Nurix Therapeutics, Inc. · NASDAQ:NRIX
Nurix Therapeutics — 6th Annual Targeted Protein Degradation Summit (October 2023)
31 slides from Nurix Therapeutics's conference presentation, Oct 31, 2023
Slide 1: Overcoming Acquired Inhibitor Resistance & Addressing Novel Scaffolding Functions of BTK in the Clinic
Leader in Targeted Protein Modulation Overcoming Acquired Inhibitor Resistance & Addressing Novel Scaffolding Functions of BTK in the Clinic Gwenn M Hansen, Ph.D. Chief Scientific Officer 6th Annual Targeted Protein Degradation Summit Boston, MA Oct 31, 2023 1
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: Ligase Discovery May Unlock Unique TPM Opportunities
Ligase Discovery May Unlock Unique TPM Opportunities 96 Ligases in Unlock novel targets and pathways Discovery 35 Improve target coverage and Ligases selectivity with Ligands 5 100 NX Ibrutin Overcome inhibitor resistance %Viable 75 50 25 0 0.1 00 0 1 1 10 0 00 00 0.0 10 10 00 10 10 Compound (nM) >6
Slide 5: A New Therapeutic Class: Degrader-Antibody Conjugates (DACs)
A New Therapeutic Class: Degrader-Antibody Conjugates (DACs) Achieving Tissue-Selective Degradation Using Antibodies TPD DAC Target • DACs combine the catalytic activity of a Binder Targeted Protein Degrader (TPD) with Ab the specificity of an antibody Ligase • DACs represent a next generation of Bi
Slide 6: DACs: Cell and Tissue-Specific Delivery of Potent Protein Degraders
DACs: Cell and Tissue-Specific Delivery of Potent Protein Degraders The next generation of ADCs • Degraders replace highly toxic ADC payloads • DACs allow for selective delivery of degraders to target cells and tissues; example: cancer cells • Degraders eliminate driver proteins essential for cancer
Slide 7: 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 NX-2127 BTK-IKZF B-cell malignancies NX-5948 BTK B-cell malignancies NX-0479 / Rheumatoid arthritis and
Slide 8: Evolution of BTK Targeted Therapies
Evolution of BTK Targeted Therapies Degraders Non-Covalent Inhibitors NX-5948 Addressing NX-2127 Inhibitor Next Generation Pirtobrutinib Resistance Covalent inhibitors 1st Generation Acalabrutinib Covalent inhibitor Zanubrutinib Ibrutinib 8
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 BTK Inhibitors Is Evolving
Treatment-Emergent Resistance to BTK 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 Cells Calcium Ion Flux in TMD8 Cells Montoya et al., ASH 2022 11
Slide 12: Enzymatic and Structural Studies Confirm BTK Scaffolding Function
Enzymatic and Structural Studies of BTKi-Resistant Mutations Confirm BTK Scaffolding Function BTKi-resistant mutations V416L and L528W Mutations revealed by non-covalent inhibitors lack kinase activity interrupt the catalytic C-spine of the kinase domain 600 C481S Peptide Phos (RFU/min) T474I Kinase
Slide 13: BTK inhibitors Rendered Ineffective by Spectrum of Resistance Mutations
BTK inhibitors Rendered Ineffective by Spectrum of Resistance Mutations 150 150 BTK-WT TMD8 tumor cell killing BTK-C481S %Viability %Viability 100 100 BTK-C481R GI-50 (nM) BTK-V416L 0 Most potent 50 50 BTK-T474I Pirtobrutinib 19 24 84 4692 5000 5000 cell killing 0 BTK-L528W 0.01 0.1 1 10 100 1000 10
Slide 14: 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 15: 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 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-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 cell killing % BTK Remaining CD86 Expression (DMSO = 100)
Slide 18: Not All BTK Degraders Are Created Equal
Not All BTK Degraders Are Created Equal BTK Degradation Tumor Cell Killing GI-50 (nM) DC-50 (nM) 0 Most 0 Most NX-5948 0.04 0.20 0.59 0.13 0.06 0.25 potent NX-5948 1 2 2 2 3 5 potent NX-2127 2.08 9.46 9.19 3.86 1.94 1.70 200 NX-2127 7 24 31 17 13 10 1000 BeiGene Cmpd. 9 [2] 2.52 4.28 4.97 107.51 8.2
Slide 19: Proteomics Study Demonstrates NX-5948 is Selective for BTK
Proteomics Study Demonstrates NX-5948 is Selective for BTK Human TMD8 ABC DLBCL cells incubated for 6 h with 50 nM NX-5948 c-FLIP is an anti-apoptotic protein required to maintain survival of FDR adjusted p-value (-log10) c-FLIP BTK ABC DLBCL cells that is regulated by the BCR/NF-κB signaling axis B
Slide 20: No Significant Degradation of IKZF1/3 with NX-5948
No Significant Degradation of IKZF1/3 with NX-5948 at Therapeutically Relevant Concentrations Human T cells Human TCR stimulated T cells IKZF3 Degradation IKZF1 Degradation IL-2 Secretion 100 100 4 IL-2 (Fold change over % IKF3 Remaining %IKZF1 Remaining 75 stimulation alone) 75 3 50 50 2 25 25 1 0
Slide 21: Degradation of BTK by NX-5948 Correlates with Significant 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 22: NX-5948 Degrades BTK in Brain Microglia of Naïve Mice
NX-5948 Degrades BTK in Brain Microglia of Naïve Mice NX-5948 administered orally QD x 3 days to naïve C57BL/6J mice. BTK levels assessed 8 h after 3rd dose by flow cytometry. Microglia Perivascular Macrophage Monocytes and Macrophage 100 100 100 Vehicle **** NX-5948 10 mg/kg % BTK Remaining % BTK R
Slide 23: NX-5948 Degrades BTK and Prolongs Survival in a Mouse CNS Lymphoma Model
Oral Administration of NX-5948 Degrades BTK in Tumor Cells and Prolongs Survival in a Mouse Model of CNS Lymphoma 5 x 105 TMD8 cells implanted by intracranial injection on Day 0 NX-5948 administered orally QD Days 1-11 (left) or Days 1-54 (right) BTK levels assessed 24 h after the 11th dose by flow
Slide 24: NX-5948 Cellular Potency and Cross-species PK
NX-5948 Cellular Potency and Cross-species PK O O NH2 O H HN N N N H O N N N N N O N N Degradation Results BTK DC50 (Dmax): WT/C481S TMD8 cells @4h 0.32 nM (97%) / 0.21 nM (97%) BTK DC50 Primary human B Cells 0.034 nM (98%) Mouse Rat Dog Cynomolgus Monkey Clobs (mL/min/kg), 1 mpk IV bolus 6 31 68 39
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: 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 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 29: Nurix BTK Degrader: Two BTK Degraders to Cover the Landscape of B-Cell Malignancies
Nurix BTK Degrader: 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 30: Targeted Protein Degradation Has the Potential to Address Significant Limitations of Current Targeted Therapies
Targeted Protein Degradation Has the Potential to Address Significant Limitations of Current Targeted Therapies for Cancer Target Ligase Complex • The use of BTK inhibitors for treating B-cell malignancies Emergent BTKi-Resistant has led to the development of acquired mutations that confer Mutations
Slide 31: Thank you
Thank you
Nurix Therapeutics — 6th Annual Targeted Protein Degradation Summit (October 2023) on 6ix