Several major pharmaceutical companies have struggled to develop effective therapies against four challenging disease targets, according to a May 26 article. These targets—TIGIT, RIPK1, myc, and alpha-synuclein—have attracted significant investment and research but have yet to yield successful treatments.
Gilead Sciences and Arcus Biosciences reported promising early results with their anti-TIGIT monoclonal antibody domvanalimab in stomach cancer. However, after underwhelming Phase 3 data in gastric and esophageal cancers last December, the companies discontinued its development for those indications. Other attempts at targeting TIGIT by GSK, Merck, and Roche also ended unsuccessfully due to disappointing efficacy or safety concerns.
Another target that has challenged drugmakers is RIPK1. Eli Lilly ended its partnership with Rigel Pharmaceuticals after failing to make progress on this inflammatory pathway. Stuti Mahajan of DelveInsight said clinical translation for RIPK1 inhibitors has been more difficult than expected: “Clinical translation has been more difficult than initially expected,” she said, with RIPK1-targeting molecules showing “modest or inconsistent” therapeutic benefits. Several other companies—including GSK, Sanofi/Denali Therapeutics, and Roche—also halted their programs after disappointing trial results.
The oncogene myc remains undruggable despite being highly expressed in many cancers. Peter Smith of Racura Oncology explained that the structure of myc makes it hard for drugs to bind effectively: “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.” Past efforts by Aptose Biosciences and Dicerna Pharmaceuticals were abandoned following poor outcomes.
STING (stimulator of interferon genes) agonists also failed to meet expectations in immunology and oncology trials due largely to toxicity management issues and challenges delivering drugs effectively. Despite initial promise—including large investments from GSK into Mersana Therapeutics—the field saw setbacks such as clinical holds related to patient deaths. Arunima Dabral of DelveInsight cited toxicity management as a key hurdle but noted ongoing efforts using new technologies.
Alpha-synuclein is another target where industry investment has not translated into approved therapies for neurodegenerative diseases like Parkinson’s disease. Biogen discontinued cinpanemab after lackluster mid-stage results; Roche/Prothena’s prasinezumab also failed primary endpoints but continues into Phase 3 based on some biomarker signals. Mahajan said most approaches fail because they do not adequately address intracellular aggregates responsible for disease progression.
