Pipeline

Cutaneous T-cell lymphoma (CTCL) is a rare, progressive form of non-Hodgkin’s Lymphoma (NHL) characterized by localization of neoplastic T lymphocytes to the skin. Accounting for 4% of non-Hodgkin’s lymphomas, CTCL is generally considered incurable with currently available therapies, which exhibit suboptimal disease control. Consequently patients often cycle through multiple therapies.

BNZ-1 is a selective inhibitor of three members of the IL-2 family: IL-2, IL-9, and IL-15. The profile of BNZ-1 is promising as a long-term therapy capable of transforming the standard of care in CTCL as data implicates the dysregulation of IL-2/IL-9/IL-15 as responsible for disease pathology. Bioniz conducted a Phase 1/2 study in CTCL, in which BNZ-1 exhibited a substantial improvement in safety and efficacy relative to standard of care. On the strength of these results, we plan to initiate a Phase 3 trial in the second half of 2021.

For our latest CTCL trial information, please refer to our entries on clinicaltrials.gov. More about our data is available at this link.

Alopecia areata is an immune mediated hair loss that afflicts more than 500,000 people annually, making it amongst the most common autoimmune disorders in the U.S. with 40% of patients under age 18. There is no FDA approved therapy for alopecia areata, and treatment is limited to the use of topical or intralesional injections of steroids. Current understanding of the etiology of alopecia areata suggests a substantial role for IL-2, IL-9, and IL-15 in the immune dysregulation that increases T-cell proliferation following the initial loss of immune privilege in and around hair follicles, and that results in attacks on the follicular system by cytotoxic CD8 cells.

Since the discovery of IL-2, IL-15, and IFN-Γ as key drivers of alopecia pathology, JAK inhibitors have been used in lieu of molecules with more targeted mechanisms. Their modest efficacy has proven the relevance of the JAK pathway to the manifestation of the disease, but as in other use-cases, their broad inhibition retains off target effects. Nonetheless, the JAK pathway is important in the context of BNZ-1 since it is one out of three downstream pathways to IL-2, IL-9, and IL-15 signaling. Modulation of IL-2 and IL-15 will also indirectly regulate IFN-Γ as well. Therefore, complete inhibition of these cytokines by BNZ-1 should elicit a more potent blockade of cytokine signaling. This hypothesis was confirmed by our preclinical studies since treatment with BNZ-1 resulted in a substantial decrease in cytotoxic CD8 T-cell activation, reduced numbers of activated cytotoxic CD8 cells around the hair follicles, and durably reversed hair loss. We believe the unique ability of BNZ-1 to selectively and completely inhibit each of the cytokines implicated in disease pathology is necessary for the successful treatment of alopecia areata, and our data generated to date provide strong rationale to commence a Phase 2 trial.

Celiac disease is an immune mediated disease that targets the gastrointestinal (GI) tract following an initial immune reaction to gluten, a protein found in many dairy and grain foods. It is estimated that the prevalence of celiac disease in the US is approximately 3 million with approximately 30% remaining symptomatic following the adoption of a 100% gluten-free diet (GFD). There are currently no FDA approved treatments for those whose disease is refractory despite maintaining a GFD. Refractory celiac disease is associated with further immune mediated disease. Previous attempts to treat celiac disease via inhibition of only IL-15 resulted in a non-statistically significant improvement relative to placebo, but outcomes did show clinical improvement in some parameters. A growing body of evidence also implicates IL-21 in celiac disease, providing a strong rationale to pursue trials with our ability to target both cytokines in disease pathogenesis.

BNZ-2 is also an inhibitor of members of the IL-2 family. It is a Phase 1 ready selective inhibitor of IL-15 and IL-21. In preclinical toxicology studies, BNZ-2 treatment resulted in a dose-dependent decrease of both B-cells and CD8-effector cells, indicating the inhibition of both IL-15 and IL-21. Furthermore, BNZ-2 was shown to completely protect the integrity of the gut in an animal model of celiac disease and to prevent a key disease burden, infiltration of lymphocytes to the gut epithelial layer.

BNZ-3 is an inhibitor of IL-15 and IL-21 that is designed for an oral route of administration. BNZ-3 retains the same binding motifs to inhibit IL-15 and IL-21 as BNZ-2, while remaining stable in stomach and intestinal fluid. An oral formulation that retains efficacy could substantially increase the addressable market for IL-15/IL-21 inhibitors, particularly in immune mediated diseases of the GI tract. BNZ-3 is also the template for our future efforts to create additional multi-cytokine inhibitors that can be delivered orally.

We intend to build on our leadership in developing selective multi-cytokine inhibitors for the IL-2 family and to expand to other families of cytokines. Ultimately, we believe we can create customizable multi-cytokine therapies to target different combinations of cytokines implicated in any immune mediated disease so that we can treat an increasingly complex set of currently untreatable, complex immune disorders and conditions.