Experts suggest potential cure in sight A single infusion of a gene therapy for hemophilia A led to normalization of factor VIII levels that persisted for a year, British investigators reported here. Six of seven patients treated with the highest dose of the engineered therapy had factor VIII levels >50 IU/dL, and the seventh patient had therapeutic levels of factor VIII at 1 year. The high-dose cohort averaged 16 bleeding episodes a year before treatment and one episode afterward. The most frequent adverse event was elevated serum alanine aminotransferase (ALT), reported K. John Pasi, MB ChB, PhD, of the Royal London Hospital, at the American Society of Hematology (ASH) meeting. The results were published simultaneously in the New England Journal of Medicine. "Increases in factor VIII activity levels were dose dependent, with all seven participants in the high-dose cohort sustaining therapeutic levels at 1 year after gene transfer," Pasi's group noted in the published article. "In conjunction, the frequency of participant-treated bleeding episodes decreased markedly, with resultant cessation of factor VIII use. The absence of spontaneous bleeding in patients with severe hemophilia A factor VIII replacement therapy, regardless of the product half-life." The study is the first successful demonstration of gene therapy for hemophilia, as three previous trials with different genetically engineered products either failed to show a benefit, they added. Combined with reported success for gene therapy for the less common hemophilia B, the results suggest that a cure for hemophilia may soon be within reach, according to the author of an accompanying editorial. "These landmark studies ... are leading the way to a cure for hemophilia," wrote H. Marijke van den Berg, MD, PhD, of PedNet Hemophilia Research Foundation in Baarn, the Netherlands. "Prophylaxis with coagulation products could be discontinued in each study, and bleeding rates were reduced to zero, which is to be expected when factor VIII and factor IX levels are sustained at levels exceeding 5 IU per deciliter." If the initial results hold up in additional clinical evaluations, "children born with this devastating disease could benefit from a life without bleeding and other sequelae of the disease," van den Berg added. During an advance ASH media preview, Robert Brodsky, MD, of Johns Hopkins in Baltimore, included the gene therapy trial in a small group of abstracts that he characterized as "home run-type" studies. Like van den Berg, he said the impressive 52-week results suggest the engineered therapy offers a potential cure for hemophilia A. The small clinical trial evaluated the safety and efficacy of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain-deleted human factor VIII (AAV5). Until the successful results presented by Pasi's group, the large size of the factor VIII coding region had posed a seemingly insurmountable obstacle improved outcomes in hemophilia A with gene therapy. Preclinical evaluations of AAV5 (valoctocogene roxaparvovec) showed dose-dependent increases in factor VIII expression in mouse and nonhuman primate models of hemophilia A, providing a rationale for clinical evaluation. Investigators evaluated three doses of the gene therapy in a total of nine men with severe hemophilia A. Low and intermediate doses of the gene therapy (administered to one patient each) failed to achieve and maintain therapeutic levels of factor VIII. Safety was the primary objective of the trial, and clinical efficacy was a secondary objective. The seven participants in the high-dose cohort and the patient who received the lowest dose of the gene therapy had increased ALT, which was asymptomatic and resolved without intervention or sequelae. All seven patients in the high-dose cohort achieved therapeutic levels of factor VIII by week 16, the prespecified time point for efficacy assessment. The 5 IU/dL definition for therapeutic level is the cutoff between moderate and mild hemophilia. "After week 20, the factor VIII activity level was consistently more than 50 IU per deciliter in six of seven participants, and in the remaining participant, the level typically ranged from 12 to 32 IU per deciliter," the authors noted. At week 52, the median factor VIII activity level for the high-dose cohort was 77 IU/dL. In addition to the decline in bleeding episodes that accompanied the increase in factor VIII levels, the requirement for factor VIII also declined dramatically. The median annualized use of factor VIII decreased from 138 infusions per year pre-study to two infusions per year following gene therapy. Analysis of biologic fluids and stool samples showed that residual vector DNA decreased over the course of the study period. The authors pointed out that they did not assess the possibility of vector integration, and that the study protocol was not "designed to measure whether AAV5 infection was present in family members or close contacts." Source
