ASH Annual Meeting and Exposition

ASH Annual Meeting and Exposition

December 03, 2018
3 min read

Gene therapy shows long-term activity in severe hemophilia B

You've successfully added to your alerts. You will receive an email when new content is published.

Click Here to Manage Email Alerts

We were unable to process your request. Please try again later. If you continue to have this issue please contact

SAN DIEGO — Patients with severe hemophilia B demonstrated stable therapeutic expression of the factor IX gene over an 8-year period without late toxicities after systemic administration of a gene therapy called scAAV2/8-LP1-hFIXco, according to a study presented at ASH Annual Meeting and Exposition.

The gene therapy involves a self-complementary adeno-associated virus (scAAV) vector containing a codon-optimized factor IX gene under control of a synthetic liver-specific promoter and pseudotyped with serotype 8 capsid.

Researchers also found that a new formulation of the gene therapy that removed empty AAV capsids to reduce the capsid load did not reduce the rate of hepatoxicity in patients with severe hemophilia B, suggesting other factors are at play.

“Over time since then, liver function has remained in the normal range regardless of vector dose or if the participant had or had not experienced vector-induced transaminitis,” Ulrike M. Reiss, MD, associate faculty member, director of the clinical hematology division and director of hemophilia treatment center at St. Jude Children’s Research Hospital, said during her presentation.

This research is an 8-year follow-up to a previous study — published in 2014 in The New England Journal of Medicine — that showed a single IV administration of scAAV2/8-LP1-hFIXco resulted in a dose-dependent increase in plasma factor IX gene levels among 10 patients with severe hemophilia B.

Although factor IX gene expression remained stable over 3 years, there were questions about whether it would decline over time due to natural hepatocyte turnover.

The only vector-associated adverse event was asymptomatic rise in liver enzymes accompanied by a decline in factor IX levels in two-thirds of patients treated with a dose of 2 x 1012 vector genomes(vg)/kg. Because the regimen contained empty capsids that did not have a full-length viral genome, researchers hypothesized this may cause an immune response against transduced hepatocytes.

Thus, researchers changed the regimen so that most of the empty capsids were removed by caesium chloride density centrifugation to reduce the risk for hepatoxicity.

The current analysis includes a report on the evaluation of the new vector preparation — with two patients with severe hemophilia B receiving a dose of 2 x 1012 vg/kg and two receiving a dose of 5 x 1012 vg/kg — as well as 8-year follow-up data from the original cohort of patients. In the original cohort, two patients each received 2 x 1011 vg/kg and 6 x 1011 vg/kg, and six patients received 2 x 1012 vg/kg.


After a median follow-up of 6.7 ± 1 years in the original cohort, transgenic factor IX activity remained stable in all 10 patients. Mean levels were 1.9 ± 0.6 IU/I in the low-dose cohort, 2.3 ± 0.3 IU/I in the middle-dose cohort and 5.1 ± 1.4 IU/I in the high-dose cohort.

Annual factor IX gene concentrate usage dropped by 66% and annual bleed rate declined by 82% compared with pre-gene therapy levels.

No late toxicity occurred and neutralizing antibodies to factor IX genes were not detected. However, high titres of anti-AAV8 capsid-specific antibody levels persisted in nine patients.

Median follow-up for the new cohort was 2.1 ± 1.4 years.

Mean factor IX gene activity with a dose of 2 x 1012 vg/kg was 2.6 ± 0.7 IU/I, which appeared lower than previously observed at this dose level but not significantly.

Mean steady state factor IX gene levels with the 5 x1012 vg/kg dose was 17 ± 5 IU/I.

Results showed the new regimen at both doses did not reduce the risk for hepatoxicity. Three of the 4 patients experienced elevated serum alanine aminotransferase that was treated with corticosteroids.

“Empty capsid reduction did not prevent transaminitis,” Reiss said. “However, this supports the observation that anti-AAV8 antibody response is strong.” – by John DeRosier

References :

Nathwani AC, et al. N Engl J Med. 2014;doi:10.1056/NEJmoa1407309.

Reiss U, et al. Abstract 491. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.

Disclosures : Reiss reports no relevant financial disclosures. Please see the abstract for all authors’ disclosures.