efficacy and safety of valoctocogene roxaparvovec in men with severe hemophilia A, defined as a factor VIII level of 1 IU per deciliter or lower. Participants who were at least 18 years of age and did not have preexisting anti-AAV5 antibodies or a history of development of factor VIII inhibitors and who had been receiving prophylaxis with factor VIII concentrate received a single infusion of 6×10
vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in factor VIII activity (measured with a chromogenic substrate assay) during weeks 49 through 52 after infusion. Secondary end points included the change in annualized factor VIII concentrate use and bleeding rates. Safety was assessed as adverse events and laboratory test results.
Overall, 134 participants received an infusion and completed more than 51 weeks of follow-up. Among the 132 human immunodeficiency virus-negative participants, the mean factor VIII activity level at weeks 49 through 52 had increased by 41.9 IU per deciliter (95% confidence interval CI, 34.1 to 49.7; P<0.001; median change, 22.9 IU per deciliter; interquartile range, 10.9 to 61.3). Among the 112 participants enrolled from a prospective noninterventional study, the mean annualized rates of factor VIII concentrate use and treated bleeding after week 4 had decreased after infusion by 98.6% and 83.8%, respectively (P<0.001 for both comparisons). All the participants had at least one adverse event; 22 of 134 (16.4%) reported serious adverse events. Elevations in alanine aminotransferase levels occurred in 115 of 134 participants (85.8%) and were managed with immune suppressants. The other most common adverse events were headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%). No development of factor VIII inhibitors or thrombosis occurred in any of the participants.
In patients with severe hemophilia A, valoctocogene roxaparvovec treatment provided endogenous factor VIII production and significantly reduced bleeding and factor VIII concentrate use relative to factor VIII prophylaxis. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.).
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.
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.
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).
Introduction
Turoctocog alfa is a recombinant factor VIII (FVIII) molecule, approved for treatment and prophylaxis of bleeding in patients with haemophilia A. In the guardian 1 (adolescents/adults) ...and guardian 3 (children) phase 3 trials, turoctocog alfa demonstrated a favourable efficacy and safety profile. Guardian 1 or 3 completers could enrol in the guardian 2 extension. Final guardian 2 results are reported here.
Aim
Investigate long‐term safety and efficacy of turoctocog alfa administered for prophylaxis and treatment of bleeds.
Methods
In this phase 3b open‐label trial, previously treated males of all ages with severe haemophilia A received prophylaxis regimens of turoctocog alfa or on‐demand treatment of bleeds. The primary safety endpoint was frequency of FVIII inhibitor development. Efficacy endpoints included annualized bleeding rate (ABR) during prophylaxis, haemostatic response in treatment of bleeds and number of injections required to treat bleeds.
Results
Overall, 213 patients were dosed with turoctocog alfa; 207 patients received prophylaxis; 19 received on‐demand treatment. No FVIII inhibitors (≥0.6 BU) were reported. For all patients on prophylaxis, overall median ABR was 1.37 bleeds/y; success rate for treatment of bleeds was 90.2%; and 88.2% of bleeds were controlled with 1‐2 injections of turoctocog alfa. For the on‐demand regimen, overall median ABR was 30.44 bleeds/y; success rate for treatment of bleeds was 96.7%; and 94.9% of bleeds were controlled with 1‐2 injections of turoctocog alfa.
Conclusion
Extended use of turoctocog alfa is safe and effective for prevention and treatment of bleeding episodes in previously treated patients with haemophilia A across all ages.
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