The Ballad of TIGIT
3 hours ago
- #clinical trials
- #immunotherapy
- #drug development
- Amyloid-beta drugs for Alzheimer's are widely seen as disappointments, though their story is nuanced, with potential limited early-stage benefits.
- TIGIT drugs emerged from cancer immunotherapy research, inspired by Keytruda's success, as a promising new immune-system brake target.
- TIGIT inhibitors were theorized to block immune checkpoints more effectively than Keytruda, leading to massive investments and parallel trials by companies like Roche and Merck.
- Initial phase 2 results for Roche's tiragolumab showed promise, but subsequent phase 3 trials failed, including a flagship lung cancer trial missing progression-free and overall survival.
- Merck's vibostolimab program also failed due to safety issues and lack of efficacy, leading to discontinuation.
- An Fc-silent antibody hypothesis (to avoid killing cancer-fighting T-cells) was tested with domvanalimab but also failed in phase 3.
- Other companies like BeiGene, GSK, and Novartis faced similar failures, with billions spent and thousands of patients enrolled in trials.
- AstraZeneca's rilvegostomig remains as a last hope, but prospects are dim given prior failures.
- The broader failure is attributed to biological complexity: TIGIT's role in immune signaling may be too context-dependent for a one-size-fits-all therapy.
- Despite solid scientific rationale and early signals, TIGIT drugs exemplify how even well-founded drug candidates can fail unexpectedly in clinical development.