Zasocitinib (TAK-279), an innovative oral allosteric inhibitor of tyrosine kinase 2 (TYK2), is showing promise in treating psoriasis and psoriatic arthritis, thanks to an AI-assisted design process that enhances its selectivity and safety profile. The drug's development involved a collaboration with Nimbus Therapeutics and Schrödinger, optimizing the compound to precisely fit into the target enzyme's pocket.
AI-Driven Design for Precision Inhibition
According to Graham Heap, MBBS, PhD, vice president and global program lead at Takeda Pharmaceuticals, AI significantly increased the throughput of compound design and screening, leading to a molecule that optimally fits the target enzyme. This AI-assisted approach has resulted in zasocitinib demonstrating 1.7 million times greater binding affinity to TYK2 than to JAK1, as noted by trial investigator Christopher Bunick, MD, PhD.
Phase 2b Trial Results
In a phase 2b trial, various doses of zasocitinib (2, 5, 15, and 30 mg) were evaluated against placebo over 12 weeks. Melinda Gooderham, MD, MSc, FRCPC, reported that the study found no significant changes in laboratory parameters like creatine kinase and liver enzymes, emphasizing the drug's consistent safety profile. This allosteric inhibition mechanism differentiates zasocitinib from other TYK2 inhibitors, reducing the risk of binding to competitive active sites of other JAK family molecules, potentially leading to better safety outcomes, especially concerning blood cell counts.
Potency and Selectivity
Zasocitinib's unique attributes were further elaborated on by Dr. Bunick, who highlighted its unprecedented selectivity for the TYK2 allosteric domain over JAK1. This selectivity is crucial for reducing off-target effects while maximizing therapeutic efficacy. Furthermore, the drug's pharmacokinetic profile maintains plasma concentrations above the IC50 level for TYK2 throughout the day, inhibiting an estimated 91% of TYK2 signaling daily, contrasting with the shorter efficacy duration of currently approved TYK2 inhibitors like deucravacitinib (Sotyktu).
Implications for Clinical Practice
The implications of these findings are significant for clinicians, particularly the lack of required laboratory monitoring with zasocitinib, which could enhance patient adherence and comfort. This ease of use is a compelling advantage for both patients and healthcare providers, aligning with the growing preference for oral therapies. The ongoing phase 3 clinical trials for zasocitinib in psoriasis (NCT06550076, NCT06088043, and NCT06108544) and psoriatic arthritis (NCT05153148) are progressing well, with investigations into other inflammatory conditions like inflammatory bowel disease (NCT06233461) and ulcerative colitis (NCT06254950) also underway, highlighting its broad therapeutic potential.
Future Directions
The continued investigation into zasocitinib’s applications in other inflammatory conditions highlights its broad therapeutic potential. Zasocitinib represents the benefits of next-generation TYK2 or JAK inhibitor design, driven in part by AI, outperforming existing TYK2 inhibitors. This advancement is particularly exciting for dermatology, with potential applications beyond psoriasis to psoriatic arthritis and atopic dermatitis.
