Trillium Looks To Lead The Immuno-Oncology Pack In CD47 Inhibition

Emerging Company Profile: Toronto biotech thinks it will differentiate from the current IO paradigm with CD47 inhibition, and from competitors in its space by directly targeting a receptor found in the tumor microenvironment.

Canada's Trillium Therapeutics Inc. is looking to lead the next wave in cancer immunotherapy with novel therapeutics that target the innate immune system by inhibiting the CD47 signaling pathway, an approach it believes could offer wide application across a range of solid and liquid tumor types.

While the anti-CD47 approach is differentiated from the current paradigm in immuno-oncology – such as PD-1/PD-L1 inhibitors, which target the adaptive immune system – Trillium still must face down some serious competition in the CD47 space, including firmly entrenched cancer stalwart Celgene Corp. and Palo Alto, Calif.-based Forty Seven Inc., which holds a formidable intellectual property position thanks to its licensing of research at nearby Stanford University. (Also see "Science Matters: CD47 Pathway Links To CV Disease, New Drug Development Opportunities" - Scrip, 29 Aug, 2016.)

Still, no company targeting CD47 has a significant lead in clinical development. Celgene has anti-CD47 antibody CC-90002 in Phase I; Forty Seven likewise has an antibody candidate (Hu5F9-G4) in Phase I; and Trillium has its lead candidate, a SIRP (Signal Regulatory Protein) alpha fusion decoy receptor, in Phase I in hematologic malignancies; the company is also poised to begin a second Phase I trial in solid tumors. In addition, Alexo Therapeutics Inc., NovImmune SA and Tioma Therapeutics Inc. have anti-CD47 candidates for cancer in preclinical development.

Trillium CEO Niclas Stiernholm explained in an interview that his company believes its non-antibody approach gives it an edge, but the other two companies that have reached the clinic may hold a financial lead: Forty Seven raised a $75m Series A round in March, while Celgene ended the second quarter with roughly $6.4bn in cash. (Also see "Forty Seven Raises $75 Million For Possible 'Universal' Cancer Therapy" - Scrip, 3 Mar, 2016.)

In an Oct. 6 note initiating coverage of Trillium with a "buy" rating, BTIG Equity Research analyst Dane Leone projected a $31m R&D cash-burn by Trillium in 2017. At that pace, he said the biotech would have about $25m on hand by second-quarter 2017 and be badly in need of a cash infusion.

Trillium CEO Niclas Stiernholm

Trillium Therapeutics

When the time to raise funds comes, Stiernholm will have to sell potential investors on a new field of immuno-oncology. "The main difference here is that while the current PD-1 and CTLA antibodies are all targeting the adaptive immune system, targeting T-cell pathways, CD47-blockade is actually targeting the innate immune system, specifically involving macrophages," he told Scrip. "That's why we and others tend to think about this as the next generation, certainly a far less explored area."

Pursuing CD47 Inhibition’s Next Generation

CD47 proteins emanating from tumor cells transmit a "do not eat" signal to macrophages within the tumor microenvironment. While Celgene and Forty Seven are trying the more conventional antibody approach to CD47 inhibition, however, Trillium is directly targeting the SIRP alpha receptor on macrophages to inhibit the CD47 protein's signal.

"So the concept is to break that silencing, allowing the macrophages to attack the tumor," Stiernholm explained. "Our approach is that we took the ligand or the target on macrophages, SIRP alpha, and we solubilized it by fusing it to an antibody FC portion."

One of the potential advantages TTI-621 may offer to its anti-CD47 competitors is that it has been shown preclinically to not bind to human red blood cells (RBCs), which are expressed significantly on CD47 proteins.

"In fact, CD47 is involved in the lifespan regulation of red blood cells," noted Stiernholm. "We were quite surprised when SIRP alpha FC didn't bind to RBCs, but delighted at the same time because that meant that we didn't have to have concerns about causing anemia [or] about the huge antigen sink that RBCs represent, so that's a clear point of differentiation between the two approaches."

Trillium Therapeutics Inc.

Location: Toronto

R&D Focus: Trillium is a clinical-stage immuno-oncology company focused on novel therapies that prevent the CD47 protein from delivering inhibitory signals that prevent the innate immune system from attacking cancer cells. Its Phase I SIRP alpha fusion protein candidate TTI-621 is being tested in a Phase I hematologic cancer study and the company is planning to launch a second Phase I study in solid tumors. Trillium also has a proprietary medicinal chemistry platform that uses fluorine chemistry to create new chemical entities from validated drugs and drug candidates with improved pharmacological properties.

Disease area: Cancer immunotherapy

Founding date: Founded in 2004 as Stem Cell Therapeutics Corp. Became Trillium Therapeutics in 2014 when Stem Cell Therapeutics merged with its Trillium subsidiary, acquired for C$2.8m in 2013. [See Deal]

Financing to date: Publicly traded, NASDAQ. Netted $51.8m by selling 1.75m common and preferred shares at $19.50 per share in April 2015. [See Deal]

Another point of differentiation between Trillium and Forty Seven, the exec added, is that the other company's candidate targets immunoglobulin-4 (IgG4), which he called "a fairly inert region" with limited effector functions, while TTI-621 uses IgG1, the most active human fusion protein region. That region "has full effector functions and so the potency between our two approaches, we predict, will be very different," he said. "We can already tell from preclinical data published by Forty Seven Inc. and the Stanford [research team] that there's a clear difference in terms of our fusion protein being much more potent."

Going After Hematological Malignancy First

TTI-621 is in an ongoing Phase Ia/Ib trial to establish safety and the optimal minimum dose. The Phase Ia portion is dosing the drug in relapsed or refractory lymphoma patients, because while very ill, they still have relatively robust bone marrow function, Stiernholm said, which will help Trillium to distinguish whether results are due to drug effect or disease progression.

In the Phase Ib portion, the drug will be tested in a variety of leukemias, where there is impaired bone marrow function. Trillium plans to report the Phase Ia dose-escalation data at the American Society of Hematology meeting this December in San Diego, but the company doesn’t expect to have data from the Phase Ib portion until the end of 2017.

Meanwhile, it is moving toward initiation of another Phase I study in solid tumors, but will not employ the basket trial approach used by Celgene and Forty Seven.

"They've enrolled quite a bit of different types of solid tumors, all comers, so that's certainly one approach," Stiernholm said. "But we thought that a different approach would be more useful to us and a better use of capital, so we decided to do an intra-tumoral delivery in percutaneously accessible tumors like melanoma, Merkel cell carcinoma, breast cancer, head-and-neck cancers."

"[These are] cancers where you can target the tumor directly and make sure that you can get very high concentration of drug in the tumor and then do serial biopsies and study exactly what is happening in the tumors as a result of these high levels of CD47 blockade," he added.

The solid tumor data should help Trillium determine what types of combination therapy might be most viable for TTI-621. However, the company’s goal with the solid tumor study is twofold – to delineate a regulatory path forward and to better understand the biology of the tumor microenvironment, Stiernholm said.

Modality Results From IP Necessity

The difference in modality compared to Celgene and Forty Seven was necessitated by the patent estate situation in anti-CD47 research. Trillium's technology derives from research conducted by the University Health Network and the Hospital for Sick Children, both in Toronto.

"It's really a decision that was made for us by the inventors," Stiernholm explained. "When they got started, they had the foresight to look at the patent literature and they noticed that there were already several filings by the Stanford group on monoclonal antibodies, so in order to avoid having to fight that in the future, they decided to take an alternative approach and use what people often refer to as a ligand trap or a decoy receptor.”

Stiernholm said considering the competing anti-TNF biologics Enbrel (etanercept) and Remicade (infliximab) illustrates the difference, with the former employing a ligand trap approach to therapy while the latter takes an antibody approach.

Going forward, Trillium knows it may need to partner, but it isn't currently seeking a deal, the exec said.

"We think that if this target is as promising as we think, there's going to be broad applicability and we cannot realistically do all the trials on our own," he said. But Trillium isn’t in a position where it would need to partner merely for financial reasons, he added, so it could set some parameters for the kind of deal it wants, which would not be a straight out-licensing with no further involvement in drug development.

Trillium will want an active role in ongoing drug development and some option to co-promote an approved product, he said. "That's the trend that you see now. I keep close track of the [deal-making] in this space and have seen a good 12-15 recent partnerships in which there is an opportunity to co-commercialize in your home continent."

When the time comes to attract investors or partners, market analysts seem bullish on Trillium's prospects. BTIG's Leone thinks the biotech may have an edge with its differentiated approach to CD47 inhibition, compared to Celgene and Forty Seven.

"Finding targets that utilize the innate system has been challenging, as there are few known targets that provide the specificity where an acceptable balance of toxicity is maintained between normal tissue and tumor tissue," he wrote Oct. 6. "We believe that Trillium’s approach of using a SIRP alpha decoy receptor, versus the anti-CD47 mAb or monomer approaches being used by competitors, may provide a differentiated toxicity balance, and help potentiate a better combination with other immune therapies that are currently being used clinically or under development. We are optimistic that the ongoing Phase Ia/Ib trial of TTI-621 in the treatment of relapsed or refractory hematologic malignancies may support TTI-621 as a leading compound within the CD47 class of therapies."

Also optimistic is Leerink Partners' analyst Michael Schmidt, who rated Trillium shares "outperform" in an Aug. 16 note. He thinks Trillium could hold an edge, because of its preclinical data showing that TTI-621 does not bind to red blood cells. "This is important as it lowers the risk of anemia in patients and potentially improves the biodistribution of the drug," he wrote.

From the editors of Start-Up