On December 5, 2020 Bioniz Therapeutics, Inc., ("Bioniz") reported positive clinical data in an oral presentation at the 62nd ASH (Free ASH Whitepaper) Annual Meeting And Exposition (ASH 2020) from the company’s Phase 1/2 clinical study of BNZ-1 for the treatment of patients with relapsed or refractory cutaneous T-cell lymphoma (rCTCL), a rare, aggressive cancer (Press release, Bioniz Therapeutics, DEC 5, 2020, prnewswire.com/news-releases/bioniz-announces-positive-clinical-data-of-bnz-1-first-anti-cytokine-therapy-to-demonstrate-efficacy-in-treating-refractory-cutaneous-t-cell-lymphoma-301186824.html [SID1234572268]). BNZ-1, a novel immuno-modulator drug candidate, is a multi-cytokine inhibitor of three interleukins (IL-2, IL-9, and IL-15) and is the lead asset from the company’s platform of first-in-class peptide therapeutics that selectively and simultaneously inhibits multiple cytokines to treat cancer and autoimmune diseases.

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"These data validate our platform technology with the first efficacy demonstration of BNZ-1, a novel multi-cytokine inhibitor, and assisted us in the design of a pivotal clinical trial for CTCL, which the company expects to begin in 2021," said Dr. Nazli Azimi, Founder, President, and CEO of Bioniz Therapeutics and co-inventor of BNZ-1. "We believe the efficacy of BNZ-1 in rCTCL, a challenging and progressive disease, is due to the drug’s multi-modal mechanism of action. BNZ-1 was specifically designed as a multi-cytokine inhibitor to integrate inhibition of malignant cells, activation of tumor immunity, and suppression of inflammation. In addition to the positive efficacy data, we are extremely encouraged that the BNZ-1 treatment was well tolerated, which could support long-term treatment for these patients."

The Phase 1/2 clinical study was designed as a multi-center, open-label, dose-escalation study of BNZ-1 to assess its safety and activity as a single systemic agent in rCTCL patients that have failed the standard of care and other available treatment options (up to seven prior skin-directed and systemic therapies). The primary endpoint of the study was overall safety after four weeks of treatment. There was a three-month treatment extension to further evaluate safety and clinical response at week 17. Long-term extension (LTE) was available for patients who benefited from BNZ-1 treatment.

In the dose ranging part of the study, 15 patients (stages IB and IVB) were enrolled across the four dose cohorts (0.5, 1, 2, and 4 mg/kg) for intravenous weekly dosing. BNZ-1 showed activity in all doses as determined by early signs of clinical efficacy and pharmacodynamic biomarkers. The 2 mg/kg dose was selected based on pharmacokinetic/pharmacodynamic (PK/PD) relationship and clinical efficacy, and the cohort was expanded to 19 patients. A total of 30 patients were treated in the study. Clinical efficacy was measured by Modified Severity Weighted Assessment Tool (mSWAT) and Global Response Score (GRS), as defined previously (Olsen E. et al. 2011).

In the expanded cohort of 2 mg/kg (n=19), BNZ-1 demonstrated overall response rate of 63.2% as measured by GRS, which is primarily driven by the mSWAT score. A positive response typically occurred soon after treatment initiation, persisted for the duration of treatment, and in a number of patients, improved over time with this positive trend extending into the follow-up period off-treatment. Twelve patients participated in the LTE, and 11 patients achieved and sustained their response (ORR of 91.7%). BNZ-1 treatment was well tolerated with no dose-limiting toxicities, drug-related serious side effects, or lab abnormalities.

"CTCL is incurable with current standard therapies, which are typically tolerated by patients only for a limited time due to many side effects that are associated with these approved treatments," said Dr. Christiane Querfeld, Director of the Cutaneous Lymphoma Program at the City of Hope, and principal investigator of the study. "On average, these CTCL patients have disease that had progressed and failed up to seven prior skin-directed and systemic therapies, so it’s extremely encouraging to see the impressive safety and robust efficacy with BNZ-1. A therapy that can stabilize this progressive disease and is well tolerated without major side effects will be a major advancement in helping CTCL patients."

Additional data from the efficacy study of 19 patients (2 mg/kg) are as follows:

Two patients reached a partial response as early as four weeks after initiating BNZ-1 treatment; one patient reached a complete response at 13 weeks, and the response persisted until 30 weeks when the study was closed-out.
Seven patients (37%) had stable disease with BNZ-1 treatment; no disease recurrence or relapse was observed during the study period.
Three patients who enrolled early during the dose-ranging part of the study and responded to BNZ-1 treatment participated in the study for 73 weeks (about 17 months); the duration of response for these patients was about 62 weeks (about 15 months).
For patients that were enrolled later as part of the cohort expansion, the duration of the treatment ranged from four to 30 weeks, and the duration of response ranged from four to 26 weeks (median 12 weeks). The shorter duration of treatment was due to study close out per protocol.
The PD analysis revealed a dose-dependent reduction of Treg cells which plateaus at 2 mg/kg dose (expanded cohort); BNZ-1 also lowered the CD8 T-cell activation markers in some patients that responded to BNZ-1 treatment.
Dr. Azimi explained, "The reduction in Treg cells may contribute to the BNZ-1 efficacy by unleashing the patients’ immune response that drives the anti-tumor attack. The lowered CD8 T-cell activation might help with controlling the inflammation that is commonly associated with this disease." She also added, "Our drug candidates are small peptides that target a shared receptor in a family of cytokines, but only selectively inhibit functionally redundant cytokines. Therefore, in terms of functionality, they are similar to bi- or multi-specific antibodies. We believe this to be an elegant approach to block disease-driving cytokines that utilize a common receptor, without interfering with the rest of the healthy cytokine network. This can provide better target specificity and safety relative to agents, such as JAK inhibitors, that non-specifically inhibit the signaling pathways downstream to all the cytokines."

About Refractory Cutaneous T-cell Lymphoma (rCTCL)
Cutaneous T-cell lymphomas (CTCLs) are a rare, aggressive, heterogeneous group of non-Hodgkin’s lymphomas that manifest primarily in the skin. Although a wide array of therapeutic options are available for early-stage CTCL, not all patients respond, resulting in refractory CTCL (rCTCL) with limited treatment options and a poor prognosis.

About BNZ-1
The company’s lead product candidate, BNZ-1, is a selective inhibitor of cytokines IL-2, IL-9, and IL-15, which are potent T-cell growth factors and key disease drivers in CTCL. Bioniz is also evaluating BNZ-1 for the treatment of autoimmune diseases, including alopecia areata and vitiligo, which are also driven by unregulated T-cell biology.