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Blazing a New Path in Medicine Investor Presentation November 2023
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plans; our future performance, prospects and strategies; future conditions, trends, and other financial and business matters; our current and prospective drug candidates; the planned timing and conduct of the clinical trial programs for our drug
candidates; the planned timing for the provision of clinical updates and initial findings from our clinical studies; the potential benefits of our collaborations, including potential milestone and sales-related payments; the potential advantages of
our DELigase platform and drug candidates; the extent to which our scientific approach, our DELigase platform, targeted protein modulation, and Degrader- Antibody Conjugates may potentially address a broad range of diseases; the extent
animal model data predicts human efficacy; and the timing and success of the development and commercialization of our current and anticipated drug candidates. Forward-looking statements reflect Nurix's current beliefs, expectations, and
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statement. Such risks and uncertainties include, but are not limited to: (i) risks and uncertainties related to Nurix's ability to advance its drug candidates, obtain regulatory approval of and ultimately commercialize its drug candidates;
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Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. The statements in this presentation speak only as of the date of this presentation, even if subsequently made available by Nurix on its website or
otherwise. Nurix disclaims any intention or obligation to update publicly any forward-looking statements, whether in response to new information, future events, or otherwise, except as required by applicable law. Certain information contained in
this presentation relates to or is based on studies, publications, surveys and other data obtained from third-party sources and the Company's own internal estimates and research. While the Company believes these third-party sources to be
reliable as of the date of this presentation, it has not independently verified, and makes no representation as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. In addition, all of the market
data included in this presentation involves a number of assumptions and limitations, and there can be no guarantee as to the accuracy or reliability of such assumptions. Finally, while we believe our own internal estimates and research are reliable,
such estimates and research have not been verified by any independent source. 2
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 ligated to Degradation
target proteins to tag them for degradation by (TPD) the proteasome 3
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 IRAK4 other
inflammatory diseases GS-6791 TPD Oncology / autoimmune Undisclosed Multiple disease Undisclosed Undisclosed Multiple Undisclosed Undisclosed Multiple TPE CBL-B Immuno-Oncology NX-1607 DAC Undisclosed Oncology Multiple 4
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
research, antibody drug conjugates (ADCs) development, regulatory and commercial milestone payments Mid-single to low double-digit tiered royalties on future product sales Option for U.S. profit sharing and co- promotion on up to two
products arising from the collaboration 5
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 Targets Target 6
Difficult-to-Drug Targets Target 7 Target 8 Novel ligands identified for multiple unprecedented targets $52M in drug discovery milestones achieved as of 9/30/2023 Target 9 $20M licensing payment from Gilead for IRAK4 degrader
Target 10 Option to co-develop and co-promote 4 drug candidates 6 Note: Status of programs as of April 2023
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
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 destroying the
scaffolding function of the protein 8
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
treatment emergent resistance mutations to both covalent and BTK DEGRADATION non-covalent inhibitors & IMMUNOMODULATION BTK degraders may expand the market for BTK targeted agents into other B-cell malignancies such as DLBCL and potentially into
autoimmune diseases NX-5948 and NX-2127 are two distinct drugs with differentiated profiles, each with the potential to be multi-billion dollar B-cell malignancy therapeutic franchises 9
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 26,200 Chronic
Lymphocytic Waldenstrom's Mantle cell Marginal Zone Diffused Large Follicular Leukemia macroglobulinemia lymphoma Lymphoma B-Cell Lymphoma Lymphoma NX-2127 for aggressive NHL and advanced CLL NX-5948 potential in combination NX-5948 including BTK
inhibitor resistance NX-2127 in 3L+ NX-2127 mutations Goal: Expand role for BTK target Goal: Displace BTKi in indications where single-agent BTKi is standard of care therapy and address BTKi resistance mutations BTK, Bruton tyrosine kinase; DLBCL,
Diffuse large B cell lymphoma; CLL, Chronic lymphocytic leukemia, SLL, small lymphocytic lymphoma; MCL, Mantle cell lymphoma; WM, Waldenstrom's macroglobulinemia; MZL, Marginal zone lymphoma; FL, Follicular lymphoma; NHL, non-Hodgkin lymphoma
Estimates based on 2020 incidence from DRG, GlobalData and secondary research; EU comprised of France, Germany, Italy, Spain and UK 10
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 4000
Opportunity for Nurix 3000 BTK degraders to expand 2000 the market in other B cell malignancies and 1000 autoimmune diseases 0 2016 2017 2018 2019 2020 2021 2022 Ibrutinib Acalabrutinib Zanubrutinib 11
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
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
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 or a knock-in BTK
mutation (C481S) were incubated with NX-5948 for 24 hours, and BTK degradation was assessed by flow cytometry. 14 % BTK Remaining % BTK Remaining
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 domain C481S
600 T474I WT 400 M437R 200 L528W V416L 0 0 50 100 150 [ATP] ( M) 15 Montoya et al., ASH 2022 and unpublished data Kinase Activity Peptide Phos (RFU/min)
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 2000
Pirtobrutinib 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) 125 125 Acalabrutinib 3000 100 100 75 75 Zanubrutinib 4000 50 50 Nemtabrutinib 25 25 Ibrutinib Pirtobrutinib 0 0 0.001 0.01 0.1 1 10 100 1000 0.001
0.01 0.1 1 10 100 1000 Average of n = 3 independent Ibrutinib (nM) Pirtobrutinib (nM) experiments 72 hr time point 125 125 100 100 75 75 50 50 All inhibitors have resistance mutation liabilities 25 25 Acalabrutinib NX-5948 displays
potent cell killing and maintains suppression Zanubrutinib 0 0 of CD86 in the context of key resistance mutations 0.001 0.01 0.1 1 10 100 1000 0.001 0.01 0.1 1 10 100 1000 Acalabrutinib (nM) Zanubrutinib (nM) 16 Average of n = 3 independent
experiments +/- SEM BTK-WT BTK-C481S BTK-V416L BTK-T474I BTK-L528W CD86 Expression CD86 Expression (DMSO = 100) (DMSO = 100) % BTK Remaining CD86 Expression CD86 Expression CD86 Expression (DMSO = 100) (DMSO = 100) (DMSO = 100)
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 R MB ) N + BTK 100 60 DDB1 60 80 CRBN (1 M) + 40 40 CRBN 60 20 20 = 2.5 40 IC No CRBN 0 50 0 = 20 -20 -20 IC with CRBN (1 M) 0.00001 0.0001 0.001 0.01 0.1 1 50
0.00001 0.0001 0.001 0.01 0.1 1 0 [compound] uM -20 0.00001 0.0001 0.001 0.01 0.1 1 NX-2127 120 BTK L528W BTK T474I No CRBN 100 120 120 80 CRBN (1 M) + 120 100 100 60 No CRBN Positive Cooperativity ( >1) 100 80 80 40 80 CRBN (1
M) + Stable ternary complex 60 60 20 60 40 40 0 40 Induced protein-protein interactions 20 20 -20 20 = 3.2 = 3.9 Greater tolerance for reduced binary 0.00001 0.0001 0.001 0.01 0.1 1 0 0 0 -20 -20 -20
affinity 0.00001 0.0001 0.001 0.01 0.1 1 0.00001 0.0001 0.001 0.01 0.1 1 0.00001 0.0001 0.001 0.01 0.1 1 [compound] uM CRBN, cereblon; DDB1, DNA damage binding protein 1 (component of the ubiquitin ligase complex) % Probe Binding % Probe
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 & 450 mg biologically active dose DLBCL or MCL (n=20) Dose level 4 Evaluate PK/PD Prior anti-CD20 CIT + 1 LoT 300 mg Dose level 3 200 mg FL, MZL, WM (n=20) Dose level 2 2 prior LoT 100 mg Dose level 1 PCNSL (n=20) 50 mg Who
have progressed or had no response to 2 prior LoT Oral daily dosing BTK, Bruton tyrosine kinase; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; LoT, line of therapy; MCL, mantle cell
lymphoma; MZL, marginal zone lymphoma; PCNSL, primary CNS lymphoma; PD, pharmacodynamics; PK, pharmacokinetics; WM, Waldenstrom's macroglobulinemia 18
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) 5000
Dose escalation ongoing DLBCL 2500 in patients with MZL relapsed/refractory B cell 0 MCL malignancies 0 5 10 15 20 25 30 Day BTK levels are evaluated in real time in a FACS-based assay on whole blood from patients treated with NX-2127 19 BTK
MFI (Background subtracted)
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 Assess safety and tolerability Failed 2 or more prior treatments including a BTK inhibitor and CLL Phase 1b expansion cohort Identify maximum tolerated dose (MTD) regardless of baseline BTK ongoing for patients
currently on & biologically active dose mutation status (up to 40 pts) study Dose level 3 Evaluate PK/PD 300 mg DLBCL Phase 1b expansion cohort DLBCL (300 mg) ongoing for patients currently on Dose level 2 Failed 2 or more prior
treatments 200 mg study (up to 20 pts) Dose level 1 MCL Phase 1b expansion cohort 100 mg ongoing for patients currently on MCL (300 mg) study Dose level -1 Failed 2 or more prior treatments 50 mg including a BTK inhibitor Phase
1a dose escalation is ongoing for patients currently on Oral daily dosing (up to 20 pts) study with NHL BTK, Bruton tyrosine kinase; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell
lymphoma; MZL, marginal zone lymphoma; NHL, non-Hodgkin lymphoma; PCNSL, primary CNS lymphoma; PD, pharmacodynamics; PK, pharmacokinetics; WM, Waldenstrom's macroglobulinemia 20
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 therapy,
median (range) 5 (2-11) 4 (2-11) BTKi, n (%) 23 (100) 31 (86.1) Pirtobrutinib, n (%) 8 (34.8) 11 (30.6) BTKi and BCL2i, n (%) 18 (78.3) 19 (52.8) cBTKi, ncBTKi, and BCL2i, n (%) 7 (30.4) 7 (19.4) a BTK mutation present , n (%) 10 (48) 11
(35) C481 5 (24) 5 (16) L528W 4 (19) 4 (13) T474 3 (14) 4 (13) V416L 1 (5) 1 (3) a BCL2 mutation present , n (%) 4 (19) 4 (13) a PLCG2 mutation present , n (%) 0 (0) 1 (3.2) a Specific mutations are not additive as some patients have multiple BTK
mutations Mutations were tested by NGS centrally in those patients with available samples (n=31 in total population; n=21 in CLL population) Data cutoff: September 21, 2022 21
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 HMPCORE1 (Rules 10 15000
Based Medicine) 1250 10000 0 0 5000 0 5 10 15 20 25 30 LLOQ= 59-64 pg/mL 0 Days of treatment C1D1 C1D8 Visit BTK MFI in B cells (n=18) Plasma trough concentration (n=14) Daily treatment with NX-2127 resulted in a rapid and sustained