XENCOR TRIAL RESULTS WEBCAST - XENCOR INC

Explicit Guidance:

• Clinical Milestones: Expectation to initiate a Phase 3 pivotal trial in 2027 (specifically "during 2027" and "pivotal year").
• Regulatory Timeline: Target an End-of-Phase I meeting with the US FDA in the first half of 2027.
• Data Updates: Submission of Subcutaneous (SC) dose data in the first half of 2027; confirmatory analysis set for the IV 400 µg/kg cohort (N≈20) to be finalized and presented by early 2027.
• Target Dose: Selection of 400 µg/kg IV as the putative Recommended Phase 3 Dose (RP3D) for advanced clear cell Renal Cell Carcinoma (RCC).
• Market Projections: Near-term commercial focus to address a global addressable market of > $11 billion (projected to grow through 2030); U.S. eligible patient pool for post-IO/two prior VEGFR TKI lines estimated at >9,000 patients annually.
• Long-term Commercialization: Goal to achieve multiple regulatory approvals and maximize commercial access across treatment lines starting by 2030.

Business-Segment Outlook:

• Pipeline Progression: XMAB819 expected to become the third Zencore asset to enter pivotal studies, following ASP2138 (Astellas) and Zaloridamig (Amgen).
• Indication Expansion: Plans to move XMAB819 into earlier lines of treatment and explore combination therapies (e.g., with PD-1 inhibitors) for frontline studies.
• Basket Study Expansion: Enrollment opened for papillary RCC, microsatellite-stable (MSS) colorectal cancer, and non-squamous non-small cell lung cancer (NSCLC), contingent on high ENPP3 expression by IHC.
• Combination Strategy: Exploration of rational combinations with standard-of-care agents; initial focus on PD-1 inhibitors to avoid overlapping toxicities and enhance activity, while aiming to discontinue reliance on VEGFR TKIs in later lines.
• Partnership Status: Awaiting updates from partner J&J on the combination of Pasiridamig with J&G 9401 (XNAB CD28 bispecific); Astellas program (ASP2138) currently in Phase 3.

Market and Competitive Outlook:

• Competitive Positioning: XMAB819 demonstrates an unprecedented 45% confirmed ORR in a monotherapy setting for post-IO/two prior VEGFR TKI patients (IV 400 µg/kg cohort), exceeding response rates of current standard-of-care monotherapies (e.g., tivozanib, belzutifan) in heavily pre-treated, poor-intermediate risk populations.
• Standard of Care Disruption: Anticipated to shift the standard of care by reducing reliance on VEGFR TKI recycling in later lines and offering a first-in-class 2+1 T-cell engager with a distinct tolerability profile (non-cumulative toxicity post-priming).
• Target Audience Growth: The "triple-class exposed" market (IO, VEGFR TKI, HIF-2 inhibitor) is expected to grow substantially following recent approvals of belzutifan and lenvatinib in the U.S. post-IO setting.
• Market Opportunity: Frontline setting identified as the largest market currently dominated by pembrolizumab/nivolumab combinations; XMAB819 aims to capture value in this space via future combination trials.

Macro / Industry Outlook:

• Regulatory Pathway: Aiming for Accelerated Approval in a select, high-unmet-need patient population (e.g., triple-class exposed) followed by a confirmatory Full Approval Phase 3 trial against tivozanib (active control).
• Study Design Expectations: Primary analysis for accelerated approval expected to be single-arm, powered on Objective Response Rate (ORR) lower bounds and Median Duration of Response (MDOR) rather than survival metrics.
• Manufacturing Strategy: Utilization of robust, high-titer cell banks (scaling to 2,000 L) and commercially validated U.S. CDMOs; drug stability established for 60+ months in liquid formulation.
• Administration Trends: Pursuing a path to reduced inpatient monitoring (peeling back overnight stays during priming) to enable community-based administration, leveraging precedents set by peers (e.g., Amgen's Tarlatamab).

Strategic Initiatives:

• Platform Optimization: Leveraging the XMAP 2+1 platform to tune affinity/avidity for improved tumor-normal selectivity and safety profiles compared to 1+1 bispecifics.
• Formulation Development: Parallel development of Subcutaneous (SC) vs. Intravenous (IV) presentations; SC data expected in H1 2027 to inform final commercial strategy (lifecycle play vs. primary formulation).
• Safety Mitigation: Implementation of optimized pre-medication regimens (acetaminophen, diphenhydramine, IV saline, dexamethasone, tocilizumab) to reduce Cytokine Release Syndrome (CRS) and rash incidence during priming.
• Patient Enrollment: Continued enrollment in the 400 µg/kg IV cohort (N>20) to finalize dose confirmation; rapid ramp-up of basket studies for new histologies.

Risks and Headwinds to Outlook:

• Regulatory Uncertainty: Final approval pathway (accelerated vs. full) and patient population size depend on outcomes of discussions with the FDA in H1 2027.
• Clinical Variability: Efficacy in new tumor types (colorectal, lung) may differ due to varying tumor biology and T-cell distributions despite similar safety expectations.
• Data Maturity: Current efficacy metrics (ORR, PFS) in the 400 µg/kg cohort are based on relatively short follow-up (median ~7 months); durability and long-term response deepening require continued monitoring.
• Competition: Standard of care remains aggressive; potential for new entrants or combination strategies in the heavily pre-treated RCC space.
• Operational Risks: Execution of reduced monitoring protocols (outpatient dosing) and management of dosing logistics for SC formulation.

Management Tone on the Future:

• Confidence Level: High confidence and enthusiasm regarding the "high watermark" nature of the Phase 1 data in heavily pre-treated RCC; described as "optimistic" about the position for accelerated approval and "very excited" about the pathway to commercialization.
• Strategic Focus: Management views XMAB819 as the first potential commercial program wholly owned by Zencore, with resource allocation matched to this priority.
• Differentiation: Emphasis on the unique "2+1" modality's ability to bypass primary progressive disease in IO-resistant settings and its non-cumulative toxicity profile compared to TKIs.
• Momentum: View 2027 as a "pivotal year" with a concentrated sequence of milestones (sub-Q data, RP3D confirmation, FDA meeting) to support the 2030 commercial launch ambition.

Miscellaneous:

• Safety Profile: No treatment discontinuations due to toxicity in the reported cohorts; 45.5% ORR at 400 µg/kg with 81.8% disease control rate; transaminase elevations noted as transient and self-limited.
• Patient Case: Highlighted a case of a patient with <25% ENPP3 expression achieving a Complete Response at 16 months after progressing on prior VEGFR TKI/IO/HIF-2i therapy.
• Scan Timing: Acknowledged potential for "pseudoprogression" or early new lesions that resolve; planning to normalize scan timing to 8–10 weeks in future pivotal studies to avoid misclassification of Responders.