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SOUTH SAN FRANCISCO, Calif.—There's some recent good news for patients with hemophilia, as biopharmaceutical company Catalyst Biosciences Inc. announced this quarter that CB 2679d/ISU304, its next-generation coagulation Factor IX, had garnered encouraging preclinical results in a well-validated preclinical model of hemophilia B. Catalyst’s Factor IX preclinical program was presented at this year's International Society on Thrombosis and Haemostasis (ISTH) meeting.
Hemophilia B is typified by a lack or defective version of Factor IX, a clotting protein. Though it is a genetic disorder, the National Hemophilia Foundation reports that roughly a third of hemophilia B cases are the result of a spontaneous mutation. The U.S. Centers for Disease Control and Prevention report that about one in 5,000 live births are hemophilic, and some 20,000 individuals in the United States have either hemophilia A or B (though hemophilia A is four times more common than hemophilia B). The standard of care for treating hemophilia consists of regular infusions of a recombinant factor product to replace the version the body fails to make properly.
At present, according to Catalyst, “The leading recombinant human Factor IX on the market for treating acute bleeding episodes in individuals with hemophilia B is delivered intravenously (due to its short half-life) and is therefore not ideal for prophylactic treatment. Extended half-life agents used for prophylaxis require intravenous dosing and have a prolonged period of low activity levels with increased risk of spontaneous bleeding. CB 2679d has shown significantly higher potency in preclinical studies compared with other FIX products on the market and in development.”
The ISTH presentation on CB 2679d/ISU304, “Pharmacokinetics and Pharmacodynamics of Daily Subcutaneously Administered CB 2679d/ISU304 In Hemophilia B Dogs,” studied Factor IX antigen and activity in dogs for six days. It found that the compound corrected severe hemophilia to normal in dogs after six daily subcutaneous doses, with no emergent clinical adverse events. After the six doses, peak Factor IX activity levels were at 60 and 53 percent at 126 hours, and trough activity levels 24 hours after the six doses were 56 and 40 percent, respectively. In addition, the increase in activity levels supported the initiation of the Phase 1/2 proof-of-concept subcutaneous dosing studies with the goal of achieving normal Factor IX activity trough levels.
“Catalyst’s CB 2679d corrected severe hemophilia to normal coagulation activity in hemophilia B dogs after only six daily subcutaneous doses,” Dr. Howard Levy, chief medical officer of Catalyst, said in a press release. “Given the potency and pharmacokinetic profile of CB 2679d observed in our preclinical studies, we are looking forward to open-label results from the ongoing Phase 1/2 subcutaneous dosing study in individuals with hemophilia B, as well as daily dosing results, towards the end of this year.”
Based on the results, Catalyst's partner, ISU Abxis, initiated a Phase 1/2 proof-of-concept clinical trial of CB 2679d for subcutaneous prophylaxis in patients with hemophilia B. The trial will enroll up to 17 individuals diagnosed with severe hemophilia B, with an expected completion date in 2018.
Catalyst also presented a poster detailing results for its Factor VIIa product, “Pharmacokinetics and Pharmacodynamics of Subcutaneously Administered Marzeptacog Alfa (Activated) in Hemophilia B Mice.” This product is a high-potency next-generation Factor VIIa initially under development for the subcutaneous prophylactic treatment of individuals with severe hemophilia A and B with inhibitors. Inhibitors are possible complications in hemophilia patients undergoing factor replacement therapy that result from the body generating antibodies against the replacement factor.
They found that daily subcutaneous dosing at 0.5 mg/kg resulted in trough levels of marzeptacog alfa (activated) 29.9 to 76.9 ng/mL (mean 43.4), which increased two hours after administration to 267.4 to 362 ng/mL (mean 323.9). Daily dosing at 1 mg/kg led to trough levels of marzeptacog alfa (activated) 50 to 80.9 ng/mL (mean 63.7) and increased two hours after dosing to 230.8 to 729.5 ng/mL (mean 471.9). As noted in a press release, the “Increased potency of marzeptacog alfa (activated), blood drug levels and reduction in activated partial thromboplastin time (aPTT) achieved, support the initiation of a Phase 2/3 subcutaneous dosing study in individuals with hemophilia A and B with inhibitors, with a target of achieving normal coagulation pharmacodynamics.”
“We made significant progress in both our clinical programs and strengthened our balance sheet in the second quarter,” Dr. Nassim Usman, Catalyst’s president and CEO, said in a press release announcing the company's Q2 financial results. “The Factor IX program was initiated on schedule and we expect to report interim results from the Phase 1/2 subcutaneous dosing study in individuals with hemophilia B by year-end. We also intend to initiate a Phase 2 clinical trial for our Factor VIIa product candidate Marzeptacog alfa by the end of the year. With the additional capital we raised in April, we are well positioned to report clinical data from both programs over the next 12 months.”