Trillium Therapeutics Inc. (NASDAQ:TRIL) (TSX:TRIL) announced on 6/14/2018 that it has initiated dosing in its phase 1 clinical trial of TTI-622 (SIRPaFc-IgG4), a checkpoint inhibitor of the innate immune system, in relapsed or refractory lymphoma or myeloma.
TTI-622 is a fusion protein that blocks the inhibitory activity of CD47, a molecule that is overexpressed by a wide variety of tumors. CD47 binds to SIRPa on macrophages and delivers a “do not eat” signal that inhibits the ability of macrophages to engulf and destroy cancer cells. Preclinical studies have shown that TTI-622 has anti-tumor activity across a range of hematologic tumors.
TTI-622 is the second SIRPaFc decoy receptor that Trillium has advanced into the clinic. TTI-621 (SIRPaFc-IgG1), which consists of the same CD47-binding domain of human SIRPa as TTI-622 but linked to an IgG1 Fc region, is currently in two multicenter trials and has produced positive signals of activity in mycosis fungoides, Sézary syndrome and diffuse large B-cell lymphoma patients. The different pharmacologic properties of TTI-621 and TTI-622 will allow Trillium to explore the relationships between the level of CD47 blockade, Fc isotype, tolerability and anti-tumor activity in patients.
“This is an exciting time for Trillium as we initiate clinical development with our second CD47 blocking agent,” commented Dr. Yaping Shou, Trillium’s Chief Medical Officer. “TTI-622 deepens our presence in the CD47 space, and its minimal binding to human erythrocytes could confer best-in-class status among IgG4-based blocking agents currently in development.”
A two-part, multicenter, open-label, phase 1a/1b study of TTI-622 in patients with advanced relapsed or refractory lymphoma or multiple myeloma has been initiated. In the phase 1a dose-escalation part, patients will be enrolled in sequential dose cohorts to receive TTI-622 once weekly to characterize safety, tolerability, pharmacokinetics, and to determine the maximum tolerated dose. In the phase 1b part, patients will be treated with TTI-622 in combination with rituximab, a proteasome inhibitor-containing regimen, or a PD-1 inhibitor. Rituximab and proteasome inhibitors may provide additional “eat” signals that could enhance the efficacy of TTI-622. A PD-1 inhibitor may help amplify any anti-tumor T cell response generated by TTI-622.
Trillium's lead product, TTI-621, is is a SIRPαFc fusion protein also designed to block the CD47 "do not eat" signal and activate both the innate and adaptive immune systems. It is currently in Ph I trials for relapsed or refractory hematologic malignancies, selected solid tumors, and mycosis fungoides. TTI-621 has been granted orphan drug status by the FDA for the treatment of cutaneous T-cell lymphoma.
