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Catalyst Biosciences Announces Positive Results From a Phase 1 Clinical Trial of Its Next Generation Coagulation Factor VIIa in Patients With Hemophilia A or B and Preclinical Results

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Catalyst Biosciences, Inc., a privately held biopharmaceutical company, today announced positive results from a Phase 1 clinical trial of CB 813d/PF-05280602, its next-generation and long-acting coagulation Factor VIIa. Results showed that single doses of CB 813d were well tolerated when administered to hemophilia A and B patients, and there were no instances of antibody response or thrombosis. CB 813d demonstrated pharmacological efficacy as measured by significant shortening of aPTT (activated partial thromboplastin time) and PT (prothrombin time) for up to 48 hours post dosing. The results were presented in a poster session at the International Society on Thrombosis and Haemostasis (ISTH) Meeting being held in Toronto, Canada from June 20 to 25, 2015.

"These results demonstrate the initial safety and pharmacologic activity of CB 813d and support further clinical development of this coagulation factor for the potential treatment of bleeding in hemophilia patients with inhibitors," said Nassim Usman, Ph.D., President and Chief Executive Officer of Catalyst. "If we can demonstrate in a larger clinical trial of longer duration that CB 813d is able to control bleeding episodes in hemophilia patients with lower and fewer doses, we would hope to someday tap the global $1.5 billion market for Factor VIIa offerings."

"A significant number of hemophilia A patients and, to a lesser extent, hemophilia B patients develop neutralizing antibodies that inactivate their first line therapies, Factor VIII and Factor IX. The short duration of action of second line therapy – typically Factor VIIa products – for these 'inhibitor' patients significantly limits the efficacy of preventative or prophylactic treatment regimens, creating one of the most acute unmet needs in the hemophilia area. Consequently, we wanted to invent and develop longer acting Factor VIIa variants that are expected to provide better therapeutic options for these patients," said Edwin Madison, Ph.D., Chief Scientific Officer of Catalyst.

Factor VIIa Phase 1 Study Design and Results

CB 813d is an improved next-generation and long-acting coagulation Factor VIIa variant and Catalyst's most advanced clinical development program. The open label, multicenter Phase 1 trial evaluated the safety and tolerability of CB 813d as well as pharmacokinetics, pharmacodynamics and coagulation (i.e., clot forming) activity of CB 813d when given intravenously to 25 non-bleeding hemophilia patients in single ascending dose cohorts who were then observed for up to 60 days post treatment.

Evidence of pharmacological activity was observed with dose-dependent changes in aPTT, PT, PF1+2 (prothrombin fragments 1 + 2), and TGA (thrombin generation activity). CB 813d was well tolerated across all dose groups. No treatment emergent serious adverse events were observed. There was no evidence of antibody immune or "inhibitor" response to treatment with CB 813d at days 15, 30 or 60 of the study.

Catalyst plans to initiate a clinical efficacy trial in hemophilia A and B "inhibitor" patients in 2016.

In addition to the FVIIa clinical results, Catalyst and its collaborators, also presented preclinical data at the meeting related to Catalyst's proprietary coagulation compounds, next generation variants of Factor VIIa, Factor IX, and Factor Xa.

"In our preclinical research, CB-FIX demonstrated a significantly longer duration of action in murine hemophilia B bleeding models compared with FIX products on the market and with others in development and therefore may provide hemophilia B patients with improved prophylactic therapeutic regimens," commented Dr. Madison. "Our Factor Xa preclinical research has also produced interesting lead molecules that, in murine models, exhibit both improved efficacy and safety compared with the most advanced, competing molecule."

Additional presentations are summarized below:

Factor IX: CB 2679d/ISU 304 is a next-generation coagulation Factor IX variant that is in advanced preclinical development. In an oral presentation entitled CB-FIX: an improved second generation FIX drug candidate, Madison et al. evaluated the procoagulant activity of Catalyst's Factor IX compared with existing coagulation factors such as BeneFIX® (coagulation factor IX (recombinant)) and other advanced second generation FIX variants. CB-FIX exhibited enhanced procoagulant activity, improved efficacy in inhibiting blood loss, and prolonged duration of action in bleeding and non-bleeding preclinical models. Based on these findings, CB-FIX may represent a novel second-generation FIX variant.

Factor Xa: CB-FXa is an advanced lead molecule that is in preclinical research. In an oral presentation entitled CB-FXa: an improved second generation FXa variant, Madison et al. evaluated the procoagulant activity of Catalyst's FXa variant. CB-FXa exhibited enhanced potency, greater co-factor dependence, and improved safety (in murine models) compared with various FXa proteins, including an existing clinical candidate. Based on improved in vitro and in vivo properties, CB-FXa may represent a novel second-generation FXa variant.

Factor VIIa: CB 813d/PF-05280602. Two additional Factor VIIa poster presentations were also presented and are summarized as follows:

PF-05280602, a Factor VIIa variant with enhanced in vitro potency compared to wild-type Factor VIIa in hemophilic hemostasis assays, Patel-Hett et al.

In preclinical models of hemophilia, using plasma or whole blood from hemophilia A and B patients, CB 813d exhibited enhanced potency compared with a currently marketed, wild type FVIIa in both coagulation and global hemostatic assays. This improved potency of CB 813d was similar in assays containing hemophilic plasma with or without "inhibitors".

A systems biology model for the coagulation network describes biomarker changes observed in a clinical study with FVIIa variant, Hua et al.

In a translational model comparing a currently available FVIIa (Eptacog Alfa) with CB 813d, the model was able to describe dose-dependent biomarker data and to predict the role of specific kinetic rates on the enhanced potency of CB 813d.

About Hemophilia and Factor Replacement Therapy

Hemophilia, for which there is no cure, is a rare but serious bleeding disorder that results from a genetic or an acquired deficiency of a protein required for normal blood coagulation. There are two major types of hemophilia, A and B, that are caused by alterations in Factor VIII or Factor IX genes, respectively, with a corresponding deficiency in the affected proteins. The prevalence of hemophilia A and B in the United States is estimated to be around 20,000 people, with more than 400,000 cases worldwide. Hemophilia patients suffer from spontaneous bleeding episodes as well as substantially prolonged bleeding times upon injury. In cases of severe hemophilia, spontaneous bleeding into muscles or joints is frequent and often results in permanent, disabling joint damage and can become life threatening. Treatment usually involves management of acute bleeding episodes or prophylactic treatment through factor replacement therapy by infusion of patients' missing Factor VIII or IX. With the frequent infusion schedule of current therapies, adherence is difficult. In addition, convenient access to peripheral veins is often a problem, and many children require use of central venous access devices, with the concomitant risks of infection and thrombosis.

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