By harnessing covalent chemistry to tackle immune targets previously considered out of reach, Matchpoint Therapeutics is building a new class of oral small molecule drugs, and Novartis is betting up to $1 billion that the approach could reshape treatment for inflammatory diseases.
The US biotech will receive $60 million upfront in a newly announced R&D collaboration, with the potential for more than $900 million in milestones and option fees if Novartis licenses and commercializes any resulting programs. Matchpoint will retain control of early research, while Novartis gains exclusive global rights should the partnership yield a viable candidate.
The deal gives Novartis access to Matchpoint’s Advanced Covalent Exploration™ (ACE™) platform, which applies chemoproteomics, fragment-based screening, and machine learning to map previously undruggable sites across the immune proteome.
“This collaboration highlights the potential of our targeted approach to covalent chemistry to unlock novel mechanisms and achieve superior pharmacology,” said Andre Turenne, CEO of Matchpoint, in the press release.
Covalent tools for undruggable targets
Covalent drugs are designed to form a permanent chemical bond with their protein targets, usually through a reactive amino acid such as cysteine. This irreversible binding locks the protein in an inactive or altered state, often leading to prolonged inhibition compared to traditional non-covalent drugs that bind reversibly. This mode of action offers several advantages, including improved potency, enhanced selectivity, prolonged duration of action, and beneficial pharmacokinetic profiles.
Covalent inhibitors are not new; in fact, both aspirin and penicillin are covalent drugs. However, the rational design of covalent binders is a relatively recent phenomenon, driven by breakthroughs in structural biology, proteomics, and electrophile screening. These recent advances have brought covalent drug discovery into the spotlight, with several medicines gaining regulatory approval in the last decade. For instance:
- Ibrutinib, commercialized by Johnson & Johnson Innovative Medicine and Pharmacyclics, has been approved for multiple blood cancers. It irreversibly binds BTK (Bruton's tyrosine kinase), shutting down receptor signaling in malignant B cells, triggering apoptosis and cutting off tumor-supporting blood supply.
- Osimertinib, manufactured by Astrazeneca, targets mutant forms of EGFR (epidermal growth factor receptor) in non-small cell lung cancer (NSCLC). By forming a covalent bond, it stops oncogenic signaling and causes tumor regression.
- Sotorasib, developed by Amgen, was the first approved covalent inhibitor to target the KRAS (Kirsten rat sarcoma) G12C mutation, a historically “undruggable” oncogene, in NSCLC.
These successes have propelled renewed interest and investment in covalent modalities across therapeutic areas, including inflammation and autoimmune diseases, where many key proteins have proved challenging for traditional drug approaches.
Inside the platform
Matchpoint’s ACE™ platform focuses on identifying reactive amino acids, such as cysteines, that are unique to a disease-causing protein or variant. By locking these proteins in an inactive state, covalent inhibitors can suppress the production of pro-inflammatory cytokines and chemokines.
This approach allows Matchpoint to hit targets that traditional drugs often miss, especially those with shallow or cryptic binding sites. Using proprietary chemoproteomics, machine learning, and predictive models of protein behavior, the company is prioritizing high-value targets and guiding the design of a tailored covalent screening library.
Its growing compound library spans from fragments, which are ideal for probing hard-to-drug sites, to more advanced, drug-like compounds ready for preclinical development. This helps to accelerate discovery while improving selectivity, durability, and therapeutic index.
“Our platform maximizes the potential for detecting novel covalent labels of active, allosteric, and cryptic sites on targets that have historically proved elusive,” said Nathanael Gray, Matchpoint co-founder and Stanford professor, in a press release. “The range of applications of this platform is very exciting given that it is as well suited for the discovery of covalent inhibitors as it is for covalent degraders and covalent molecular glues.”
Why Novartis — and why now
Novartis has long been a leader in immunology R&D, with approved therapies like Cosentyx® (secukinumab) treating a broad spectrum of inflammatory diseases. But not all its bets have paid off. The company recently discontinued development of ianalumab, a B-cell depleting antibody for hidradenitis suppurativa, after it failed to meet efficacy thresholds in a Phase 2 trial.
The Matchpoint deal signals a pivot toward mechanism-first, chemistry-led programs, a recognition that many inflammatory diseases remain poorly served by current immunomodulators.
By investing early, Novartis gains access to a proprietary discovery engine capable of tackling targets long thought undruggable, and doing so with oral small molecules that may offer convenience, durability, and a broader therapeutic window. Chronic inflammation has long resisted effective treatment, but with this collaboration, Novartis clearly believes the future of precision immunology may be irreversible.
