ASH Annual Meeting and Exposition
ASH Annual Meeting and Exposition
December 10, 2018
2 min read

Researchers refine gene therapy approach for hemophilia A

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SAN DIEGO — Patients with severe hemophilia A achieved factor VIII activity levels sufficient to reduce or prevent spontaneous hemorrhage after a single IV infusion of AAV8-HLP-hFVIII-V3, according to results of a phase 1/phase 2, open-label, nonrandomized dose-escalation trial presented at ASH Annual Meeting and Exposition.

Researchers observed the factor VIII levels in this trial using lower doses of adeno-associated viral (AAV) vector than in previous gene therapy studies for hemophilia A.

“A single infusion of AAV8-HLP-hFVIII-V3 was well tolerated by patients with [severe hemophilia A],” Pratima Chowdary, MD, co-center director for the hemophilia center at Health Service Laboratories, said during her presentation. “Transgenic factor VIII expression was achieved in all patients at both vector doses.”

Previous studies in hemophilia B have shown that a single peripheral vein administration of AAV vectors expressing the factor IX transgene leads to stable long-term expression of transgenic factor IX at therapeutic levels without long-term toxicity.

The use of adeno-associated vectors in hemophilia A gene therapy, however, have been limited because of inefficient expression of transgenic factor VIII and the large size of the factor VIII cDNA.

Chowdary and colleagues developed two AAV-factor VIII expression cassettes with a small synthetic liver specific promoter driving the expression of codon optimized factor VIII variants to overcome these challenges for the use of gene therapy for hemophilia A.

Previous results from the first of these cassettes — AAV-HLP-hFVIII-SQ encoding a B-domain deleted factor VIII variant — showed sustained normalization of factor VIII activity in six of seven participants following a single IV infusion of AAV serotype 5 pseudotyped vector. However, researchers had to use high vector doses, which they hypothesized was due to its manufacture using the insect cell/baculovirus system.

The second FVIII cassette — AAV-HLP-hFVIII-V3 — contains a 17 amino-acid peptide comprising six N-linked glycosylation motifs from the human factor VIII B-domain. Murine studies showed AAV-HLP-hFVIII-V3 mediated factor VIII expression at threefold-higher levels than AAV-HLP-hFVIII-SQ.

The current analysis included three adult men with severe hemophilia A with factor VIII activity levels of 1% or less of normal who received a single IV infusion of AAV8-HLP-hFVIII-V3.

The first patient received a dose of 6 x 1011 vg/kg, whereas the other two received a dose of 2 x 1012 vg/kg.

Researchers followed patients for 13 to 47 weeks.

Results showed detectable transgenic factor VIII within 2 weeks of the infusion.


Factor VIII activity levels reached more than 5 IU/dl by 6 weeks of gene transfer in all three patients and remained steady at 7 IU/dl (± 1 IU/dl) in the first patient through a period of 47 weeks.

The second patient, who was in his 20th week after infusion at the time of the presentation, had steady-state factor VIII activity of 6 IU/dl (± 2 IU/d)l.

The third patient had steady-state factor VIII activity almost 10 times higher than the second patient, at 69 IU/dl (± 7 IU/dl).

Elevated serum alanine aminotransferase occurred in patients 1 and 3 between weeks 4 and 6 after gene transfer and reached peak levels that were 1.5 times the upper limit of the normal range. Both of those patients were treated with corticosteroids within 48 hours of transaminitis and experienced no loss of transgene expression.

None of the patients developed a factor VIII inhibitor. – by John DeRosier


Chowdary P, et al. Abstract 489. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.

Disclosures : This study received research funding from Novo Nordisk, CSL Behring and Pfizer. Chowdary reports honoraria from or consultant/advisory roles with Baxalta, Bayer, Biogen, Freeline, Novo Nordisk, Pfizer and Sobi.