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43rdAnnual J.P. Morgan Healthcare ConferenceSean McCarthy, D.Phil.Chief Executive Officer and ChairmanJanuary 15, 2025
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Forward-Looking Statements 2 This presentation may contain projections and other forward-looking statements regarding future events. All statements other than statements of historical facts contained in this presentation, including statements regarding our future financial condition, technology platform, development strategy, prospective products, preclinical and clinical pipeline and milestones, regulatory objectives, expected payments from and outcomes of collaborations, and likelihood of success, are forward-looking statements. Such statements are predictions only and involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. These risks and uncertainties include, among others, the costs, timing and results of preclinical studies and clinical trials and other development activities; uncertainties inherent in the initiation and enrollment of clinical trials; uncertainties on the availability and timing of data from clinical trials; the risk that initial clinical data may not reflect later clinical trial results; the unpredictability of the duration and results of regulatory review; the uncertainty of market acceptance for approved products and innovative therapeutic treatments; competition; the potential not to receive partnership milestone, profit sharing or royalty payments; the possible impairment of or inability to obtain intellectual property rights; possible safety or efficacy concerns with our drug candidates; and general business, financial and accounting risks and litigation. Because forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified and some of which are beyond our control, you should not rely on these forward-looking statements as predictions of future events. More information concerning us and such risks and uncertainties is available on our website and in our press releases and in our public filings with the U.S. Securities and Exchange Commission. We are providing this information as of its date and do not undertake any obligation to update or revise it, whether as a result of new information, future events or circumstances or otherwise. Additional information may be available in press releases or other public announcements and public filings made after the date of this presentation.This presentation concerns products that have not yet been approved for marketing by the U.S. Food and Drug Administration (FDA). No representation is made as to their safety or effectiveness for the purposes for which they are being investigated.
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Company SnapshotAddressing Major Unmet Need in Oncology 33 PROBODY®Platform: Unique antibody masking strategies for tumor localization and enhancement of therapeutic indexClinical Programs:•Wholly-Owned: CX-2051 (EpCAM ADC) and CX-801 (IFN-b)•Partnered: CX-904 (EGFR-CD3) – Amgen Co-developmentPartners: Bristol Myers Squibb, Amgen, Astellas, Regeneron, ModernaFinancials:~$118M cash balance as of Q3 2024 with cash runway into Q2 2026, excluding any potential milestones or new business developmentOrganization: ~70 employees; integrated R&D capabilities South San Francisco, CA
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Multi-Modality Pipeline of Masked PROBODY®Therapeutics 2025 Priority Focus on Development of CX-2051 (EpCAM ADC) in CRC 4 Commercial Rights2025 MilestonesPhase 1b/2Phase 1aIndicationTargetProduct CandidateInitial Phase 1 data in CRC in the first half of 2025Determine Phase 1b dose(s)Advanced CRCEpCAMCX-2051Initiate Keytruda®combinationInitial Phase 1 data in advanced melanoma in the second half of 2025Advanced MelanomaIFN-α2bCX-801Plans for Ph1a completion and potential Ph1b are pending resourcing and discussions with development partner, AmgenEGFR+ Solid TumorsEGFRxCD3CX-904 Clinical pipeline entering a data rich period in focused indications with high unmet needKEYTRUDA®is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA
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PROBODY®Platform Technology Enhances Therapeutic Index for Potent Biologics By Reducing On Target ToxicityThe First Masking Platform to:Demonstrate clinical responses Demonstrate molecular activation in patient biopsiesAchieve TCE clinical responses with minimal CRSIndustry Leading Platform Expertise:Clinically validated & proprietary substrate libraryMultiple fit-for-purpose proprietary masking technologiesApplication across multiple modalities (T-cell engagers, Antibody Drug Conjugates, Cytokines)5 Masking Limits Binding in Healthy TissuesMaskSubstrate linkerTarget Tumor Associated Proteases Remove Mask in TMEProteases in TumorTarget
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CX-2051: Masked PROBODY®ADC Targeting EpCAM
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EpCAM (Epithelial Cell Adhesion Molecule) has Potential as a Pan-Tumor ADC Target with High Expression in Colorectal Cancer (CRC) 7 EPCAM / Trop-1Cancer Cell NSCLCH-Score = 250TNBCH-score = 260 CRCH-Score = 300OvarianH-Score = 200 Tumor tissueLung Normal tissueBreast Colon Ovary •EpCAM highly expressed on cancer cells•Moderate expression in normal tissue•Functional role in cancer signaling
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EpCAM Has Been Clinically Validated But Not as a Systemic TherapySystemic therapies limited by high grade gastrointestinal toxicities 8 DLTs*PhaseMOACompanyAsset• Grade 3+ diarrhea from upper GI inflammation• Grade 3+ elevation in liver enzymes1EpCAM x CD3 BiTEAmgenSolitomab• Pancreatitis1EpCAM mAbXOMAING-1• Pancreatitis1EpCAM mAbGSK3622W94•VicineumTMfusion protein: anti-EpCAM scFv linked to a truncated form of Pseudomonas exotoxin A • Delivered by intravesical administration • ~40% 3-month complete response in bladder cancer Prior systemic EpCAMapproaches discontinued due to on-target toxicityLocally administered EpCAM therapies have been validated in the clinic•Removab®:EpCAM x CD3 bispecific• Delivered by intraperitoneal infusion • Approved for treatment of malignant ascites– Being relaunched in Europe by Pharmanovia Sesen BioInsys Therapeutics*Sources: Kebenko, et.al. 2018; de Bono, et. al. 2004
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9 CX-2051: A First in Class EpCAM Targeting ADCTopo-1 inhibitor payload selected for EpCAM-expressing indications including CRC•High affinity EpCAM antibody with masking efficiency >100x by ELISA•Validated protease-cleavable linker and with broad cleavability across multiple tumors •TAL payload-antibody linker designed to have similar cleavability profile as deruxtecan (DXd) and optimized for bystander effect•CAMP59 payload shows similar potency to DXd in multiple cell lines and preclinical models including CRC*Sources: Wei Let, et. al 2019, CytomX Internal Data L-ala-L-ala-L-ala (TAL) cleavable linkerCX-2051SDAR 8Maleimido caproylCAMP59Linker/payloadSubstrate linkersMasksTAL-CAMP59
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CX-2051 Leverages Masking to Open a Therapeutic Window for EpCAMMasking designed to mitigate on target EpCAM toxicities 10CR-1461 PDX CRC ModelDosing regimen: 6 mg/kg Q2W x 3 CX-2051(Masked)CX-2052Unmasked Improved TolerabilityImproved Tolerability CX-2052UnmaskedEquivalent EfficacyEquivalent Efficacy DoseOpen Therapeutic WindowOpen Therapeutic Window CX-2051(Masked)CX-2052(Unmasked)CX-2051(Masked)Dose(Q2Wx3)Not tolerated90 mpkTolerated 60 mpkTolerated 30 mpkNot toleratedTolerated10 mpkNHP Pilot toxPredicted Active Range*Sources: World ADC 2023, CytomX Internal Data
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CX-2051 Development Strategy Initially Focused in CRC 11 EPCAM / Trop-1Cancer Cell NSCLCH-Score = 250TNBCH-score = 260 CRCH-Score = 300OvarianH-Score = 200 Tumor tissueLung Normal tissueBreast Colon Ovary •EpCAM highly expressed on cancer cells•Moderate expression in normal tissue•Functional role in cancer signalingMasked PROBODY ADCs are designed to preserve the therapeutic index when target is expressed in normal tissue
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The CRC Market is Large with Significant Unmet NeedEpCAM expressed at high levels in >90% of patients 12 •124,000 CRC drug treatable cases in the U.S. annually •Over 90% of CRC cases estimated to have high EpCAM expression•CRC is 2ndleading cause of cancer death in the U.S.•Increased incidence and mortality in patients 50 years and younger•Increasing percentage of CRC cases classified as advanced at diagnosisSignificant Unmet Need In Colorectal Cancer Sources: Siegel, et. al, 2023, American Cancer Society, Colorectal Caner Statistics, 2023; 2029 Drug-treatable patient by tumor type from DRG = *EpCAM High = >50% IHC 2+/3+ 124,000 CRC patients>90% EpCAM High*CX-2051Initial Development Focus in CRC CytomX Internal prevalence study, EpCAM High ≥50% cells with 2+/3+ EpCAM Intensity
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CX-2051 CRC Development OpportunitiesReplace irinotecan (IRI) in 1L/2LNovel combinationsMonotherapy, e.g. in late-line CRC CRC Treatment Landscape CX-2051 has the potential to be a foundational CRC therapy MSS Metastatic CRC Landscape*1L2L3L+WT KRAS/WT BRAF(~40%)KRAS-mut(~50%)Bevacizumab + FOLFOXIRI or FOLFOXEGFR mAB + FOLFIRI or FOLFOXBRAF-mut(~6-7%)Encorafenib + CetuximabTrifluridine/tipiracil + BevacizumabBev. + FOLFIRI (post-OX);KRAS G12C inh. + EGFRmAB (KRAS G12C)Source: Package Inserts; Epidemiology data source: DRGFruquintinib; Regorafenib;Trifulridine/tipiracil*Excludes HER2 and NTRK mutations estimated at 5 – 7% of patients
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Significant Unmet Need and Poor Patient Outcomes in Late-line CRC 14 Median OS (months)Median PFS(months)DCR (%)ORR (%)Treatment LineTreatment7.12.044%2%3L+Trifluridine/tipiracil10.85.677%6%3LTrifluridine/tipiracil + Bevacizumab6.42.041%1%2/3L+Regorafenib7.43.756%2%4LFruquitinib•Single Agent ORR in 4th line CRC in low single digit percentages and less than 4 months progression free survival (PFS)•CX-2051 could potentially improve upon the approved standard of care in 3L/4L+ CRC•Future combinations provide opportunity to move to earlier lines of therapySources: Lonsurf®, Fruzaqla®, Stivarga®package inserts.
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CX-2051 Phase 1 Designed to Demonstrate Proof of Concept in CRCStudy commenced Q2 2024. Encouraging progress to date. Escalation continues. 15DL 1 & 2DL 3DL 4 DL 6Currently enrollingDL 7+Single patient cohorts at predicted sub-therapeutic dosesDoses predicted to be biologically active based on preclinical modelingPart 1: Phase 1 Dose Escalation, Q3W•Enrolling unselected, advanced CRC, generally 4L+•Currently enrolling 6thdose level; limited backfilling initiated•Current dose levels (DL) predicted to be in biologically active range•MTD/RP2D expected to be driven by potential Topo-1 payload toxicities including cytopenias, nausea/vomiting, diarrhea Part 1:Dose Escalation; Part 2: Dose ExpansionPatient Population:• Metastatic or locally advanced, unresectable disease• Measurable disease by RECIST v1.1• Unselected for EpCAM expression• No prior treatment with Topo-1 ADCPrimary Objectives:• Safety and tolerability of CX-2051• Determine the recommended Phase 2 dose (RP2D)Secondary Objectives include:• Objective response rate, Duration of response, Progression free survival, Disease control Rate, Overall survival CTMX-2051-101 OverviewDL 5
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Beyond CRC: CX-2051 is a “Pipeline in a Product” OpportunityBroad development potential in EpCAM+ indications 1680-83%CytomX Internal prevalence study, ≥50% cells with IHC 2+/3+ EpCAM Intensity2029 Drug-treatable patient by tumor type from DRG Potential Future Development AreasTNBC21,000 PatientsNSCLC206,000 PatientsGastric 31,000 PatientsOvarian 45,000 PatientsEndometrial 26,000 Patients79%83%83%73%80%% of Patients with EpCAM High Tumors (>50% IHC ≥ 2+/3+)>350,000 EpCAM+ Patients= *EpCAM High = >50% IHC 2+/3+ 124,000 CRC patients>90% EpCAM High*Initial Development Focus in CRC
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CX-2051 Phase 1a Goals & Next Steps2025 Goals:•Continued Phase 1 Dose escalation and potential backfills focused in advanced metastatic CRC•Initial Phase 1 data in advanced metastatic CRC in first half of 2025–Safety:Determine safety/tolerability profile, including characterization of on-target and payload toxicities–Efficacy: Initial signs of disease control and tumor reductions•Determine Phase 1b dose(s)Additional Development Opportunities:•CRC combinations including in earlier lines of therapy•Additional EpCAM-expressing indications beyond CRC, potentially selecting for EpCAM expression level17
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CX-801: Masked PROBODY®Cytokine, IFNα-2b
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IFNα-2b is a Powerful Cancer Immunotherapy With a Dual Mechanism of Action and Ideal Properties to Combine with PD-1 Therapy 19 Why IFN-2b?Mechanism of Action• IFN-2b provides an orthogonal activity to IL-12, IL-2 and IL-15in the cancer immunity cycle− IFN-2b can kill cancer cells directly leading to immunogenic cell death, and − IFN-2b stimulates antigen presenting cells to activate T cells –distinct from IL-2, IL-12, and IL-15 that are restricted to proliferative effects via IFN• Approved for treating melanoma (Sylatron ), renal (Avastin®+ IFN), and bladder cancer (Adstiladrin®)• Potential to treatCPI-resistant indications Adapted from Green et al., Mol. Ther. Onc. 2021IFNstimulatesIFNstimulates Dendritic cellsIFNinduces MHC-1IFNdirect killingIFNstimulates NK cells
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CX-801: Dually-Masked, Conditionally Activated PROBODY®IFN2b IFNα2b•Dual-mechanism of action•Proven single agent activity•Increases APCs to enhance PD-1 blockade20Masking & Substrates Design Strategy•Dual-masking strategy with steric and affinity mask (peptide) •1000X masking efficiency based on preclinical models•Preclinically, Probody IFNα is effectively unmasked in the tumorValidated, High Potential Target•Approved immunotherapy in multiple tumors•Enhanced anti-cancer activity in combination with PD-1•Limited clinical use due to poor tolerabilityCX-801Affinity MaskingSteric Masking(Fc Portion) EFFECTOR PRODOMAIN TARGET
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CX-801 Preclinical Profile Suggests Clinical Synergy with PD-1 and Enhanced Safety Compared to Unmasked IFNα2b 21 % Change in Tumor Volume from VehicleSingle Agent and Synergistic Activity with PD-1 Observed with Probody IFNα2B in Preclinical Models Source: Povinelli, et. al. SITC 2023 Anti-PD-1Pb-IFNα-A/D+ Anti-PD-14/2411/24>50% Change>50% ChangeMasking of IFNα Significantly Increases Tolerability and Lowers Peripheral ActivityMurine Models Each bar = 1 tumor from 1 modelIFNa-A/D(Unmasked)Pb-IFNa-A/D(Masked)DoseNot tolerated2400 gTolerated1200 gTolerated 500 gNot Tolerated20 gTolerated5 g
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CX-801 Preferentially Inflames the Tumor Microenvironment and Demonstrates Synergistic Activity with Anti-PD-1 22Cxcl10Gzmb Pb-IFNa-A/DComboAnti-PD-1Vehicle Lymph NodeSpleenMaskedVehicleUnmaskedMaskedVehicleUnmaskedCX-801 Stimulates T-Cell Activation Preferentially to Tumor MicroenvironmentT-cell Activation Source: Povinelli, et. al. SITC 2023 RNA-seq from Tumors IFN stimulated genes and markers of T-cell activationPhase 1 translational data key focus for clinical proof of concept
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Metastatic Melanoma Landscape 23 1LAnti-PD-1 mAB±Anti-CTLA-4 or Anti-LAG31, 2, 3, 4, 5BRAF WT (~50%)BRAF Mutations (~50%)BRAF inh. + MEK inh.Opdualag8Lifileucel (TIL)Salvage Chemotherapy (Decarbazine)92L+Ipi. + Nivo.6orPembrolizumab7High Unmet Need in PD-1 Refractory Melanoma Patients CX-801 has potential to enhance responsiveness to checkpoint inhibitors CX-801 Development Opportunities in MelanomaCombine with anti-PD-1 inhibitors in post-PD-1 setting–Improve on activity of PD-1 inhibitors (7% ORR)10–Safe and tolerable alternative to TIL therapyNovel IO combinations to enhance activity in earlier-line settings1 Robert et al. 2015; 2Robert et al. 2023; 3 Tawbi et al. 2022; 4Wolchock et al. 2017; 5Wolchock et al.2022; 6 VanderWalde et al.; 7 Olson et al. 2021 2023; 8Ascierto et al. 2023; 9 Robert et al. 2011
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Phase 1 Dose Escalation is Designed to Assess CX-801 Clinical Profile as Monotherapy and in Combination with KEYTRUDA®Monotherapy Dose EscalationCombination Dose Escalation Source: Package Insert - SYLATRONTM Focused in Advanced Melanoma CX-801 + Keytruda®DL 3CX-801 + Keytruda® DL 4CX-801 ≤ Monotherapy MTD/MAD + Keytruda®DL 1CX-801 + Keytruda®DL 2 CX-801Dose Level 1CX-801DL 2CX-801DL 3CX-801DL 5+CX-801DL 424Combination Dose Escalation to Occur in Parallel Upon Clearance of Certain Monotherapy Dose Levels•Announced 1stPatient Dosed in September 2024•Initial CX-801 Phase 1 translational data expected in the 2ndhalf of 2025Dose levels 2+ exceed approved doses of IFN Alpha in melanomaCurrently enrolling KEYTRUDA®is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USAKEYTRUDA®to be administered on approved dose and schedule
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CX-801 Phase 1a Goals & Next Steps2025 Goals:•Continued Phase 1 Dose escalation as monotherapy•Initiate CX-801 combination with KEYTRUDA®•Initial Phase 1 data in advanced melanoma in the second half of 2025–Safety:Determine safety/tolerability profile including vs. unmasked interferon–Efficacy: Translational and pharmacodynamic data consistent with interferon MOAAdditional Development Opportunities:•Earlier lines of therapy in melanoma in combination with PD-(L)1•Other indications with known clinical activity such as RCC and HNSCC•Indications not responsive or refractory to immunotherapies25KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA
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CX-904: Masked PROBODY®T-Cell Engager Targeting EGFR and CD3
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CX-904: Masked PROBODY®T-Cell Engager Targeting EGFR and CD3Format and therapeutic conceptSubstrate linkersMasksCD3EGFR•Finely tuned masks and protease substrates•Distinct “Prodomains” on EGFR and CD3 to optimize therapeutic window•Fc domain to mimic PK of approved T-cell engagers CX-904Fc 27 •Prevalent EGFR expression in many cancer types•CX-904 masked EGFR TCE designed to address large unmet need and market opportunity•Initial Phase 1a safety and monotherapy activity demonstrated supportive of masking•Opportunity to combine with immunotherapy or other targeted agentsTCE Designed to Address EGFR+ Tumors
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CX-904 Phase 1a Current Status>70 Patients enrolled to date, current focus on escalating to higher doses Target Dose: 0.007 mg – 6 mg(8 cohorts)Target Dose Level 1: 5 mgTarget Dose Level 2: 10 mgTarget Dose Level 3: 15 mgNon-Step DosingStep Dosing Key Eligibility Criteria• Age ≥ 18 years• Locally advanced/metastatic disease• Tumors with known EGFR expression; unselected• Measurable disease per RECIST 1.1• Adequate organ function• ECOG 0-1Key Objectives• PrimaryoSafety and tolerabilityoDetermine MTD and RP2D• SecondaryoAnti-tumor activityoPharmacokinetics• Indications enrolled include: CRC, PDAC, NSCLC, HNSCC, Gastric, Esophageal• Schedules tested with 1 or 2 steps with 7 or 14 days between successive doses to achieve target dose• Once target dose is reached, subsequent doses administered Q2W• Current step-dosing schedule:o3 mg -7d- 5 mg -7d – target doseCurrently Enrolling Source: 1.CytomX Internal Data 28 Target Dose Level 4
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CX-904 Phase 1 Summary & Next Steps 29 •Over 70 patients enrolled to date. The 15 mg target step-dose level has been cleared and the maximum tolerated dose has not been reached. •Current and 2025 enrollment prioritizing escalation to higher dose levels based on ongoing clinical observations to-date.•Plans for Phase 1a completion and potential advancement to Phase 1b are pending ongoing consideration of 2025 program resourcing given CytomX current capital constraints and discussions with our partner Amgen. Substrate linkersMasksCD3EGFRCX-904Fc
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30Company Priorities and 2025 Milestones
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Multi-Modality Pipeline of Masked PROBODY®Therapeutics 2025 Priority Focus on Development of CX-2051 (EpCAM ADC) in CRC 31 Commercial Rights2025 MilestonesPhase 1b/2Phase 1aIndicationTargetProduct CandidateInitial Phase 1 data in CRC in the first half of 2025Determine Phase 1b dose(s)Advanced CRCEpCAMCX-2051Initiate Keytruda®combinationInitial Phase 1 data in advanced melanoma in the second half of 2025Advanced MelanomaIFN-α2bCX-801Plans for Ph1a completion and potential Ph1b are pending resourcing and discussions with development partner, AmgenEGFR+ Solid TumorsEGFRxCD3CX-904 Clinical pipeline entering a data rich period in focused indications with high unmet needKEYTRUDA®is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA
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43rdAnnual J.P. Morgan Healthcare ConferenceSean McCarthy, D.Phil.Chief Executive Officer and ChairmanJanuary 15, 2025