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1
Development of A Novel Multi-Cytokine
Inhibitor, BNZ-1, for the Treatment of
Moderate to Severe Alopecia Areata
Paul A. ...
2
• 20+ INDs, 40+ clinical trials in
immunology, oncology, neurology,
hematology
• Approvals/+ Phase 3: Raptiva (Psoriasis...
3
Bioniz Development Pipeline
Research Preclinical Phase 1 Phase 2 Phase 3
BNZ- 1 (IL-2/IL-9/IL-15 Inhibitor)
T-Cell Malig...
4
Selective Immunomodulation Using Multi-Cytokine Inhibitors
IL-2 family of cytokines share the common gc receptor signali...
5
BNZ-1 MOA: Blockade of the Cytokine Receptor Produces a Greater
Reduction in Cytokine Signaling
Cytokines activate downs...
6
IL-9
Mast cells
CD4+cells
IL-4
IL-13
BNZ-1: Selective Targeting of the Cytokine-Driven, CD8+ Cytotoxic
T-Cell Mediated D...
7
BNZ-1 Reverses Immune-Mediated Hair Loss
Humanized NSG mouse model of immune-mediated hair loss (ie, Alopecia Areata)
• ...
8
Safety and PK Results from Single & Multiple Ascending
Dose Studies in Healthy Volunteers with IV BNZ-1
SAD Study MAD St...
9
Dose Dependent Pharmacodynamics of BNZ-1 by
Flow Cytometry of PBMCs from Healthy Subjects
Key PD Endpoints:
• % Change f...
10
Visits Every 2 Weeks
Visits Every 2 Weeks
Visits Every 2 Weeks
Visits Every 2 Weeks
Visits Every 2 Weeks
Phase 2 Study ...
11
Acknowledgements
Bioniz Team
Nick Doerr, PhD
Woo Jae Kim, PhD
Laith Al-Mawsawi, PhD
Asjad Basheer, PhD
Rebecca Rathgebe...
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Development of a Novel Multi-Cytokine Inhibitor, BNZ-1, for the Treatment of Moderate to Severe Alopecia Areata

Paul Frohna is Chief Medical Officer of Bioniz Therapeutics where he oversees clinical and regulatory strategy and operations for the company’s platform of multi-cytokine inhibitors that are in development for alopecia areata, cutaneous T cell lymphoma, and a variety of other autoimmune diseases

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Development of a Novel Multi-Cytokine Inhibitor, BNZ-1, for the Treatment of Moderate to Severe Alopecia Areata

  1. 1. 1 Development of A Novel Multi-Cytokine Inhibitor, BNZ-1, for the Treatment of Moderate to Severe Alopecia Areata Paul A. Frohna, MD, PhD, PharmD Chief Medical Officer Alopecia Areata Research Summit 2018
  2. 2. 2 • 20+ INDs, 40+ clinical trials in immunology, oncology, neurology, hematology • Approvals/+ Phase 3: Raptiva (Psoriasis), Tarceva (NSCLC), Ranexa (Angina), Raplixa (hemostasis), Ozanimod (RMS) Bioniz Therapeutics, Inc. • Founded in 2010 by Dr.’s Nazli Azimi (CEO) and Yutaka Tagaya, who worked together in the laboratory of Dr. Thomas Waldmann at the NIH studying the IL-2 family of cytokines • Privately held biotechnology company located in Irvine, CA, with 12 full-time employees • Technology platform focused on the development of peptides that function as selective, multi- cytokine inhibitors for the treatment of immune-mediated diseases (e.g., AA, T-cell cancers, CeD) World-Class AA Clinical Advisory Board: Dr.’s Maria Hordinsky, Elise Olsen, Wilma Bergfeld, Jerry Shapiro, Julian Mackay-Wiggan, Amy McMichael President & CEO Nazli Azimi, Pharm.D., Ph.D. Chief Operating Officer Fredrik Wiklund Chief Medical Officer Paul Frohna, M.D., Ph.D., Pharm.D. • NIH team discovered IL-15, IL-15R, IL-2R • Co-inventor of Bioniz technology • Raised >$250M, including 2 IPOs • ~$1B Partnership/M&A transactions
  3. 3. 3 Bioniz Development Pipeline Research Preclinical Phase 1 Phase 2 Phase 3 BNZ- 1 (IL-2/IL-9/IL-15 Inhibitor) T-Cell Malignancies (rCTCL, LGLL) Alopecia Areata Other Immune Indications (e.g., vitiligo, GvHD) BNZ-2 (IL-15/IL-21 Inhibitor) Autoimmune Diseases of the GI Tract (i.e., Refractory Celiac, IBD, EoE) BNZ-3 (Targets not disclosed) Immune Indications Top-line Results 2019 Phase 2: Start-up Ongoing IND 2019
  4. 4. 4 Selective Immunomodulation Using Multi-Cytokine Inhibitors IL-2 family of cytokines share the common gc receptor signaling subunit (purple) BNZ peptides are designed to exploit this redundancy RESULT: simultaneously and selectively block certain members of the gc cytokine family, which is dependent on the therapeutic target(s) BNZ-1 inhibits IL-2, IL-9 & IL-15, and has no effect on IL-4, IL-7 & IL-21 BNZ-1: a helical, 24aa peptide IL-2/Gamma Chain (gc) Family of Cytokines X X X
  5. 5. 5 BNZ-1 MOA: Blockade of the Cytokine Receptor Produces a Greater Reduction in Cytokine Signaling Cytokines activate downstream JAK/STAT, PI3K/AKT, and ERK/MAPK pathways These 3 pathways are independent of each other and need to be inhibited in order to shut down pathologic signaling in disease BNZ-1 Inhibits All 3 Signaling Pathways JAKi Only Inhibits JAK/STAT PathwayMEMBRANE NUCLEUS 1 Proliferation Immune Activation Apoptosis 2 1 BNZ-1 2 JAKi IL-2 +BNZ-1 STAT-3 STAT-1 STAT-5 PI3K/AKT Vinculin P38 (MAPK) IL-2 +Ruxo IL-2 IL-2- -
  6. 6. 6 IL-9 Mast cells CD4+cells IL-4 IL-13 BNZ-1: Selective Targeting of the Cytokine-Driven, CD8+ Cytotoxic T-Cell Mediated Disease Process in AA Multiple groups have confirmed IL-2, IL-15/IL-15RA, IL-2RA/IL-2RB, and IFNg, and CD8+CTL, and more recently IL-9 and mast cells to be part of AA immunopathology(1)(2)(3) 1. Xing et. al. Nat Med. 2014 Sep;20(9):1043-9, 2. Suarez-Farinas et al., J Allergy Clin Immunol 2015;136:1277-87ç, 3. Bertolini et al., PLOS One 9(5):e94260, 2014 X X X BNZ-1 directly inhibits IL-2, IL-9 and IL-15 (X) resulting in decreased production of IFNg, IL-4 and IL-13 (X), which prevents the CD8+ CTL-mediated attack on the hair follicle and restores the immune privilege status of the hair follicle X X X X X
  7. 7. 7 BNZ-1 Reverses Immune-Mediated Hair Loss Humanized NSG mouse model of immune-mediated hair loss (ie, Alopecia Areata) • Human PBMCs injected into NSG mice  GvH response creates immune-mediated hair loss • ~4-5 weeks post-transplant, mice are sick, have developed severe immune-mediated hair loss (Day 0) • Results: BNZ-1 treatment rescues mice, reverses hair loss, and decreases activated CD8 CTLs in the skin and inflammatory cytokines NSG Mice transplanted w/ human PBMCs BNZ-1 Treatment 2.0 mg/kg 2x/week x 2 wks Day -30 Day 0 Day 7 Day 14 Day 28Day 21 BNZ-1 Reduces Proinflammatory Cytokine Levels IL-6 and IFN-g Ruxo BNZ-1 untreated BNZ-1 reduces CD8+ Cytotoxic T-cell Perforin ExpressionBaseline Placebo BNZ-1 IgG Control CD8 AB A B C FD E Baseline PBO D14 BNZ-1 D14 IHC of CD8+T-cells in Skin Biopsies
  8. 8. 8 Safety and PK Results from Single & Multiple Ascending Dose Studies in Healthy Volunteers with IV BNZ-1 SAD Study MAD Study 1 10 100 1000 0 7 14 21 28 Mean 0.2 mg/kg Mean 0.4 mg/kg Mean 0.8 mg/kg Mean 1.6 mg/kg Mean 3.2 mg/kg Mean 6.4 mg/kg Study Day BNZ-1Concentration(mg/mL) Overall Safety Summary: 43 healthy subjects treated with BNZ-1 across studies × No dose-limiting toxicities × No serious treatment-emergent adverse events (TEAEs) × No clinical lab abnormalities ― Hematology, liver enzymes, coagulation × No severe TEAEs × No infusion reactions Screening 6.4 mg/kg (n=3) Screening 3.2 mg/kg (n=3) Screening 1.6 mg/kg (n=3) Screening 0.8 mg/kg (n=3) Screening 0.4 mg/kg (n=3) IV Dose of BNZ-1 PD blood sample (PBMCs for flow cytometry) Screening 0.2 mg/kg (n=3) Day -28 -1 1 4 15 31 IV Dose of BNZ-1 PD blood sample (PBMCs for flow)Screening 0.5 mg/kg QW Safety Follow-up1 Screening 1.0 mg/kg QW Safety Follow-up2A Screening 1.5 mg/kg QW Safety Follow-up3A Screening 2.0 mg/kg QOW Safety Follow-up2B Screening 3.0 mg/kg QOW Safety Follow-up3B Day -30 1 8 15 22 29 36 43 50 30-Day Safety Monitoring
  9. 9. 9 Dose Dependent Pharmacodynamics of BNZ-1 by Flow Cytometry of PBMCs from Healthy Subjects Key PD Endpoints: • % Change from baseline of NK cells in total PBMC (IL-2 & IL-15 target) • % Change from baseline of Tregs in CD4+ T cells (IL-2 target) • % Change from baseline of Tcm in CD8+ T cells (IL-15 target) Flow Panel: T cells (CD4+, CD8+, Tregs, Central Memory (Tcm)), B cells, NK cells, Monocytes *SAD and MAD CSRs completed and available for review BNZ-1 has a robust, dose-dependent effect on NK, Tregs & Tcm No trends observed for other major leukocyte populations AI Dosing Range Onc Dosing Range Multiple Dose Effects of BNZ-1* • Multiple doses of BNZ-1 produced exposure- dependent decreases of Tregs, NKs, and Tcm that were maintained during one month of dosing • Effects washed out within 30 days after dosing stopped • Supports weekly dosing with lower doses or every other week dosing at higher doses
  10. 10. 10 Visits Every 2 Weeks Visits Every 2 Weeks Visits Every 2 Weeks Visits Every 2 Weeks Visits Every 2 Weeks Phase 2 Study Trial of BNZ-1 in Moderate to Severe AA (NCT03532958) 1◦ Endpoints: • % Change in hair loss by SALT • Safety 2◦ Endpoints • IGA, PGA • SALT 50/75/90/100 • AASIS, DLQI (QoL measures) Biomarkers: flow cytometry, cytokines, IHC Design: RDBPCT in 125 patients (100 completers) Patients: • >50-100% hair loss on the scalp • Diagnosis >6 months, <10 years; includes AT & AU Assessments: • Severity of Alopecia Tool q month • Safety (DSMB) • Investigator and Patient Global Assessments Clinical Conduct: 15-20 US sites, derm CRO identified 4-week Screening Randomization 3-Month Treatment Period 2-Month Follow-up 1.5 mg/kg/wk IV BNZ-1 (n=25) 0.25 mg/kg/wk IV BNZ-1 (n=25) 0.5 mg/kg/wk IV BNZ-1 (n=25) 1 mg/kg/wk IV BNZ-1 (n=25) Weekly IV Placebo (n=25))
  11. 11. 11 Acknowledgements Bioniz Team Nick Doerr, PhD Woo Jae Kim, PhD Laith Al-Mawsawi, PhD Asjad Basheer, PhD Rebecca Rathgeber, BSN, RN University of Maryland, Inst of Human Virology Team Yutaka Tagaya, MD, PhD Juan Zapata, PhD Xisorong Wu

Paul Frohna is Chief Medical Officer of Bioniz Therapeutics where he oversees clinical and regulatory strategy and operations for the company’s platform of multi-cytokine inhibitors that are in development for alopecia areata, cutaneous T cell lymphoma, and a variety of other autoimmune diseases

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