Gene-transfer therapy corrects FVIII levels in haemophilia A
Gene-transfer therapy using adeno-associated virus in patients with severe haemophilia A resulted in sustained levels of coagulation factor VIII (FVIII) expression within 1 year of observation, reducing spontaneous bleeds and FVIII infusions in most patients, interim results of a phase 1/2 dose-escalation study have shown.
“Twenty weeks after gene infusion, six of the seven patients in a dose cohort have achieved normal factor VIII levels,” said lead investigator Professor John Pasi, consultant haematologist from Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK. FVIII activity plateaued by 20 weeks and median FVIII levels were within the normal range (89–122 IU/dL) after week 20. Individual FVIII levels ranged from19–164 IU/dL. FVIII expression persisted over the course of the study. [ISTH 2017 Congress, abstract LB 01-1]
Patients (n=15) were men 18 years and older with severe haemophilia A (FVIII levels <1 IU/dL). Each received a single intravenous dose of adeno-associated virus type 5 (AAV5) containing the B-domain deleted form of the FVIII gene (BMN270) at one of four doses: 6x1012 vg/kg, 2x1013 vg/kg, 4x1013 and 6x1013 vg/kg. The dose was further escalated in patients whose FVIII expression was less than 5 IU/dL at week 3 of infusion. As a precautionary measure, some patients received prophylactic corticosteroids. All patients switched to an on-demand FVIII regimen after the gene therapy infusion.
AAV5 infusions at 6x1013 vg/kg led to normal blood levels of FVIII in 6 of 7 patients, eliminating spontaneous bleeds and the need for exogenous FVIII infusions during trauma or surgery.
“One patient did not achieve the lower limit of normal [50–150 IU/dL] and was running around 20 IU/dL, which is still way more significant than our original target of 5 IU/dL,” Pasi said. “When expression levels hit >5 percent, the ABR [annualized bleeding rate] in the [dose] cohorts basically collapsed to zero. This is quite impressive.”
Median annualized FVIII infusions also decreased from 139 (105–159) infusions/year to zero. Gene therapy was safe and well tolerated across all doses. “Not one patient developed an inhibitor, which is clearly an important question in haemophilia A gene therapy,” said Pasi. All patients in the higher-dose cohort had improvement in the quality-of-life scores (as measured on the Haem-A-QoL index) at week 16 and through week 52.
The B-domain was deleted because previous attempts at gene-transfer therapy have been obviated by the size of the FVIII gene, which is too large to be readily accommodated in gene transfer vectors.
Current FVIII-replacement proteins are given several times weekly and produce “a sawtooth-response pattern” in blood levels. With very low levels, patients are at risk for microbleeds, Pasi said.
By contrast, gene infusion could be given once or only a few times in a patient’s lifetime without diminishing therapeutic efficacy, making this approach an attractive alternative for correction of FVIII deficiency in patients with severe haemophilia A.