Pipeline
We employ biologics that are designed to enhance the ability of the patient’s own immune system to detect and destroy cancer cells. Our two lead molecules, TTI-621 and TTI-622, are innate immune checkpoint inhibitors targeting CD47.
Target
Target
STING Agonist
Target
Undisclosed – immuno-oncology Targets
TTI-622
TTI-622 is Trillium’s second SIRPαFc fusion protein. TTI-622 consists of the same extracellular CD47-binding domain of human SIRPα as TTI-621 but has an IgG4 Fc region instead of an IgG1 Fc.
The IgG4 Fc region of TTI-622 has more limited interactions with Fc receptors than IgG1, and thus TTI-622 is predicted to deliver a moderate “eat me” signal to macrophages. Preclinical studies suggest that IgG4-based SIRPαFc fusion proteins have greater tolerability but lower potency than IgG1-based fusion proteins. We therefore expect to achieve higher levels of TTI-622 in patients compared to TTI-621, leading to greater and more sustained CD47 blockade. Thus, TTI-622 will allow us to assess how higher CD47 blockade with an IgG4-based agent in patients compared to lower CD47 blockade with the IgG1-based TTI-621. Due to lower potency of the IgG4Fc, we expect that TTI-622 is likely to be more effective in combination with agents that provide additional “eat me” signals to macrophages or other forms of immune activation. Importantly, TTI-622 has been shown not to bind appreciably to human red blood cells, unlike many other CD47 blocking agents.
TTI-622 is being studied in a two-part, multicenter, open-label, phase 1a/1b study in patients with advanced relapsed or refractory lymphoma or multiple myeloma (NCT03530683). In the phase 1a dose-escalation part, patients are being 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 other agents. Currently, the 4.0 mg/kg top dose cohort has been completed with no DLTs or drug-related serious adverse event observed. Enrolment in the 8.0 mg/kg dose cohort is currently in progress.
TTI-621
Intravenously administered TTI-621 is currently being evaluated in a multicenter, open-label phase 1 trial in patients with relapsed/refractory hematologic malignancies (TTI-621-01; NCT02663518). The study consists of four parts: (a) completed Parts 1-3 in hematologic malignancies, with dosing up to 0.5 mg/kg; and (b) ongoing Part 4 in cutaneous T-cell lymphoma patients, utilizing revised dose-limiting toxicity (DLT) criteria for thrombocytopenia and an amended protocol to allow for dosing above 0.5 mg/kg. Parts 1-3 involved over 200 patients receiving doses ranging from 0.05 to 0.5 mg/kg. TTI-621 was generally well tolerated with the most frequent drug related adverse events being low grade infusion reactions and transient thrombocytopenia that was not associated with bleeding. Importantly, monotherapy activity was observed in patients across a range of hematologic malignancies, including cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and diffuse large B-cell lymphoma. Notably, most patients were at an advanced stage of their disease and heavily pretreated, with median number of prior systemic treatments between 3 and 5. Part 4 of the study is ongoing with dosing in the 2.0 mg/kg cohort in progress.
More details of this study can be found in the Patients section.
An exploratory study evaluating the use of TTI-621 in solid tumors is also being planned.
TTI-621 was evaluated as an intratumoral agent in a multicenter, open-label phase 1b/2 study in patients with relapsed and refractory solid tumors and mycosis fungoides, the most common form of cutaneous T cell lymphoma (Study TTI-621-02; NCT02890368). Intratumoral TTI-621 was well tolerated and reduction in CAILS scores, which measures local lesion responses, was observed in 91% (20/22) mycosis fungoides patients with 41% exhibiting reductions of 50% or greater. These responses occurred rapidly within two weeks of first administration. Having served its purpose of providing clinical proof-of-concept this trial has been closed and we are now focused on intravenous delivery of TTI-621.
TTI-621 has been extensively tested in preclinical laboratory studies. Key findings from these studies are summarized below:
- TTI-621 triggers the phagocytosis of a wide range of human cancer cells in vitro.
- TTI-621 is active across a range of different types of human macrophages (M0, M1, M2a, M2b, M2c).
- TTI-621 monotherapy reduces the growth of human tumors in mice.
- TTI-621-mediated enhancement of tumor cell phagocytosis leads to enhanced T cell responses in vitro.
UNDISCLOSED TARGETS
Efforts to discover novel cancer therapeutic targets are ongoing. We are applying our expertise in biologics and medicinal chemistry to generate novel, patentable compounds against undisclosed immuno-oncology targets.
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100 Cambridgepark Drive, Suite 510
Cambridge, MA 02140
USA
Tel: +1 857.412.7029
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Mississauga, ON L5L 1J9
Canada
Tel: +1 416.595.0627
INVESTOR RELATIONS
James Parsons
Chief Financial Officer
Tel: +1 416.595.0627 x232
james@trilliumtherapeutics.com