Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A

Mahlangu, Johnny; Kaczmarek, Radosław; Drygalski, Annette von; Shapiro, Susan; Chou, Sheng-Chieh; Ozelo, Margareth C.; Kenet, Gili; Peyvandi, Flora; Wang, Michael; Madan, Bella; Key, Nigel S.; Laffan, Michael; Dunn, Amy L.; Mason, Jane; Quon, Doris; Symington, Emily; Leavitt, Andrew D.; Oldenburg, J.; Chambost, Hérvè; Reding, Mark T.; Jayaram, Kala; Yu, Hua; Mahajan, Reena; Chavele, Konstantia-Maria; Reddy, Divya; Henshaw, Joshua; Robinson, Tara M.; Wong, Wing Yen; Pipe, Steven W.

doi:10.1056/nejmoa2211075

Cited by 115 publications

(144 citation statements)

References 26 publications

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“…Haemophilia B patients can expect to achieve mean endogenous FIX concentrations of approximately 35%, with a limited risk of needing immunosuppressive therapy to control a secondary hepatic reaction 12 and with a prolonged durability of FIX expression of at least 10 years if not more, as recently predicted 13 . The long‐term risks for haemophilia A and B are unclear and durability of haemophilia A gene therapy is currently of concern 14,15 …”

Section: Figurementioning

confidence: 95%

“…13 The long-term risks for haemophilia A and B are unclear and durability of haemophilia A gene therapy is currently of concern. 14,15 Finally, replacement therapy for haemophilia A has just made a giant leap forward with the development and validation of a FVIII that can be described as ultra-long (UL). This factor is decoupled from endogenous VWF and has a prolonged half-life through a triple modification resulting in a unique fusion protein consisting of a VWF-D'D3 domain fused to one immunoglobulin-G1 Fc domain, B-domain deleted FVIII fused to the second Fc domain, and 2 XTEN polypeptides to slow degradation.…”

mentioning

confidence: 99%

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Towards achieving a haemophilia‐free mind

Hermans

Pierce

2023

Haemophilia

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Section: Figurementioning

confidence: 95%

mentioning

confidence: 99%

Towards achieving a haemophilia‐free mind

Hermans

Pierce

2023

Haemophilia

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“…[16][17][18] At 104 weeks post-infusion, annualised rates of bleeding events and FVIII utilisation were significantly improved in the rollover participants compared with their baseline values (when receiving FVIII prophylaxis) collected in the non-interventional study. 18 As enrolment in GENEr8-1 excluded individuals using investigational products-which included emicizumab prophylaxis at the time of the study start-an internal comparison of valoctocogene roxaparvovec and emicizumab is not available. 16 Here, we present indirect comparisons of valoctocogene roxaparvovec treatment outcomes from GENEr8-1 with emicizumab treatment outcomes from HAVEN 3 using matching-adjusted indirect comparison (MAIC) methods to account for differences between study populations at baseline.…”

Section: Introductionmentioning

confidence: 94%

“…Valoctocogene roxaparvovec (AAV5‐hFVIII‐SQ) uses an adeno‐associated virus vector to transfer a B‐domain‐deleted human FVIII‐coding sequence controlled by a liver‐selective promoter, resulting in endogenous production of FVIII protein in hepatocytes 11–16 . Efficacy of a single 6 × 10 13 vg/kg dose of valoctocogene roxaparvovec was assessed in the multicentre, open‐label, single‐arm, phase 3 GENEr8‐1 trial (NCT03370913) in 134 adult male participants who had previously been receiving regular prophylaxis with exogenous FVIII, 22 of whom enrolled directly and 112 of whom “rolled over” after participating in the prospective, non‐interventional, longitudinal 270−902 study 16–18 . At 104 weeks post‐infusion, annualised rates of bleeding events and FVIII utilisation were significantly improved in the rollover participants compared with their baseline values (when receiving FVIII prophylaxis) collected in the non‐interventional study 18 .…”

Section: Introductionmentioning

confidence: 99%

Matching‐adjusted indirect comparison of bleeding outcomes in severe haemophilia A: Comparing valoctocogene roxaparvovec gene therapy, emicizumab prophylaxis, and FVIII replacement prophylaxis

Astermark

Buckner²,

Frenzel

et al. 2023

Haemophilia

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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 × 10 13 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 prophylaxisas 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.

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“…administration. These have now become commercially available gene therapies, indicated for adult patients affected by hemophilia 14,15 .…”

Section: Mainmentioning

confidence: 99%

Spatio-temporal dynamics of the liver shapes hepatocytes heterogeneity and impacts in vivo gene transfer and editing

Cantore

Starinieri

Milani

et al. 2023

Preprint

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The liver is a central organ for metabolism and hepatocytes are the main cell type responsible for most of its functions. Several previous studies investigated the cell types involved in tissue homeostasis and regeneration1–4, however the mechanisms underlying post-natal liver growth and establishment of the mature hepatocyte phenotypes remain to be fully understood. Here we investigate liver tissue dynamics in mice during growth and adulthood, by spatial transcriptomics5, clonal analysis, and lineage tracing. We observe progressive establishment of metabolic zonation of hepatocytes following weaning, with specification of the centrilobular identity only in adults. We report that only a fraction of hepatocytes proliferates in the newborn liver, generating most of the adult tissue and that preferential genetic modification (either gene transfer or gene editing) of the more proliferating hepatocytes allows expansion of the genetically engineered liver area, stably maintained throughout tissue homeostasis. We also describe age-dependent differences in the efficiency and distribution of lentiviral in vivo gene delivery, with higher efficiency of gene transfer in young compared to adult animals and a skewed localization within the liver lobule. We identify high proteasome activity in the peri-central lobular area as the major determinant of the observed outcome and successfully revert it by proteasomal inhibition before gene transfer. Overall, our findings provide new insights into the spatio-temporal dynamics of the liver during post-natal growth and hepatocyte heterogeneity, which extends our understanding of liver biology and have important implications for therapeutic applications.

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Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A

Cited by 115 publications

References 26 publications

Towards achieving a haemophilia‐free mind

Towards achieving a haemophilia‐free mind

Matching‐adjusted indirect comparison of bleeding outcomes in severe haemophilia A: Comparing valoctocogene roxaparvovec gene therapy, emicizumab prophylaxis, and FVIII replacement prophylaxis

Spatio-temporal dynamics of the liver shapes hepatocytes heterogeneity and impacts in vivo gene transfer and editing

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