Nurix Therapeutics, Inc. · NASDAQ:NRIX
Nurix Therapeutics — ASH Event Presentation 2022
52 slides from Nurix Therapeutics's conference presentation, Dec 12, 2022
Slide 1: Nurix Therapeutics: Blazing a New Path in Medicine
Leader in Targeted Protein Modulation Nurix Therapeutics Blazing a New Path in Medicine ASH Event Presentation December 12, 2022
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 Harness ligases (TPE) to decrease specific protein levels Inhibit ligases to increase specific protein levels Targeted Protein Ubiquitin is ligate
Slide 4: Nurix Is Advancing Four Wholly Owned Clinical Programs
Nurix Is Advancing Four Wholly Owned Clinical Programs with a Deep Pipeline of Proprietary and Partnered Novel Targets MOA Drug program Target/delivery Therapeutic area Preclinical Phase 1 Phase 2 Phase 3 NX-2127 BTK-IKZF B-cell malignancies Degrader Oral TPD NX-5948 BTK B-cell malignancies Degrader
Slide 5: A First-In-Class Franchise of BTK Degraders: NX-2127 & NX-5948
A First-In-Class Franchise of BTK Degraders: NX-2127 & NX-5948 NX-2127 NX-5948 BTK DEGRADATION BTK DEGRADATION & IMMUNOMODULATION • Active against clinically emergent BTK • Active against clinically emergent BTK inhibitor-resistant mutations inhibitor-resistant mutations • Robust BTK degradation and
Slide 6: Today's Agenda
Today's Agenda NX-2127 Clinical Data: First Targeted Protein Degradation Drug in Hematologic Malignancies NX-2127-001, a first-in-human trial of NX-2127, a Anthony Mato, M.D. MSCE Bruton’s Tyrosine Kinase-targeted protein degrader, Former Director, CLL in patients with relapsed or refractory chronic
Slide 7: NX-2127-001 first-in-human trial in relapsed or refractory CLL and B-cell malignancies
NX-2127-001, a first-in-human trial of NX-2127, a Bruton’s Tyrosine Kinase-targeted protein degrader, in patients with relapsed or refractory chronic lymphocytic leukemia and B-cell malignancies Anthony Mato,1 William G. Wierda,2 Weiyun Ai,3 Ian Flinn,4 Michael Tees,5 Manish R. Patel,6 Krish Patel,7
Slide 8: Acquired resistance to BTK inhibitors presents a new and growing challenge in CLL
Acquired resistance to BTK inhibitors presents a new and growing challenge in the treatment of CLL • Targeted therapy focusing on two key pathways (BTK/BCL2) is standard of care in CLL and has changed the treatment landscape in front-line and relapsed/refractory settings • Emerging patterns of resis
Slide 9: Resistance to non-covalent BTK inhibitors presents a new challenge
Resistance to non-covalent BTK inhibitors presents a new and growing challenge to treatment BTK mutations identified from patients progressing on the non-covalent inhibitor pirtobrutinib Wang et al. N Engl J Med 2022;386:735–43 9
Slide 10: NX-2127: first-in-class targeted protein degrader of BTK
NX-2127: first-in-class targeted protein degrader of BTK Utilizing the ubiquitin-proteasome pathway to degrade BTK, a well-validated target in B-cell malignancies BTK, Bruton tyrosine kinase; CRBN, cereblon 10
Slide 11: NX-2127 has the potential to address emerging BTK mutations
NX-2127 has the potential to address emerging BTK mutations • NX-2127 degrades wild-type and mutant BTK, including the recently described kinase dead mutations • NX-2127 kills DLBCL tumor cells harboring wild-type BTK and mutant BTK BTK-WT BTK-C481S BTK-V416L BTK-T474I BTK degradation Cell viability
Slide 12: NX-2127-001: trial design
NX-2127-001: trial design Phase 1 trial in adults with relapsed/refractory B-cell malignancies Dose escalation Dose expansion options • CLL Phase 1b expansion cohort at 100 mg dose Objectives: CLL failed 2 or more prior treatments − MTD not established • Assess safety and tolerability including a BT
Slide 13: NX-2127-001: patient disposition
NX-2127-001: patient disposition Phase 1 trial in adults with relapsed/refractory B-cell malignancies Screened • Causes for screen failure: (N=54) − Inadequate organ reserve (n=5) Screen failure − Subject withdrawal (n=3) (n=18) − Disease progression/other cancer (n=2) − Administration of prohibited
Slide 14: 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 15: 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 16: 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 17: NX-2127 preliminary efficacy (patients with CLL)
NX-2127 preliminary efficacy (patients with CLL) 100 Two or more prior treatments including: Disease-evaluable patients n=15 BTKi Maximim % change in SPD from baseline Objective response rate,a % (95% CI) 33 (12–62) BTKi and BCL2i (‘Double exposed’) 50 Best response, n (%) * BTK mutation at baseline
Slide 18: Outcomes and time on therapy with NX-2127 (patients with CLL)
Outcomes and time on therapy with NX-2127 (patients with CLL) Responses seen in double and triple exposed patients * * * Two or more prior treatments including: * BTKi * BTKi & BCL2i (‘Double exposed’) cBTKi, ncBTKi, & BCL2i (‘Triple exposed’) Treatment ongoing Patient * * BTK BTK mutation detected
Slide 19: 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 20: Conclusions
Conclusions • Early Phase 1 data of NX-2127, a first-in-class BTK degrader with immunomodulatory activity, demonstrates BTK degradation and clinically meaningful responses independent of prior treatments or BTK mutational status − ORR 33% (95% CI 12–62%) in heavily pre-treated patients with relapsed
Slide 21: Kinase Dead BTK Mutations Confer Resistance but Are Susceptible to BTK Degraders
Kinase Dead BTK Mutations Confer Resistance to Covalent and Noncovalent BTK Inhibitors but Are Susceptible to Clinical Stage BTK Degraders Skye Montoya, Jessie Bourcier, Meghan C. Thompson, Mark Noviski, May Tan, Eric Wang, Xiaoli Mi, Nivetha Brathaban, Carla Barrientos Risso, Daniel Tsai, Jordan Ye
Slide 22: Diverse BTK mutations cause resistance to covalent & non-covalent BTK inhibitors
Diverse BTK mutations cause resistance to covalent & non-covalent BTK inhibitors
Slide 23: Several BTK mutations abrogate BTK phosphorylation
Several BTK mutations abrogate BTK phosphorylation Questions: 1. What is the impact of BTK drug resistant mutants on BTK enzymatic activity & BCR signaling? 2. How can we overcome resistance to BTK enzymatic inhibitors? Wang, Mi, Thompson, et al. NEJM 2022
Slide 24: Emerging BTKi-resistant mutations abolish BTK kinase activity
Emerging BTKi-resistant mutations abolish BTK kinase activity How do these mutations activate BCR signaling despite lack of BTK kinase activity?
Slide 25: Proteomic characterization of BTK drug resistance mutants
Proteomic characterization of BTK drug resistance mutants
Slide 26: Kinase dead BTK mutants recruit unique interacting proteins
Kinase dead BTK mutants recruit unique interacting proteins
Slide 27: Can we target the scaffold function of BTK?
Can we target the scaffold function of BTK?
Slide 28: NX-2127: a first-in-class targeted protein degrader of BTK
NX-2127: a first-in-class targeted protein degrader of BTK CRBN, cereblon 28
Slide 29: NX-2127 binds to BTKi resistance mutants
NX-2127 binds to BTKi resistance mutants NX-2127 120 NX-2127 Pirtobrutinib Ibrutinib BTK BTK Degrader Non-covalent Inhibitor 100 % Probe Binding Covalent Inhibitor 80 Proteins NX-2127 60 IC50 (nM) IC50 (nM) Kinact/Ki (M-1*s-1) 40 20 WT 9 0.7 2 x 105 0 -20 C481S 19 0.8 6 nM (IC50) 01 10 1 1 01 01 1 0
Slide 30: NX-2127 induces positive cooperativity between BTK and CRBN
NX-2127 induces positive cooperativity between BTK and CRBN BTK WT 120 100 % Probe Binding 80 BTK No CRBN DDB1 60 CRBN 40 + CRBN (1 μM) 20 α = 2.5 IC50 No CRBN 0 α= -20 IC50 with CRBN (1 μM) 0.00001 0.0001 0.001 0.01 0.1 1 NX-2127 BTK T474I BTK L528W 120 120 • Positive Cooperativity (α>1) 100 100 %
Slide 31: NX-2127 degrades both wild-type and kinase dead mutant BTK
NX-2127 degrades both wild-type and kinase dead mutant BTK and suppresses Ca2+ signaling
Slide 32: NX-2127 suppresses downstream biomarkers and displays potent cell killing
NX-2127 suppresses downstream biomarkers and displays potent cell killing Cell viability
Slide 33: BTK degradation by NX-2127 overcomes pirtobrutinib resistance mutations in a patient
BTK degradation by NX-2127 overcomes pirtobrutinib resistance mutations in a patient • 73 year-old man diagnosed with CLL at age 59. • Treated with pirtobrutinib on clinical trial after prior treatment with FCR, ibrutinib and venetoclax. • After initial response to pirtobrutinib had PD on therapy (d
Slide 34: Treatment with NX-2127 leads to BTK degradation and clinical response irrespective of mutation status
Treatment with NX-2127 leads to BTK degradation and clinical response irrespective of mutation status in CLL patients 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 BTK Kinase Dead 50 5000 BT
Slide 35: Conclusions
Conclusions • Multiple BTK mutations (including L528W, V416L, M437R, and T474I) confer resistance to noncovalent and covalent BTK inhibitors. • We define distinct classes of BTK alterations based on enzymatic activity and a differential interactome. • Kinase dead BTK mutations interact with other ki
Slide 36: NHL Update: First Report of NX-2127 in non-GCB DLBCL
CASE STUDY NHL Update First Report of Targeted Protein Degrader NX-2127 Initial experience in non-GCB in Diffuse Large B cell DLBCL patients Lymphoma (DLBCL) 36
Slide 37: 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 ~65% 5-year survival1,2,3 DLBCL treatments are the same for all patients, even though it is
Slide 38: 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 39: Two Heavily Pre-Treated Patients with Non-GCB DLBCL Enrolled in NX-2127 Phase 1
Two Heavily Pre-Treated Patients with Non-GCB DLBCL Enrolled in NX-2127 Phase 1 Dose-Escalation Patient #1 Patient #2 Non-GCB (ABC subtype) Subtype Non-GCB (ABC subtype) Double-hit, BCL2/BCL6 Dose 100 mg 300 mg Time on Study 3.5 months 5 months and ongoing Priors 4 4 Response(s) Stable Disease (SD)
Slide 40: Rapid BTK Degradation and Confirmed Complete Response Following NX-2127 Therapy
Rapid BTK Degradation and Confirmed Complete Response Following NX-2127 Therapy FDG-PET CT Scan Disease Assessment Baseline Week 16 % BTK remaining in CD19+ B cells 100 Bladder Bladder (Relative to C1D1 Pre-dose) Patient #2 300 mg 80 % BTK Remaining 60 40 20 0 0 5 10 15 20 25 30 Day % BTK calculated
Slide 41: NX-2127: First-in-Class BTK Degrader Demonstrates Early Signs of Clinical Activity in CLL and NHL
NX-2127: First-in-Class BTK Degrader Demonstrates Early Signs of Meaningful Clinical Activity in Both CLL and NHL Chronic lymphocytic leukemia (CLL) • Objective responses observed in heavily pretreated CLL patients including those receiving prior covalent BTK inhibitors, non-covalent BTK inhibitors,
Slide 42: NX-5948: Initial PK/PD data
NX-5948 Initial PK/PD data 42
Slide 43: 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.K. CLL/SLL without C481 mutation • Assess safety and tolerability (up to 20) • Plans to i
Slide 44: Preliminary Data Suggests NX-5948 Exhibits Linear PK and Supports Daily Dosing
Preliminary Data Suggests NX-5948 Exhibits Linear PK and Supports Daily Dosing • Half-life ~12 hours 15 50 mg plasma conc (ng/mL) Mean (±SE) NX-5948 100 mg 12 • Tmax of 2-3 hours 9 • Exposures (both AUC 6 and Cmax) increase linearly with dose 3 0 0 4 8 12 16 20 24 Nominal Time (h) 44
Slide 45: NX-5948 Induces Rapid and Robust BTK Degradation in All Patients
NX-5948 Induces Rapid and Robust BTK Degradation in All Patients BTK Levels in Circulating B cells BTK Levels in Circulating B cells 17500 15000 Patient 1 (50 mg) * 15000 Patient 2 (50 mg) Patient 2 (50 mg) 12500 Patient 3 (50 mg) * Patient 7 (100 mg) 12500 Patient 4 (50 mg) * 10000 Patient 8 (100 m
Slide 46: NX-5948: BTK Degrader Without Immunomodulatory Activity Demonstrates Rapid BTK Degradation
NX-5948: BTK Degrader Without Immunomodulatory Activity Demonstrates Rapid and Sustained BTK Degradation Phase 1a Dose Escalation • Early evidence of target engagement • Rapid and sustained BTK degradation in all patients • No evidence of immunomodulatory associated adverse events (e.g. neutropenia)
Slide 47: Wrap up
Wrap up ” nurix
Slide 48: NX-2127 Combines Activity of Two Blockbuster MOAs: BTK Inhibition and Immunomodulation
NX-2127 Combines Activity of Two Blockbuster MOAs: BTK Inhibition and Immunomodulation Established Targets Immuno- BTK modulatory (e.g., Ibrutinib-$7B) Both (e.g., lenalidomide-$13B) B-CELL MALIGNANCIES ANNUAL INCIDENCE (US & EU) CLL WM MCL MZL DLBCL FL Chronic Lymphocytic Leukemia (CLL) 39,700 Diff
Slide 49: Delivering Key Clinical Milestones in 2022
Delivering Key Clinical Milestones in 2022 Targeted Protein Degradation Targeted Protein Elevation NX-2127 NX-5948 NX-1607 DeTIL-0255 • Initiate Phase 1b trial • Dose first patient in • Present Phase 1a • Dose first patient in in mid-2022 Phase 1a trial in PK/PD in H2 2022 Phase 1 trial in H1 H1 202
Slide 50: Delivering Key Clinical Milestones in 2022
Delivering Key Clinical Milestones in 2022 Targeted Protein Degradation Targeted Protein Elevation NX-2127 NX-5948 NX-1607 DeTIL-0255 Initiate Phase 1b trial Dose first patient in Present Phase 1a Dose first patient in in mid-2022 Phase 1a trial in PK/PD in H2 2022 Phase 1 trial in H1 H1 2022 20
Slide 51: Nurix Today
Nurix Today • World-class small molecule discovery capabilities focused on ligase-based medicines • Four wholly owned and internally developed Phase 1 clinical assets and five preclinical programs • Pharma partners dedicated to pursuing first-in-class and best-in-class drugs funding an additional te
Slide 52: Q&A
Q&A 52