BBI-02 is currently being evaluated in a first-in-human Phase 1 trial, with topline results from the SAD and MAD parts of the study expected to be announced by early 2023. BBI-02 is covered by strong patent protection in the U.S. and other key countries through at least 2038 (excluding patent term extension).
A first-in-class, oral DYRK1A inhibitor with strong preclinical validation and broad potential to treat autoimmune diseases, including atopic dermatitis, rheumatoid arthritis, type 1 diabetes, and other debilitating conditions.
How is BBI-02 differentiated?
Oral administration of BBI-02 has yielded promising efficacy and significant cytokine reduction in several preclinical models of autoimmune disease providing an encouraging profile to current standard-of-care treatments, such as JAK inhibitors and anti-TNF biologics. Many of the current treatments for autoimmune conditions aim primarily to broadly suppress the immune system, which may result in increased risk for developing serious infections that may even lead to hospitalization or death. Unlike many existing therapies, as well as those currently under development, BBI-02 aims to restore immune homeostasis which represents a paradigm shift in the treatment of autoimmune and inflammatory diseases.
How does BBI-02 work?
BBI-02 has a dual mode of action that modulates adaptive and innate immune responses, which aims to re-balance immune homeostasis in patients whose immune system has become imbalanced due to an underlying autoimmune disease.
Firstly, BBI-02 shifts the T cell balance by increasing differentiation of regulatory T cells (TREG) while also decreasing pro-inflammatory effector T cells (TEFF), such as TH17 and TH1 cells. This has been confirmed by external research using knockdown studies of DYRK1A and inhibitory tool compounds. TREG cells act as critical suppressors of immune system activity by inhibiting TEFF cells. In patients with autoimmune and chronic inflammatory conditions, increasing the number and activity of TREG cells may be a promising therapeutic approach.
Secondly, BBI-02 has successfully demonstrated inhibiting the phosphorylation of IRAK4 and its respective downstream signaling pathway. This is achieved through induction of alternative splicing of MyD88 (Myeloid differentiation factor 88), a central hub in inflammatory responses involved in the downstream signaling of TLRs (toll-like-receptors) and other cytokine receptors of the IL-1 receptor family. BBI-02 treatment shifts the balance so that MyD88 is preferentially spliced into the short form, MyD88s. In the presence of MyD88s, IRAK1/4 is not phosphorylated and does not activate downstream NF-κB, making MyD88s a negative regulator of IL-1R/TLR/MyD88- associated innate immune responses.
By targeting both the innate and adaptive immune response, BBI-02 has the potential to treat a wide array of autoimmune conditions.
1. Khor, B. et al. The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells. Elife 4, 1–27 (2015).
2. Talk by Dr. Bernard Khor, Benaroya Research Institute
3. De Arras, L. & Alper, S. Limiting of the Innate Immune Response by SF3A-Dependent Control of MyD88 Alternative mRNA Splicing. PLOS Genet. 9, e1003855 (2013).
4. Burns, K. et al. Inhibition of Interleukin 1 Receptor/Toll-like Receptor Signaling through the Alternatively Spliced, Short Form of MyD88 Is Due to Its Failure to Recruit IRAK-4. J. Exp. Med. 197, 263 (2003).
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