AI-Powered Innovation: Zasocitinib’s Journey to Precision Inhibition

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“By leveraging artificial intelligence, [researchers] can massively increase the throughput of the number of compounds they start to design and screen. It’s a really efficient tool to increase the throughput and to try to really get a molecule that fits as well as it possibly can into the specific site of the enzyme they’re trying to block,” said Graham Heap, MBBS, PhD, vice president and global program lead at Takeda Pharmaceuticals. In an interview with Dermatology Times, Heap highlighted the revolutionary role of artificial intelligence (AI) in the development of zasocitinib (TAK-279), an innovative oral allosteric inhibitor of tyrosine kinase 2 (TYK2).

A collaboration with Nimbus Therapeutics and Schrödinger allowed researchers to optimize the design process, ensuring that the compound fits precisely into the target enzyme’s pocket. This AI-assisted approach not only enhances efficiency in screening potential candidates but also significantly improves selectivity, as evidenced by zasocitinib’s binding affinity, which trial investigator Christopher Bunick, MD, PhD, says is 1.7 million times greater to TYK2 than to JAK1.

Bunick, associate professor of dermatology and translational biomedicine at the Yale University School of Medicine in New Haven, Connecticut, and Dermatology Times’ 2024 Winter editor in chief, said that zasocitinib’s promising phase 2 clinical trial results for psoriasis (NCT04999839) and psoriatic arthritis (NCT05153148) reflect the potential of this next-generation therapy.¹ As seen in ongoing phase 3 trials (NCT06550076, NCT06088043, and NCT06108544), the implications of AI-driven design in creating highly selective treatments could pave the way for improved patient outcomes in dermatology and beyond.²

Phase 2b Trial and Findings

Melinda Gooderham, MD, MSc, FRCPC, medical director at the SKiN Centre for Dermatology in Peterborough, Ontario, and a key investigator in the phase 2b trial of the drug discussed the study’s results shortly after presenting them at the European Academy of Dermatology and Venereology Congress 2024 in September. The trial evaluated various doses of zasocitinib (2, 5, 15, and 30 mg) compared with placebo over 12 weeks. Importantly, the study monitored laboratory parameters, such as creatine kinase and liver enzymes, and found no significant changes. “We observed flat lines across all of the labs,” Gooderham noted, emphasizing the drug’s consistent safety profile.

Gooderham pointed out that the mechanism of action of zasocitinib differentiates it from other TYK2 inhibitors. “When you have allosteric inhibition, you are not at risk of binding to the competitive active sites of the other JAK family molecules,” she explained. She said this selectivity can lead to better safety outcomes, particularly regarding blood cell counts, which can be affected by other JAK inhibitors.

Potency and Selectivity

Bunick elaborated on the unique attributes of zasocitinib at the European Society for Dermatological Research meeting in September.¹ He stated, “What we found was that the zasocitinib can select or inhibit the TYK2 allosteric domain 1.7 million–fold more selectively than the JAK1.” He says this unprecedented level of selectivity is crucial for reducing off-target effects while maximizing therapeutic efficacy.

Bunick also highlighted the drug’s pharmacokinetic profile, noting that it maintains plasma concentrations above the IC⁵⁰ level for TYK2 throughout the day. “It’s estimated that zasocitinib inhibits 91% of the TYK2 signaling on a daily basis,” he said, contrasting this with the lower efficacy seen with currently approved TYK2 inhibitors such as deucravacitinib (Sotyktu), which maintains efficacy for only 3 hours.

The Role of AI in Designing Zasocitinib

One of the standout features of zasocitinib is its design process, which leveraged AI technology. Heap explained that this innovative approach allowed researchers to explore a vast array of molecular candidates efficiently, homing in on those with the best potential for selective TYK2 inhibition.

“What we found was that zasocitinib binds really strongly to that specific site, which is kind of what we expected based on the AI design features and what the compound had been designed to achieve,” Heap said. This means that rather than relying solely on traditional trial-and-error methods, the design team could predict how well a compound would fit into the target enzyme’s specific pocket. Such precision is crucial for developing a selective inhibitor that minimizes off-target effects.

Furthermore, this innovative design not only facilitates higher selectivity but also contributes to the overall efficacy and safety profile of the drug, Heap said. By ensuring that zasocitinib remains above the inhibitory threshold for TYK2 throughout the dosing period, the AI-assisted design underscores the potential of this next-generation therapy.

All 3 experts agreed that this application of AI in drug development signifies a shift in how treatments can be designed for complex diseases such as psoriasis. With the promise of improved patient outcomes and reduced laboratory monitoring, zasocitinib exemplifies how technology can enhance the therapeutic landscape. “We think selective inhibition is really the key to achieving patient goals here,” Heap said, highlighting the potential benefits that this innovative approach could bring to the dermatology field.

Implications for Clinical Practice

Gooderham says the implications of these findings for clinicians are significant. She emphasized that the lack of required laboratory monitoring with zasocitinib could enhance patient adherence and comfort. “I tell my patients that they won’t need to keep coming in for blood tests,” she remarked. This ease of use is a compelling advantage for both patients and health care providers, aligning with the growing preference for oral therapies.

Heap echoed these sentiments, noting the importance of balancing efficacy and safety in treatment options. “There’s really an ongoing need for potential compounds that are balanced in their benefit-risk profile that also balance convenience and tolerability. That’s really what the goal of the development process for this compound was,” he said.

Future Directions

Looking ahead, the phase 3 clinical trials for zasocitinib in psoriasis and psoriatic arthritis are underway. “We’ve been very pleased with the recruitment in those trials, and they’re moving along at a really nice pace,” Heap said. The continued investigation into zasocitinib’s applications in other inflammatory conditions, such as inflammatory bowel disease (NCT06233461) and ulcerative colitis (NCT06254950), also highlights its broad therapeutic potential.

Bunick underscored the importance of ongoing research, saying, “What zasocitinib represents is the benefit that we can get as a specialty from that next generation of TYK2 or JAK inhibitor design. Here we have a molecule that’s, in part, AI driven in its design, and it’s outperforming by all measures the existing TYK2 inhibitor on the market. I think dermatology should be incredibly excited about what zasocitinib can bring initially for [patients with] psoriasis, and then hopefully beyond to [those with] psoriatic arthritis, atopic dermatitis, and other diseases.”

Conclusion

The investigators agreed that zasocitinib’s design and clinical data present an exciting advancement in the treatment landscape for psoriasis. With its high selectivity, robust safety profile, and the convenience of oral administration, it holds promise as a transformative option for patients. “You just feel that comfort, that this is doing what we think it’s doing, and to have that comfort and confidence moving forward,” Gooderham said. “It could absolutely be 1 pill once a day, no laboratory monitoring for patients with psoriasis. I think that’s what a lot of patients are looking for.”

References

1. Gooderham M, Bunick C, Kircik L, et al. Zasocitinib (TAK-279) displays high TYK2 inhibition and no inhibition of JAK 1/3 versus licensed inhibitors. Presented at: the European Society for Dermatological Research Meeting; September 4-7, 2024; Lisbon, Portugal.

2. Armstrong AW, Gooderham M, Lynde C, et al. Tyrosine kinase 2 inhibition with zasocitinib (TAK-279) in psoriasis: A randomized clinical trial. JAMA Dermatol. Published online August 21, 2024. doi:10.1001/jamadermatol.2024.2701