Pfizer has agreed to acquire Trillium Therapeutics for $2.26 billion, the companies said today, in a deal designed to bolster the buyer’s oncology drug portfolio by adding Trillium’s two lead molecules, both early clinical stage candidates designed to fight blood cancers by targeting CD47.

The acquisition will add to Pfizer’s pipeline Trillium’s TTI-621 and TTI-622, both designed to block a key immune checkpoint in blood cancers, the signal-regulatory protein α (SIRPα)–CD47 axis. Both SIRPα-Fc fusion proteins are now in Phase Ib/II development across several hematological malignancies.

CD47 is a protein that allows cancer cells to avoid destruction, thus allowing a patient’s own innate immune system to engulf and eradicate those cancer cells—an effect nicknamed “don’t eat me.”

TTI-621 is under study as a monotherapy in patients with several relapsed or refractory blood cancers. The study’s Phase I portion (TTI-621-01; NCT02663518) consists of three completed parts with dosing from 0.05 to 0.5 mg/kg in more than 200 patients; and an ongoing Part 4 in cutaneous T-cell lymphoma patients (CTCL), utilizing revised dose-limiting toxicity criteria for thrombocytopenia and an amended protocol to allow for dosing above 0.5 mg/kg. The study’s estimated primary completion date is December 2021.

According to data announced in April by Trillium, TTI-621 showed monotherapy activity in patients across a range of blood cancers, including CTCL (19% objective response rate or ORR, n=62), peripheral T-cell lymphoma (18% ORR, n=22), and diffuse large B-cell lymphoma (DLBCL) (29% ORR, n=7). Most patients were at an advanced stage of their disease and heavily pretreated. Emerging translational data from patient samples suggested that NK cell activation plays a key role in the anti-tumor activity of TTI-621, in addition to inhibition of the “don’t eat me” signal and delivery of a pro-phagocytic signal, the company noted.

Another Phase I/II study (TTI-621-02; NCT02890368) provided clinical proof-of-concept for TTI-621 by evaluating it as an intratumoral agent in patients with relapsed and refractory solid tumors and mycosis fungoides, the most common form of CTCL. Intratumoral TTI‐621 was well tolerated and resulted in a reduction in Composite Assessment of Index Lesion Severity (CAILS) scores within two weeks of first administration.

IgG4 vs. IgG1

Trillium’s other lead candidate, 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. Because the IgG4 Fc region of TTI-622 has more limited interactions with Fc receptors than IgG1, Trillium reasons that it expects to achieve higher levels of TTI-622 in patients compared to TTI-621, leading to greater and more sustained CD47 blockade.

“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,” Trillium stated on its website.

TTI-622 is under study in a two-part, multicenter, open-label, Phase Ia/Ib study (TTI-622-01; NCT03530683) in patients with advanced relapsed or refractory lymphoma or multiple myeloma. In the Phase Ia 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. The 150-participant study has an estimated primary completion date of April 30, 2022.

In April, Trillium announced data from the study showing TTI-622 monotherapy yielded a 33% ORR in relapsed/refractory (R/R) lymphomas at 0.8–18 mg/kg doses.

“The proposed acquisition of Trillium builds on our strong track record of leadership in oncology, enhancing our hematology portfolio as we strive to improve outcomes for people living with blood cancers around the globe,” Andy Schmeltz, global president & general manager, Pfizer Oncology, said in a statement. “Our deep experience in understanding the science of blood cancers, along with the diverse knowledge base we have developed across our growing hematology portfolio of eight approved and investigational therapies, provide us with a foundation to advance these important potential medicines to patients who need them.”

Trillium has offices in Cambridge, MA, and Mississauga, ON, Canada. The company was formed in Ontario and named after the province’s official flower, Trillium grandiflorum, then underwent reorganization in 2019 and re-prioritized its focus on intravenous products in large hematology-oncology indications and solid tumors.

“For Pfizer, this additional investment is consistent with the company’s focus on tuck-in acquisitions in areas of existing development interest,” Geoffrey C. Porges, MBBS, Director of Therapeutics Research and a senior research analyst with SVB Leerink, wrote in a research note. “We expect Pfizer to explore combinations of TTI-622 and TTI-621 with other medicines, including CD19 therapy with Ruxience, PFE’s rituximab biosimilar, and elranatamab, PFE’s anti-BCMAxCD3 bispecific for multiple myeloma.”

Taking a $25M stake

Pfizer had taken an equity stake in Trillium last year, when its Pfizer Breakthrough Growth Fund made an initial $25 million investment in the company—2,297,794 shares at $10.88 a share—in September 2020. As part of that investment, Pfizer’s Jeff Settleman, PhD, senior vice president and CSO, oncology, worldwide research, development & medical, agreed to join Trillium’s Scientific Advisory Board.

At $2.26 billion, Pfizer’s purchase price for Trillium amounts to $18.50 a share—a 118% premium to the 60-day weighted average price for Trillium. Investors responded to the deal with a buying surge that sent the price of Trillium shares nearly tripling in trading today, closing at $17.59—up about 189% from Friday’s closing price of $5.86.

Trillium shares had been down 59% year-to-date, Jefferies analyst Michael Yee noted in a research note, “so it [the Pfizer acquisition] may remind investors that M&A can still occur as we get into H2 and YE especially with numerous biotechs down meaningfully YTD.”

Yee speculated that another developer of a CD47-blocking cancer drug, ALX Oncology Holdings, could be of strategic interest for biotech and pharma especially with first Phase I MDS data reading out in Q4.”

In snapping up Trillium, Pfizer joins two other biopharma giants that have moved to co-develop CD47-targeting cancer drugs.

In September 2020, AbbVie agreed to partner with I-Mab to develop and commercialize I-Mab’s anti-CD47 monoclonal antibody lemzoparlimab (TJC4). AbbVie gained exclusive rights to lamzoparlimab worldwide except greater China, in return for paying I-Mab $180 million upfront, $20 million tied to achieving positive Phase I results, and up to $1.74 billion tied to achieving milestones ($840 million based on clinical development and regulatory approval milestones, the rest based on commercial milestones).

Earlier last year, Gilead Sciences acquired Forty Seven for $4.9 billion cash, in a deal that gave the buyer control of magrolimab three months after it generated positive Phase Ib data in combination with azacitidine in untreated patients with higher-risk myelodysplastic syndrome (MDS) and untreated patients with acute myeloid leukemia (AML) who were ineligible for induction chemotherapy.

In February of this year, the magrolimab-azacitidine combination generated additional positive Phase Ib data in patients with untreated AML, according to “The First-in-Class Anti-CD47 Antibody Magrolimab Combined with Azacitidine Is Well-Tolerated and Effective in AML Patients: Phase 1b Results,” presented at the 62nd American Society of Hematology Annual Meeting and Exposition.