The tragic tale of TIGIT is well known. However, RIPK1, myc, STING and alpha-synuclein have also left a trail of failed clinical trials, canceled partnerships and sunk investments in their wake.
For a while, Gilead Sciences and Arcus Biosciences seemed like they could defy the TIGIT odds.
In November 2023, their monoclonal antibody domvanalimab achieved a 59% overall response rate when used alongside anti-PD-1 treatment and chemotherapy in a Phase 2 stomach cancer trial. Domvanalimab maintained this efficacy beyond two years, the partners reported in 2024, while also demonstrating progression-free survival.
Encouraged by these findings, Gilead and Arcus pushed the asset into Phase 3. But in December last year, the duo announced they were dropping development of domvanalimab in gastric and esophageal malignancies after an underwhelming performance—adding another chapter to the long and troubled tale of anti-TIGIT therapies.
TIGIT, short for T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domain, is a receptor that, when activated, exerts immunosuppressive effects. TIGIT is overexpressed in many malignancies, with cancer cells exploiting its natural function to weaken the body’s anti-cancer response.
Many companies have sought to treat cancer by disrupting the TIGIT pathway, but to date, none have succeeded. GSK, for instance, teamed up with Belgian biotech iTeos Therapeutics in 2021 to advance its TIGIT therapy belrestotug. Disappointing mid-stage lung cancer data for the drug eventually forced GSK to pull the plug on the program and the partnership in May 2025. Not long after, iTeos shuttered its operations.
Merck and Roche have also been thrown by TIGIT. The former was stymied by safety concerns while the latter failed to see a survival advantage in lung cancer.
This dilemma stretches across biopharma: Promising disease targets attract a rush of investments from major drugmakers—only to leave behind a trail of disappointing readouts, discontinued studies and doomed partnerships.
BioSpace takes a look at four of those targets, digging into the science behind their therapeutic potential and taking stock of the sponsors that have failed to bear these mechanisms out in the clinic.
Big Pharma runs into RIPK1 rough patch
Last month, Eli Lilly abandoned Rigel Pharmaceuticals after struggling failing to crack another difficult drug target: RIPK1.
RIPK1—short for receptor-interacting serine/threonine-protein kinase 1—is “a central signaling node,” Stuti Mahajan, consulting manager at DelveInsight, told BioSpace in an email.
“The target gained major attention after preclinical studies showed that RIPK1 inhibition could suppress inflammatory cell death and reduce tissue damage across conditions such as ALS [amyotrophic lateral sclerosis], multiple sclerosis, rheumatoid arthritis, psoriasis, and inflammatory bowel disease,” she said.
GSK led the industry’s charge, winning the FDA’s first go-ahead in 2014 to conduct clinical trials on a RIPK1 candidate. Sanofi and Denali Therapeutics followed soon after with 2018 agreement to go after the target in neurological and inflammatory diseases. By 2021, Eli Lilly was playing catch-up to its Big Pharma peers, fronting $125 million and promising up to $835 million in milestones to collaborate with Rigel.
But the modality’s initial promise soon gave out under the weight of clinical reality, Mahajan told BioSpace. “Clinical translation has been more difficult than initially expected,” she said, with RIPK1-targeting molecules showing “modest or inconsistent” therapeutic benefits.
GSK’s candidate, dubbed GSK2982772, failed to significantly improve disease severity in a Phase 2 ulcerative colitis study, according to an August 2021 paper in BMJ Open Gastroenterology. The asset is no longer listed on the pharma’s pipeline page.
Sanofi and Denali were also foiled by RIPK1 and were forced in October 2024 to abandon a mid-stage multiple sclerosis study after a disappointing performance from their candidate oditrasertib. Sanofi earlier that year also pulled the plug on a Phase 2 trial of oditrasertib in ALS, similarly due to underwhelming efficacy.
Roche added to RIPK1’s losing streak in March of this year, electing to end a Phase 2 study for its asset flizasertib for acute kidney injury in patients undergoing cardiac surgery. The drug was “unable to demonstrate a statistically significant clinical benefit,” according to a federal trials database.
Myc, crucial cancer driver, remains undruggable
Like TIGIT, myc has long been an attractive but elusive cancer target. Myc refers to a broad family of transcription factors that regulate several key cellular processes, such as growth, division and metabolism. Under healthy conditions, the myc gene is tightly regulated. But in most—if not all—malignancies, it is highly expressed, leading to deregulated pathways that drive cancer.
In fact, myc “holds the distinction of being the first oncogene to be found amplified in tumor cells,” according to a 2024 review article published in the journal Signal Transduction and Targeted Therapy.
“MYC is over expressed in 70% of malignancies where it drives cell division at an accelerated pace; promotes a hostile tumor microenvironment; and is responsible for resistance against multiple drug classes,” Peter Smith, executive chairman of Racura Oncology, told BioSpace in an email.
Despite its prevalence, however, myc remains a largely undruggable target in cancer, owing largely to its structure—"or lack thereof,” Smith said, pointing to the oncogene’s “basic helix-loop-helix transcription factor.” This overall simple structure makes it nearly impossible for drugs to stick to it, he explained.
“Using the classic lock and key analogy for a drug interacting with its target, MYC simply has no lock, no well-defined tertiary structure for a drug to bind with high affinity,” Smith added.
Currently, there are no small molecule myc inhibitors in development, according to Smith, but that’s not for want of trying. Many drugmakers over the years have tried and failed to advance a myc-directed drug.
Aptose Biosciences, for instance, was banking on an asset called APTO-253, which it had been testing in an early study of relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome. APTO-253 was designed to suppress the expression of myc but was discontinued in 2021 after “an internal review of the product profile and performance” and prioritization of other more advanced assets.
Dicerna Pharmaceuticals also took a crack at myc with its RNA interference therapy DCR-MYC, which was supposed to drive down expression of the problematic gene. The company shelved the asset in 2016 when preliminary results failed to meet the company’s expectations for further development.
Faced with a string of failures, “it appears that the majority of major pharmaceutical companies, after decades of research, have simply given up trying,” Smith concluded.
STING stymies immunology, oncology advancements
Another target that has tripped up the industry is STING (stimulator of interferon genes), a protein involved in various immune cascades.
“Activation of the STING pathway induces type I interferon production, dendritic cell activation, and downstream T-cell priming,” Arunima Dabral, assistant project manager, Clinical & Pipeline Analysis at DelveInsight, told BioSpace in an email. Preclinical data supported this mechanism, she said, not only showing potential for immune-mediated diseases but also for cancer.
This promise attracted “substantial industry investment,” Dabral said, including from GSK, which in 2022 put $1.4 billion on the line to partner with Mersana Therapeutics. At the heart of this deal was the biotech’s lead asset XMT-2056, an antibody-drug conjugate (ADC) that activates the STING pathway.
The partners were supposed to develop the molecule for HER2-positive cancers. GSK and Mersana had a hard time with XMT-2056, however, running into a clinical hold in March 2023 linked to a death in a Phase 1 study that was deemed related to the asset. That pause was lifted in November that year, but that wasn’t enough to make GSK stick around. The pharma ultimately axed XMT-2056 in the first quarter of this year.
Merck has also been stymied by STING. The pharma was working on an oral STING agonist ulevostinag, also called MK-1454, which it was studying as a monotherapy or as part of a combo regimen with Keytruda, for solid tumors or lymphomas. Phase 1 data in 2018 showed no partial or complete responses in patients given the STING agonist alone. Merck has since discontinued the asset.
Several challenges prevent STING-targeted drugs from succeeding in the clinic, Dabral explained. “Managing the toxicity associated with systemic immune activation, ensuring effective delivery to tumor sites, and overcoming tumor heterogeneity and resistance mechanisms are critical hurdles,” she said.
Nevertheless, “the STING field remains active,” Dabral continued, with newer players incorporating novel technologies such as nanoparticle delivery and more selective pathway targeting. Daiichi Sankyo, for instance, is leveraging its ADC platform to advance the STING-targeting DS3610, which in November last year entered Phase 1 testing. The asset seeks to achieve more “precise tumor targeting,” Ken Takeshita, global head of R&D, said in a statement at the time.
Alpha-synuclein aggravates in neuro
Outside of cancer and immunology, there’s alpha-synuclein, which, owing to its central role in the pathology, is “one of the leading targets” in Parkinson’s disease, DelveInsight’s Mahajan said.
Alpha-synuclein (α-syn) is a protein found in neurons that, under healthy conditions, plays a critical role in regulating the secretion of neurotransmitters. In certain neurodegenerative diseases, however, α-syn is wrongly folded, forming toxic clumps that ultimately trigger the destruction of neurons.
“Aggregated alpha-synuclein is a defining pathological hallmark of Parkinson’s disease” and related conditions, such as dementia with Lewy bodies and multiple system atrophy, Mahajan explained.
Because of its central role in neurodegenerative diseases, many of the industry’s biggest players have invested heavily α-syn-targeting approaches, but results have been mixed. Biogen, for instance, shelled out $32.5 million—and promised $395 million in contingent payments—in December 2010 to acquire a Neurimmune subsidiary, gaining an α-syn-targeting antibody that would later be named cinpanemab.
But more than a decade later, in February 2021, Biogen scrapped cinpanemab following a disappointing mid-stage performance. The asset, the company said at the time, failed to show significant benefit in patients with Parkinson’s and “did not achieve proof-of-concept.”
Before being discontinued, Biogen was setting cinpanemab up to compete with Roche and Prothena Biosciences’ prasinezumab, another antibody designed to target α-syn. This latter asset, however, did not fare much better. In December 2024, the partners announced that prasinezumab failed the Phase 2b PADOVA study, showing no significant benefit on motor progression.
Still, Roche and Prothena are pushing the asset forward to Phase 3, buoyed by signals of efficacy in the mid-stage study, such as positive trends in biomarker outcomes.
A major stumbling block for drugmakers, Mahajan explained, is the “difficulty of targeting intracellular pathogenic aggregates using extracellular antibodies”—the modality of choice for both Biogen and Roche/Prothena.
The result, she continued, is that most therapies target α-syn found outside the cells, whereas it’s the intracellular aggregates that drive disease.
The good news is that α-syn development “remains highly active,” Mahajan said, as the industry continues to refine its strategies toward earlier-stage intervention and better targeting mechanisms.
