Hyperactive Factor IX Variant “FIX-TripleL” for Hemophilia B
Superior activity! Safety! Efficacy!
Targeted indication
1. Replacement therapy of Hemophilia B
2. Gene therapy of Hemophilia B
Status
Pre-clinical studies
Key features
- One injection lasting >>3 years.
- Higher activity at lower dosage than competitors.
- No thrombosis risk or genotoxicity in a long-term follow up animal model.
Market
The technology of the team is that we have developed a supra-active FIX molecule called FIX-TripleL. Combining our self-owned global patented FIX-TripleL technology with AAV-8 vector, we have completed POC and validated the therapeutic efficacy of FIX-TripleL in gene therapy using a hemophilia B mouse model. FIX-TripleL is therapeutically effective when used at a supra-low dose, as low as 50 times less than what has currently been used in hemophilia B gene therapy trials. Lowering viral doses is the emerging goal of gene therapy. FIX-TripleL, having extremely high activity, shows powerful potential in the market for hemophilia B gene therapy. In addition, the team is about to complete the GLP toxicology test and safety assessment under the grant supported by the Ministry of Science and Technology, Executive Yen, Taiwan. Taken together, the team's technology will become the first gene therapy clinical product that is entirely accomplished by Taiwan from development, mass production to GLP testing.
MODE OF ACTION
FIX-TripleL exhibited 22-fold higher specific clotting activity and 15-fold increased binding affinity to activated FVIII compared to FIXWT. FIX-TripleL increased the therapeutic potential of FIX-Triple by nearly 100% as demonstrated with calibrated automated thrombogram and thromboelastography. Under physiological conditions, no signs of adverse thrombotic events were observed in long-term AAV-FIX-treated C57BL/6 mice.
EXPERIMENTAL RESULTS
FIXa-TripleL had a 15-fold greater binding affinity to FVIIIa than FIXa-WT, which difference in the apparent Kd compared to FIXa-WT. FIX-TripleL with 21- to 22-fold higher specific activity than FIX-WT exhibited significantly greater patterns of thrombin generation and thrombus formation than FIX-Triple or FIX-R338L.
FIX-TripleL gene therapy is more potent by 10-fold higher binding affinity for human FVIIIa. 13-fold clotting activity than WT, 2.5-fold activity superior than competitor.
AAV-FIX-TripleL–infected C57BL/6 mice were monitored for 17 months. This long-term expression of FIX variants in mice does not increase the risk of thrombosis as shown by on increase of thrombotic markers. Moreover, hyperfunctional FIX-TripleL for gene therapy may allow delivery of low AAV vector doses, which gives tremendous advantages, e.g., avoiding the risk of genotoxicity.
- FIX-TripleL, having extremely high activity, shows powerful potential in the market for hemophilia B gene therapy.
- Lowering the viral dose is the emerging goal for gene therapy, combine with extremely FIX-TripleL high activity to achieve the supra-low therapeutic dose.
INTELLECTUAL PROPERTY
SELECTED PUBLICATIONS
Lin et al.; J Thromb Haemost 2010;
Kao et al.; Thromb Haemost 2010; 2013 Wu et al.; Cell Transplant 2010
Chang et al.; J Biol Chem 1998
BUSINESS OPPORTUNITY
License and/or Collaboration and Sponsored Research
CONTACT
service@biip-dcc.org