Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A

Abstract

BACKGROUNDValoctocogene 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. METHODSWe 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 13 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. RESULTSOverall, 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. CONCLUSIONSIn 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.

Application of in-vitro-cultured primary hepatocytes to evaluate species translatability and AAV transduction mechanisms of action

“… 13 , 16 In a phase 3 trial, participants who received 6 × 10 13 vg/kg experienced a significant increase from baseline in FVIII activity at 2 years post-infusion, as well as significantly reduced FVIII utilization and bleeding compared with their baseline values while receiving FVIII prophylaxis pre-infusion. 17 , 18…”

Impact of novel hemophilia therapies around the world

“…AAV vector-mediated gene therapy trials for hemophilia A and B clinical have shown promising results. Some participants have presented meaningful expression of FVIII [51][52][53][54][55][56] or FIX, [57][58][59][60][61][62][63] shifting their phenotype from severe to mild or even achieving normal factor levels after a single vector injection. Table 3 shows the ongoing hemophilia A and B gene therapy clinical trials.…”

“…Despite the encouraging results of the recent hemophilia gene therapy clinical trials, several issues remain unclear and unresolved. The variability in FVIII and FIX expression levels among the clinical trial participants and the unpredictable responses are observed in both hemophilia A 52,53,54,55,64 and B gene therapy trials. 59,60,61,62,63,65,66 Furthermore, the cellular immune response is AAV vector dose dependent, and the ideal immunosuppressive therapy still needs to be determined.…”

Gene Therapy for Hemophilia A: How Long Will It Last?

“… 4 With the phase 3 data now available, it is clear that this decline seems too optimistic. The FVIII expression after the first year was 43 IU/dL, but 24 IU/dL after 2 years, 2 indicating a decline of 44%.…”