Results of a Phase 2 Safety, Efficacy, and Pharmacokinetic Study of TOL-101, an Anti-TCR Monoclonal Antibody for the Prophylaxis of Acute Rejection in Kidney Transplantation
Cleveland Clinic Foundation, Cleveland
Barnabas Health, West Orange
Dallas Transplant Institute, Dallas Fort Worth
Tolera Therapeutics Inc, Kalamazoo
University of Kentucky, Lexington
University of Michigan, Ann Arbor
University of Utah, Salt Lake city
University of Colorado, Denver
Northwestern University, Chicago
Meeting: 2013 American Transplant Congress
Abstract number: 163
Purpose: Induction therapy using anti-lymphocytic antibodies is a potent tool for the prevention of early rejection after kidney transplantation. TOL-101, an IgM monoclonal antibody, with specificity for the ΑΒTCR and absence of mitogenicity, is well suited for this purpose.
Methods: After local IRB approval 13 centers enrolled 28 low-moderate risk kidney recipients (crossmatch negative, ABO compatible with <20% PRA, EBV IgG+, age 21-60 years) in a dose finding study using a maintenance regimen of tacrolimus-mycophenolate-steroids. The six-month trial used GPC/FDA guidelines to evaluate safety parameters, cytokine release syndrome, standard laboratory tests, BPAR, and renal function. The ability of TOL101 to modulate the T-lymphocyte count was used as the pharmacodynamic endpoint, targeting absolute CD3 counts <25/mm3.
Results: Ascending IV doses (delivered days 0-5) ranging from 0.28-42mg of TOL-101 were given to 28 subjects in cohorts of 2-4; demonstrating greater downregulation of T cells. Infusion reactions were rare, and significant cytokine release (IL6, TNF, IFN-Γ) was absent. An unanticipated but transient first dose rash occurred in 10/28 patients, maximal at 42mg, This resulted in defining a best escalating 14-21-28-42-42-42mg daily schedule. There have been no deaths or graft losses at 6 months. There were 35 SAEs in 11 patients (one possibly study drug related-pneumonia) with GI Disorders (8) most reported. No malignancies or serious (opportunistic, etc.) infections have been observed. There were 4 (14%) treated BPAR (Banff 1a=1, Banff 2a=3). The overall mean plasma elimination T½ of TOL-101 was 23 hours (range 15-31) over 4 cohorts. The mean iothalamate GFR at 6 months was 55.7 mL/min/1.73m2.
Conclusions: The initial use of TOL-101 appears to be a safe and well tolerated after 6 months, at doses that have substantial T-cell modulating effects, supporting phase 3 initiation in 2013.
Wiseman, A.: Employee, Tolera. Getts, D.: Employee, Tolera.
To cite this abstract in AMA style:
Flechner S, Mulgaonkar S, Melton L, Waid T, Sung R, Shihab F, Wiseman A, Getts D. Results of a Phase 2 Safety, Efficacy, and Pharmacokinetic Study of TOL-101, an Anti-TCR Monoclonal Antibody for the Prophylaxis of Acute Rejection in Kidney Transplantation [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/results-of-a-phase-2-safety-efficacy-and-pharmacokinetic-study-of-tol-101-an-anti-tcr-monoclonal-antibody-for-the-prophylaxis-of-acute-rejection-in-kidney-transplantation/. Accessed December 5, 2024.« Back to 2013 American Transplant Congress