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iStock/ Afry Harvy TIGIT-targeting therapies have largely disappointed in recent months, with failed studies, terminated partnerships and shuttered businesses. Here are five biopharma players staying alive with differentiated candidates against the once promising immuno-oncology target. When GSK turned its back on development partner iTeos Therapeutics in May, a terminal countdown began for the Massachusetts-based biotech. Weeks later, time ran out and iTeos was forced to shutter operations. The biotech is only the latest casualty in a therapeutic space that is turning into a drug development wasteland. The asset that led to iTeos’ ultimate demise was belrestotug, an anti-TIGIT therapy that was being assessed for multiple solid tumors, including non-small cell lung and head and neck cancer. Though the partners did not reveal specific data, iTeos noted in May that even when used with GSK’s PD-1 blocker Jemperli, belrestotug was unable to improve progression-free survival in patients with NSCLC versus Jemperli alone. Findings in patients with head and neck cancer were likewise disappointing. Belrestotug is just one therapy in the long line of TIGIT assets that have run into insurmountable clinical roadblocks. Found in certain cells of the immune system, TIGIT —which stands for T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domain—is a receptor with immunosuppressive effects. Under healthy circumstances, TIGIT helps regulate the release of cytokines, in turn suppressing the activity of T cells. TIGIT is overexpressed in many cancers , allowing tumor cells to inhibit the immune system’s anti-cancer response. Many biopharma players have seized on this mode of action, identifying molecules that can block TIGIT in cancers in hopes of boosting the body’s antitumor activity. But none have been successful so far, and the experience of GSK and iTeos has become the unfortunate standard. In July 2024, Roche’s tiragolumab failed to improve survival in patients with NSCLC in the closely watched SKYSCRAPER-06 trial . A few months later, another study of tiragolumab, SKYSCRAPER-01, flopped . Merck has also been stymied by TIGIT. In May 2024, the pharma scrapped a late-stage study for its anti-TIGIT antibody vibostolimab due to treatment toxicity that led to a high rate of study dropouts. Safety concerns also led to the demise of another Phase III study later that same year, this time in extensive-stage small-cell lung cancer. A key reason behind these failures, according to Padmanee Sharma, a professor in the department of Genitourinary Medical Oncology at MD Anderson Cancer Center, is that much remains unknown about how this pathway specifically works. Other proteins may also be involved in the overall TIGIT mechanism, she told BioSpace in an email, or TIGIT itself may have a role to play in other cellular functions. “TIGIT is a complex biologic target,” Sharma said. “The exact mechanism is not clear.” Still, many persist in developing a TIGIT therapy, largely because its signals of efficacy are encouraging. “Pre-clinical data indicate that TIGIT is a relevant pathway to pursue,” Sharma said, particularly for antibodies, which in lab studies have shown “anti-tumor responses.” But a more complete picture of the TIGIT pathway, including the biological pathways that regulate TIGIT, are required to set the field up for success. Here, BioSpace looks at four companies that claim differentiated approaches. Will they succeed where their peers have failed? AstraZeneca’s Sprawling Development Program for Rilvegostomig AstraZeneca’s TIGIT rilvegostomig is enrolled in an extensive late-stage development program, with 10 Phase III studies underway in NSCLC, gastric cancer, biliary tract cancer and other solid tumors, Shubh Goel, the company’s global franchise head of oncology, told BioSpace in an email. AstraZeneca is also leveraging its partnership with Daiichi Sankyo to test combinations of the TIGIT with the antibody-drug conjugate Datroway for specific subtypes of NSCLC. The goal of such a broad development push, Goel explained, is to establish rilvegostomig as a “best-in-class [immuno-oncology therapy] and the preferred IO backbone for combination therapies.” Aside from these late-stage programs, AstraZeneca is also running multiple early studies of rilvegostomig “across different tumor settings and in combination with a range of standard of care and novel agents,” Goel said. AstraZeneca’s steep investment into rilvegostomig is underpinned by what Goel called a “differentiated” mechanism of action. The molecule’s bispecific structure “optimizes dual PD1/TIGIT check point control.” Rilvegostomig first anchors itself to TIGIT before targeting PD-1, in turn “leading to enhanced immune activation and improving anti-tumor responses,” Goel explained, as compared with dosing patients with separate PD-1 and TIGIT agents. Simultaneously, rilvegostomig minimizes the unwanted depletion of effector immune cells that also express TIGIT, which results in a cleaner safety profile. Aside from a differentiated molecule, AstraZeneca is also being deliberate with its trials, focusing on patients most likely to respond to PD-1/TIGIT co-inhibition, Goel said. So far, AstraZeneca’s strategy seems to be working, at least in NSCLC. At the American Society of Clinical Oncology meeting in May, the pharma presented Phase Ib data showing that rilvegostomig plus Datroway could elicit a 57.5% confirmed overall response rate (ORR) and a 95% disease control rate as a first-line treatment for patients with advanced or metastatic NSCLC. Gilead, Arcus Forge New TIGIT Path With ‘Silent’ Killer Joining AstraZeneca in the late-stage TIGIT field are Gilead and Arcus Biosciences, which are co-developing the monoclonal antibody domvanalimab for solid tumors. Unlike rilvegostomig, domvanalimab only targets TIGIT. To address a second immune checkpoint, the partners are co-administering it with Arcus’ zimberelimab, an investigational PD-1 inhibitor, plus chemotherapy. The companies are proposing this regimen as a first-line therapy for NSCLC and upper gastrointestinal cancer—both programs are in late-stage development —and for head and neck carcinoma, currently in mid-stage studies. What sets domvanalimab apart from the rest of the TIGIT field, according to Ashish Jhingan, program strategy leader of oncology at Gilead, is its Fc-silent properties. That is, the antibody tail—the part that isn’t involved in binding to its targets—has been rendered inert. Such an approach, which goes against the current trend in the TIGIT space, minimizes the likelihood of inadvertently killing cells other than the malignant target, according to Arcus’ website . “By binding to TIGIT with Fc-silent properties, domvanalimab is believed to work by freeing up immune-activating pathways and activate immune cells to attack and kill cancer cells without depleting the peripheral regulatory T cells important in avoiding immune-related toxicity,” Jhingan told BioSpace in an email. This silent approach has so far worked well for the partners. In November 2023, they released data from the Phase II EDGE-Gastric trial, demonstrating a 59% ORR in patients after treatment with the domvanalimab-based regimen. This effect was stronger in those with high PD-L1 expression level, hitting 80% ORR. Six-month progression-free survival (PFS) at the time was 77%. Follow-up results in June 2024 showed that the domvanalimab combo could maintain its efficacy through a median of 49.4 weeks on treatment. ORR dipped only slightly to 58.5% while 12-month progression-free survival (PFS) reached 57.6% in the overall study population. Gilead and Arcus have moved domvanalimab into late-stage development. The partners are running the STAR-221 study, which will test the same regimen of domvanalimab plus zimberelimab and chemotherapy in locally advanced unresectable or metastatic HER2-negative gastric, gastroesophageal junction or esophageal adenocarcinoma. Enrollment began in June 2024 , with initial findings expected in 2026, according to Jhingan. Agenus Pushes Ahead After Losing Powerhouse Partner In May 2021, when the TIGIT space was still young, Bristol Myers Squibb sought to get ahead of its cancer competitors with a $200 million spot payment to Agenus , licensing the biotech’s anti-TIGIT therapy AGEN1777. The deal included up to $1.36 billion in development, regulatory and commercial milestone payments. But ultimately, BMS found the partnership to be more burdensome than beneficial. In August 2024, the company walked away from the pact and returned AGEN1777 to Agenus, a move that was attributed to the “broader strategic realignment of [BMS’] development pipeline,” according to an Aug. 2, 2024 SEC document from Agenus. The contract termination formally took effect on Jan. 26. According to the regulatory filing, under the partnership, Agenus and BMS were able to generate “significant safety data” in early studies, with “indications of clinical activity.” With these in hand, Agenus in August said it intends “to explore further development and/or relicensing” of AGEN1777, but has yet to provide concrete plans for the molecule. Among these development prospects is the possibility of combining the asset with Agenus’ other immuno-oncology therapies. It might take some time, however, before Agenus provides next steps for its TIGIT program, since the biotech is currently in the midst of a strategic realignment initiative aimed at lowering its cash burn to $100 million during the 2025 fiscal year. Mereo Seeks Strategic Sponsors for Etigilimab Rounding out this list is Mereo BioPharma and its troubled program etigilimab , an IgG1 monoclonal antibody designed to target TIGIT, in turn, potentially “improving the activation and effectiveness of T-cell and NK [natural killer] cell anti-tumor activity,” as per its website. Unlike Gilead and Arcus, Mereo has decided against silencing the Fc domain of etigilimab, instead deliberately giving the TIGIT therapy the added functionality of reducing regulatory T cells while also maintaining the levels of CD8-positive cytotoxic T cells. In turn, etigilimab retains the immune system’s cancer-killing action while also delivering a clean safety profile, the biotech claims . Early testing of the mechanism suggests promise in the clinic so far. Phase Ib/II data published in October 2023 demonstrated an ORR of 25% in 40 treated patients, including three who achieved a complete response and seven who saw a partial response. Eleven patients had stable disease beyond 120 days, while seven maintained clinical benefit for more than a year. Despite a promising mechanism and clinical profile, however, Mereo has struggled to rally the support it needs to take etigilimab forward. In June 2019—just months before it would be swallowed by BMS in a $74 billion acquisition—Celgene decided not to exercise an option to license etigilimab. This was despite Mereo advancing the antibody as part of a two-therapy combo with BMS’ PD-1 blocker nivolumab. Since then, and even through a mid-stage readout in 2023, the industry has continued to overlook etigilimab. In a 2024 year-end report, Mereo revealed that it has put TIGIT on the backburner . “We intend to out-license or sell etigilimab . . . to third parties for the further development, recognizing the need for greater resources to take [this asset] to market,” the company wrote.