Domvanalimab

Created with Canva Dreamlab † Leading companies spent $1.4 billion upfront on licensing deals and embarked on vast R&D programs. Clinical setbacks mean many companies are unlikely to ever recoup their investments. TIGIT was once the hottest target in immuno-oncology. Just a few years later, the pipeline has thinned significantly as a who’s who of drugmakers have retreated from the mechanism in response to lackluster clinical data. Some R&D programs are ongoing, but the rapid retreat means the industry has already burnt billions of dollars on deals and development for failed candidates. Bristol Myers Squibb , Gilead, GSK and Novartis paid $1.4 billion upfront between them to join Merck and Roche in the TIGIT race. The figure excludes the $175 million Gilead paid to enter into a multi-asset deal that gave it the right to license candidates including Arcus Biosciences’ domvanalimab, but includes the $275 million the big biotech handed over when it took up its option on the anti-TIGIT antibody. The deals collectively included more than $5 billion in milestones. However, the overwhelming majority of them were unpaid when BMS, GSK and Novartis dropped their TIGIT programs. Gilead is still developing its asset and could owe Arcus up to $500 million in milestones tied to approvals in the U.S. Even without the regulatory milestones, Gilead has bet more on TIGIT than some of its peers. The outlay includes $740 million in equity investments in Arcus. Gilead paid an average of $27.58 per share across the three purchases. Arcus currently trades below $10. The fate of domvanalimab will go a long way in determining what return, if any, Gilead gets on its investment in Arcus. TIGIT Development Costs TIGIT development costs are embedded in the vast R&D budgets of the biopharma companies advancing the candidates. Roche’s broad tiragolumab development program accounted for some of the almost $15 billion the Swiss drugmaker spent on R&D last year, but publicly available figures lack details of the company’s spending on TIGIT. Similarly opaque accounts obscure TIGIT spending at other companies. Programs partnered with smaller biotechs shed some light on TIGIT development costs. GSK and iTeos Therapeutics agreed to spend $900 million on the global development plan for their TIGIT drug. The asset’s failure in Phase II means GSK and iTeos likely only spent a fraction of that amount, but the figure provides a ballpark estimate of what companies with large late-phase programs may have invested. Roche has tested tiragolumab in 10 Phase III studies with a collective enrollment target of almost 4,600 patients. Merck’s Phase III vibostolimab program spanned five studies with a collective enrollment target of more than 4,600 patients. Gilead, Arcus and AstraZeneca, which is partnered on a domvanalimab trial, have sponsored three Phase III studies that are enrolling almost 3,000 patients among them. If GSK and iTeos’ spending plan is indicative of R&D costs at other companies, Gilead, Merck and Roche may have spent billions of dollars between them taking their TIGIT assets through mid- and late-phase trials. Gilead’s relationship with Arcus provides another datapoint. Arcus received between $161 million and $165 million from its collaboration partners as reimbursement for R&D costs in 2022, 2023 and 2024. Mechanisms other than TIGIT will account for some of the spending. Equally, the figures do not capture spending on Gilead-led activities, which Arcus said increased in 2024. ITeos’ accounts provide another glimpse at the cost of TIGIT development. As of the end of March, the biotech had raised more than $1.1 billion across public and private financing rounds and its deal with GSK. ITeos, which is closing down over its TIGIT flop, had $624 million in cash and investments. The difference between the amount iTeos had raised and the amount it was holding was more than $500 million. A History of Failed Oncology Bets Spending on TIGIT adds to the mountain of money that drug developers have plowed into an alphabet soup of targets that at one time were seen as the next big thing in cancer immunotherapy. IL-2 attracted interest in 2018 and 2019, when BMS paid Nektar Therapeutics $1.85 billion to co-develop a molecule and Sanofi acquired Synthorx for $2.5 billion. Both programs ended in failure. Other companies placed bets on CD47. Gilead acquired Forty Seven for $4.9 billion in 2020 and Pfizer snapped up Trillium Therapeutics for $2.3 billion the following year. Pfizer continues to list maplirpacept, a CD47 candidate acquired in the Trillium takeover, in its pipeline, but Gilead’s travails have dampened expectations. Gilead gave up on Forty Seven’s magrolimab last year after a series of setbacks. TIM-3, 4-1BB, ICOS, OX40 and CD73 are among the other targets that have attracted heavy investment, including triple-digit upfront licensing fees, over the years. Active clinical development is continuing in some areas but the targets are yet to live up to the early excitement, such as the report that 4-1BB drug candidates were driving “pretty phenomenal responses” in cancer patients. Work on LAG-3 delivered an approved drug, BMS’ Opdualag, but sales have been fairly modest by the standards of leading immuno-oncology products. Opdualag, a fixed-dose combination of PD-1 and LAG-3 blockers, generated sales of $928 million last year. BMS is on course to reach the blockbuster threshold this year, with sales in the first quarter coming in at $252 million. As excitement about TIGIT and the other targets has faded, PD-1/L1xVEGF-A bispecifics have emerged as the industry’s next big hope. With China’s Akeso validating the mechanism, albeit without allaying concerns about overall survival and efficacy in global trials , leading biopharma companies have moved swiftly to secure riders in immuno-oncology’s new hottest race. In the nine months since Akeso’s ivonescimab beat Keytruda, BioNTech, BMS, Merck and Pfizer have paid more than $4 billion upfront among them for rights to PD-1/L1xVEGF-A bispecifics. The outlay will rise by at least $2 billion as BMS makes noncontingent payments and could top $20 billion if the deals hit their milestones. The fallout from failure would make the TIGIT turmoil look like a tempest in a teapot.

“People went for Fc-competent [TIGITs] because it worked best in mice,” said Leerink Partners analyst Daina Graybosch, Ph.D. “They couldn\'t help themselves.\"\n Once hailed as the future of immuno-oncology, it’s been a tough few months for any remaining fans of anti-TIGIT antibodies.In April, BeOne Medicines, formerly known as BeiGene, announced it was scrapping ociperlimab over a disappointing phase 3 outlook two years after Novartis handed back the asset. Specifically, the study’s independent data monitoring committee deemed the trial unlikely to show that a combination of ociperlimab and BeOne’s own PD-1 inhibitor Tevimbra would beat Keytruda in patients with PD-L1-high non-small cell lung cancer (NSCLC).The following month brought more tough times for TIGITs, as GSK halted development of its own candidate belrestotug after deciding the iTeos Therapeutics-partnered drug in combination with anti-PD-1 inhibitor Jemperli wouldn’t score a phase 2 win in a similar NSCLC population.Even executives at Roche, whose tiragolumab appeared to buck the trend with a caveated phase 3 win in esophageal cancer in 2024, reaffirmed to Fierce Biotech earlier this year that “we stopped all of the tiragolumab trials that we could stop, and those that couldn\'t be stopped are just running out.”With Big Pharma having pumped $6 billion into this modality, what went so wrong for TIGITs?Daina Graybosch, Ph.D., a senior research analyst at Leerink Partners who covers immuno-oncology, traces the problems back to the exuberant reaction to Roche’s impressive phase 2 tiragolumab data that read out across 2020 and 2021. The Cityscape trial demonstrated that the TIGIT drug in combination with Roche’s own PD-L1 blocker Tecentriq shrank tumors in 31% of patients with metastatic lung cancer—twice as many patients as Tecentriq alone.“That\'s probably the biggest point where the field went wrong, in that they looked at this massive benefit in the small phase 2, and everybody ran after it in a parallel and broad way,” Graybosch told Fierce in an interview.“We had randomized phase 2 data from Roche, from Arcus-Gilead, from iTeos-GSK, and they all consistently showed benefit in response rate and in [progression-free survival],” she added.“I think the challenge ultimately was: How much benefit is there really? Is it enough benefit to be clinically meaningful? And are we developing the drugs in the right way, in the right format, to optimize and bring that benefit to patients?”The industry’s “overenthusiasm” for the potential of TIGITs led to a “simplistic approach” to how other companies planned to develop their own candidates, according to Graybosch.If pharmas had anticipated a “more realistic demonstration of benefit,” as seen in the failed Skyscraper-01 phase 3 study in NSCLC, “I think everybody would have developed [TIGITs] differently,” she suggested.Companies swimming in the TIGIT space have broadly fallen into two camps. Roche’s tiragolumab, along with Merck & Co.’s vibostolimab, GSK and iTeos’ EOS-448, and BeOne’s ociperlimab, are all Fc-enabled. These antibodies retain a fully functional Fc region, meaning they can bind to Fc receptors found on the cell surface and contribute to the protective antitumor functions of the immune system.The theory behind Fc-enabled anti-TIGIT antibodies is that they have enhanced tumor-killing effects. However, the risk is that they could possibly also eliminate certain regulatory T cells and therefore lead to unwanted immune responses.In fact, side effects did cast a shadow over some of the Fc-enabled TIGIT trials, with Merck halting a phase 3 trial of vibostolimab due to a higher than expected rate of discontinuations blamed on “immune-mediated adverse experiences.”“Toxicity that may lead patients to discontinue I think ended up being a contributing factor across the Fc-enabled TIGITs that are all now dead,” Graybosch said.The last TIGITs still standing—Arcus Biosciences and Gilead’s domvanalimab, as well as AstraZeneca’s TIGIT/PD-1 bispecific antibody rilvegostomig—have mutated out the Fc function. This should mean they are less toxic for patients.“People went for Fc-competent because it worked best in mice,” Graybosch explained. “They couldn\'t help themselves, even though they knew there was some risk of depleting T effector cells that are actually what you need to fight your tumor.” Focusing on \'modest benefit\'So, what would a more measured approach to the TIGIT gold rush have meant in practice?“I think you ultimately do what Astra is doing,” said Graybosch, referring to AstraZeneca’s ongoing phase 3 trials of its bispecific rilvegostomig in a range of phase 3 studies for NSCLC or stomach cancer, including in combination with its Daiichi Sankyo-partnered antibody-drug conjugates Enhertu or Datroway.“Astra is recognizing the modest benefit,” she explained. “Their bispecific is very safe because it\'s Fc silent. And in some ways, Astra can\'t lose because [rilvegostomig] doesn\'t need to work that much for a lot of their trials to be successful.”AstraZeneca’s Puja Sapra, Ph.D., senior vice president for biologics engineering and oncology target discovery, was also upbeat about rilvegostomig’s prospects when she spoke to Fierce back in April. She pointed to the fact that engineering the bispecific to reduce Fc effector functionality should reduce unwanted side effects, while blocking both PD-1 and TIGIT at the same time “should hopefully help us increase the response rate and durability.”“At least in preclinical studies, we see that a bispecific molecule has better responses than a combination of both agents alone,” Sapra said at the time. “The molecule is doing very well in the clinic so far, so we continue to believe in this molecule.”Gilead is also staying loyal to its TIGIT candidate, which is being evaluated in phase 3 trials for first-line NSCLC as well as for locally advanced unresectable or metastatic gastric, gastroesophageal junction and esophageal adenocarcinoma.The pharma’s chief medical officer Dietmar Berger, M.D., Ph.D., told Fierce earlier this month that the Arcus-partnered domvanalimab still has a chance, pointing to its Fc-silent character.“We believe there is differentiation but, of course, we need to see how those studies read out,” Berger said. “Any additional activities around that will be based on what we see in those studies.”With AstraZeneca and Gilead still holding a candle for their Fc-silent candidates, Leerink’s Graybosch doesn’t think “it\'s fair to completely write off TIGIT.”“But if you ask 99% of average investors, generalists or specialists and [key opinion leaders], I think they’ll tell you it\'s dead,” she added.Angus Liu contributed to this reporting.