Hemophilia
Hemophilia is a rare but serious bleeding disorder that results from a genetic or an acquired deficiency of a protein required for normal blood coagulation, such as factor VIII (hemophilia A) or factor IX (hemophilia B). The disease varies in severity depending on the extent of residual activity for the deficient factor that can be detected in the circulation of individual patients. Hemophilia patients suffer from both spontaneous bleeding episodes as well as substantially prolonged bleeding times upon injury that can become life threatening. In cases of severe hemophilia, spontaneous bleeding into muscles or joints is frequent and often results in permanent, disabling joint damage.
FVIIa – Partnered with Pfizer
Hemophilia patients are initially treated by replacement therapy, receiving purified versions of the clotting factor for which they are deficient. However, a significant fraction of hemophilia A patients develop inhibitory antibodies against factor VIII and therefore become refractory to treatment with this factor. These inhibitor patients are then treated with recombinant human factor VIIa (rhFVIIa, NovoSeven® marketed by Novo Nordisk), an enzyme that can both initiate blood clotting and, at high doses, “bypass” the factor VIII dependent step in coagulation. However, administration of multiple doses of rhFVIIa is often required to control bleeding episodes. Sales of NovoSeven® were reported to reach $1.6 B in 2010.
Catalyst has created a broad portfolio of improved FVIIa molecules, several of which have shown enhanced activity and longer pharmacodynamic half-life. Catalyst’s lead compound CB 813d, an improved FVIIa for treatment of acute bleeding in hemophilia patients with inhibitors, was partnered to Pfizer in 2009, renamed PF-05280602, and is now in Phase 1 clinical development. Catalyst's approach focused on the design of a molecule that combines higher clot-generating activity targeted to the site of bleeding and improved duration of action in vivo. We anticipate that both lower and fewer doses of the improved FVIIa will be required to control acute bleeding episodes.
Catalyst signed a worldwide exclusive licensing agreement with Wyeth Pharmaceuticals, now a subsidiary of Pfizer, in June 2009. Catalyst is responsible for discovery and research of novel FVIIa variants, including improved FVIIa proteases that may allow their use in a prophylactic setting for hemophilia patients and for the control of bleeding in normal patients in a surgical or trauma setting. Pfizer is responsible for preclinical and clinical development, manufacturing and commercialization of resulting FVIIa products.
FIX – Catalyst Biosciences
Based on the success of the improved FVIIa program, Catalyst initiated a research program directed at improving the pharmacokinetic and pharmacodynamic properties of factor IX. Market studies have shown that while BeneFIX®, the leading recombinant human factor IX on the market, is well accepted for treating acute bleeding episodes in hemophilia B patients, its short half-life is not practical for prophylactic treatment, the current unmet medical need. Catalyst has created a library of improved FIX proteases that are in preclinical testing. Based on data from animal studies, Catalyst’s improved FIX proteases may provide hemophilia B patients with a viable prophylactic therapy requiring dosing only once every month. Catalyst has selected a FIX development candidate and is currently seeking a development partner.
FXa – Catalyst Biosciences
Based again on the success of the improved FVIIa program, Catalyst initiated a research program in late 2009 directed at improving the pharmacokinetic and pharmacodynamic properties of factor Xa. Factor Xa is downstream of hemophilic lesions in the coagulation cascade and thus has the potential of being used as a universal pro-coagulant, both as a bypass agent in hemophilia patients and in the general population for control of bleeding in surgery and trauma. However, wild type FXa is toxic at therapeutic levels in humans. Catalyst has employed its protease engineering expertise to discover a library of improved FXa variants that are more potent than wild type FXa and are not toxic at therapeutic doses in murine bleeding models. Catalyst's FXa program is in active preclinical development and is available for partnering.
