BOSTON–Nimbus Therapeutics has begun dosing participants in a Phase 1 clinical trial of NDI-225673, an investigational oral drug designed to treat immune-mediated inflammatory diseases by targeting pathways involved in inflammation and tissue repair.
The Boston biotechnology company said the first healthy volunteers have received the experimental treatment, marking the first human testing of its highly selective salt-inducible kinase 2 (SIK2) inhibitor.
The Phase 1 study will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of NDI-225673 following single and multiple ascending oral doses. The trial represents an early step in determining whether selectively inhibiting SIK2 could offer a new treatment approach for inflammatory conditions, including ulcerative colitis and rheumatoid arthritis.
SIK2 belongs to a family of three closely related enzymes, SIK1, SIK2 and SIK3, that regulate biological processes involved in inflammation and immune responses.
According to Nimbus, SIK2 plays a role in controlling inflammatory activity and its resolution, particularly in immune cells known as macrophages.
In preclinical studies, selective inhibition of SIK2 reduced several inflammatory signaling proteins, including TNFα, IL-6, IL-23 and IL-1β. These proteins are already established targets for approved biologic treatments used in inflammatory diseases.
The company also reported that SIK2 inhibition increased levels of IL-10, an anti-inflammatory cytokine, along with tissue-repair mediators such as amphiregulin and thrombospondin-1.
These findings suggest that targeting SIK2 could potentially reduce inflammation while supporting the body’s natural processes for resolving inflammatory responses and repairing damaged tissue.
“Many patients with immune-mediated inflammatory diseases, such as ulcerative colitis and rheumatoid arthritis, do not reach durable remission on current therapies,” said Peter Tummino, Ph.D., President of Research and Development at Nimbus.
“Our goal with selective SIK2 inhibition is to go beyond suppressing individual inflammatory cytokines by engaging biological pathways that regulate inflammation and tissue repair. NDI-225673 represents years of research to achieve a high degree of SIK isoform selectivity, and this Phase 1 study gives us the opportunity to begin testing the SIK2 hypothesis directly in humans.”
NDI-225673 was developed using Nimbus’ proprietary high-resolution crystal structures and computational drug discovery technologies to selectively target SIK2 while minimizing activity against the related enzymes SIK1 and SIK3.
The company said this selectivity could be important for safety because inhibition of SIK1 has been associated with cardiovascular risks, while loss of SIK3 function has been linked to skeletal abnormalities and fertility-related effects.
Preclinical testing demonstrated that NDI-225673 had potent cellular activity at nanomolar concentrations and maintained a high degree of selectivity for SIK2.
In laboratory studies involving human macrophages, the compound reduced multiple pro-inflammatory cytokines while increasing IL-10 and proteins associated with tissue repair.
Animal studies also produced encouraging findings. In mouse models of colitis, SIK2 inhibition reduced disease activity and improved markers associated with intestinal barrier integrity, including mucin and occludin. In a separate mouse model of arthritis, the treatment reduced joint inflammation.
Nimbus believes the compound could eventually have applications across several therapeutic areas, including gastroenterology, rheumatology and dermatology.
However, NDI-225673 remains in early clinical development, and its safety and effectiveness in patients with inflammatory diseases have not yet been established. The Phase 1 trial is designed to generate initial human safety and pharmacological data rather than demonstrate clinical efficacy.
