Following phase 2 success, the FDA provided Bioniz Therapeutics with guidance for the design of a phase 3 trial of BNZ-1 in patients with relapsed or refractory cutaneous T-cell lymphoma.
Based on positive feedback provided by the FDA, Bioniz Therapeutics announced it intends to launch a phase 3 clinical trial of the multi-cytokine inhibitor, BNZ-1, for the treatment of patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL).1
The FDA provided the company with guidance for the design of the phase 3 trial as well as for subsequent submission of the new drug application (NDA) that would follow.
Bioniz indicated the phase 3 trial should begin enrolling patients in the second half of 2021.
“The successful completion of our end of phase 2 meeting with the FDA for BNZ-1 is another key milestone for this drug, which is the lead candidate from our platform of novel multi-cytokine inhibitors designed to treat cancer and autoimmune diseases driven by unregulated T-cell biology,” Nazli Azimi, PharmD, PhD, founder, president, and CEO of Bioniz Therapeutics and coinventor of BNZ-1, said in a press release. “Based on the feedback from the FDA and the data from our recently completed phase 1/2 clinical study, we believe BNZ-1 can be a major advancement in helping [patients with CTCL] stabilize their disease without significant and treatment-limiting side effects.”
Positive clinical data from a phase 1/2 clinical study (NCT03239392) of BNZ-1 for the treatment of patients with relapsed or refractory CTCL were recently reported in an oral presentation at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.2,3
The multi-center, open-label, dose-escalation study was designed to evaluate the safety and activity of BNZ-1 in patients with relapsed or refractory CTCL in whom standard of care and other available treatment options had failed, including up to 7 prior skin-directed and systemic therapies. The study’s primary end point was overall safety following 4 weeks of treatment.
Of note, there was a 3-month treatment extension to further assess safety and clinical response at week 17, with long-term extension made available to those who benefitted from BNZ-1 treatment.
In the dose-ranging portion of the study, 15 patients with stages IB and IVB disease were enrolled across the 4 dose cohorts of 0.5, 1.0, 2.0, and 4.0 mg/kg for intravenous weekly dosing. Overall, BNZ-1 demonstrated activity across doses as determined by early signs of clinical efficacy and pharmacodynamic biomarkers. Notably, 3 patients who enrolled early during the dose-ranging portion of the study and responded to BNZ-1 also participated in the study for 73 weeks, or about 17 months; the duration of response for these individuals was about 62 weeks, or about 15 months.
Based on the pharmacokinetic/pharmacodynamic relationship and clinical efficacy observed in the dose-ranging portion of the study, the 2-mg/kg dose was selected and the cohort was expanded to 19 patients. A total of 30 patients were treated in the study.
Importantly, the pharmacodynamic analysis revealed a dose-dependent reduction of T-regulatory (Treg) cells which plateaus at a dose of 2 mg/kg. Additionally, BNZ-1 also lowered the CD8 T-cell activation markers in some patients that responded to treatment with BNZ-1.
“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,” Azimi added in the release. “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 nonspecifically inhibit the signaling pathways downstream to all the cytokines.”
Among those included in the expanded cohort, BNZ-1 showed an overall response rate of 63.2% as measured by Global Response Score (GRS), which is primarily driven by the Modified Severity Weighted Assessment Tool (mSWAT) score. Moreover, investigators found a positive response generally occurred shortly after treatment initiation, continued for the duration of treatment, and improved over time in some with this positive trend extending into the follow-up period off-treatment.
More specifically, 2 patients achieved a partial response as early as 4 weeks after starting treatment with BNZ-1, 1 patient reached a complete response at 13 weeks which continued until the study was closed-out at 30 weeks, and 7 (37%) had stable disease. No disease recurrence or relapse was observed during the study period.
Of those who were enrolled later as part of the cohort expansion, treatment durations ranged from 4 to 30 weeks and response duration ranged from 4 to 26 weeks (median 12 weeks). The shorter treatment duration was because of study close-out per protocol.
A total of 12 patients participated in the long-term extension, 11 of whom achieved and sustained their response, for an overall rate of response of 91.7%.
Regarding safety, treatment with BNZ-1 was well tolerated, and no dose-limiting toxicities, drug-related serious adverse events, or lab abnormalities were reported.
“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,” Christiane Querfeld, MD, PhD, director of the Cutaneous Lymphoma Program at the City of Hope and principal investigator of the study, said in the release. “On average, these…patients have disease that had progressed and failed [on] up to 7 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 [patients with CTCL].”
1. Bioniz Announces Positive End of Phase 2 Meeting with the FDA for BNZ-1 for the Treatment of Refractory Cutaneous T-Cell Lymphoma. News release. Bioniz Therapeutics. Published January 4, 2021. Accessed January 13, 2021. https://www.prnewswire.com/news-releases/bioniz-announces-positive-end-of-phase-2-meeting-with-the-fda-for-bnz-1-for-the-treatment-of-refractory-cutaneous-t-cell-lymphoma-301199939.html
2. Bioniz announces positive clinical data of BNZ-1, first anti-cytokine therapy to demonstrate efficacy in treating refractory cutaneous t-cell lymphoma. News release. Bioniz Therapeutics. Published December 5, 2020. Accessed January 13, 2021. https://bioniz.com/bioniz-announces-positive-clinical-data-of-bnz-1-first-anti-cytokine-therapy-to-demonstrate-efficacy-in-treating-refractory-cutaneous-t-cell-lymphoma/
3. Querfeld C, William BM, Sokol L, et al. Co-Inhibition of IL-2, IL-9 and IL-15 By the Novel Immunomodulator, Bnz-1, Provides Clinical Efficacy in Patients with Refractory Cutaneous T Cell Lymphoma in a Phase 1/2 Clinical Trial. Blood. 2020;136(suppl 1):37. Abstract 43. doi: 10.1182/blood-2020-143135