Gene therapy promising in severe haemophilia B
Systemic administration of the gene therapy scAAV2/8-LP1-hFIXco to patients with severe haemophilia B led to stable therapeutic expression of the factor IX gene over 8 years without evidence of late toxicities from treatment, according to a long-term follow-up study.
This meant fewer bleeding episodes and less reliance on factor IX prophylaxis in this patient group. However, hepatotoxicity remains a concern.
Using new vector preparation to reduce the capsid load failed to reduce hepatoxicity rate in these patients, suggesting that other factors may be at play. “Over time, liver function remained in the normal range regardless of the vector dose or whether patients had or had not experienced vector-induced transaminitis,” said lead investigator Dr Ulrike Reiss, paediatric hematologist-oncologist and director of the Haemophilia Treatment Center, St. Jude Children’s Research Hospital, Memphis, Tennessee, US. [ASH 2018, abstract 491]
The original study published in 2014 showed that a single intravenous administration of scAAV2/8-LP1-hFIXco led to a dose-dependent increase in circulating factor IX gene levels among patients with severe haemophilia B treated for over 3 years. There was a consistent increase in the factor IX level to a mean of 5.1 percent in over half of the patients, leading to less bleeding episodes and fewer use of prophylactic factor IX concentrate. The gene therapy involves administration of a self-complementary adeno-associated virus with a codon-optimized factor IX gene controlled by a synthetic liver-promoter and pseudotyped with serotype 8 capside. There was a transient elevation in the mean alanine aminotransferase (ALT) level in some patients, but this was attenuated by a short, tapering course of prednisolone. [N Engl J Med 2014;371:1994-2004]
Long-term therapeutic factor IX expression is associated with clinical improvement. But the question haematologists had in mind then was whether factor IX gene expression would remain stable over time, considering the natural hepatocyte turnover. As the regimen in the main study involved empty capsids without full-length viral genome, investigators said this may have caused immune responses vs transduced hepatocytes. To address this, they removed most of the empty capsids through caesium chloride centrifugation in the follow-up study, aiming for reduction in hepatoxicity.
After a median follow-up of >6 years, transgenic factor IX activity remained stable in all patients. Annual bleed rate dropped by 82 percent and annual factor IX gene concentrate usage dropped by 66 percent vs baseline levels. Empty capsid reduction however did not prevent transaminitis. No treatment-related late toxicity was observed and neutralizing antibodies to factor IX genes were not detected.
Prevention of bleeding episodes is the cornerstone of treatment in patients with severe haemophilia B. The findings appeared promising but more research in haemophilia B setting is clearly warranted to establish the safety of this therapy, experts said.