Nurix Therapeutics, Inc. · NASDAQ:NRIX
Nurix Therapeutics — Investor Presentation (November 2023)
40 slides from Nurix Therapeutics's investor presentation, Nov 13, 2023
Slide 1: Leader in Targeted Protein Modulation
Exhibit 99.1 Leader in Targeted Protein Modulation Nurix Therapeutics Blazing a New Path in Medicine Investor Presentation November 2023
Slide 2: Important notice and disclaimers
Important notice and disclaimers This presentation contains statements that relate to future events and expectations and as such constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. When or if used in this presentation, the words “anticipa
Slide 3: Nurix Drugs Engage Ligases for the Treatment of Cancer
Nurix Drugs Engage Ligases for the Treatment of Cancer Targeted Protein Modulation: TPM = TPD + TPE A Powerful Targeted Protein Cellular System Elevation (TPE) Harness ligases to decrease specific protein levels Inhibit ligases to increase specific protein levels Targeted Protein Ubiquitin is ligate
Slide 4: Pipeline of Proprietary and Partnered Programs in Oncology and Autoimmune/Inflammatory Diseases
Nurix Is Advancing a Pipeline of Propriety and Partnered Programs in Oncology and Autoimmune/Inflammatory Diseases MOA Drug program Target Therapeutic area Discovery IND enabling Phase 1a Phase 1b BTK-IKZF B-cell malignancies NX-2127 BTK B-cell malignancies NX-5948 NX-0479 / Rheumatoid arthritis and
Slide 5: Advancing a New Therapeutic Class: Degrader-Antibody Conjugates (DACs)
Advancing a New Therapeutic Class Degrader-Antibody Conjugates (DACs) • DACs combine the catalytic activity of a Deal Terms Targeted Protein Degrader (TPD) with the specificity of an antibody • $60 million upfront cash payment • DACs represent the next generation of • $3.4 billion in potential resea
Slide 6: Leveraging Gilead and Sanofi Partnerships To Advance a Broad Pipeline
Leveraging Gilead and Sanofi Partnerships To Advance a Broad Pipeline of Targeted Protein Degraders DC Partner Ligand Degrader Cellular In vivo Oral nomination License Discovery Discovery Profiling Profiling exposure IRAK4 (Gilead) NX-0479/ GS-6791 Target 2 Target 3 Target 4 Target 5 Druggable Targe
Slide 7: Targeted Protein Degradation
Targeted Protein Degradation Harnessing the ubiquitin proteosome system to eliminate disease proteins NX-5948 MOA BTK Destroyed by the Proteasome Nurix degrader E2 Ubiquitin drugs BTK Degrader Cereblon recycling E3 Ligase Complex BTK BTK Poly Ubiquitinated Proteins Ubiquitination of Protein 7
Slide 8: Degraders More Completely Disrupt BCR Signaling
Degraders More Completely Disrupt BCR Signaling Nurix Degraders: 1) Are effective against resistance mutations through binding cooperativity between BTK and the ligase complex 2) Eliminate the scaffolding function of BTK oncogenic signals Removal of BTK disrupts the signaling complex, effectively de
Slide 9: A First-In-Class Franchise of BTK Degraders: NX-5948 & NX-2127
A First-In-Class Franchise of BTK Degraders: NX-5948 & NX-2127 – The Big Picture NX-5948 BTK degraders have the potential to displace inhibitors in the SELECTIVE BTK markets where BTK inhibitors currently dominate (e.g., CLL) DEGRADATION Nurix has demonstrated that BTK degraders can overcome NX-2127
Slide 10: Nurix BTK Degrader Franchise: Two BTK Degraders To Cover B-Cell Malignancies
Nurix BTK Degrader Franchise: Two BTK Degraders To Cover the Landscape of B-Cell Malignancies B-Cell Malignancies Annual Incidence (U.S. & EU) NX-5948 for BTK inhibitor resistance DLBCL mutations in CLL CLL FL with potential for MZL early lines of MCL WM therapy 39,700 6,300 6,200 10,700 55,100 26,2
Slide 11: Blockbuster Opportunity in BTK Market
Blockbuster Opportunity in BTK Market $8.4 billion in annual sales BTK Yearly Sales • Next generation 9000 BTK inhibitors are currently taking market 8000 share from Imbruvica 7000 • Nurix BTK degraders have the potential to be game 6000 changing and take shares 5000 from the inhibitor market in CLL
Slide 12: Evolution of BTK Targeted Therapies
Evolution of BTK Targeted Therapies Degraders Non-Covalent NX-5948 Inhibitors Resistance NX-2127 Is Futile Next Generation Pirtobrutinib Covalent inhibitors st 1 Generation Acalabrutinib Covalent inhibitor Zanubrutinib Ibrutinib 12
Slide 13: Emerging Unmet Medical Need with Resistance Mutations to Existing BTK Inhibitors
Emerging Unmet Medical Need with Resistance Mutations to Existing BTK Inhibitors NX-5948 and NX-2127 can degrade all treatment emergent inhibitor mutations identified to date 13
Slide 14: NX-5948 Designed for Potent and Rapid Degradation of Wildtype and C481S-Mutated BTK
NX-5948 Was Designed for Potent and Rapid Degradation of Wildtype and C481S-Mutated BTK WT BTK TMD8 Cells BTK-C481S TMD8 Cells 100 100 DC50=0.028 nM DC50=0.0184 nM 80 75 60 50 40 25 20 0 0 0.001 0.01 0.1 1 10 100 1000 0.001 0.01 0.1 1 10 100 1000 NX-5948 (nM) NX-5948 (nM) TMD8 cells harboring WT BTK
Slide 15: Structural and Enzymatic Studies of New BTKi-Resistant Mutations
Structural and Enzymatic Studies of New BTKi-Resistant Mutations Confirms BTK Scaffolding Function Some mutations that confer resistance to BTK inhibitors Mutations revealed by non-covalent inhibitors lack kinase activity yet still potentiate BCR signaling interrupt the catalytic C-spine of kinase d
Slide 16: NX-5948 Is More Potent and Broadly Active Than All BTK Inhibitors Tested
NX-5948 Is More Potent and Broadly Active Than All BTK Inhibitors Tested BTK degradation and activation marker suppression in TMD8 tumor cells TMD8 tumor cell killing BTK degradation 125 125 EC50 (nM) 100 100 Most potent 1e-002 75 75 cell killing NX-5948 50 50 1000 25 Ibrutinb 25 NX-5948 NX-5948 0 0
Slide 17: NX-2127 Induces Positive Binding Cooperativity Between BTK and Cereblon
NX-2127 Induces Positive Binding Cooperativity Between BTK and Cereblon BTK WT 120 120 100 No CRBN 100 120 80 80 CRBN N o (1 C μR MB ) N + BTK 100 60 DDB1 60 80 CRBN (1 μM) + 40 40 CRBN 60 20 20 α = 2.5 40 IC No CRBN 0 50 0 α = 20 -20 -20 IC with CRBN (1 μM) 0.00001 0.0001 0.001 0.01 0.1 1 50 0.0000
Slide 18: NX-5948-301: Trial Design
NX-5948-301: Trial Design Phase 1 trial in adults with relapsed/refractory B-cell malignancies Dose escalation Potential Phase 1b dose expansions Dose level 6+ Objectives: CLL/SLL (n=20) 600 mg • Assess safety and tolerability Prior BTKi and BCL-2i Dose level 5 • Identify maximum tolerated dose & 45
Slide 19: First Report of BTK Degradation with NX-5948 in Patients
First Report of BTK Degradation with NX-5948 in Patients with B Cell Initial proof of mechanism Malignancies • Rapid and sustained Dose level 1 (50 mg) 15000 degradation of BTK FL 12500 MCL • Robust BTK degradation DLBCL 10000 observed in all patients MZL tested to date 7500 Dose level 2 (100 mg) 50
Slide 20: NX-2127-001: Trial Design
NX-2127-001: Trial Design Phase 1 trial in adults with relapsed/refractory B-cell malignancies • Enrollment of new patients paused Dose escalation Dose expansions due to partial clinical hold, pending alignment with FDA on introduction Objectives: of new chirally controlled drug CLL (100 mg) product
Slide 21: Baseline Characteristics
Baseline Characteristics Elderly population with multiple prior lines of targeted therapies and acquired mutations CLL Overall population Characteristics (n=23) (N=36) Median age, years (range) 75 (61–90) 75 (50–92) Female, n (%) 9 (39.1) 13 (36.1) Male, n (%) 14 (60.9) 23 (63.9) Lines of prior ther
Slide 22: NX-2127 Leads to Robust BTK Degradation and Decrease in B-cell Activation
NX-2127 plasma trough concentration (ng/mL) NX-2127 Leads to Robust BTK Degradation and Decrease in B-cell Activation Circulating plasma CCL4 Patients with CLL (100 mg) 5000 30 in patients with CLL (100 mg) 30000 3750 20 CCL4 measured in 25000 patient plasma with an 2500 ELISA-based assay 20000 HMPC
Slide 23: NX-2127 Preliminary Efficacy: Positive Initial Findings in CLL
NX-2127 Preliminary Efficacy Positive Initial Findings in CLL Two or more prior treatments including: 100 Disease-evaluable patients n=15 BTKi BTKi and BCL2i (‘Double exposed’) a Objective response rate, % (95% CI) 33 (12–62) 50 BTK mutation at baseline * Best response, n (%) Treatment ongoing CR 0
Slide 24: First Demonstration of Clinical Activity of a Degrader Against a Range of BTK Mutations
First Demonstration of Clinical Activity of a Degrader Against a Range of BTK Mutations NX-2127 Preliminary Efficacy in Patients with CLL BTK degradation in CLL patients Disease-evaluable patients 100 with known BTK mutation status BTK WT 6000 BTK Kinase Dead BTK WT; n=11 50 5000 BTK Kinase Dead (C4
Slide 25: Rapid and Sustained Complete Response on Single-Agent NX-2127
Rapid and Sustained Complete Response on Single-Agent NX-2127 FDG-PET CT Scan Disease Assessment Baseline Confirmatory Week 16 Scan Bladder • 84-year-old woman with multiply relapsed ABC- Bladder DLBCL following 4 lines of aggressive therapy (including combination of rituximab, ibrutinib, and lenali
Slide 26: Smart Start: Ibrutinib, Lenalidomide, and Rituxan + Chemo in Newly Diagnosed Non-GCB DLBCL
Phase 2 Smart Start: Ibrutinib, Lenalidomide, and Rituxan + Chemo in Newly Diagnosed Non-GCB DLBCL RLI RLI + EPOCH or CHOP Cycles 1-2 Cycles 3-8 N = 58 N = 56 N = 55 21 (36%) “The combination of RLI alone and with chemotherapy 42 resulted in high response rates and promising survival (75%) 52 outcom
Slide 27: Targeting CBL-B Enhances Antitumor Response
s l l e c r o m u T l l i K d n a e z i n g o c e R n o i t a r t l i f n i r o m u t d n a c i f f a r T Targeting CBL-B Enhances Antitumor Response A Master Orchestrator of the Immune System CBL-B mediated mechanisms strongly restrains a productive anti-tumor response Lymph node T cell CBL-B Blood
Slide 28: NX-1607 Mechanism of Action: Intramolecular Glue
NX-1607 Mechanism of Action: Intramolecular Glue Substrate protein E2 E2 Y363 p NX-1607 Y363 pY363 1. Kinase RING RING TKB TKB TKB TKB 2. E2/substrate NX-1607 acts as an Closed State Opened State Phosphorylation locks intramolecular glue INACTIVE CBL-B in the ACTIVE forcing CBL-B in its Conformation
Slide 29: NX-1607 Increases IL-2 and IFN-γ Secretion in Stimulated Primary Human T cells
NX-1607 Increases IL-2 and IFN-�� Secretion in TCR Stimulated Primary Human T cells IL-2 Anti-CD3 IL-2 Anti-CD3/CD28 NX-1607 increases TCR stimulation-dependent production of IL-2 and IFN-�� in primary human T cells IFN-�� Anti-CD3 IFN-�� Anti-CD3/CD28 NX-1607 has no impact in the absence of T cell
Slide 30: Single-Agent NX-1607 Induces Antitumor Response in Multiple Models
Single-Agent NX-1607 Induces Antitumor Response in Multiple Models NX-1607 NX-1607 NX-1607 Reduced Tumor Volume Prolonged Survival Reduced Tumor Volume Colorectal Triple-Negative Breast B Cell Lymphoma Vehicle 1400 100 Vehicle NX-1607 1200 NX-1607 75 1000 <0.0001 p= 800 50 600 p<0.0001 400 25 200 0
Slide 31: NX-1607 and Anti-PD-1 Synergize to Enhance Anti-Tumor Effects
NX-1607 and Anti-PD-1 Synergize to Enhance Anti-Tumor Effects and Survival of Mice in Multiple Tumor Models Colorectal (CT26) Colorectal (MC38) Triple-Negative Breast (4T1) Day 28 4T1 Lung Metastases p<0.01 15000 p<0.01 10000 5000 200 100 0 Vehicle NX-1607 anti-PD-1 NX-1607+anti-PD-1 Shaded area ind
Slide 32: NX-1607-101: Phase 1 First-in-Human Clinical Trial Design
NX-1607-101: Phase 1 First-in-Human Clinical Trial Design Phase 1 trial testing both monotherapy and combination with paclitaxel in relapsed or refractory tumors Dose Escalation Potential Cohort Expansion Objectives: Melanoma • Assess safety and tolerability Squamous Cell Carcinoma of the • Identify
Slide 33: UbiScan Identified Direct CBL Substrates Within the TCR Signaling Cascade
UbiScan Identified Direct CBL Substrates Within the T Cell Receptor (TCR) Signaling Cascade Decreased signal represents direct substrates ubiquitinated by CBL-B ligase activity Inhibiting CBL-B decreases ubiquitination of important T Cell receptor signaling molecules 33
Slide 34: Phospho-Protein Flow Cytometry Assay Identified Proximal Biomarkers
Phospho-Protein Flow Cytometry Assay Identified Proximal Biomarkers • Human PBMCs were stimulated with or without CBL-B inhibition Phosphorylation of proximal biomarkers in CD8+ T cells • Expression levels were determined for phospho- proteins downstream the TCR signaling • Overlapping results from
Slide 35: Dose Dependent Increases of CBL-B Proximal Biomarker Correlate with Antitumor Effects
Dose Dependent Increases of CBL-B Proximal Biomarker Correlates with Antitumor Effects of NX-1607 Pharmacodynamic relationship in mice following NX-1607 dosing 100 80 60 Efficacious 40 Range 20 0 0.1 1 10 100 NX-1607 (mg/kg) In vivo efficacy observed between 10-60 mpk which corresponds to ~20-60% pH
Slide 36: Novel Biomarker and First Evidence of Target Engagement for a CBL-B Inhibitor
Characterization of a Novel Biomarker and First Evidence of Target Engagement for a CBL-B Inhibitor in the Clinic Human whole blood and dose projection modeling Clinical data Maximal % pHS1+ expressing CD8+ T cells observed in C1D1 36
Slide 37: CBL-B Inhibition Potential as Small Molecule Centerpiece of Immuno-Oncology Therapy
CBL-B Inhibition Has the Potential To Be the Small Molecule Centerpiece of Immuno-Oncology Therapy Post-ICI (Melanoma, NSCLC, Prostate, MSS Colorectal Ovarian, Gastric DLBCL (including Richter’s) TNBC, Meso, Urothelial, etc.) Low-Immunogenicity Tumors Suppressive TME Acquired Resistance T-Cell Dysfu
Slide 38: Anticipated Upcoming Clinical Data Disclosures
Anticipated Upcoming Clinical Data Disclosures Targeted Protein Degradation Targeted Protein Elevation NX-5948 NX-2127 NX-1607 • Updated Phase 1 clinical data in patients with CLL at ASH • First disclosure of Phase 1a • First disclosure of Phase 1a clinical 2023, including more patients clinical dat
Slide 39: Strong Financial Position
Strong Financial Position $329M includes funds as of August 31, 2023, plus $60M from Seagen deal Partnerships Generate Cashflow and Reduce Need for Dilutive Financing • $409 million generated through discovery 450 400 partnership payments 350 300 • Potential for profit 250 splits on up to 6 200 prog
Slide 40: Thank you
Thank you
Nurix Therapeutics — Investor Presentation (November 2023) on 6ix