Vera Therapeutics, Inc. · NASDAQ:VERA
Vera Therapeutics — IIg ANN Symposium 2023
49 slides from Vera Therapeutics's conference presentation, Sep 30, 2023
Slide 1: Targeting the Source of IgA Nephropathy
Targeting the Source of IgA Nephropathy Saturday September 30 | 7:30–8:30 JST Sponsored by © 2023 VERA THERAPEUTICS, INC.
Slide 2: Forward-Looking Statements
Forward-Looking Statements Disclaimer Material relating to Vera Therapeutics, Inc. ("we", "us", "our", or the "Company") has been made available to you with the consent of the Company. Statements in this presentation that are not statements of historical fact are forward-looking statements. Such for
Slide 3: Agenda
Agenda The Potential Role of BAFF and APRIL in the Pathogenesis of IgA Nephropathy: Implications for Dual Inhibition Chee Kay Cheung, MD, PhD, FRCP Consultant Nephrologist and Honorary Associate Professor, The Mayer IgA Nephropathy Laboratories, University of Leicester, Leicester, UK Emerging Therap
Slide 4: The Potential Role of BAFF and APRIL in the Pathogenesis of IgA Nephropathy
The Potential Role of BAFF and APRIL in the Pathogenesis of IgA Nephropathy: Implications for Dual Inhibition Chee Kay Cheung, MD, PhD, FRCP Consultant Nephrologist & Honorary Associate Professor, The Mayer IgA Nephropathy Laboratories University of Leicester & John Walls Renal Unit, UK © 2023 VERA
Slide 5: COI Disclosure
COI Disclosure • I have the following relationships to disclose any COI for this presentation within the period of 36 months. • Consultancy agreements: Vera Therapeutics, George Clinical • Advisory boards: Calliditas, CSL Vifor, Novartis • Research funding: GlaxoSmithKline, Travere Therapeutics • St
Slide 6: Introduction
Introduction • IgAN is the most common form of primary glomerular disease worldwide • Peak incidence is in 2nd to 3rd decade of life, but may occur at any age • Marked variations in its clinical presentation and prognosis • Overall, there is a substantial lifetime risk of developing kidney failure;
Slide 7: Pathogenesis of IgAN: Multi-Hit Hypothesis
Pathogenesis of IgAN: Multi-Hit Hypothesis Hit 1 Hit 2 1. Increase in circulating galactose- deficient IgA1 (Gd-IgA1) Hit 3 2. Formation of anti-Gd-IgA1 antibodies 3. Formation of Gd-IgA1-containing immune complexes 4. Mesangial deposition Hit 4 7 © 2023 VERA THERAPEUTICS, INC. Adapted from Magistro
Slide 8: Pathogenesis of IgAN
Pathogenesis of IgAN BAFF APRIL BAFF APRIL BAFF-R Adapted from Gesualdo L, et al. Semin Immunopathol 2021;43:657-68. APRIL = A Proliferation-Inducing Ligand; BAFF = B-cell Activating Factor. 8 © 2023 VERA THERAPEUTICS, INC.
Slide 9: Rituximab Not Effective in IgAN
Rituximab Not Effective in IgAN No effect on proteinuria Rituximab Control • No effect on proteinuria or eGFR • No reductions in Gd-IgA1 or IgG No effect on eGFR autoantibodies despite adequate Rituximab Control depletion of peripheral B cells eGFR (mL/min/1.73m2) Red line represents average data Ad
Slide 10: BAFF and APRIL
BAFF and APRIL • B-cell Activating Factor (BAFF) and A PRoliferation-Inducing Ligand (APRIL) are members of the TNF family of signaling proteins BAFF-R • Act via shared B cell receptors • Important roles in – B cell proliferation – B cell survival and maturation – Class switching • Inhibitors of APR
Slide 11: BAFF Overexpression Leads to Increased IgA From the Intestinal Lamina Propria
BAFF Overexpression Leads to Increased IgA From the Intestinal Lamina Propria that Deposits in the Kidney Elevated Serum IgA and Gut IgA+ Plasma Cells 60 102 * Serum IgA (mg/mL) % IgA+ PCs in LP 101 45 Increased IgA Deposition in the Kidney 100 30 10-1 10-2 15 WT 10-3 0 WT BAFF Tg WT BAFF Tg Increas
Slide 12: Serum BAFF Overexpression Correlates with Serum IgA
Serum BAFF Overexpression Correlates with Serum IgA, and May Lead to IgA-associated Nephropathy Kidney IgA Levels Associate with BAFF IgA Mesangial Matrix Increased Proteinuria 10 p<0.0001 (8-month male) 8 BAFF-Tg Urine albumin/creatinine ratio IgM IgG IgA 6 100 100 100 4 2 10 10 10 2.0 Ig (mg/mL) 1
Slide 13: BAFF Overexpression Leads to Increased Polymeric Aberrantly Glycosylated IgA
BAFF Overexpression Leads to Increased Levels of Polymeric Aberrantly Glycosylated IgA Increased Levels of Polymeric IgA Increased Levels of Aberrantly Glycosylated IgA Void 670 158 44 17 kDa Void 670 158 44 17 kDa 2.0 +Neuraminidase 15 400 P<0.0001 BAFF-1 Tg 1.5 C57BL/6 300 RCA/IgA ratio 10 Ig (μg/
Slide 14: IgA-associated Nephropathy in BAFF Mouse Model Dependent on Commensal Flora
IgA-associated Nephropathy in a BAFF Overexpressing Mouse Model is Dependent on Commensal Flora Elevated Serum IgA Increased IgA Deposits in Kidney Increased IgA+ Plasma Cells in Gut WT BAFF-Tg WT BAFF-Tg WT BAFF-Tg * SPF 12 wk *** *** *** 105 *** *** 50 Serum IgA (μg/mL) % IgA+B220- of LPL 104 40 1
Slide 15: BAFF Associates with Circulating IgA1 and Kidney IgA Deposits
BAFF Associates with Circulating IgA1 and Kidney IgA Deposits in Patients with IgAN 20 Level of serum index (ng/mL) **## 15 10 *## 5 0 IgAN MGA Normal IgAN MGA Normal IgA1 BAFF 20 6 5 Density of renal IgA deposition 15 level (ng/mL) Serum IgA1 4 10 3 2 5 1 0 0 0 2 4 6 8 10 0 2 4 6 8 Serum BAFF level
Slide 16: Serum BAFF is Elevated in IgAN and Associated with Adverse Pathology
Serum BAFF is Elevated in Patients with IgAN and is Associated with Adverse Pathological Features **P=0.000 **P=0.000 **P=0.000 **P=0.000 **P=0.000 14 14 N=55 N=116 N=37 N=55 N=26 N=127 Serum BAFF (ng/mL) Serum BAFF (ng/mL) 12 12 10 10 8 8 *P=0.000 6 6 *P=0.000 14 4 4 N=55 N=20 N=153 12 2 2 Serum BA
Slide 17: Serum BAFF is Increased in IgAN and Associated with Reduced Kidney Function
Serum BAFF is Increased in IgAN and is Associated with Reduced Kidney Function Adapted from Xin G, et al. J Nephrol 2013;26:683-90. 17 © 2023 VERA THERAPEUTICS, INC.
Slide 18: BAFF Levels are Elevated in IgAN and Associated with Disease Severity
BAFF Levels are Elevated in IgAN and are Associated with Disease Severity Urinary protein excretion (g/24h) 800 5 120 * * 600 * 4 * CCr (mL/min) BAFF (ng/L) 80 * 3 * * 400 * * * 2 * 40 200 1 * 0 0 0 c I II III IV c I II III IV c I II III IV Glomerular Pathological Score Glomerular Pathological Score
Slide 19: BAFF Can Directly Increase Expression of Fibrosis and Inflammation Factors
BAFF Can Directly Increase the Expression of Factors Associated with Fibrosis and Inflammation in Mesangial Cells 8 TRAF6 6 ** * NF-κBP65 * FN TRAF6 6 * P-NF-κBP65/NF-κBP65 Relative protein level Relative mRNA level * CTGF 4 FN * * CTGF # 4 # # # # # 2 2 # # # # # * # # * 0 0 Control BAFF BAFF TRAF6
Slide 20: APRIL Levels are Elevated in IgAN and Correlate with Gd-IgA1
APRIL Levels are Elevated in IgAN and Correlate with Gd-IgA1 Levels p=0.009 r=0.570 1.0 50 p=0.021 40 30 0.8 15 APRIL (ng/mL) Gd-IgA1/IgA1 0.6 10 0.4 5 0.2 0 0.0 IgAN Healthy Control -3 -2 -1 0 1 Adapted from Zhai Y-L, et al. Medicine 2016;95:e3099. Log (APRIL ng/mL) 100 Cumulative risk of doubling
Slide 21: Anti-APRIL Antibodies Effective in Murine IgAN Model
Anti-APRIL Antibodies Effective in Murine IgAN Model Control Ab Anti-APRIL Ab 8 Histologic score 6 4 * 2 0 5.0 glomerular IgA Density of Non-treated Control Ab Anti-APRIL Ab 4.5 4.0 * 5.0 glomerular IgG Density of 4.5 4.0 Control Ab Anti-APRIL Ab Adapted from Kim YG, et al. PLOS One 2015;10:e0137044
Slide 22: Dual BAFF and APRIL Blockade Required for Plasma Cell Inhibition
Dual BAFF and APRIL Blockade is Required for Plasma Cell Inhibition ***p=0.0001 ***p=0.0002 ns ns 50 NP28+ ASCs/5×105 Bone Marrow • APRIL KO mice or heterozygous littermate controls 40 ***p=0.0001 were immunized with KLH antigen and treated with Plasma Cells fusion proteins for 3 weeks, after which
Slide 23: Dual BAFF/APRIL Inhibition Prevented Proteinuria in Mouse Lupus Model
Dual BAFF/APRIL Inhibition Prevented Proteinuria in Mouse Lupus Model Compared to BAFF or APRIL-Only Inhibitors Anti-dsDNA increase CD138+ in Bone Marrow (for titers <100 at W24) Proteinuria 10 5 80 Evolution of anti-dsDNA IgG ns ns ns ns *** *** (log10 of fold increase) Mice with Proteinuria, % CD1
Slide 24: Dual Blockade Does Not Impact Long-lived Bmemory Cell Survival
Dual BAFF and APRIL Blockade Does Not Impact Long-lived Ag-specific Bmemory Cell Survival and Function ns ns 6.0×104 ns 6.0×104 mFc4 Bmemory cells/spleen 5.0×104 5.0×104 TACI-Ig 4.0×104 4.0×104 3.0×104 3.0×104 2.0×104 2.0×104 • PE-immunized mice treated with TACI-Ig 1.0×104 1.0×104 showed no differe
Slide 25: Blocking APRIL Alone May Lead to Upregulation of BAFF Signaling
Blocking APRIL Alone May Lead to Upregulation of BAFF Signaling with Potential Consequences on Efficacy BAFF Elevation in Patients with SLE and RA BAFF Elevation in a Patient with After B Cell Depletion with Rituxan Treatment1 APRIL Deficiency (CVID)2 SLE RA APRIL (ng/mL) BAFF (ng/mL) 25 p=0.0057 8
Slide 26: Alterations in Tonsillar Microbiome of IgAN Patients
Alterations in Tonsillar Microbiome of IgAN Patients Dominant Tonsillar Genus Appears IgAN Patients Have A Greater Abundance Different in IgAN Patients of Neisseria Genus (Tonsils) 1 1.0 Most abundant genus 0.8 0.8 0.0056 Neisseria Relative Abundance Proportion of Samples Porphrymonas Moraxella 0.6
Slide 27: Enhanced Anti-commensal IgA Response in IgAN Patients
Enhanced Anti-commensal IgA Response in IgAN Patients p<0.01 Ratio plasma anti-Neisseria IgA/IgG p<0.01 80 60 40 20 4 3 2 1 0 Nme Commensal Nme Commensal IgAN Control Adapted from Currie EG, et al. JCI Insight 2022;7:e141289 27 © 2023 VERA THERAPEUTICS, INC.
Slide 28: N. Meningitidis-reactive IgA Cells in Kidneys of BAFF Transgenic Mice
N. Meningitidis-reactive IgA Cells in Kidneys of BAFF Transgenic/Nme Infected Mice BAFF-Tg x hCEACAM+ ANOVA p=0.01 40 Anti-Nme IgA ASC/ 106 cells in kidney 30 adj. p=0.01 20 BAFF-Tg x hCEACAM− 10 0 BAFF tg wt tg wt hCEACAM1 + + − − Adapted from Currie EG, et al. JCI Insight 2022 Mar 8;7(5):e141289.
Slide 29: Conclusions: Dual Blockade of BAFF and APRIL in Treatment of IgAN
Conclusions: Dual Blockade of BAFF and APRIL May Play an Important Role in the Treatment of IgAN • BAFF and APRIL levels are both elevated in patients with IgAN and are each associated with clinical severity1-3 • In preclinical studies, overexpression of BAFF alone can lead to the development of kid
Slide 30: Emerging Therapies in IgA Nephropathy: Targeted Mechanisms and Clinical Implications
Emerging Therapies in IgA Nephropathy: Targeted Mechanisms and Clinical Implications Richard Lafayette, MD, FACP Professor, Medicine (Nephrology), Director, Glomerular Disease Center, Stanford University Medical Center © 2023 VERA THERAPEUTICS, INC.
Slide 31: COI Disclosure
COI Disclosure I have the following relationships to disclose any COI for this presentation within the period of 36 months. • Consultant for Vera, Omeros, Calliditas, Chinook, Alexion, Otsuka, Novartis, GSK, Alnylam • Employee of Stanford University Medical Center, which has received research fundin
Slide 32: IgAN Therapies in Clinical Development
IgAN Therapies in Clinical Development B Cell Maturation and Class-Switching Systemic Circulation Glomerulonephritis Gd-IgA1 BAFF Lymphoid tissue IgA1 Peyer’s Patch B Plasma cell B Immune Complexes APRIL Glomerulus Bacteria B Intestinal Tract ETA antagonist Sparsentan Atrasentan B-cell modulators BA
Slide 33: IgAN Therapies in Clinical Development
IgAN Therapies in Clinical Development B Cell Maturation and Class-Switching Systemic Circulation Glomerulonephritis Gd-IgA1 BAFF Lymphoid tissue IgA1 Peyer’s Patch B Plasma cell B Immune Complexes APRIL Glomerulus Bacteria B Intestinal Tract ETA antagonist Sparsentan Atrasentan B-cell modulators BA
Slide 34: B-cell Modulators in Development for IgAN Treatment
B-cell Modulators in Development for IgAN Treatment Investigational Agent Mechanism of Action Development Phase Primary Endpoint Dual BAFF/APRIL UPCR change from baseline at Atacicept Phase 3: ORIGIN 3 inhibitor week 36 UPCR change from baseline at Dual BAFF/APRIL Telitacicept Phase 3 (China only) w
Slide 35: Atacicept is a Dual Inhibitor (BAFF and APRIL) of Plasma Cells and B Cells
Atacicept is a Dual Inhibitor (BAFF and APRIL) of Plasma Cells and B Cells with Potential to Address Multiple Autoimmune Diseases BAFF APRIL Atacicept • Fully humanized TACI-Ig fusion protein, subcutaneously administered • Low nanomolar potency vs BAFF (Kd 1.45 nM) and APRIL (Kd 0.672 nM) • Atacicep
Slide 36: Atacicept Targets Upstream Hits of IgAN Pathogenesis
Atacicept Targets Upstream Hits of IgAN Pathogenesis B Cell Maturation and Class-Switching Systemic Circulation Glomerulonephritis Lymphoid tissue BAFF IgA1 2 Plasma cell Plasma cell 6 APRIL mistrafficking to the Gd-IgA1-containing systemic circulation immune complexes deposit in glomeruli 1 B cell
Slide 37: Phase 2a JANUS Study: Change in Anti-Gd-IgA1 by Visit
Phase 2a JANUS Study Percent Change from Baseline in Anti-Gd-IgA1 by Visit Placebo Atacicept 25 mg Atacicept 75 mg Anti-Gd-IgA11 Immune Complexes2 100 20 Mean ± SD % Change from Baseline 10 50 0 0 -10 20 -50 -30 -100 -40 0 4 12 24 48 72 0 4 12 24 48 72 Week Week n= n= 5 5 5 5 3 5 5 5 5 3 6 5 5 3 3 6
Slide 38: Phase 2a JANUS Study: Serum IgG, IgA, IgM Change Through Week 72
Phase 2a JANUS Study Serum IgG, IgA, and IgM % Change Through Week 72 Placebo Atacicept 25 mg Atacicept 75 mg IgG IgA IgM 40 40 40 Mean ± SE % Change from Baseline 20 20 20 0 0 0 -20 -20 -20 -40 -40 -40 -60 -60 -60 -80 -80 -80 -100 -100 -100 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 0 4
Slide 39: ORIGIN Phase 2b IgAN Trial: Study Design and Objectives
ORIGIN Phase 2b IgAN Trial: Study Design and Objectives Multinational, randomized, placebo-controlled trial Double-Blind Treatment Open-label Extension Placebo n=30 Atacicept 25 mg qwk n=15 Atacicept 150 mg qwk Atacicept 75 mg qwk n=30 Atacicept 150 mg qwk n=30 Week 0 24 36 96/ET 1° Endpoint 2° Endp
Slide 40: UPCR % Change with Atacicept at Week 36
UPCR % Change with Atacicept 150 mg at Week 36 ITT Analysis PP Analysis1 20 Mean ± SE % Change from Baseline in UPCR-24h 10 3% 5% 0 -10 -20 -30 Δ 35% -33% -40 p=0.012 Δ 43% -40% p=0.003 -50 Placebo Atacicept 150 mg Placebo Atacicept 150 mg n=34 n=33 n=26 n=26 p-values, percentage changes from baseli
Slide 41: eGFR Change with Atacicept Through Week 36
eGFR Change with Atacicept 150 mg Through Week 36 Mean ± SE % Change from Baseline in eGFR 15 10 5 1.6% Δ 11% p=0.038 0 5.8 mL/min/1.73 m2 -5 Absolute difference in mean change at week 36 -10 -8.5% -15 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Week n= Placebo 34 34 34 34 34 30 Atacicept 15
Slide 42: Gd-IgA1 % Change Through Week 36
Gd-IgA1 % Change Through Week 36 20 Mean ± SE % Change from Baseline in 0 -7% -20 * Gd-IgA1 * * * * -40 * -39% * * -60 * -62% * -64% * * -80 0 4 8 12 16 20 24 28 32 36 Week n= Placebo 33 33 33 33 29 Atacicept 25 mg 16 16 16 15 15 Atacicept 75 mg 33 33 33 33 33 Atacicept 150 mg 32 32 30 30 30 ITT ana
Slide 43: Dose-dependent Reductions in Serum IgG, IgA, and IgM Through Week 36
Dose-dependent Reductions Observed in Serum IgG, IgA, and IgM Through Week 36 IgG IgA IgM 0 0% 0 0 -4% -3% * Mean ± SE % Change from Baseline * * * * -14% * -20 * -20 * -20 * * * * * * * -32% -32% * -37% -40 * -40 * * -40 * * * * * * * -54% * -60 -60 * -60 * -59% -63% * * * * -70% * -73% -80 -80 * *
Slide 44: Treatment-Emergent Adverse Events Through Week 36
Treatment-Emergent Adverse Events Through Week 36 Atacicept 25 mg Atacicept 75 mg Atacicept 150 mg Placebo Patients, n (%) n=16 n=33 n=33 n=34 TEAEs 11 (69) 24 (73) 25 (76) 27 (79) Study drug-related TEAEs1 6 (38) 17 (52) 19 (58) 14 (41) Serious TEAEs 0 1 (3)2 1 (3)3 3 (9)4 TEAEs leading to study dr
Slide 45: Summary of Clinical Safety Data Through Week 36
Summary of Clinical Safety Data Through Week 36 Atacicept was generally well tolerated in IgAN patients, with no reported deaths, low rate (2%) of serious AEs overall, and 1 patient (1%) discontinued atacicept due to AE Infections were balanced between atacicept and placebo No study drug-related ser
Slide 46: Atacicept Safety Profile in Over 1,000 Patients from Other Indications
Prior Integrated Safety Analysis Atacicept Safety Tolerability Profile in Over 1,000 Patients from Prior Trial Experience in Other Indications Summary of AEs >5% in any arm, by dose in the double-blind placebo-controlled set Atacicept Atacicept Atacicept • A total of 1,000+ patients have received at
Slide 47: Initiated Phase 3 Pivotal Trial in June 2023
Initiated Phase 3 Pivotal Trial in June 2023 Atacicept Once Weekly SC Injection Formulation in Phase 3, Same as Phase 2b Double-Blind Treatment Open-label Extension Placebo Atacicept 150 mg qwk Atacicept 150 mg qwk Week 0 36 104 156 1° Endpoint 2° Endpoint UPCR: n=200 eGFR: n=376 Inclusion Criteria
Slide 48: Summary
Summary • Treatment landscape is changing rapidly in IgAN • In IgAN, overactive B-cells lead to elevated serum levels of Gd-IgA1, autoantibodies, and immune complexes which progressively damage the kidneys • New therapies in development with dual inhibition of BAFF and APRIL may provide additional d
Slide 49: Thank you
Thank you Sponsored by © 2023 VERA THERAPEUTICS, INC.