Development and evaluation of a truncated recombinant ADAMT13 micro-particle with extended release and enhanced protease plasmatic activity

Background

Blood coagulation is an essential physiological process where the blood changes from a liquid form into a thicker, gel-like form in response to a blood vessel injury thereby preventing excessive blood loss. There are, however, several pathological conditions where blood clotting occurs inside intact blood vessels leading to blood flow blockage and major organs’ failure. Thrombotic thrombocytopenic purpura (TTP) is one such conditions where blood clots are formed inside small blood vessels in association with decreased number of platelets, leading to the damage to multiple organs, mainly kidneys and the brain. Further studies identified the deficiency of ADAMTS13 (disintegrin-like and metalloprotenase with thrombospondin type 1 motif 13) enzyme as the basic pathology behind the condition.

Depending on the underlying etiology, the treatment of TTP mainly includes the control of the cause, like immune modulation, and the infusion of fresh frozen plasma (FFP) and/or platelets for replenishing the factors necessary to regulate the coagulation and control the thrombosis process. While this approach is effective, there are multiple complications associated with it, including the risk of allergic and life-threatening anaphylactic reactions as well as the risk of infections.

Due to the severity of complications associated with plasma perfusion techniques, the development of recombinant ADAMTS13 (rADAMTS13) provided a new hope for treatment of TTP as well as other conditions with clotting disorders. Initial trials to test the rADAMTS13 in adult patients with TTP proved the efficacy of this therapy; however, the limited half-life of the rADAMTS13 required repeated administration of the therapy for long term treatment. This limitation of the therapy represents the main challenge for utilizing rADAMTS13 to treat a wide range of hemorrhagic thromboembolic disorders, all of which are severe conditions that require accurate dose of treatment.

Technology Overview

Dr. Kohane and his team at Boston Children’s Hospital developed a novel, modified rADAMTS13 which, after extensive research, proved to have extended length of action as well as a superior efficacy in cleaving the VWF (Von Willebrand factor), the specific action responsible for controlling the underlying pathology.

Applications

• Treatment of Thrombotic Thrombocytopenia Purpura (TTP) of different etiologies including the acute life-threatening phase of TTP as well as the subacute phase to prevent organ damage, especially kidney failure.
• Acute ischemic stroke. Studies found that ADAMTS13 has promising effect of treating acute ischemic strokes that are resistant to tPA thrombolytic treatment.
• Patients with sickle cell disease were found to have higher levels of VWF, leading to higher tendency for thromboembolism. Using rADAMTS13 on a long-term basis in these patients can prevent the acute episodes of thromboembolism as well as possible long-term complications of organ damage.
• Studies proved that using the rADAMTS13 following trauma can restore the ADAMTS12-VWF axis and prevent life-threatening complications.
• Some mice studies demonstrated the efficacy of ADAMTS13 in reducing thrombosis and inflammation in myocardial injury. Therefore, it has the potential to reduce myocardial damage and inflammation following acute myocardial infarctions.

Advantages

• Increased efficacy of cleaving the VWF in TTP and other thromboembolic conditions, providing quick reversal of the thromboembolic state; making it a life-saving therapy.
• Accurate adjustment of the dosage required for acute and chronic therapy, according to each individual, ensuring high efficacy with reduced complications.
• Compared to blood products, like plasma and platelets, rADAMTS13 has no risk of infection, allergy, or anaphylactic reactions that might result from having antibodies in the blood.
• High cost-effectiveness, in comparison to the current protocol of treating TTP and other conditions like MI and stroke.
• The ability to use this therapy along with other treatments in addressing the underlying cause of a specific disease, like steroids in the case of autoimmune TTP.

Publications

1. Scully M, Knobi P, Kentouche K, et al: recombinant ADAMTS13: first-in-human pharmacokinetics and safety in congenital thrombotic thrombocytopenic purpure. Blood;130(19):2055-2063. 2017.
2. Vergouwen MD, Knaup L, Rollogs TH et al: Effect of recombinant ADAMTS13 on micro-thrombosis and brain injury after experimental subarachnoid hemorrhage. J of Thromb and Hemost. 12:943-947. 2014
3. Witsch T, Martinod K, Serville N et al: Recombinant Human ADAMTS13 Treatment Improves Myocardial Remodeling and Functionality AFTEr Pressure overload Injury in Mice. J Am Heart Assoc 2018;7:e007004. \DOI:10.1161/JAHA.117. pg. 1-13,
4. A Study of SHP655 (rADAMTS13) in Sickle Cell Disease (RAISE) gov Identifier: NCT03997760