UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
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FORM 8-K
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CURRENT REPORT
Pursuant to Section 13 or 15(d)
of The Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): January 13, 2025
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(Exact name of registrant as specified in its charter)
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Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
Securities registered pursuant to Section 12(b) of the Act:
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Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company o
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. o
Item 2.02. Results of Operations and Financial Condition.
Xencor, Inc. (the “Company”) preliminarily estimates that its cash, cash equivalents and marketable debt securities as of December 31, 2024 were approximately $707 million, compared to $697.0 million as of December 31, 2023. Based on current operating plans, Xencor expects to have cash to fund research and development programs and operations into 2028.
These preliminary estimates are not a comprehensive statement of the Company’s financial results for the year ended December 31, 2024 and have not been audited, reviewed, or compiled by its independent registered public accounting firm. The Company’s actual cash, cash equivalents and marketable debt securities as of December 31, 2024 may differ from these estimates due to the completion of the Company’s year-end closing and auditing procedures.
The information furnished under this Item 2.02 of this Current Report on Form 8-K shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or incorporated by reference in any filing under the Securities Act of 1933, as amended (the “Securities Act”), or the Exchange Act, except as shall be expressly set forth by specific reference in such filing.
Item 7.01. Regulation FD Disclosure.
On January 13, 2025, the Company posted a presentation on the “Investors” section of the Company’s website (www.xencor.com), which includes (i) a preliminary estimate for cash, cash equivalents and marketable debt securities as of December 31, 2024 (unaudited); (ii) new preclinical data demonstrating the selectivity of XmAb541 (CLDN6 x CD3) for binding to CLDN6 over CLDN9; (iii) data demonstrating deep peripheral B-cell depletion observed with plamotamab (CD20 x CD3) in a Phase 1 study in patients with lymphoma; (iv) the status of XmAb808 (B7-H3 x CD28) as having resumed dose escalation; and (v) completion of enrollment in the three ongoing studies of vudalimab (PD-1 x CTLA-4). The information contained in, or that can be accessed through, the Company’s website is not a part of this filing. A copy of the presentation is furnished as Exhibit 99.1 to this Current Report on Form 8-K and incorporated herein by reference. The presentation is current as of January 13, 2025 and the Company disclaims any obligation to update this material.
The information furnished under this Item 7.01 of this Current Report on Form 8-K, including Exhibit 99.1 hereto, shall not be deemed “filed” for purposes of Section 18 of the Exchange Act or incorporated by reference in any filing under the Securities Act or the Exchange Act, except as shall be expressly set forth by specific reference in such filing.
Item 9.01. Financial Statements and Exhibits.
(d)Exhibits.
| Exhibit No. | Description | ||||
| 99.1 | |||||
| 104 | Cover Page Interactive Data File, formatted in Inline Extensible Business Reporting Language (iXBRL). | ||||
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
Date: January 13, 2025 | XENCOR, INC. | |||||||
| By: | /s/ Celia Eckert | |||||||
| Celia Eckert | ||||||||
| General Counsel & Corporate Secretary | ||||||||
® Proteins by Design® XmAb® Antibody Therapeutics Corporate Overview January 2025
2 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 regarding Xencor's development plans and timelines; potential regulatory actions; expected use of cash resources; the timing and results of clinical trials; the plans and objectives of management for future operations; and the potential markets for Xencor's product and development candidates. Forward-looking statements are based on the current expectations of management and upon what management believes to be reasonable assumptions based on information currently available to it, and involve numerous risks and uncertainties, many of which are beyond Xencor's control. These risks and uncertainties could cause future results, performance or achievements to differ significantly from the results, performance or achievements expressed or implied by such forward-looking statements. Such risks include, but are not limited to, potential delays in development timelines or negative preclinical or clinical trial results, reliance on third parties for development efforts and changes in the competitive landscape including changes in the standard of care, as well as other risks described in Xencor's filings with the Securities and Exchange Commission (SEC). Xencor expressly disclaims any duty, obligation or undertaking to update or revise any forward-looking statements contained herein to reflect any change in Xencor's expectations with regard thereto of any subsequent change in events, conditions or circumstances on which any such statements are based, except in accordance with applicable securities laws. For all forward-looking statements, we claim the protection of the safe harbor for forward looking statements contained in the Private Securities Litigation Reform Act of 1995.
3 • 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: 3 novel TCEs advancing in Phase 1 studies; narrow focus for vudalimab in mCRPC and 1L NSCLC • Autoimmune: Study initiations and plans • 4Q’24: XmAb942 (Xtend TL1A) • 1H’25: Plamotamab (CD20xCD3) in RA • 2H’25: XmAb657 (CD19xCD3) • More than 15 technology license partnerships greatly broadens scope with little-to-no effort • Multiple commercialized XmAb antibodies ULTOMIRIS® MONJUVI®/MINJUVI® Proven Power of XmAb® Engineering: Proteins By Design® AstraZeneca Rare Disease Small changes, big functional impacts Advancing an optimized portfolio of XmAb drug candidates Partnerships leverage modular XmAb technology Registered trademarks: Ultomiris® (Alexion Pharmaceuticals, Inc.), Monjuvi® & Minjuvi® (Incyte Holdings Corp.) COLLABORATION PORTFOLIO INCLUDES XmAb Bispecific T-cell Engagers (TCEs) Xtend Antibodies with Potential Best-in-class Half-life Extension PLUG & PLAY TOOLKITS FOR RAPID PROTOTYPING RATIONALLY ENGINEERED XMAB DRUG CANDIDATES
4 World-leading protein engineers and proven XmAb® Fc platforms, supported by strong financial position of approximately $707 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 biological engineering problems Long-term potential benefit for patients through strict evaluation of data and competition to drive internal advancement towards commercialization or collaboration Xencor’s Disciplined Drug Development Strategy Validated Best-in-Class XmAb® Platforms Optimally Engineered Novel Drug Candidates Maximize Outcomes for All Stakeholders Focused Clinical Execution XmAb® Drug Development Model * Unaudited. As of 12/31/2024. Includes cash, cash equivalents & marketable debt. Updated 13-Jan-2025.
5 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 Ovarian cancer, oncology XmAb Program Undisclosed TCE Bispecific, Xtend Solid tumor oncology Solid Tumor Oncology: T-cell Selective, Dual Checkpoint Inhibitor Vudalimab PD-1 x CTLA-4 Bispecific, Xtend mCRPC 1L NSCLC Immunology Programs Plamotamab CD20 x CD3 Bispecific Rheumatoid Arthritis XmAb942 TL1A Xtend, FcKO Inflammatory Bowel Diseases (IBD) XmAb657 CD19 x CD3 2+1 Bispecific, Xtend Autoimmune Diseases XmAb Program TL1A x IL23 Bispecific, Xtend Autoimmune Diseases + chemotherapy Solid tumors Immunology + pembrolizumab +/- chemotherapy Key ccRCC clear cell renal cell carcinoma NSCLC non-small cell lung cancer mCRPC metastatic castration-resistant prostate cancer FcKO Fc knock out 1H’25 2H’25 Planned Study Initiation Next-Gen XmAb® Drug Design in Oncology & Autoimmune Diseases Pipeline focus on T-cell engagers and bispecific mechanisms
6 XmAb® Technologies Create Numerous Differentiated Antibodies for Technology Partners Selected Programs Fc Domain Indications Preclinical Phase 1 Phase 2 Phase 3 Marketed Commercial Rights Ultomiris® Xtend PNH, aHUS, gMG, NMOSD Monjuvi® Cytotoxic DLBCL Obexelimab Immune Inhibitor IgG4-RD, wAIHA Tobevibart (VIR-3434) Cytotoxic Xtend Hepatitis B Hepatitis D Xaluritamig STEAP1 x CD3 2+1 Bispecific Prostate cancer Efbalropendekin alfa IL15/IL15Rα-Fc Bispecific Xtend r/r multiple myeloma ASP2138 CLDN18.2 x CD3 2+1 Bispecific Oncology JNJ-9401 PSMA x CD28 Bispecific Prostate cancer JNJ-1493 CD20 x CD28 Bispecific Heme-Onc Technology licensing expands pipeline with very little opportunity cost AstraZeneca Rare Disease + cevostamab XmAb BispecificKey XmAb Tech (Non-BsAb)Xevudy® (sotrovimab), with Xencor’s Xtend Fc Domain, was provided under emergency use authorization for COVID-19, but is not currently authorized in the U.S. Registered trademarks: Ultomiris® (Alexion Pharmaceuticals, Inc.), Monjuvi® (Incyte Holdings Corp.), Xevudy® (Glaxo Group Limited)
7 ® XmAb® Bispecific T Cell Engagers XmAb 2+1 Bispecific Antibody Format XmAb819 (ENPP3 x CD3) XmAb541 (CLDN6 x CD3) XmAb808 (B7-H3 x CD28)
8 XmAb® T Cell Engagers Use Multiple Formats and Affinity Designs to Customize for Each Tumor Target 1 ScFv Targets: CD3 or CD28 Targets: tumor antigen (e.g., ENPP3, STEAP1, Claudin 18.2, B7-H3)Targets: tumor antigen (e.g., CD20, CD38) Examples Xaluritamig CD3 ASP2138 CD3 XmAb819 CD3 XmAb541 CD3 CD3 affinity tuned for reduction of cytokine release syndrome and off-tumor cell killing Tumor antigen binding affinity tuned for tumor expression density and to match format Example Plamotamab CD3 1 scFv Targets: CD3 or CD28 1 Fab 2 Fabs XmAb808 CD28 XmAb® 2+1XmAb® 1+1 Tuned 2+1 Format = Selective Reactivity < Tumor cellNormal cell
9 XmAb®819: CD3 T-cell Engager for Renal Cell Carcinoma in Phase 1 Encouraging Initial Data in Ongoing Dose Escalation in ccRCC XmAb819 (ENPP3 x CD3) Phase 1 Dose Escalation Study Selective T cell directed cytotoxicity Hi ENPP3 Lo ENPP3 XmAb 2+1 Design ENPP3: high RCC; low healthy tissues • Dose escalation ongoing in relapsed/refractory clear cell RCC • Nearly uniform high ENPP3 expression in ccRCC • In parallel, intravenous and subcutaneous cohorts dosing weekly, with priming and step-up doses • Following determination of RP2D, expansion cohorts planned in ccRCC and other histologies with high ENPP3 expression • Companion diagnostic under development for potential patient selection in other histologies • Evaluation of expansion into additional tumor types is ongoing Observed in dose escalation (update 09-Sep-2024) • Clear initial evidence of anti-tumor activity, including RECIST responses, in recent cohorts • Duration of treatment for several patients in earlier dose cohorts has extended beyond one year • Cytokine release syndrome (CRS) manageable • No MTD reached; tolerability from recent dose cohorts continues to support dose escalation • Investigators remain highly engaged, and enrollment into new dose cohorts has been rapid • Clinical update and first dose expansion cohort expected to start during 1H’25 Bispecific Fc Domain anti-ENPP3 2 Fabs NCT05433142 anti-CD3 1 scFv
10 XmAb®541: CD3 T-cell Engager for Ovarian Cancer & Solid Tumors XmAb541 (CLDN6 x CD3) Phase 1 Dose Escalation StudyXmAb 2+1 Design Highly selective for CLDN6 over CLDN9 • Differential expression in cancerous tissue presents CLDN6 as an intriguing target • CLDN family members, which are small membrane proteins, have high sequence identity, complicating antibody design • XmAb541 engineered for CLDN6 selectivity over similar CLDN9, CLDN3 and CLDN4 anti-CD3 1 scFv Bispecific Fc Domain anti-CLDN6 2 Fabs NCT06276491 Xtend 0 1 2 3 4 5 6 0 5,000 10,000 Log [Antibody (pM)] M FI (A F6 47 ) GCT Endometrial Ovarian Representative IHC from enrollment • Ongoing Phase 1 study, initiated in 1H24 • Enrolling patients with ovarian, endometrial and germ cell tumors • CLDN6 CDx pre-screening for patients with ovarian and endometrial cancers, but not required for GCT CLDN6 CLDN9
11 XmAb541 Extensively Engineered for High Selectivity Against CLDN6 Versus Closest Family Members 0.1 1 10 10 0 10 00 10 00 0 10 00 00 10 00 00 0 0 5000 10000 Conc. (ng/mL) M FI (A F6 47 ) CLDN17 CLDN8 CLDN4 CLDN3 CLDN9 CLDN6 0.5 1.5 2.0 0.5 1.5 2.0 Normalized CLND6 Binding N or m al iz ed C LD N 9 Bi nd in g Single Mutation Double/Triple Mutation Parent Clone 0 0 Fv in XmAb541 AACR 2021 XmAb541 Parent clone data presented at AACR, April 2021.
12 CD28 Bispecific Antibodies Provide a Boost to T Cell Activation XmAb® CD28 T cell engagers feature low affinity, monovalent binding • Avoid historic CD28 safety concerns (superagonism) • Well behaved: stable, silent FcγR interactions, with Xtend Fc technology • Potential to combine with anti-PD1 and/or CD3 T cell engagers Multiple wholly owned early-stage and actively advancing programs • Ongoing Phase 1 study of XmAb808 (B7-H3 x CD28) in combination with pembrolizumab in solid tumors • Presented preclinical data from multiple research-stage programs targeting CEACAM5, STEAP1, ENPP3, Trop2 and MSLN Two narrow, target-limited collaborations with J&J for CD28 bispecifics • JNJ-9401 (PSMA x CD28; Phase 1) for combination with J&J CD3 bispecifics; collaboration includes access to J&J prostate-cancer franchise for clinical combinations across Xencor’s portfolio • JNJ-1493 (CD20 x CD28; Phase 1) for J&J’s use in combination with agents, such as CD3 bispecifics CD28 provides “Signal 2” activation (Signal 1) (Signal 2) TAA 2 CD3 Bispecific or Checkpoint Inhibitor CD28 CD3 TCR MHC CD28 Bispecific
13 XmAb808: Tumor-specific CD28 T-cell Engager Targeted to Broadly Expressed Tumor Antigen B7-H3 in Phase 1 Phase 1 Dose Escalation Study • Dose-escalation cohorts are continuing per protocol1, enrolling patients with multiple tumor types (prostate, ovarian, HNSCC, urothelial and others), majority with mCRPC • Combination with anti-PD1 (Signal 1); pembrolizumab added on third dose, included in all dose escalation cohorts • Tolerability 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 of XmAb808 and pembrolizumab, along with cohorts that use a four-week XmAb808 monotherapy run-in period • For the subgroup of mCRPC patients, biologic activity of XmAb808 has been observed with PSA declines during the four-week monotherapy run-in period, but higher doses are expected to be needed to trigger more meaningful clinical activity2 • Clinical update and dose expansion expected to start during 1H’25 XmAb 2+1 Design B7-H3 is Broadly Expressed in Solid Tumors High expression in prostate cancer and others (kidney, breast, lung, etc.) XmAb CD28 T Cell Engagers B7-H3 RNA expression (TCGA) Primary Tumor B7-H3 Normal Tissue B7-H3 NCT05585034. 1 As of 13-Jan-2025 2 Update 09-Sep-2024 Designed to enhance selective T cell activation through CD28 (Signal 2) when in the presence of tumor cells • Feature low affinity, monovalent binding to CD28 • Avoid CD28 safety concerns (superagonism) • Well behaved: stable, silent FcγR interactions, with Xtend Fc technology • Potential to combine with anti-PD1 and/or CD3 T cell engagers (Signal 1) anti-CD28 1 Fab anti-B7-H3 2 Fabs Xtend Bispecific Fc Domain
14 ® New Pipeline Programs: B-cell Depleting T-cell Engagers Plamotamab (CD20 x CD3) XmAb657 (CD19 x CD3)
15 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 demonstrated promise for patients with severe rheumatic and inflammatory autoimmune disorders in small academic studies, and depth of B-cell depletion has been linked to better clinical outcomes in larger randomized controlled trials Newly published data shows potential for multiple types of bispecific antibodies in autoimmune disease Nat Med. 2024 EULAR 2024 Front. Immunol. 2023 Lancet Gastroenterol Hepatol. 2023
16 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 & granzymes CD3ε Rheumatoid arthritis Multiple sclerosis Systemic lupus erythematosus ANCA-associated vasculitis Idiopathic inflammatory myopathy Myasthenia gravis NMOSD Pemphigus vulgaris Sjogren’s syndrome Systemic sclerosis 1 Schett G, et al. Ann Rheum Dis 2024;0:1-12.
17 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 share, with >$5bn in US sales reported during 202312 BENLYSTA US annual sales of >$1bn with high unmet need remaining for moderate-to-severe SLE12 B-cell depletion has demonstrated broad benefit across a wide-range of autoimmune diseases: ANCA-associated vasculitis5 Idiopathic inflammatory myopathy6 Myasthenia gravis7 NMOSD8 Pemphigus vulgaris9 Sjogren’s syndrome10 Systemic sclerosis11 ~2.2m Patients with RA in US by 20302 ~1.1m Patients with MS in US by 20303 >200k Patients with advanced SLE4 >700k Patients with other B-cell mediated diseases 1 Based on randomized controlled trials with positive primary endpoints (Schett G, et al. Ann Rheum Dis 2024;0:1–12. 2 J Manag Care Spec Pharm. 2018; 24(10):1010-1017. 3 JAMA Neurol. 2023; 80(7):693-701. 4 Arthritis Rheumatol. 2021 Jun; 73(6): 991–996. 5 J Clin Med. 2022;11(9):2573. 6 BMC Musculoskelet Disord. 2012; 13: 103. 7 Front Neurol. 2024; 15:1339167. 8 Mult Scler. 2024; 13524585231224683. 9 JAMA Dermatol. 2019; 155(5): 627-629. 10 Arthritis Care Res (Hoboken). 2017; 69(10):1612-1616. 11 J Manag Care Spec Pharm. 2020 Dec;26(12):1539-1547. 12 GlobalData.
18 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 • Robust manufacturing process with high yield and excellent formulation stability data • N=154 from dose escalation and expansion cohorts with both IV and SC formulations in B-cell cancers • Comparable preliminary efficacy data to leading commercial CD20 x CD3 in patients with prior CAR-T • IV & SC dosing regimens with improved CRS data vs. leading commercial CD20 x CD31 • Existing inventories of drug product and drug substance for seamless integration into the next phase of clinical development Bispecific Fc Domain anti-CD3 scFv anti-CD20 Fab Planned proof-of-concept for the T-cell engager class in autoimmune and inflammatory disease BsAb bispecific antibody IV intravenous SC subcutaneous NHP non-human primate CRS cytokine release syndrome 1 No head-to-head trial has been conducted evaluating plamotamab against other data included herein. Differences exist between clinical trial design, patient populations and the product candidates themselves, and caution should be exercised when comparing data across trials.
19 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 lin e) -7 0 7 14 21 28 0.0 0.2 0.4 0.6 0.8 1.0 1.2 Low dose High dose Day 0 (Predose) Day 4 Day 8 Day 30 0.0 0.5 1.0 1.5 2.0 2.5 B ce ll / T c el l ( C D 40 + / C D 8+ ) Low dose High dose
20 >95-99% Peripheral B-cell Depletion Observed in Lymphoma Patients with IV & SC Plamotamab in Phase 1 Monotherapy Study Significant Reduction in B-cell Count Percent Reduction of B Cells in Bone Marrow Percent Reduction of B Cells in Whole Blood % R ed uc tio n in B -c el l C ou nt b y Fl ow C yt om et ry U nt il C 2D 26 Be st % R ed uc tio n in B -c el l C ou nt b y Fl ow C yt om et ry W ith in F irs t 6 0 D ay s Patients Patients • Absolute CD19+ B-cell count in bone marrow (on C1D1 and C1D26) and whole blood (on C1D1 and timepoints up to C55D1) measured by flow cytometry • >90% decrease in B cells in both bone marrow (baseline vs post- dose) and whole blood across the dose cohorts C = cycle; D = day. Data includes patients from Parts A-D. No bone marrow samples were collected in Part D. Patients with LBCL were included if their baseline B-cell count was >10 cell/uL.
21 Plamotamab: Plan for Phase 1b/2a RA Study Start Maximal efficiency to clinical proof of concept in rheumatoid arthritis • Quickly refine priming/step-up dosing regimens used in lymphoma studies • Assess SC and IV routes, and pre-medication regimen including corticosteroids, to be run in parallel on a staggered start • Assess safety, biomarkers, initial efficacy in RA patients Plamotamab Control Phase 2a 24 week duration Phase 1b Dose regimen A Phase 1b/2a Study Initiation Planned for 1H’25 Dose regimen B Dose regimen … • Advance selected dosing regimen into placebo-controlled trial in RA patients • Single-cycle dosing in line with other B-cell depleting agents • 24-week efficacy endpoint with interim efficacy analysis at week 12 with paired biomarker assessment Single 1b/2a study for seamless transition to randomized proof-of-concept trial
22 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 2024 and subsequent updates of CD19 CAR-T clinical data highlighted potential issues with CAR-T approach on efficacy and safety • Rational design of XmAb657 supports best-in-class potential for clinical outcomes • Current timeline to FIH study in 2H25 puts Xencor on-track to be a leading CD19 x CD3 program within autoimmune disease • High affinity and stability anti-CD19 binder • Bivalent to efficiently target B cells expressing very low levels of CD19 (e.g., plasma cells and plasmablasts) • Affinity-tuned and highly stable anti-CD3 binder • Uses Xencor’s clinically validated 2+1 format • Heterodimeric Fc domain engineered to abrogate effector function and improve half-life • Xtend Fc for long half life anti-CD3 1 scFv anti-CD19 2 Fabs Xtend
23 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 80 100 5000 10000 Days post administration B c el ls /μ L of b lo od 0 7 14 21 28 0 1 2 3 4 Days post administration % B c el ls a m on g ly m ph no de le uk oc yt es 0 7 14 21 28 0 1 2 3 4 5 Days post administration % B c el ls a m on g ly m ph no de le uk oc yt es 0 7 14 21 28 0 1 2 3 Days post administration % B c el ls a m on g bo ne m ar ro w le uk oc yt es Bone marrow Lymph nodes 0 7 14 21 28 0.0 0.5 1.0 1.5 2.0 Days post administration % B c el ls a m on g bo ne m ar ro w le uk oc yt es *peripheral B cells <1 B cell per µL; ‡this data point is zero B cells per µL ‡‡ ‡ B cells were gated as CD45+CD2-/lowCD20+CD4-CD8a-CD159a-
24 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 initiated • Further plans to investigate subcutaneous dosing and priming • First-in-human study planned to initiate in 2H’25 0 7 14 21 28 Time (Days post dose) Xm A b6 57 s er um c on c. [n g/ m L] , l og s ca le Long half life with Xtend Fc technology (~15 days in NHP) has potential for durable B-cell depletion 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 0 7 14 21 28 0.0 0.5 1.0 1.5 2.0 Days post administration % B c el ls a m on g bo ne m ar ro w le uk oc yt es Peripheral B cells Lymph node B cells
25 ® New Pipeline Programs: TL1A Portfolio XmAb942 (Xtend TL1A) XmAb TL1A x IL-23
26 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 Global IBD drug spend projected to be $23bn+ by 20302 Two common forms: Crohn’s disease Ulcerative colitis ~3m Estimated diagnoses in the U.S.1 Significant Health Burden • Impaired quality of life • Lower life expectancy • Surgeries, hospitalization • Increased risk for intestinal resection • Increased risk for colorectal cancer Severe Symptoms of IBD • Fatigue • Fever • Reduced appetite • Mental health Current Standards of Care are Lacking S1P modulator 5-ASA Cortico- steroid α-TNF α-IL23 α-integrin JAK inhibitor Patients cycle through suboptimal treatments • Suboptimal efficacy: ~10-20% disease remission3 • Adverse events: Infection, malignancy, thromboembolism, cardiac • Burdensome regimens: poor patient compliance
27 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 Xtend + FcKO Bispecific Fc Domain • Building upon proof-of-concept studies with TL1A targeted therapy and combination therapies for the treatment of Ulcerative Colitis (UC) and Crohn’s Disease (CD) • Validated best-in-class Xtend half-life extension in XmAb942 • First-in-class potential of TL1A x IL-23 to target dual pathway inhibition anti-TL1A 2 Fabs anti-TL1A 1 Fab anti-IL23 1 Fab 1 Sourced from Roivant presentation of TUSCANY, Entyvio (anti-integrin) and Humira (anti-TNF) data from VARSITY P3 study, S1P receptor modulator data from ELEVATE 52 P3 study 2 Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA); Feagan and Shao et al.; The Lancet G&H; Feb 2023 First-Gen TL1A Therapeutics vs SoC Biologics UC Cross-Study Comparison: Placebo Adjusted Clinical Remission – Induction Period1 VEGA Ph2a Clinical Remission of UC at Week 382 48% 31% 21% Combination (anti- TNF + anti-IL23) Guselkumab (anti- IL23) Golimumab (anti- TNF) 12% 16% 25% 23% 27% vedolizumab (anti-α4β7) risankizumab (anti-IL23p19) MK7240 (anti-TL1A) RG6631 (anti-TL1A) TEV48574 (anti-TL1A)
28 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-life extended >4X as compared to parental (71 days vs 15 days)2 Similar safety and immunogenicity risk as parental antibodies in studied antibodies using Xtend Fc domains3,4,5 Antibody thermostability maintained in studied antibodies using Xtend Fc domains6,7 Superior or comparable to other HLE technologies (e.g., YTE) across multiple studies and parameters6,7,8 Typical HLE scaling from cyno to human is ~3.5x9 Clinical Half-Life and Maintenance Dosing Ultomiris vs. Soliris10 Product Half-life (days)11 Dosing Interval1,12 Ultomiris (with Xtend ) 49.7-64.3 Q8W Soliris 11.33-12.1 Q2W 1 Ultomiris & Soliris drug labels 2 Ledgerwood Clin Exp Imm 2015 3 Lee et al. Blood 2019 4 Gaudinski et al. PLOS Med 2018 5 Vu et al. J Neurol 2023 6 Ko et al. Exp Mol Med 2022 7 Internal Data 8 Ko et al. Nature Letter 2014 9 Haraya & Tachibana. BioDrugs (2023) 37:99–108 10 Data adapted from FDA and EMA drug labels 11 Reported Half-life across approved indications 12 Maintenance dosing interval in adults Proprietary Xtend Fc Domain has been incorporated into ≥ 35 molecules that have been tested in clinical studies Xtend is commonly referred to as ‘LS’ in academic literature
29 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, 23 days, supports Q8W to Q12W dosing in humans • High concentration formulation for subcutaneous dosing • Preclinical discovery and characterization presented during UEG Week 2024 • First-in-human clinical study in healthy volunteers initiated 4Q’24 Company Program1 Potent SC Dosing Q8-12W Dosing Half-life extension Low Immunogenicity Xencor XmAb942 Merck (Prometheus)2,3 tulisokibart Roche (Roivant)4,5 RG-6631 Sanofi (Teva)6 duvakitug TBD Predicted 1 No head-to-head trial has been conducted evaluating XmAb942 against other data included herein. Differences exist between clinical trial design, patient populations and the product candidates themselves, and caution should be exercised when comparing data across trials 2 PRA023 Progress Update (Prometheus presentation) 3 Feagan et al. The Anti-TL1A Antibody PRA023 Demonstrated Proof-of-Concept in Crohn’s Disease: Phase 2a APOLLO-CD Study Results (DOP87) Abstract citation ID: jjac190.0127 4 Banfield et al. Br J Clin Pharmacol. 2020;86:812–824 5 Clarke et al. mAbs. 2018;10:4, 664-677 6 Danese et al. Clin Gastroenterology and Hepatology. 2021;19:11, 2324-32.e6
30 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 • Lead selection in 2025 IL-23 Ab Control TL1A Ab Control TL1A x IL-23 Prototype 2 TL1A x IL-23 Prototype 1 0.0 01 0.0 1 0.1 1 10 10 0 0 5×103 1×104 1.5×10 4 2×104 2.5×10 4 Concentration (nM) R LU XmAb protein engineering allows for a range of stable molecular structures Prototype TL1A x IL-23p19 bispecifics are functionally active on both axes
31 ® T Cell Selective, Dual Checkpoint Inhibitor Vudalimab (PD-1 x CTLA-4)
32 Vudalimab: Selective PD-1 x CTLA-4 Bispecific Antibody • Monotherapy generally well tolerated, with a potentially differentiated profile from two-antibody combination therapy (PD-1 + CTLA-4) • Xencor’s initial focus on tumors with poor PD-1 inhibitor activity: e.g., prostate cancer anti-PD-1 scFv anti-CTLA-4 1 Fab Xtend Bispecific Fc Domain • Tumor infiltrating lymphocytes (TILs) coexpress multiple checkpoints (Matsuzaki 2010, Fourcade 2012, Gros 2014) • Bivalent binding increases avidity Periphery Strong bivalent interactions on double-positive cells TIL Activation Weak monovalent interactions on single-positive cells No Activation Tumor Environment Tumor PD1 only CTLA4 only Double- positive TILs Vudalimab is Designed to Promote Tumor-Selective T Cell Targeting
33 Vudalimab Development Program for mCRPC and NSCLC XmAb717-05: Phase 2 vudalimab monotherapy in high-risk mCRPC cohort Vudalimab monotherapy has been associated with clinical response in 5 out of 12 evaluable mCRPC patients with visceral or lymph node metastases • Findings consistent with observations of durable responses (41 and 27 weeks) in Phase 1 mCRPC cohort in 2 patients with visceral and lymph node metastases (extrapelvic and/or intrapelvic) Vudalimab monotherapy safety profile has been consistent with other checkpoint inhibitor therapies • Low rate of discontinuation of treatment due to AEs Additional data will inform future development efforts in monotherapy, and/or contribution of monotherapy to combination treatment Phase 1b/2 Study in 1L NSCLC in combination with chemotherapy Encouraging proof-of-concept data in NSCLC supports evaluation of vudalimab in 1L Volrustomig (PD-1 x CTLA-4) in checkpoint-naïve NSCLC shows superior PFS over pembrolizumab • Volrustomig + chemo vs. pembrolizumab + chemo Vudalimab Phase 1 activity in 3-4L patients (Cohort C: 20 patients with NSCLC) • Heavily-pretreated population: 95% checkpoint experienced, 40% ≥ 2 prior checkpoints, median 3 prior therapies • 14% objective response rate (2 partial responses of 14 evaluable); 50% disease control rate (7/14) mCRPC NSCLC 1H25: XmAb717-04 and XmAb717-05 expansion readout 1H25: Evaluate chemo combination safety NCT05032040. NCT06173505 mCRPC metastatic castration-resistant prostate cancer NSCLC non-small cell lung cancer Completed enrollment in ongoing vudalimab studies year-end 2024 Data presented February 27, 2024. 2021 2022 2023 2024 2025 Phase 2 Vudalimab + chemotherapy or PARPi in molecularly defined mCRPC Phase 2 Vudalimab monotherapy in high-risk mCRPC cohort Phase 1 Vudalimab dose- escalation and expansion study in mixed solid tumors Study: DUET-2 Study: XmAb717-04 Study: XmAb717-05 Two ongoing studies of vudalimab in mCRPC
34 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 CD3 Advance toward target dose levels Mono & combo cohort expansion readout Evaluate chemo combination safety XmAb942 Xtend TL1A IBD+ SAD readout MAD readout and Phase 2 start Plamotamab CD20 x CD3 Rheumatoid arthritis Initiate Phase 1/2 study XmAb657 CD19 x CD3 Autoimmune Initiate FIH study 1H’25 2H’25 Immunology Portfolio As presented 13-Jan-2025 SAD Single ascending dose MAD multiple ascending dose FIH first-in-human
® Proteins by Design® XmAb® Antibody Therapeutics Corporate Overview January 2025