Nurix Therapeutics, Inc. · NASDAQ:NRIX
Nurix Therapeutics — Protein Degradation & Targeting Undruggables Congress Europe 2023
41 slides from Nurix Therapeutics's conference presentation, Sep 19, 2023
Slide 1: Targeted Protein Degraders for the Treatment of Hematologic Malignancies
Leader in Targeted Protein Modulation Targeted Protein Degraders for the Treatment of Hematologic Malignancies: Addressing the Mutational Resistance of BTK in the Clinic Gwenn M Hansen, Ph.D. Chief Scientific Officer Protein Degradation & Targeting Undruggables Congress Europe Basel, Switzerland Sep
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: Nurix Is Advancing a Pipeline of Proprietary and Partnered Programs
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 TPD NX-2127 BTK-IKZF B-cell malignancies TPD NX-5948 BTK B-cell malignancies TPE NX-1607 CBL-B Immuno-O
Slide 5: Advancing a New Therapeutic Class: Degrader-Antibody Conjugates
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: DACs: Tumor-Specific Delivery of Potent Degraders
DACs: Tumor-Specific Delivery of Potent Degraders The next generation of ADCs • Degraders replace highly toxic ADC payloads • DACs allow for selective delivery of degraders to tumor cells • Degraders eliminate driver proteins essential for cancer cell growth and survival Note: Four degraders shown p
Slide 7: Evolution of BTK Targeted Therapies
Evolution of BTK Targeted Therapies Degraders Non-Covalent Inhibitors NX-2127 Resistance NX-5948 is Futile Next Generation Pirtobrutinib Covalent Inhibitors 1st Generation Acalabrutinib Covalent Inhibitor Zanubrutinib Ibrutinib 7
Slide 8: Nurix BTK Degraders: Two BTK Degraders to Cover B-Cell Malignancies
Nurix BTK Degraders: Two BTKs Degraders to Cover the Landscape of B-Cell Malignancies B-Cell Malignancies Annual Incidence (US & EU) NX-5948 for BTK inhibitor resistance mutations in CLL DLBCL with potential for CLL FL MZL early lines of WM MCL therapy 39,700 6,300 6,200 10,700 55,100 26,200 Chronic
Slide 9: B-cell Malignancies Respond to BTK inhibitors, But Patients Eventually Progress
B-cell Malignancies Respond to BTK inhibitors, But Patients Eventually Progress as a Consequence of Inhibitor Resistance • BTK is a nonreceptor tyrosine kinase and plays a crucial role in the B-cell receptor (BCR) signaling pathway • Inhibition of BTK enzymatic activity has been established as an ef
Slide 10: Treatment-Emergent Resistance to Inhibitors Is Evolving
Treatment-Emergent Resistance to Inhibitors Is Evolving: Noncovalent BTK inhibitor Resistance Shows Broader Mutation Profile Wang, Mi, Thompson, et al. NEJM 2022 10
Slide 11: Inhibitor-Induced BTK Mutations Propagate Downstream BCR Signaling
Inhibitor-Induced BTK Mutations Abrogate Phosphorylation Yet Propagate Downstream BCR Signaling: Mutant BTK is ‘Undruggable’ BTK Y223 Phosphorylation in TMD8 Cell Calcium Ion Flux in TMD8 Cell Montoya et al., ASH 2022 11
Slide 12: Enzymatic and Structural Studies of BTKi-Resistant Mutations
Enzymatic and Structural Studies of BTKi-Resistant Mutations Confirm BTK Scaffolding Function Some mutations that confer resistance to BTK lack Mutations revealed by non-covalent inhibitors kinase activity yet still potentiate BCR signaling interrupt the catalytic C-spine of kinase domain 600 C481S
Slide 13: BTK Degraders Offer an Approach to Better Control BCR Signaling
BTK Degraders Offer an Approach to Better Control BCR Signaling Scaffolding Function of BTK was Previously Unrecognized as a Signaling Driver Degraders Have the Potential to Eliminate Both the Enzymatic and Scaffolding Function of BTK Degraders May be More Effective for Treating BCR-signaling Driven
Slide 14: NX-5948 is a Potent and Selective Degrader of BTK
NX-5948 is a Potent and Selective Degrader of BTK Targeted Degradation of Bruton’s Tyrosine Kinase Can Address BTKi Resistance BCR Complex NX-5948 BTK Malignant B cell Ubiquitin Cereblon Ligase BTK Complex Proteasome NFKB Pathway Loss of survival signals SURVIVAL/PROLIFERATION DEATH 14
Slide 15: NX-2127 Dual Mechanism of Action
NX-2127 Dual Mechanism of Action Targeted Degradation of BTK and IKZF1/3 Provides Both Intrinsic and Extrinsic Anti-Tumor Cell Activities NX-2127 Ub IKZF1/3 BCR complex Cereblon T cell ligase complex NX-2127 Proteasome BTK TCR MHC I Malignant B cell Ub IKZF1/3 Cereblon BTK ligase complex Granzyme B
Slide 16: Nurix BTK Degraders Designed for Potent and Rapid Degradation
Nurix BTK Degraders Were Designed for Potent and Rapid Degradation of Wildtype and C481S-Mutant BTK • NX-5948 degrades WT and mutant forms of BTK with sub-nanomolar potency in ABC DLBCL TMD8 cells • BTK degradation is observed within 1 hour and is complete within 2 hours in Ramos cells WT BTK TMD8 C
Slide 17: NX-2127 Demonstrates Binding to Recurrent Acquired Resistant BTK Mutants
NX-2127 Demonstrates Binding to Recurrent Acquired Resistant BTK Mutant Variants NX-2127 BTK 120 Binding of Binding Determined by FRET Displacement Assay 100 NX-2127 NX-2127 IC50 (nM) % Probe Binding BTK Protein 80 Determined by SPR Kd (nM) NX-2127 Pirtobrutinib Ibrutinib 60 40 WT 18 10 0.76 1
Slide 18: NX-2127 Degrades Both Wild-Type and Kinase Dead BTK
NX-2127 Degrades Both Wild-Type and Kinase Dead BTK and Suppresses Ca++ Signaling BTK degradation Montoya et al., ASH 2022 18
Slide 19: NX-2127 Is Potent and More Broadly Active Than All BTK Inhibitors Tested
NX-2127 Is Potent and More Broadly Active Than All BTK Inhibitors Tested BTK degradation and activation marker suppression in TMD8 tumor cells TMD8 tumor cell killing 125 BTK degradation 125 EC50 (nM) 100 100 Most potent % BTK Remaining CD86 Expression 1e-002 (DMSO = 100) 75 75 NX-2127 cell killing
Slide 20: 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 GI-50 (nM) 125 BTK degradation 125 0 Most potent 100 100 NX-5948 3 4 5 6 13 % BTK Remaining CD86 Expression cell killing (DMSO = 100)
Slide 21: Nurix BTK Degraders Form Stable Ternary Complexes
Nurix BTK Degraders Form Stable Ternary Complexes Between BTK and CRBN Irrespective of Mutation Status BTK WT BTK T474I BTK L528W 120 120 120 100 % Probe Binding 100 No CRBN % Probe Binding 100 80 80 80 60 60 60 + CRBN (1 μM) 40 α = 2.2 40 α = 3.1 40 α = 3.7 20 20 20 0 0 0 IC50 No CRBN -20 0.00001 0
Slide 22: Not All BTK Degraders Are Created Equal
Not All BTK Degraders Are Created Equal TMD8 tumor cell killing GI-50 (nM) 0 Most potent NX-5948 3 4 5 6 13 cell killing 1000 NX-2127 12 39 28 18 15 2000 The ability of NX-5948 and NX- Haisco Cmpd [1] 160 178 1598 2341 1156 2127 to induce TMD8 tumor-cell 3000 killing was compared to other reported d
Slide 23: Targeted Protein Degraders Can Display Exquisite Selectivity
Targeted Protein Degraders Can Display Exquisite Selectivity Global Proteomics Analysis in Human PBMCs or TMD8 DLBCL Cells NX-2127, 50 nM, 4h, human donor PBMCs NX-5948, 50nM, 6h, TMD8 DLBCL cells FDR adjusted p-value (-log10) c-FLIP BTK BTK Fold change (log2) c-FLIP is an anti-apoptotic protein req
Slide 24: Degradation of BTK by NX-5948 Correlates with Tumor Growth Inhibition
Degradation of BTK by NX-5948 Correlates with Significant Tumor Growth Inhibition Circulating B cells TMD8 Tumors TMD8 Tumor Growth 120 120 2500 Vehicle Vehicle Vehicle Tumor volume, mm3 100 3 mg/kg 100 3 mg/kg 3 mg/kg NX-5948 % BTK remaining % BTK remaining 2000 (Mean ± SEM) 10 mg/kg 10 mg/kg 10 mg
Slide 25: NX-5948-301: Trial Design
NX-5948-301: Trial Design Phase 1 trial in adults with relapsed/refractory B-cell malignancies Dose escalation Dose expansion options • Phase 1a dose escalation is ongoing at clinical sites in the Objectives: U.S. and U.K. • Assess safety and tolerability CLL/SLL failed BTKi and BCL2i • Anticipate i
Slide 26: Preliminary Data Suggest NX-5948 Exhibits Dose Proportional Pharmacokinetics
Preliminary Data Suggest that NX-5948 Exhibits Dose Proportional Pharmacokinetics Mean (± SEM) Cycle 1 Day 1 pharmacokinetic profile of Cycle 1, Day 1 patients treated with NX-5948 Cmax AUC0–last Tmax t1/2 * Dose (ng/mL) (h*ng/mL) (hours) (hours) 20 50 mg 4.52 (102) 42.1 (152) 3.0 12.8 (19.9) n=4 c
Slide 27: NX-5948 Resulted in Rapid, Robust and Sustained BTK Degradation
NX-5948 Resulted in Rapid, Robust and Sustained BTK Degradation in all Patients Dosed • NX-5948 induced sustained BTK degradation of 89±4% at Cycle 2 Day 1 across dose levels Dose level 1 (50 mg) 15000 (Background subtracted) FL 12500 MCL 10000 DLBCL BTK MFI 7500 MZL Dose level 2 (100 mg) 5000 DLBCL
Slide 28: NX-2127-001: Trial Design
NX-2127-001: Trial Design Phase 1 trial in adults with relapsed/refractory B-cell malignancies Dose escalation Dose expansions • CLL Phase 1b expansion cohort ongoing at 100 mg dose Objectives: CLL • DLBCL Phase 1b expansion • Assess safety and tolerability Failed 2 or more prior treatments cohort o
Slide 29: NX-2127 Leads to Robust BTK Degradation and Decrease in B-cell Activation
NX-2127 Leads to Robust BTK Degradation and Decrease in B-cell Activation 5000 Patients with CLL (100 mg) 30 Circulating plasma CCL4 in patients with CLL (100 mg) NX-2127 plasma trough concentration (ng/mL) 30000 3750 (MFI±SEM) BTK Levels 20 25000 CCL4 measured in 2500 patient plasma with an ELISA-b
Slide 30: First Demonstration of Clinical Activity of a Degrader Against 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 100 Disease-evaluable patients Maximim %change in SPD from baseline with known BTK mutation status BTK WT 6000 BTK WT; n=11 50 BTK
Slide 31: Mechanistic Rationale for Dual Degrader in DLBCL
Mechanistic Rationale for Dual Degrader in DLBCL Hyper-activated BCR (CD79b-mut) and TLR (MyD88-mut) signaling are hallmarks of non-GCB DLBCL: • NX-2127 targets both BCR and TLR signaling through BTK degradation • NX-2127 targets non-BTK dependent TLR signaling through its immunomodulatory activity
Slide 32: 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 Bladder • 84-year-old woman with multiply relapsed ABC- DLBCL following 4 lines of aggressive therapy (including combination of rituximab, ibrutinib, and lenali
Slide 33: Targeted Protein Degradation Holds Promise For Treating Cancer
Targeted Protein Degradation Holds Promise For Treating Cancer Target Ligase Complex • The use of BTK inhibition for treating B-cell malignancies Emergent BTKi-Resistant has led to the development of acquired mutations that confer Mutations resistance to both covalent and noncovalent BTK inhibitors
Slide 34: Thank you
Thank you
Slide 35: NX-2127 safety summary (TEAEs >15% in all patients)
NX-2127 safety summary (TEAEs >15% in all patients) Treatment-emergent AEs occurring in >15% of Any grade Grade 3+ SAE total population, n (%) (N=36) (N=36) (N=36) Fatigue 19 (52.8) – - Neutropeniaa 14 (38.9) 13 (36.1) - Contusionb 10 (27.8) – 1 (2.8) Thrombocytopeniac 9 (25) 3 (8.3) - Anemia 8 (22.
Slide 36: NX-2127 safety summary (all participants) by dose
NX-2127 safety summary (all participants) by dose All doses 100 mg* 200 mg 300 mg AEs: all grades, n (%) (n=36) (n=22) (n=8) (n=6) Fatigue 19 (53) 13 (59) 5 (63) 1 (17) Neutropeniaa 14 (39) 5 (23) 5 (63) 4 (67) Contusionb 10 (28) 4 (18) 3 (38) 3 (50) Thrombocytopeniac 9 (25) 5 (23) 2 (25) 2 (33) Hyp
Slide 37: BTK Degradation of 80%+ Drives Potent Anti-tumor Activity in Preclinical Models
BTK Degradation of 80%+ Drives Potent Anti-tumor Activity in Preclinical Models Ikaros and Aiolos degradation also achieve target range at therapeutic doses BTK Degradation in Aiolos Degradation in Ikaros Degradation in Tumor Growth Peripheral B cells TMD8 Tumor Tissue TMD8 Tumor Tissue Vehicle 10 m
Slide 38: Aiolos (IKZF3) Overexpression Drives BTK Inhibitor Resistance in CLL
Aiolos (IKZF3) Overexpression Drives BTK Inhibitor Resistance in CLL, a Rationale for a Combination Strategy “Our results thus highlight IKZF3 oncogenic function in CLL via transcriptional dysregulation and demonstrate that this pro-survival function can be achieved by either somatic mutation or ove
Slide 39: Non-GCB DLBCL Represents an Important Unmet Medical Need
Non-GCB DLBCL Represents an Important Unmet Medical Need • DLBCL is the most common form of lymphoma, representing ~30% of all NHL diagnoses1,2 • ~24,000 people diagnosed in the United States each year, with ~60% 5-year survival1,2,3 DLBCL treatments are the same for all patients, even though it is
Slide 40: A First-In-Class Franchise of BTK Degraders: The Big Picture
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 NX-2127 Nurix has demonstrated that BTK degraders can overcome
Slide 41: Phase 2 Smart Start: Ibrutinib, Lenalidomide, and Rituxan + Chemo in 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 (75%) resulted in high response rates and promising survival 52 outcom
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