Investigational gene therapy leads to sustained factor VIII expression in hemophilia A
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The novel gene therapy SPK-8011 induced sustained factor VIII expression in patients with hemophilia A, according to results of a nonrandomized phase 1/phase 2 dose-escalation study published in The New England Journal of Medicine.
The recombinant adeno-associated viral vector led to a reduction in life-threatening bleeding events and, in some cases, complete elimination of such events, researchers wrote. They also reported no major safety concerns.
Lindsey A. George, MD, director of clinical in vivo gene therapy and attending physician in the division of hematology at Children’s Hospital of Philadelphia, told Healio that she believes gene therapy possesses “the potential to alter the paradigm” of hemophilia care in providing a long-term solution to ameliorate clinical phenotype and de-medicalize patients with the bleeding disorder.
“The importance of this observation is that it demonstrates proof-of-principal that current methods that target hepatocyte expression of factor VIII can indeed be stable and durable for multiple years following adeno-associated viral-mediated gene transfer,” George said. “This contrasts observations from prior hemophilia A clinical trials in which participants lost nearly half of transgene expression from year 1 to year 2 post-gene transfer.”
The analysis included 18 men aged 18 to 52 years with congenital hemophilia A and baseline factor VIII activity that was 2% or less of the normal value, no history of factor VIII inhibitory antibodies, and SPK200 neutralizing antibody titers of no more than 1:5. Enrollment began Jan. 26, 2017, and the data cutoff for analysis was May 3, 2021.
Researchers divided the men into four dose cohorts. Men in the lowest-dose cohort received an infusion of SPK-8011 (Spark Therapeutics), an investigational adeno-associated viral vector for hepatocyte expression of factor VIII, at 5x1011 vector genomes per kilogram of body weight, whereas those in the highest-dose cohort received 2x1012 vector genomes per kilogram. Some of the men also received glucocorticoids to prevent or treat a presumed adeno-associated viral capsid immune response.
The objectives of the trial were to evaluate the safety and preliminary efficacy of SPK 8011 and the expression and durability of factor VIII.
“We hypothesized that safe and durable hepatocyte expression of factor VIII could provide sufficient endogenous prophylaxis in persons with hemophilia A,” George and colleagues wrote.
Researchers followed the men for 52 weeks after vector administration; all subsequently enrolled in a 4-year long-term follow-up trial.
Median follow-up was 36.6 months (range, 5.5-50.3).
Results showed 33 treatment-related adverse events among eight men, including 17 vector-related events, one of which was serious, and 16 glucocorticoid-related events.
Although two men lost all factor VIII expression because of an anti-capsid cellular immune response that wasn’t sensitive to immune suppression, the other 16 men maintained factor VIII expression and discontinued prophylaxis. Of them, 12 who were followed for more than 2 years had multi-year stable expression with no apparent decrease in factor VIII activity over time.
Additionally, for the difference between matched pairs (for example, a participant’s mean factor VIII activity when not receiving glucocorticoids during the period from 26 to 52 weeks vs. his mean factor VIII activity after 52 weeks), researchers reported a CI of 2.4 to 0.6. Among the 12 men with longer follow-up, the combined mean factor VIII activity when the men did not received glucocorticoids for 26 to 52 weeks (12.9 ± 6.9% of the normal value) was analogous to the combined mean factor VIII activity after more than 52 weeks (12 ± 7.1%)
In analysis of preliminary efficacy among all 18 men, with median follow-up of 33.4 months, researchers reported a 91.5% (95% CI, 88.8-94.1) reduction in the annualized rate of bleeding events, from a median 8.5 events (range, 0-43) per year before vector administration to 0.3 events (range, 0-6.5) per year after administration.
“A key observation was the durability and stability of expression 1 year post-vector, which was generally consistent with expectations from preclinical models, but differed from observations in an earlier clinical trial that observed an unexplained decline in factor VIII expression,” George said. “The next immediate step is to determine the optimal immune modulation regimen for the vector to prevent loss of expression in the setting of a capsid immune response.”
George added that, in general within hemophilia A gene therapy research, it will be important to understand why some trials see a decline in factor VIII expression, to refine variability in observed expression, and to ensure all participants obtain and maintain expression.
“(Obtaining and maintaining expression) is particularly relevant because it is unlikely repeat vector infusion is possible, and better understanding of long-term safety considerations of systemic adeno-associated viral vectors is necessary,” George told Healio.
For more information:
Lindsey A. George, MD, can be reached at Perelman School of Medicine at University of Pennsylvania, Children’s Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Blvd., Philadelphia, PA 19104; email: georgel@email.chop.edu.
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