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Factor IX gene therapy safe, effective in severe hemophilia B

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November 19, 2014

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.

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Nigel Key

Nigel Key

This paper provides 3-year follow-up data on the six patients with hemophilia B who received AAV vector-mediated Factor IX (FIX) gene therapy in a phase 1 study and were reported by the same group in December 2011 (Nathwani AC. N Engl J Med. 2011;365:2357-2365.). The current report demonstrates durability of the approach with absence of longer-term toxicity. As evidence of the reproducibility of the strategy, four additional patients who were treated with the highest vector dose experienced a similar benefit, with FIX levels that were maintained in the 3% to 7% range. However, four of the six patients who received the highest dose of vector developed transient viral capsid-mediated but steroid-responsive transaminitis, indicating that any further escalation of the vector dose — in order to achieve even longer term FIX levels — may not be well tolerated by the liver. Fortunately, there is considerable scope to avoid this limitation by using a vector with far fewer empty capsids, and/or adding a gain-of-function mutation in the FIX transgene. These trials are currently ongoing. The other barrier to widespread adoption of this gene therapy approach that is being addressed is the frequent pre-existing immunity to certain serotypes of AAV, a non-pathogenic but prevalent virus in the community.

Nigel Key, MB, CHB, FRCP
HemOnc Today Editorial Board member
University of North Carolina, Chapel Hill

Disclosure: Key reports no relevant financial disclosures.