Slide 1: Xencor R&D Strategy Call September 9, 2024
® Xencor R&D Strategy Call September 9, 2024
Slide 2: Today's Agenda
2 Today’s Agenda Overview Rationale for bispecific antibodies in autoimmune & inflammatory diseases New pipeline programs: B-cell depleting T-cell engagers Plamotamab (CD20 x CD3) XmAb657 (CD19 x CD3) New pipeline programs: TL1A portfolio XmAb942 (Xtend TL1A) XmAb TL1A x IL-23 Potential first-in-cla
Slide 3: Forward Looking Statements
3 Forward Looking Statements Certain statements contained in this presentation, other than statements of historical fact, may constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements include, but are not limited to, statements
Slide 4: Proven Power of XmAb Engineering: Proteins By Design
4 • XmAb Fc Domains augment native immune functions in molecules and/or control their structure, while preserving desired attributes • XmAb engineered antibodies are designed to solve complex biologic problems • Strong patent portfolio with over 1,600 patents issued and pending worldwide • Oncology:
Slide 5: Xencor's Disciplined Drug Development Strategy
5 World-leading protein engineers and proven XmAb® Fc platforms, supported by strong financial position of $585.0* million Experienced drug development team deliver rapid proof-of-concept clinical studies Rapidly prototype and optimize XmAb® drug candidates, designed with purpose to solve complex bi
Slide 6: Xencor pipeline programs
6 Program Targets XmAb® Platforms Indications Discovery Preclinical Phase 1 Phase 2 Phase 3 Solid Tumor Oncology: T-cell Engagers (CD3 & CD28) XmAb819 ENPP3 x CD3 2+1 Bispecific ccRCC XmAb808 B7-H3 x CD28 2+1 Bispecific, Xtend Prostate cancer, oncology XmAb541 CLDN6 x CD3 2+1 Bispecific, Xtend Ovari
Slide 7: Rebalanced Portfolio Optimized for XmAb Drug Development
7 Rebalanced Portfolio Optimized for XmAb® Drug Development Validated targets across autoimmune disease, leveraging XmAb engineering Engineering Complexity Biological Uncertainty DiscontinuedNew Clinical Stage CD20 x CD3 Plamotamab Xtend TL1A XmAb942 Oncology CD28 TCEs PD1 x ICOS XmAb104 PD1 x CTLA4
Slide 8: Rationale for bispecific antibodies in autoimmune and inflammatory diseases
8 ®Rationale for bispecific antibodies in autoimmune and inflammatory (A&I) diseases
Slide 9: New Era Emerging for Bispecific Antibody Drug Development in A&I
9 ACCESSDOSINGMANUFACTURING REGULATORYPROOF OF CONCEPTSCIENTIFIC RATIONALE New Era Emerging for Bispecific Antibody Drug Development in Autoimmune and Inflammatory Diseases Recent clinical and academic studies have highlighted exciting clinical potential of both mechanisms Multiple related signaling
Slide 10: Well Validated Targets and Bispecific Antibody Formats
10 Well Validated Targets and Bispecific Antibody Formats Could Enable New Biology to Create Breakthrough Medicines Combination therapy using two approved antibodies showed additive efficacy in Phase 2 in colitis (Janssen) and new real-world multicenter studies Highly potent B-cell depletion demonst
Slide 11: Deep B-Cell Depletion with T-cell Engagers Could Help Reset the Immune System
11 Deep B-Cell Depletion with T-cell Engagers Could Help “Reset” the Immune System for Patients with Autoimmune Disease B-cell antigen (e.g., CD19, CD20) B-cell depletion T-cell activation against autoreactive B cell XmAb® Bispecific Antibody Autoreactive B-Cell Diseases1 Cytotoxic perforins & granz
Slide 12: XmAb CD20 & CD19 TCEs Can Address Significant Unmet Needs
12 XmAb® CD20 & CD19 TCEs Can Address Significant Unmet Needs for Autoimmune Disease Responsive to Targeted B-Cell Depletion1 Currently >$20bn in annual disease modifying drug spend for treatment of rheumatoid arthritis within the US12 Ocrevus the market leader in US/EU5 with 24% global patient shar
Slide 13: Rheumatoid Arthritis: Where are we and where do we need to go?
13 ® Rheumatoid Arthritis: Where are we and where do we need to go? Roy Fleischmann, MD MACR Adjunct Professor of Medicine University of Texas Southwestern Medical Center Medical Director, Metroplex Clinical Research Center Dallas, Texas
Slide 14: Immunopathogenesis of Rheumatoid Arthritis
14 *ACPA = anti-citrullinated protein antibody. Detected as anti-CCP Ab. Citrulline is a post-translational modification of arginine, e.g. at inflammatory sites Rituximab IL6 inhibitors Abatacept 2000s Methotrexate 1980s Gold 1930sAspirin 1898 Sulfasalazine 1940s TNF inhibitors 1998 JAK inhibitors 2
Slide 15: Rheumatoid Arthritis Manifestations
15 Rheumatoid Arthritis Manifestations • Systemic, inflammatory polyarthritis that leads to joint destruction, deformity, and loss of function. • Pathology involves synovial membranes and peri-articular structures of joints, typically resulting in uncontrolled inflammation with pannus formation and
Slide 16: Even with the Most Effective Medications, 40% of RA Patients Do Not Reach Remission
16 Even with the Most Effective Medications, 40% of RA Patients Do Not Reach Remission Even If They Continue with the Medication (AO) 0 20 40 60 80 100 SELECT-COMPARE: UPA + MTX vs ADA + MTX. Vertical line at Week 26 indicates the end of the PBO-controlled period. AO As Observed PBO placebo UPA Upad
Slide 17: Consequences of Inadequately Treated RA
17 RA patients have an increased risk of CV events1,2. Risk of CVD death 50% higher vs. general population, which correlates with CV risk factors and inflammation3,4. DMARDs reduce CV event risk5,6 if disease activity reduced7. Severe disease activity in RA patients is correlated with a 70-fold incr
Slide 18: Unmet Needs in the Treatment of RA
18 Unmet Needs in the Treatment of RA Current Landscape Trends • ~ 1,300,000 patients with RA in the US2 • This means that ~ 200,000 - 230,000 patients in the U.S. alone require new therapeutic options • We do not have the necessary tools to predetermine which patient will have a complete clinical r
Slide 19: Serious infection rates and response across RA therapies
19 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Upadacitinib 30 mg n=314 Upadacitinib 15 mg n=650 Adalimumab 40 mg n=327 Rituximab 2x1000mg n=170 Rituximab 2x1000mg n=308 Adalimumab 40 mg n=162 Tocilizumab 8mg/kg n=163 SELECT-EARLY SELECT-COMPARE (+MTX) SERENE (+MTX) REFLEX (+MTX) ADACTA Serious Infection Rate Med
Slide 20: New Therapies on the Horizon in RA
20 New Therapies on the Horizon in RA JAK inhibitors Molecular degraders Potent B cell inhibitors Anti BLISS/APRIL T-Cell Engagers CAR-Ts PD-1 agonistsNeonatal Fc receptor inhibitors CD40 inhibitors
Slide 21: Favorable Benefit/Risk Profile for Patients with Rheumatoid Arthritis
21 A Highly Effective Medication with a Risk Profile That Can Be Mitigated, Has a Very Favorable Benefit/Risk Profile for Patients with Rheumatoid Arthritis Benefit Risk Infection Malignancy Major adverse CV events Venous thrombosis Other adverse events Signs / symptoms Quality of life / function Pr
Slide 22: New Pipeline Programs: B-cell Depleting T-cell Engagers
22 ® New Pipeline Programs: B-cell Depleting T-cell Engagers Plamotamab (CD20 x CD3) XmAb657 (CD19 x CD3)
Slide 23: Plamotamab: Phase Ready, Subcutaneous CD20 x CD3 BsAb
23 Plamotamab Phase 2 Ready, Subcutaneous CD20 x CD3 BsAb Positioned for SuccessXmAb® CD20 x CD3 Bispecific Design • Plamotamab designed in a 1+1 format and selected for extended activity and favorable tolerability observed in NHPs • Human half-life ~18 days; estimated 80% SC bioavailability • Robus
Slide 24: Single Dose of Plamotamab in NHPs: Durable B-cell Depletion
24 Day 0 (Predose) Day 4 Day 8 Day 30 0 1 2 3 B ce ll / T c el l ( C D 40 + / C D 8+ ) Low dose High dose Single Dose of Plamotamab in NHPs Durable B-cell Depletion Observed in Blood and Lymphoid Organs Blood B cells Lymph node B cellsBone marrow B cells Days post-dose C D 40 + B c el ls (v s ba se
Slide 25: >95-99% Peripheral B-cell Depletion Observed in Lymphoma Patients
25 >95-99% Peripheral B-cell Depletion Observed in Lymphoma Patients with IV & SC Plamotamab in Phase 1 Monotherapy Study • Patients were identified (N=5) that had baseline absolute B-cell count > 30 cells/µL in the blood • >90% reductions in B-cell count also observed at lower doses Dose B -C el l
Slide 26: Phase 1 Monotherapy Study of Plamotamab Patient Characteristics
26 Phase 1 Monotherapy Study of Plamotamab Heavily Pre-Treated Population with High Rates of Prior CAR-T Characteristics RD (IV) (n = 35) SC all cohorts (n = 20) Age, median (range) 69 (36-86) 67 (27-90) Baseline ECOG 0, n (%) 13 (37.1) 7 (35.0) 1 19 (54.3) 13 (65.0) 2 3 (8.6) 0 Bulky disease at stu
Slide 27: Plamotamab ORR Compared to Commercial CD20 x CD3
27 53% 44% 63% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Plamotamab SC Epcoritamab SC North America Epcoritamab SC Europe Epcoritamab SC ROW Plamotamab ORR Compared to Commercial CD20 x CD31 Regional differences in lymphoma prior therapy markedly impact outcomes 1 No head-to-head clinical trial ha
Slide 28: Lower Grade CRS Observed, Compared to Commercial CD20 x CD3
28 No Grade 3 CRS and Lower Grade CRS Observed, Compared to Commercial CD20 x CD31 Epcoritamab SC CRS2Plamotamab SC CRS Pooled cohorts 1 No head-to-head clinical trial has been conducted evaluating plamotamab against epcoritamab. Differences exist between trial design and patient populations, and ca
Slide 29: Plamotamab: Plan for Phase 1b/2a Rheumatoid Arthritis Study Start
29 Plamotamab: Plan for Phase 1b/2a Rheumatoid Arthritis Study Start Maximal efficiency to clinical proof of concept in multi-drug resistant rheumatoid arthritis (MDR-RA) • Quickly refine priming/step-up dosing regimens used in lymphoma studies • Assess SC and IV routes, and pre-medication regimen i
Slide 30: XmAb657 CD19 x CD3 Optimized for Autoimmune Disease
30 Positioned for SuccessRational XmAb® Design XmAb657 CD19 x CD3 Optimized for Autoimmune Disease Bispecific Fc Domain Ongoing NHP studies have shown effective B-cell depletion with single dose • Broad opportunity set of disease indications supports multiple development pathways for success • EULAR
Slide 31: Single Dose of XmAb657 in NHPs: Deep B-cell Depletion
31 0 7 14 21 28 0 20 40 60 80 100 5000 10000 Days post administration B c el ls /μ L of b lo od Single Dose of XmAb657 in NHPs Deep B-cell Depletion Sustained for at Least 28 Days XmAb 657 Single IV Dose (low) XmAb657 Single IV Dose (high) * * * * * * * *** Peripheral blood 0 7 14 21 28 0 20 40 60 8
Slide 32: Deep B-Cell Depletion in Lymph Nodes in NHPs Confirmed by CD19+ IHC
32 XmAb657: High IV Single DoseXmAb657: Low IV Single Dose Pre-dose Day -14 Study Day 8 Study Day 29 CD19+ 1x 5x 5x 5x1x 1x 1x 5x 5x 5x1x 1x Deep B-Cell Depletion in Lymph Nodes in NHPs Confirmed by CD19+ IHC Pre-dose Day -14 Study Day 8 Study Day 29 CD19+ CD19 IHC reagent antibody non-interfering w
Slide 33: XmAb657: Rationally Designed for Autoimmune Disease
33 XmAb657: Rationally Designed for Autoimmune Disease FIH Planned 2H’25 • Has been observed to demonstrate deep and durable B-cell depletion in NHPs, enabled by potentially best-in-class pharmacokinetics • Has been well tolerated in NHP with no clinical signs of CRS • GMP production campaign initia
Slide 34: New Pipeline Programs: TL1A Portfolio
34 ® New Pipeline Programs: TL1A Portfolio XmAb942 (Xtend TL1A) XmAb TLA1 x IL-23
Slide 35: Inflammatory Bowel Disease is a Devastating Disease with Significant Unmet Need
35 Inflammatory Bowel Disease (IBD) is a Devastating Disease with Significant Unmet Medical Need Abdominal pain Diarrhea Rectal bleeding Weight loss 1 Clarivate 2 GlobalData 3 Prescient whitepaper Two common forms: Crohn’s disease Ulcerative colitis Economic burden estimated at $5.4B in 20232 ~3
Slide 36: Development of XmAb942 and XmAb TL1A x IL-23 for IBD
36 Development of XmAb942 and XmAb TL1A x IL-23 for IBD Phase 2 TL1A Studies and VEGA Study Support Strategy XmAb942 Design XmAb TL1A x IL-23 Design RG6631 Phase 2 TUSCANY (Roche TL1A) (cross UC study comparison of Endoscopic Improvement)1 Xtend + FcKO Bispecific Fc Domain VEGA Ph2a (Clinical Remiss
Slide 37: Discovery Campaign for Anti-TL1A
37 Binding kinetics human & cyno TL1A Functional blockade (TF-1 apoptosis inhibition) Humanization, Biochemical evaluation, Developability assessments Functional assays, Immunogenicity risk assessment, NHP PK Nomination 25-50 8-10 XmAb lead + 3 alternates >1000 # of clones per stage Discovery Campai
Slide 38: Xtend Fc: Validated Half-Life Extension Technology
38 Xtend Fc: Validated Half-Life Extension (HLE) Technology Enabling Potential Best-in-Class Anti-TL1A Clinically validated with significantly improved half-life and dose frequency • Ultomiris half-life extended >4x as compared to Soliris; maintenance dose frequency reduced by 4X1 • VRC01LS half-lif
Slide 39: XmAb942: Novel High-Affinity Anti-TL1A mAb
39 XmAb942: Novel High-Affinity Anti-TL1A mAb Designed for Extended Half-Life, Under Development for the Treatment of IBD • XmAb942 utilizes Xtend Fc domain technology with potentially class-leading potency • Half-life in non-human primate studies >22 days supports Q8W to Q12W dosing in humans • Hig
Slide 40: XmAb TL1A x IL-23 to Have First-in-Class Potential
40 XmAb® TL1A x IL-23 to Have First-in-Class Potential First-in-Human Study Planned in 2026 TL1A Activity 0.0 01 0.0 1 0.1 1 10 10 0 1 2 3 4 Concentration (nM) Fo ld in du ct io n IL-23 Activity • Rapidly prototype in multiple formats • Optimize and tune for biological activity IL-23 Ab Control TL1A
Slide 41: Xencor Positioned for Best-in-Class TL1A Portfolio in IBD Market
41 Xencor Positioned for Best-in-Class TL1A Portfolio in $23bn+ Global IBD Market1 Tulisokibart2,3 ≈ 2027 IV Induction and Q4W Dosing with Less Potency1st RG66314,5 TEV-485746 XmAb942 (Xtend TL1A) XmAb® TL1A x IL23 Q4W Dosing and High Rate of Immunogenicity2nd Q8W+ SC Dosing with Leading PotencyBest
Slide 42: Potential First-in-Class T-Cell Engagers in Solid Tumor Oncology
42 ®Potential First-in-Class T-Cell Engagers in Solid Tumor Oncology
Slide 43: XmAb T-Cell Engager Programs Designed to Address Unmet Need
43 XmAb® T-Cell Engager Programs Designed to Address Unmet Need with Potential Across Multiple Tumor Types XmAb819 (ENPP3 x CD3) • Engineered for greater selectivity for ENPP3- expressing tumor cells compared to normal cells, which also express ENPP3 at lower levels • In development for patients wit
Slide 44: XmAb819 Status Update: Initial Data in Dose Escalation in ccRCC
44 XmAb819 Status Update1: Encouraging Initial Data in Ongoing Dose Escalation in ccRCC XmAb819 Potential first-in-class ENPP3 x CD3 Dose escalation on-track with RECIST responses in recent dose cohorts >$2bn peak sales potential in ccRCC2 1 Update provided 09-Sep-2024, based on 30-Aug-2024 data cut
Slide 45: XmAb808 Status Update: Continued Progress in Dose Escalation
45 XmAb808 Status Update1: Continued Progress in Dose Escalation Observed in escalation: • Tolerability from recent dose cohorts remains supportive of continued combination with per label dosing of pembrolizumab • Safety data have supported adding cohorts with Day 1 start for dosing the combination
Slide 46: Guidance for Progress Across XmAb Portfolio Programs in 2024
46 Guidance for Progress Across XmAb® Portfolio Programs in 2024 XmAb942 Xtend TL1A Present preclinical data during UEG Week 2024 on October 15 XmAb541 CLDN6 x CD3 Dose first patient during 1H 2024, enroll Phase 1 study Initiate first-in-human Phase 1 study in Q4 2024 XmAb Drug Candidate 2024 Priori
Slide 47: Potential Inflection Points for Xencor's Clinical Portfolio in 2025
47 Potential Inflection Points for Xencor’s Clinical Portfolio in 2025 XmAb Drug Candidate Indication Oncology Portfolio Vudalimab PD-1 x CTLA-4 mCRPC NSCLC XmAb819 ENPP3 x CD3 ccRCC Initiation of dose expansion XmAb808 B7-H3 x CD28 Solid tumor Initiation of dose expansion Ovarian+XmAb541 CLDN6 x CD
Slide 48: Xencor R&D Strategy Call September 9, 2024
® Xencor R&D Strategy Call September 9, 2024