Robert Flaumenhaft, MD, PhD
Dr. Flaumenhaft indicated no relevant conflicts of interest.
Study Title: Study to Assess Efficacy and Safety of Anti-von Willebrand Factor Nanobody in Patients With Acquired Thrombotic Thrombocytopenic Purpura (TTP) (TITAN)
Clinical Trials.Gov Identifier: NCT01151423
Study Sponsor: Ablynx
Participating Centers: This is a multi-national trial that includes 51 participating centers.
Accrual Goal: 110 patients
Study Design: TITAN is a phase II randomized, placebo-controlled trial designed to determine the efficacy of a nanobody (ALX-0681) directed against von Willebrand factor (vWF), as an adjunct to plasma exchange in the treatment of patients with TTP. Patients randomized to the experimental arm of the study will receive a 10 mg IV infusion of ALX-0681 prior to plasma exchange followed by 10 mg subcutaneous injections once or twice a day for a maximum of 90 days. The primary outcome measure for this study is time-to-recovery marked at completion of plasma exchange and defined by improvement in the platelet count and reduction in the serum LDH concentration. Secondary outcome measures are as follows: 1) the number of relapses, defined as a de novo event that occurs later than 30 days after the last plasma exchange, during a 12-month follow-up; 2) the time to first relapse of TTP; 3) the number of exacerbations that occur within 30 days after the last plasma exchange; and 4) the time to first exacerbation.
Rationale: The major cause of TTP is deficiency of the metalloprotease ADAMTS13, resulting either from a hereditary mutation of the ADAMTS13 gene or from acquisition of an inhibitory antibody directed against the enzyme. ADAMTS13 cleaves high-molecular-weight multimers of vWF. When ADAMTS13 is deficient, unprocessed ultralarge (UL)vWF complexes, capable of spontaneously binding to the platelet cell surface receptor GP1b, circulate in the bloodstream. Platelets decorated with ULvWF become caught in the microvasculature and occlude the circulation, resulting in thrombocytopenia, microangioplastic hemolytic anemia, and ultimately the end-organ failure that characterizes TTP.
Nanobodies are 12 to15 kDa recombinant proteins modeled after the heavy-chain-only antibodies found in members of the Camelidae family (e.g., camels, llamas, alpacas). They consist of an isolated variable domain of the antibody that maintains complete antigen-binding capacity. Nanobodies have advantages over conventional antibodies in that they are relatively easier to manufacture and humanize and have greater stability. ALX-0681 is a bivalent humanized nanobody that targets the A1 domain of vWF, the region of the protein responsible for binding to platelet surface receptor GP1b. ALX-0681 prevented development of laboratory abnormalities in a baboon model of TTP in which thrombocytopenia and hemolytic anemia was induced by infusion of 3H9, an antibody directed against ADAMTS13 (Callewaert F et al. Blood. 2012;120:3603-3610). Further, ALX-0681 was shown to be efficacious when infused subsequent to induction of TTP by 3H9.
Comment: Plasma exchange has been the mainstay of TTP treatment for nearly four decades and has reduced mortality from >90 percent in the era prior to plasma exchange to <20 percent in the plasma exchange era. Immunosuppressive therapy with corticosteroids or rituximab may be used in conjunction with plasma exchange. Yet 10 to 20 percent of patients will have an inadequate response to plasma exchange, and relapse remains a major concern. Much has been learned about the pathophysiology of TTP since plasma exchange for treatment of TTP was introduced, yet there are still no drugs specifically approved for TTP. Development of therapy driven by an understanding of molecular underpinnings of the thrombotic process could further improve response rates and reduce the incidence of relapse.
Agents targeting the A1 domain of vWF represent a new strategy for ameliorating the progression of TTP. In the baboon model of TTP, ALX-0681 demonstrated excellent efficacy without inducing bleeding (Callewaert F et al. Blood. 2012;120:3603-3610). Similar preclinical results using this same animal model were obtained using GBR600, a conventional antibody directed at the A1 domain of vWF (Feys HB et al. Blood. 2012;120:3611-4). Together, these studies provide compelling in vivo evidence of the efficacy of inhibiting binding of vWF to platelets as a strategy for treatment of TTP. 3H9-induced TTP, however, models the earlier stages of the disease (thrombocytopenia and microangiopathic hemolytic anemia) without eliciting end-organ changes such as renal insufficiency or neurological complications. Thus, the efficacy of AXL-0681 in the prevention or amelioration of these life-threatening sequelae of TTP remains to be proven. TITAN will be important for determining whether interference with vWF binding to platelets is an effective strategy in a clinical setting as an adjunct to plasma exchange. Although TITAN is designed to test the efficacy of AXL-0681 in conjunction with plasma exchange, success could provide the first steps on a path to replace plasma exchange with therapies that are directed at the underlying thrombotic process of the disease.
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