Gene therapy with a novel AAV8 vector safely elevated Factor IX coagulation activity and reduced bleeding episodes in patients with severe hemophilia B, according to study results.
Amit C. Nathwani, MD, ChB, PhD, of the Katharine Dormandy Hemophilia Centre and Thrombosis Unit at Royal Free Hospital in London, and colleagues sought to evaluate the long-term safety and efficacy of gene therapy mediated by a novel self-complementary adeno-associated virus serotype (AAV8) vector.
The analysis included 10 men with severe hemophilia B who received one infusion of the AAV8 vector.
Six of these patients were enrolled in the dose-escalation phase. Two patients received low doses (2x1011 vector genomes/kg), two received intermediate doses (6x1011 vector genomes/kg) and two received high (2x1012 vector genomes/kg) doses. In a subsequent phase of the trial, the other four patients all received the high-dose vector.
Four months after the vector infusion, patients demonstrated steady-state transgenic Factor IX activity that was 1% to 6% of the normal value. Data indicated Factor IX expression remained stable for a median 3.2 years after the infusion (range, 1.5-4.3).
Results showed Factor IX expression was dose-dependent. Patients who received the low-dose vector demonstrated a mean 1.8±0.7% of the normal value of Factor IX coagulation activity, and patients who received the intermediate dose expressed Factor IX coagulation activity that was a mean 2.5±0.9% greater than their normal levels.
The six patients who received the high-dose vector exhibited a 5.1±1.7% mean increase in Factor IX levels. This increase was associated with a 90% relative reduction in bleeding episodes (15.5 vs. 1.5; P=.009) and a 96% relative reduction in the use of prophylactic Factor IX concentrate (2,613 IU/kg vs. 92 IU/kg; P=.03) from 1 year prior to 1 year after vector infusion.
The most common adverse event associated with treatment was an asymptomatic elevation in alanine aminotransferase (ALT) level.
Researchers observed a transient increase in mean ALT levels to 86 IU/L (range, 36 to 202) between week 7 and week 10 in four of the six patients who received the high dose. However, treatment with prednisolone results in normalized ALT levels after a median 5 days (range, 2-35).
“A single infusion of AAV8 vector resulted in durable Factor IX expression and long-lasting amelioration of bleeding episodes in patients with severe hemophilia B,” Nathwani and colleagues concluded. “The findings with respect to the safety of this approach are encouraging, with the main vector-related adverse event being an elevated serum ALT level, an effect that appears to be readily attenuated by a short, tapering course of prednisolone.”
Disclosure: See the study for a full list of the researchers’ relevant financial disclosures.