Maplirpacept

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.

Pictured: Pacman, representing the “don’t eat me” signal broadcasted by CD47/iStock, artisteer Companies researching CD47 inhibitors can’t seem to catch a break. Gilead’s multibillion-dollar bet on the CD47-targeting antibody therapy magrolimab appears in jeopardy, and AbbVie recently ended its collaboration with I-Mab, the maker of another anti-CD47 drug, after terminating two early-phase studies of the candidate last August. What once seemed like a competitive field has thinned out considerably, leading some insiders to speculate that CD47 antibodies may be fatally flawed as a therapeutic class. But there is a glimmer of hope. Earlier this month, Bay Area–based ALX Oncology announced positive interim data from a Phase II trial of evorpacept in HER2-positive gastric cancer, bucking the recent downturns across the field. This positive readout, coupled with ALX’s concurrent announcement that it will move into a Phase III trial in the second half of 2024, underscores that the story of anti-CD47 therapies is still being written, said ALX CEO Jason Lettmann. Jason Lettmann “Like most areas of biotech, there's all sorts of ups and downs, but this one has more than its fair share of incredible highs and moments of a lot of doubt,” Lettmann told BioSpace. Still, a fundamental question remains: Why haven’t efforts by some of biotech’s biggest names translated into effective therapeutics? Experts told BioSpace that the apparent setbacks can be attributed to known safety concerns for anti-CD47 antibodies combined with an under-diversified field with too many drugs going after the same target. Even so, they remain hopeful that a CD47-targeting drug can make it to market. Toxic Contradictions CD47 is a transmembrane protein expressed in many human cells, including red blood cells, platelets and immune cells, as well as in a wide variety of cancer cells. The reason cancer cells express this protein is clear: when it binds to its receptor, CD47 inhibits the innate immune system by broadcasting a “don’t eat me” signal. In the past decade, researchers have engineered antibodies to decrease this signal in cancer cells and, in some cases, provide an unambiguous “eat me” signal to macrophages. But these antibody drug candidates often have off-target effects, said Laurence Blumberg, a biotech executive who was formerly the CEO of Arch Oncology, which shuttered earlier this year despite receiving the FDA’s Orphan Drug Designation for its anti-CD47 antibody. Laurence Blumberg “The problem is that CD47 is broadly expressed in normal cells and particularly broadly expressed in components of blood—platelets, white blood cells, red blood cells—and the big issue has been the safety and toxicity of all the different molecules,” Blumberg told BioSpace. “We haven’t gotten to the point where the efficacy has been compelling enough to justify arguably life-threatening toxicities.” Blumberg said these toxicities vary depending on the type of anti-CD47 drug. Monoclonal antibodies, for example, are often associated with conditions such as anemia and thrombocytopenia. This is because the antibodies bind to CD47 on healthy blood cells as well as cancer cells and induce macrophages to engulf and digest both the healthy and diseased cells. Indeed, safety concerns have plagued Gilead’s magrolimab. In January 2022, the FDA placed a hold on trials of the candidate, which was being tested in multiple studies in combination with azacitidine, due to “an apparent imbalance” in suspected unexpected serious adverse reactions. The hold was lifted several months later, but the FDA issued a second partial clinical hold on magrolimab in acute myeloid leukemia (AML) in August. Additionally, a Phase Ib study found that 28.7% of AML patients treated with magrolimab plus azacitidine developed anemia related to the anti-CD47 drug. Gilead has also paused or discontinued multiple clinical trials of magrolimab in recent months. “The efficacy data has been tantalizing,” Blumberg said, “but not really robust enough in light of the fact that you’re dealing with a drug class that is fraught with toxicity risks, and all the molecules have a nuanced toxicity. I don’t think it’s over for the class, but I do think that there’s headwind.” A Field in Flux Prior to the spate of disappointing results, the funding landscape for anti-CD47 immunotherapies looked rosy, buoyed by two multibillion-dollar acquisitions. In March 2020, Gilead acquired magrolimab’s manufacturer, Forty Seven, for $4.9 billion. Soon after, AbbVie entered into its agreement with I-Mab, and Pfizer purchased Trillium Therapeutics, the maker of two anti-CD47 proteins, for $2.22 billion. The acquisitions that occurred alongside promising preclinical and clinical results resulted in the field being flooded with “a lot of money to chase maybe too many drugs going after the same target,” Blumberg said. “But there was nothing wrong with the pursuit.” Some, like Lettmann, believe that many drugmakers unknowingly kneecapped their anti-CD47 antibody therapies by coupling the inhibition of the “don’t eat me” signal with the promotion of the “eat me” signal. “If you try to accomplish both as part of the same molecule, it will be very difficult to effectively target cancer over healthy [cells],” Lettmann said. Magrolimab’s makers tried to skirt the issue by switching from one subclass of immunoglobulin G to another, he continued. Pfizer has similarly stuck to this subclass. In a statement, a Pfizer spokesperson told BioSpace that its anti-CD47 candidate maplirpacept has demonstrated minimal red blood cell binding and few reported cases of anemia. Maplirpacept acts on both cancer cells and macrophages, the spokesperson said, and has demonstrated “encouraging activity” when used as a monotherapy in studies with more than 75 patients. Currently, the company is conducting Phase I and II trials in ovarian cancer, multiple myeloma and diffuse large B-cell lymphoma. ALX has approached drug development with safety in mind, Lettmann said. Evorpacept decouples anti-CD47 monoclonal antibodies’ two mechanisms of action, blocking the cancer cells’ “don’t eat me” signal without turning macrophages into indiscriminate killers—an approach that, when combined with other cancer therapies, has shown preclinical and clinical promise. This month, ALX reported that 52% of patients with gastric/gastroesophageal junction (GEJ) cancer enrolled in a Phase II trial responded to a combination of evorpacept and trastuzumab, ramucirumab and paclitaxel, compared to 22% of patients who received only the three latter drugs. ALX plans to report a final analysis from the trial next year, along with a half-dozen readouts from trials of evorpacept in combination with chemotherapy, a checkpoint inhibitor and an antibody-drug conjugate. Even so, ALX’s journey has not been without its bumps as the company recently axed CD47 programs where evorpacept attempted to treat myelodysplastic syndrome and acute myeloid leukemia—though Lettmann clarified that the mechanism tested in the two blood cancers differs from evorpacept’s mechanism of action in solid tumors. For Lettmann, winning FDA approval for evorpacept would be the culmination of a nine-year journey for ALX and its leadership. Contingent on positive final results from the Phase II trial and the commencement next year of a Phase III trial for gastric/GEJ cancer, Lettmann said he believes the company has “a very logical path to an approval” in this indication. Maddie Bender is a freelance science journalist based in Honolulu, HI. You can contact her through her website, maddiebender.com.