SOUTH SAN FRANCISCO, Calif.—In early February, Catalyst Biosciences Inc. presented preclinical proof-of-concept data for its CB 2679d-GT factor IX gene therapy in hemophilia B mice.
The adeno-associated virus (AAV)-based CB 2679d factor IX gene therapy candidate demonstrated superior results when compared with an AAV-encoded Padua vector in both reduction in bleeding times (fourfold reduction) and clotting activity (threefold improvement). The data were presented in a poster at the 12th Annual Congress of the European Association for Hemophilia and Allied Disorders (EAHAD) in Prague.
“These results are encouraging and demonstrate preclinical proof of concept for CB 2679d-GT, a gene therapy candidate encoding our engineered factor IX as a potential new treatment for hemophilia B,” said Dr. Nassim Usman, CEO of Catalyst. “The data indicate that CB 2679d-GT achieves a more rapid and robust hemostatic correction of bleeding in hemophilia B mice with a significantly improved clotting activity and four-fold reduction of bleeding time when compared with an AAV-encoding FIX-R338L Padua. We remain committed to advancing dalcinonacog alfa (DalcA – subcutaneous recombinant CB 2679d) into a Phase 2b study this quarter, and believe that CB 2679d-GT could be an important pipeline product that may provide additional treatment options for patients during their lifetime of therapy.”
According to Dr. Grant Blouse, vice president of translational research at Catalyst Biosciences, “CB 2679d-GT is a factor IX (FIX) adeno-associated virus (AAV)-based gene therapy candidate using the same gene that is behind Catalyst’s high-potency, engineered recombinant FIX dalcinonacog alfa (DalcA) for the treatment of hemophilia B. DalcA is designed to improve three key functional attributes of FIX, and when given subcutaneously, DalcA has shown more than 22-fold higher potency in early clinical studies compared with other FIX products on the market.”
“CB 2679d-GT encodes Catalyst’s high potency FIX variant that has three amino acid changes—R318Y/R338E/T343R. Current hemophilia gene therapy candidates encode the Padua or R338L variant,” Blouse continues. “The preclinical data demonstrate that CB 2679d-GT achieves a more rapid and robust hemostatic correction of bleeding in hemophilia B mice with significantly improved clotting activity and a four-fold reduction of bleeding time, when compared with an AAV-encoding FIX-R338L Padua.”
The 20-week preclinical study compared the activity of CB 2679d-GT with that of an AAV-encoding FIX-R338L Padua (FIX-Padua) in hemophilia B mice. Treatment with both CB 2679d-GT and FIX-Padua showed a reduced clotting time within the first week that remained stable up to the 20-week study endpoint. CB 2679d-GT demonstrated a statistically significant three-fold improvement in clotting activity (p <0.04) compared to FIX-Padua. When evaluated at 20 weeks, there was a four-fold reduction in bleeding time after treatment with CB 2679d-GT compared to FIX-Padua at both the 5x109 vg/mouse (p < 0.01) and the 1x1010 vg/mouse (p < 0.01) dose levels. These results suggest that CB 2679d-GT exhibits a superior hemostatic potency when compared with FIX-Padua.
“The FIX Padua variant is known to show increased activity compared with wildtype FIX, and in ongoing gene therapy trials treating individuals with hemophilia B it has demonstrated levels of FIX activity approaching the mild to normal range,” adds Blouse. “We are very encouraged and excited to see that when directly compared to an AAV-encoding FIX-R338L Padua in mice, treatment with CB 2679d-GT leads to significant additional improvements in reducing bleeding time and increasing clotting activity, thereby suggesting the possibility to provide a superior outcome.”
“We are currently focused on the continued development of our subcutaneous, recombinant DalcA product for the treatment of hemophilia B as well as our subcutaneous, recombinant Factor VIIa candidate marzeptacog alfa (activated) being developed for the treatment of hemophilia A or B with inhibitors. We plan to explore co-development opportunities for CB 2679d-GT in 2020, and view CB 2679d-GT as an important pipeline product that may provide additional treatment options for patients during their lifetime of therapy. There is a need for the continued improvement of current hemophilia gene therapy constructs and vectors, so we believe CB 2679d-GT may become an important gene therapy candidate,” he concludes.