Each year venous thromboembolism (VTE) affects up to 2 million Americans and 24 million people worldwide. VTE patients have blood clots in the legs (venous thrombosis) that may travel to the lungs (pulmonary embolism). Up to 10-20% of VTE patients die, and the annual direct U.S. healthcare costs are ~$10 billion. For more than 50 years anticoagulation has been the standard therapy for VTE. Anticoagulation has many drawbacks: 1) it does not dissolve existing thrombi; 2) up to 50% of patients develop post-thrombotic symptoms (pain, swelling, chronic sores); 3) up to 4% of patients develop chronic thromboembolic pulmonary hypertension (a severe cardiopulmonary disease); 4) it is linked to VTE recurrence in up to 30% of patients; 5) it has significant bleeding risk; and, 6) it has not been proven to save lives in a randomized clinical trial. High doses of tissue plasminogen activator (TPA)-like agents may prevent post-thrombotic complications by dissolving clots, but they: 1) are only partially successful; 2) cause bleeding and, 3) do not reduce mortality. There is a need for a safer, more-effective therapy for VTE that saves lives, reduces disability, and lowers health care costs. We (Translational Sciences, Inc. [TSI]), successfully completed a Phase I-II STTR in which we discovered and developed a therapeutic antibody (Lysimab) that dissolves blood clots through a unique mechanism. Through synergism, Lysimab increases the potency, safety and specificity of TPA, and it avoids TPA-related hemorrhage and neurotoxicity. Following FDA recommendations, in Phase I studies, we successfully developed Lysimab into a stable, clot-dissolving therapeutic suitable for clinical trials. Our Phase II STTR advanced Lysimab through preclinical studies toward human trials by: 1) demonstrating safe/effective, synergistic, therapeutic dose combinations of Lysimab and TPA in vivo in a humanized pulmonary embolism model; 2) producing and purifying Lysimab under GLP conditions; 3) characterizing Lysimab's human tissue binding char- acteristics; 4) demonstrating Lysimab's remarkable safety profile and pharmacokinetics in pivotal safety- toxicology studies in a pharmacologically relevant species; 5) completing a successful FDA pre-IND meeting; 6) raising strategic investment funds for clinical development and, 7) securing competitive selection by the NIH SMARTT regulatory team for FDA IND submission. Building on this progress, this Phase IIb proposal aims to complete a first-in-human, Phase I study of the safety, pharmacokinetics, pharmacodynamics and biomarker efficacy of Lysimab. Then we will leverage our pre-clinical/clinical data to form a strategic alliance with a Pharmaceutical partner to conduct later phase clinical trials for FDA approval of Lysimab. We project that combination TPA-Lysimab therapy could lead to the survival of an additional 17,000-36,000 patients per year and a >50% reduction in post-thrombotic symptoms and their associated costs. Upon completion of this Phase IIb project and transfer of commercialization responsibilities to our strategic partner, TSI will investigate the potential benefits of this platform technology to other patients with thrombotc diseases.
Venous thromboembolism affects about 24 million people per year worldwide, costing as much as $10 billion per year in the U.S. alone. Anticoagulation therapy is the standard of care for patients with venous thromboembolism, but anticoagulation has serious risks and, in more than 50% of patients, anticoagulation fails to prevent complications that lead to recurrent venous thromboembolism, chronic pain and disability. This Phase IIb proposal seeks to develop a novel therapy for venous thromboembolism that could markedly reduce death, disability, and healthcare costs.
