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Copyright © 2026 ProKidney Corp. All rights reserved. NASDAQ PROK American Society of Nephrology (ASN) Kidney Week Recap & Corporate Update October 27, 2026
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2 This presentation includes “forward-looking statements” within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. ProKidney’s actual results may differ from its expectations, estimates and projections and consequently, you should not rely on these forward-looking statements as predictions of future events. Words such as “expect,” “estimate,” “project,” “budget,” “forecast,” “anticipate,” “intend,” “plan,” “may,” “will,” “could,” “should,” “believes,” “predicts,” “potential,” “continue,” and similar expressions (or the negative versions of such words or expressions) are intended to identify such forward-looking statements. These forward-looking statements include, without limitation, the achievement and timing of the topline data readout of the Company’s PROACT 1 trial and other milestones provided, the Company’s beliefs that its Phase 3 REGEN-006 (PROACT 1) trial could be sufficient to support a potential BLA submission and full regulatory approval, eGFR slope can be used as a surrogate endpoint on an accelerated approval pathway for rilparencel, expectations with respect to financial results and expected cash runway, including the Company’s expectation that current cash will support operating plans into mid-2027, future performance, development and commercialization of products, if approved, the potential benefits and impact of the Company’s products, if approved, potential regulatory approvals, the size and potential growth of current or future markets for the Company’s products, if approved, the advancement of the Company’s development programs into and through the clinic and the expected timing for reporting data, the making of regulatory filings or achieving other milestones related to the Company’s product candidates, and the advancement and funding of the Company’s developmental programs, generally. Most of these factors are outside of the Company’s control and are difficult to predict. Factors that may cause such differences include, but are not limited to: disruptions to our business or that may otherwise materially harm our results of operations or financial condition as a result of our recent domestication to the United States; the inability to maintain the listing of the Company’s Class A common stock on Nasdaq; the inability of the Company’s Class A common stock to remain included in various indices and the potential negative impact on the trading price of the Class A common stock if excluded from such indices; the inability to implement business plans, forecasts, and other expectations or identify and realize additional opportunities, which may be affected by, among other things, competition and the ability of the Company to grow and manage growth profitably and retain its key employees; the risk of downturns and a changing regulatory landscape in the highly competitive biotechnology industry; the risk that results of the Company’s clinical trials may not support approval; the risk that the FDA could require additional studies before approving the Company’s drug candidates; the inability of the Company to raise financing in the future; the inability of the Company to obtain and maintain regulatory clearance or approval for its products, and any related restrictions and limitations of any cleared or approved product; the inability of the Company to identify, in-license or acquire additional technology; the inability of Company to compete with other companies currently marketing or engaged in the biologics market and in the area of treatment of kidney diseases; the size and growth potential of the markets for the Company’s products, if approved, and its ability to serve those markets, either alone or in partnership with others; the Company’s estimates regarding expenses, future revenue, capital requirements and needs for additional financing; the Company’s financial performance; the Company’s intellectual property rights; uncertainties inherent in cell therapy research and development, including the actual time it takes to initiate and complete clinical studies and the timing and content of decisions made by regulatory authorities; the fact that interim results from our clinical programs may not be indicative of future results; the impact of geo-political conflict on the Company’s business; and other risks and uncertainties included under the heading “Risk Factors” in the Company’s most recent Annual Report on Form 10-K, subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. The Company cautions readers that the foregoing list of factors is not exclusive and cautions readers not to place undue reliance upon any forward- looking statements, which speak only as of the date made. The Company does not undertake or accept any obligation or undertaking to release publicly any updates or revisions to any forward- looking statements to reflect any change in its expectations or any change in events, conditions or circumstances on which any such statement is based. Forward-looking Statements October 27, 2026 ASN Kidney Week Recap and Corporate Update
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3 Opening Remarks & Corporate Update Rilparencel MoA Findings The Quest to Save Kidneys, Hearts, and Lives: Mechanisms Matter Q&A Today’s Agenda and Speakers Bruce Culleton, MD, CEO Katherine Tuttle, MD, KOLAnthony Conway, PhD, Head of R&D 1 4 2 3 MoA = Mechanism of Action KOL = Key Opinion Leader October 27, 2026 ASN Kidney Week Recap and Corporate Update
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BRUCE CULLETON, MD, CEO Opening Remarks & Corporate Update
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5 Redefining What's Possible in the Treatment of CKD Through Innovation and Execution Building a future where advanced CKD treatment means more options, time, and hope Potential first-in-class autologous cell therapy designed to preserve kidney function in patients with advanced CKD Rilparencel Robust Clinical Data In-House Manufacturing Key Value Drivers RMAT Designation Cash Through Pivotal Data Phase 3 PROACT 1 trial in patients with Stage 3b/4 CKD and type 2 diabetes Three Phase 2 trials in Stage 3/4 CKD Pivotal Phase 3 Study Ongoing COMPLETED ONGOING (Q2 2027 readout) Over 1 million U.S. patients with Stage 3b/4 CKD and diabetes at high risk of progressing to kidney failure Large Untapped Market Opportunity RMAT = Regenerative Medicine Advanced Therapy October 27, 2026 ASN Kidney Week Recap and Corporate Update
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6 Anticipated Upcoming Milestones October 27, 2026 ASN Kidney Week Recap and Corporate Update BLA = Biologics License Application eGFR = Estimated Glomerular Filtration Rate Timing Milestones Q1 2027 Complete full enrollment for the Phase 3 PROACT 1 study. Anticipate enrolling over 500 patients (up from 470) driven by an acceleration in patient recruitment in mid-2026. Q2 2027 Topline readout for the Phase 3 PROACT 1 surrogate endpoint (eGFR slope) for accelerated approval. The efficacy analysis set is expected to include ~320 patients. Q1 2028 BLA submission of rilparencel for accelerated approval. 1H 2029 BLA accelerated approval and commercial launch of rilparencel. 2H 2029 Topline readout for the Phase 3 PROACT 1 confirmatory endpoint (composite time-to-event) to support full approval of rilparencel.
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7 Day –93 to Day 0 Screening Visit Sham Cohort Sham 1st Rilparencel Injection Sham 2nd Rilparencel Injection Sham Biopsy End of Study (EOS) 1st Rilparencel Injection 2nd Rilparencel InjectionBiopsy End of Study (EOS) PHASE 3 REGEN- 006 (PROACT 1) Rilparencel Phase 3 Registrational Study Design Topline results for the eGFR slope surrogate endpoint anticipated in Q2 2027 Key Entry Criteria Confirmatory Composite Time-to-Event Endpoint • Type 2 diabetes and CKD • 30-80 years of age • eGFR ≥20 and ≤35 mL/min/1.73m2 • UACR 300-5,000 mg/g for eGFR 30-35 • HbA1c <9.5% 3 months 3 months 3 months 3 months R 1:1 Surrogate Endpoint (Accelerated Approval Pathway) • Annualized eGFR slope is the surrogate endpoint • Efficacy analysis set is expected to contain approximately 320 patients and will include all patients with at least 6 months of follow-up after first injection • Expected to have 80% power to detect an effect size in annualized eGFR slope of 1.5 mL/min/1.73m2 3 months 3 months • At least 40% reduction in eGFR; • eGFR <15mL/min/1.73m² sustained for 30 days and/or chronic dialysis, and/or renal transplant; or • Death from renal or cardiovascular causes (The confirmatory analysis will be triggered when 122 participants have at least one event) Rilparencel Cohort n>500 October 27, 2026 ASN Kidney Week Recap and Corporate Update
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ANTHONY CONWAY , PhD, HEAD OF R&D Rilparencel Mechanism of Action (MoA) Findings
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9 Rilparencel: A patient's own cells, from biopsy to kidney therapy Rilparencel: • Made from patient’s own kidney cells • No genetic modification • No preconditioning • No lifelong immunosuppression • Outpatient procedures • Well-tolerated in Phase 2 program1 • Associated with a 78% slower annual eGFR decline in patients with advanced CKD & diabetes in cohort 1 of REGEN- 007 Phase 2 study (n=24)1 • Currently in Phase 3 study (REGEN-006 / PROACT 1), topline readout expected Q2 2027 Then frozen for preservation & shipping to site Kidney cells are isolated & expanded Tissue acquired by kidney biopsy Rilparencel injected into kidneys Injection #1: Same kidne y as bio psy Injection #2: Contralateral kidney (at time point specified per protocol) Process overview 4 2 3 1 2 3 4 x We need to uncover what’s happening in diseased kidney tissue after our product is administered to understand its mechanism of action (MoA) 9 1 Čižman et al. CJASN (2026)
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10 Utilizing translational disease models to elucidate rilparencel MoA Anticipated Results In vitro Ex vivo In vivo (rodent) In vivo (human decedent) • Quick: Fast design-test-learn cycles • High throughput: Simultaneously test multiple variables to deconvolute MoA • Cost-effective • Native tissue structure & cell-cell interactions maintained • Fast design-test-learn cycles • Medium throughput • Intact whole body physiology • Long-term post-treatment studies feasible • Most representative of clinical setting • Serial biopsies & sampling possible to uncover temporal MoA Advantages Kidney biopsy explant culture Primary kidney cells Kidney-on-chip Rodent models of CKD Rilparencel Control CKD donor • Whole genome expression profile in diseased & normal kidney cells +/- rilparencel treatment • Identification of key factors expressed by rilparencel, & the disease pathways they act upon, which are necessary & sufficient for its therapeutic effect • Multi-omic gene expression, protein, & metabolite profiles in diseased kidney, urine, & blood +/- rilparencel treatment • Single-cell & spatial datasets integrated with histopathological changes • Association of molecular biomarker findings with clinically relevant measurements
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11 Identifying the cellular origin of rilparencel from kidney biopsies 3 CKD donor kidneys Biopsy LM = late manufacturing SRC = selected renal cells (rilparencel) Stage 4 CKD Stage 2 CKD Stage 5 CKD Early Passage Late Manufacturing / Rilparencel scRNA-seq Biopsy Early Late Days in culture: 0 ~5 to 8 ~18 to 23 LM For the purpose of this presentation, rilparencel may refer to selected renal cells (SRC), which are the cells formulated in rilparencel, or may refer to SRC formulated as rilparencel
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12 Cellular trajectory from biopsy to rilparencel Cell cycle phase Biopsy Early stage Late stage Rilparencel Temporal inferred transition Late-stage expression similarity Dimension 2 (UMAP2) Dimension 1 (UMAP1) IC = Intercalated Cell CNT = Connecting Tubule TAL = Thick Ascending Limb PT = Proximal Tubule PT Nephron (functional unit of kidney) IC TAL EC & Immune CNT INT EC = Endothelial Cell INT = Interstitial Cell Cortex Medulla Actively dividing cells
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13 2 distinct lineage-associated populations in rilparencel present in 17 patient batches Lineage-associated rilparencel populations likely are derived from proximal & distal tubule epithelial cells from initial biopsies Population Markers Proximal & Distal Population Clusters Dimension 2 (UMAP2) Dimension 1 (UMAP1) Proximal Distal Dimension 2 (UMAP2) Dimension 1 (UMAP1) scRNA-Seq Unbiased Clustering
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14 Similar characterization marker expression across 17 rilparencel batches Rilparencel Characterization Panel (scRNA-Seq) Examples of Expression Trajectory from Biopsy to Rilparencel Biopsy Early Late VEGFA MGST1 CD44 THY1 Remarkably consistent product characteristics across patients despite lineage & expression heterogeneity from starting biopsies Cells of proximal & distal tubule origin exhibiting a reparative, plasticity- associated transcriptional signature with partial retention of native lineage identity Rilparencel
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15 Utilizing in vitro CKD models to assess resolution of disease state by rilparencel Primary kidney cells Kidney-on-chip Workstream Goals • Develop advanced, human-relevant in vitro disease models for rilparencel functional testing • Identify & screen mechanism-aligned functional assays to elucidate the biological activity, timing, & durability of rilparencel treatment in vitro • Support a defensible MoA hypothesis Activation of Disease State Phenotype Resolution of Disease State Phenotype Rilparencel Treatment Injury Mediators Stabilization or ResolutionDosing Models • Hyperglycemia • Hyperlipidemia • Hypoxia • Proinflammatory cytokines • Uremic toxins • ROS • Single, repeated • Concentrated • Isolated factors • Improved stabilization or resolution with treatment • Pathway-specific attenuation v
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16 In vitro functional assays measure common CKD pathway-relevant readouts Hyperglycemia Hyperlipidemia Hypoxia CKD Inducers & Drivers Common CKD Pathways Oxidative stress Metabolic dysregulation Inflammation Fibrosis Cell death Functional Assay Testing Resolution of multiple orthogonal disease state-relevant assay readouts by rilparencel Deconvolve how rilparencel may be able to preserve kidney function in patients with advanced CKD Tuttle et al. Kidney International (2022)
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17 Rilparencel co-culture in injured kidney-on-chip experimental design Key Considerations • Model captures endothelial : epithelial interface & crosstalk • Rilparencel is administered directly on ECM in the grafting chamber • Rilparencel is administered in continuous & ongoing CKD-relevant injury environment GMVEC (Vessel) RPTEC (Tubule)Rilparencel Injury media formulation (prepared in cell-specific basal media) Injury Inducer Components Concentration Glucose 4.5 g/L (25 mM) CytoMix IL-6, IL-1β, TNFα, MCP-1, CXCL8, TGF-β1 0.0325 - 2.5 ng/mL LipidMix arachidonic, linoleic, linolenic, myristic, oleic, palmitic, stearic acid, cholesterol 2 – 20 ng/mL Uremic toxins p-cresyl sulfate, indoxyl sulfate 10 µM ECM GMVEC = Glomerular Microvascular Endothelial Cells RPTEC = Renal Proximal Tubule Epithelial CellsECM = Extracellular Matrix Kidney-on-chip (MIMETAS OrganoPlate) Blood Vessels Tubules Nephron (functional unit of kidney)
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18 Rilparencel promotes endothelial junctional & barrier integrity 3D Mechanistic Discovery 3D & 2D Functional Validation Key Findings • Rilparencel improves injury-driven endothelial dysfunction at both the transcriptional & functional level Control Injury Injury+SRC 0 2000 4000 6000 8000 10000 CD31 a b c Control Injury Injury+SRC 0 500 1000 1500 2000 VE-Cadherin a b c Control Injury Injury+SRC 0 200 400 600 800 1000 ZO-1 a b c Control Injury Injury+SRC 0 1000 2000 3000 4000 5000 ICAM-1 a b c Control Injury Injury+SRC 0 200 400 600 800 αSMA a bc Control Injury Injury+SRC 0 200 400 600 N-Cadherin a b c MFI Control Injury Injury+SRC 0 5×10-6 1×10-5 1.5×10-5 Barrier Permeability Papp (cm/s) a b c Dissimilar letters indicate 𝑝𝑝<0.05 via One-Way ANOVA Mean ± SD; n=9 chips with n=3 donors
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19 Rilparencel promotes native endothelial metabolic state 1 4 0 10 20 30 Basal Respiration Days Post-Treatment OCR (pmol/min/1x103 cells) 1 4 0 10 20 30 40 Spare Respiratory Capacity Days Post-Treatment OCR (pmol/min/1x103 cells) 0 20 40 60 80 100 120 140 0 20 40 60 80 Bioenergetic Potential 4 Days Post-Treatment PER (pmol/min/1x103 cells) Glycolysis Mitochondrial Respiration OCR (pmol/min/1x103 cells) Aerobic Energetic GlycolyticQuiescent 1 4 0 20 40 60 80 Basal Glycolysis Days Post-Treatment PER (pmol/min/1x103 cells) Control IM v2.0 IM v2.0 + PK014 IM v2.0 + PK025 Rilparencel Treatment • Promotes a more native endothelial metabolic state (quiescence) than control cells at later timepoints • Strongly suggests pericyte-like endothelial cell metabolic reprogramming & stabilization OCR = Oxygen Consumption Rate PER = Proton Efflux Rate Rilparencel-treated Rilparencel-treated (2 donor batches) IM = Injury Media
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20 Rilparencel attenuates pro-inflammatory signaling & recruitment cues Control TNF-α TNF-α + Rilparencel 0.0 0.5 1.0 1.5 2.0 phospho(S536)/total p65 Fold Change over Control ✱ ns ✱ Control TNF-α TNF-α + Rilparencel 0.0 0.5 1.0 1.5 2.0 2.5 phospho(S32)/total IκBα Fold Change over Control ✱ ns ✱ NFκBIκBα 0 20 40 60 Endothelial Compartment Days in Culture HMBG-1 : LDH Ratio Fold Change over Control 7 14 17 Injury Rilparencel 0 5 10 15 20 Epithelial Compartment Days in Culture HMBG-1 : LDH Ratio Fold Change over Control 7 14 17 Injury Rilparencel Control Injury Injury + Rilparencel • Rilparencel treatment attenuates immunogenic & broad NF-κB axis signaling in vitro in a CKD-relevant stress environment Kidney-on-chip 3D in vitro testing platform (DAMP secretion assay) 2D In vitro testing platform (ELISA) Epithelial cells, 3 days post-rilparencel treatment
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21 Rilparencel lowers reactive iron species & activates a cytoprotective lipid peroxidation repair program in injured renal epithelial cells Key Findings • Rilparencel administration limits the pool of reactive iron (Fe2+) available to drive oxidative damage via the Fenton reaction • Rilparencel administration transcriptionally activates a cytoprotective lipid peroxidation repair program in injured RPTEC ControlInjury Injury+SRC 0 10 20 30 40 50 Total Iron Iron (μM/μg protein) a bb ControlInjury Injury+SRC 0 5 10 15 Fe3+/Fe2+ Ratio Fe3+ : Fe2+ a b c ControlInjury Injury+SRC 0 20 40 60 Iron Fractions Iron (μM/μg protein) Ferrous (Fe2+) Ferric (Fe3+)
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22 Rilparencel rescues oxidative damage & mitochondrial dysfunction in continuously injured renal epithelial cells Control Injury Injury + SRC Control Injury Injury+SRC 0 50 100 150 Lipid Peroxidation (% of Max) a bc Control Injury Injury+SRC 0 1 2 3 4 5 Coupling Efficiency Cellular RCRbasal a b c Control Injury Injury+SRC 0 5 10 15 Spare Capacity Cellular RCRmax a b c Key Finding • Rilparencel can promote host cell stress-adaptive regulation that preserves proximal tubular epithelial cellular functions, alleviating injury-induced metabolic dysregulation 0 2 4 6 8 0 2 4 6 Coupling Efficiency Days Post-Treatment Cellular RCRbasal 0 2 4 6 8 0 5 10 15 Spare Capacity Days Post-Treatment Cellular RCRmax 0 2 4 6 8 0 20 40 60 80 100 120 Bioenergetic Health Days Post-Treatment BHI (% of control) Control Injury Injury + Rilparencel ^# ^# ^# * * *^ ^ ^# ^# # *^ *^ *^ ^# ^# # * * * ^ ^ Rilparencel treatment: • Preserves mitochondrial coupling efficiency • Expands & improves spare respiratory capacity • Progressively improves overall bioenergetic health
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23 GPX4 activity is required for rilparencel-mediated rescue of oxidative damage & mitochondrial dysfunction in epithelial cells 0 1×104 2×104 3×104 4×104 5×104 Total Glutathione RLU (normalized to cell count) Injury 1D4 RSL3 SRC - - - - + - - - + - + - + - - + + - + + + + - - aa b a ba b b c 0.0 0.5 1.0 1.5 2.0 2.5 Glutathione Redox Balance GSH/GSSG (total/oxidized) Injury 1D4 RSL3 SRC - - - - + - - - + - + - + - - + + - + + a a a b cc cumene hydroperoxide + + - - 0 1×105 2×105 3×105 4×105 5×105 Protein Carbonylation Sensor RFU (normalized to cell count) Injury 1D4 RSL3 SRC - - - - + - - - + + - - + - + - + - - + a a b b c c cumene hydroperoxide + - + + 0 20 40 60 80 100 Lipid Peroxidation Sensor Reduced / Oxidized Injury 1D4 RSL3 SRC - - - - + - - - + + - - + - + - + - - + ab c d e e cumene hydroperoxide + - + + 0 5×105 1×106 1.5×106 2×106 Δψm TMRM intensity (normalized to cell count) Injury 1D4 RSL3 SRC - - - - + - - - + + - - + - + - + - - + aa b b c d d FCCP + - + + -10 0 10 20 30 40 Bioenergetic Health Index BHI Injury 1D4 RSL3 SRC - - - - + - - - + + - - + - + - + - + + a b b c d d + - - + Key Findings • Rilparencel-mediated lipid peroxidation detoxification serves as an essential component for RPTEC mitochondrial stabilization, restricting active oxidative damage & supporting adaptive cell survival • Parallel pharmacological studies confirm these cytoprotective effects are not exclusively mediated through GPX4 activity, supporting that rilparencel operates via complex, multimodal & multifactorial mechanisms of action Δψm = Mitochondrial Membrane PotentialRSL3 = GPX4 inhibitor1D4 = GPX4 activator
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24 Factors expressed by rilparencel with potential mechanistic relevance Key Findings • High-dimensional transcriptomics allow us to map global gene expression changes in rilparencel within a human injury context, uncovering what intrinsic factors may be critical for MoA • Rilparencel upregulates a network of acute cytoprotective & chemotactic pathways, while progressively increasing the expression of chronic tissue repair support factors as the injury model advances • These data will inform future gene editing of identified DEGs to determine whether they are active or passive drivers of potency Decreased expression of pro-fibrotic & growth factor signaling ligands Increased expression of protective paracrine & microenvironmental regulators Downregulation of baseline prostaglandin catabolism, amino acid metabolism, & steady- state matrix/receptor pathways Upregulation of chemotactic, cytoprotective, & stress- adaptation factors DEG = Differentially Expressed Gene Rilparencel
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25 Designing a multiomic approach to probe MoA in rodent CKD models HumanizedImmuno- compromised Rodent host context Readout of biodistribution & localized MoA Intracortical injection Rilparencel | Vehicle Post-dose collection to 28 days Adenine in diet induction phase 2, 4, or 7 weeks Adenine-induced CKD Tubulointerstitial injury Establish disease 1 3 7 14 28 Human cell fate hKu80 IHC Kidney pathology histochem & IHC Spatial multiomics MSI, Xenium snRNA-seq cell population & states Clin Chem & hematology mGFR over time • Preclinical proof-of-concept: Intracortically administered syngeneic selected renal cells (SRC) extended survival & stabilized renal function (sCR, BUN) in rodent (Kelley et al., 2010) & dog CKD models, improved survival & stabilized eGFR in a rodent model of diabetic kidney disease (Kelley et al., 2013) • Human SRC: Improved survival & stabilized renal function (sCr, BUN) in immunocompromised 5/6Nx rats (Guthrie et al., ASN 2014) • Adenine feeding in immunocompromised / humanized rodent models demonstrated reliable kidney injury • Rat models tested: RNU, SRG; Mouse models: NSG-IL15 ± cord blood CD34⁺ humanization • Vehicle controls were similarly injected intracortically with the excipient of rilparencel without any cells Current study design (2026)
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26 Rilparencel distributes to subcapsular & intraparenchymal renal compartments, partially persists through Day 28 1-day post-dose 28 days post-dose hKu80+ hmCD45- = Rilparencel hKu80+ hmCD45+ = Human immune cells hKu80- hmCD45+ = Mouse immune cells Vascular smooth muscle cells / Myofibroblasts (αSMA) Humanized NSG-IL15 mice fed adenine
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27 Aligning multiomic analytical modalities after rilparencel injection Human nuclei (rilparencel) All nuclei Spatial transcriptomicsIHC Rilparencel-associated gene
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28 Graft-associated cells have a distinct transcriptional signature in injected rats • Significantly upregulated genes in graft area cells 3 days post-rilparencel are associated with ECM remodeling & vascular development, including matrix organization & turnover, collagen biosynthesis, & blood vessel morphogenesis ECM remodeling Vascular development & support Rilparencel graft-associated gene signature
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29 Transcriptional signature of graft-associated cells evolves over time Rilparencel graft-associated gene signature Days post-rilparencel injection • The injured kidney’s response to rilparencel is dynamic & evolves over time • An initial higher upregulation in ECM remodeling gene expression drops over the first week after treatment but is maintained well above baseline • Accompanying this matrix remodeling signal, population enrichment of vascular support gene expression occurs by day 3 at the site of rilparencel engraftment
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30 Aligning multiomic analytical modalities after rilparencel injection Single nuclei RNA-seq Human nuclei (rilparencel) All Nuclei Spatial transcriptomicsIHC Rilparencel-associated gene Rilparencel-treated Vehicle-treated Healthy Control
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31 Cell junction & ECM adhesion signaling is upregulated in rat kidney endothelial cells • Kidney snRNA-seq at 28 days post-dose in RNU rats with adenine-induced CKD; endothelial nuclei identified using rodent kidney cell atlas from KPMP as a reference • There is a strong cell / ECM vascular program that is induced by rilparencel Mild cell-cell upregulation Strong cell-ECM upregulation Control Injury Injury+SRC 0 5×10-6 1×10-5 1.5×10-5 Barrier Permeability Papp (cm/s) a b c In Vitro Endothelial Cell Injury Rescue Model • Papp (apparent permeability coefficient) measures endothelial barrier function via FITC-dextran flux across a cell monolayer • Glomerular microvascular endothelial cell monolayers were injured for 3 days (glucose, cytokine mix, lipid mix, uremic toxins), then ± SRC for 4 days • SRC significantly reduced P app vs. Injury alone, indicating improved barrier integrity Endothelial junction & ECM programs Endothelial adhesion & stability programs
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32 Aligning multiomic analytical modalities after rilparencel injection Single nuclei RNA-seq Mass spec imaging (MSI) Human nuclei (rilparencel) All Nuclei Spatial TranscriptomicsIHC Rilparencel-associated gene PE 40:3PI O-32:0 Rilparencel-treated Vehicle-treated Healthy Control
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33 MSI reveals a distinct tissue remodeling signature at the rilparencel injection site • MSI spatially resolved protein & lipid biomarkers within an injection-defined ROI encompassing the hKu80-associated rilparencel injection site at day 3 post-injection • ROI showed enrichment of markers associated with immune responses, stromal / perivascular remodeling (↑ PDGFR-β, Vimentin), cell adhesion (↑ CD44), & autophagy (↑ LC3A) • A distinct lipid profile within the ROI (↑ PI 38:4, PI O-34:4; ↓ LPC 22:5, LPI 18:2) suggests regional differences in membrane composition & lipid remodeling Iba-1PI O-32:0 Analytes enriched outside ROI Analytes enriched inside ROI Injection Zone Signature domains Scavenging & tissue repair & remodeling M2 macrophage signature (snRNA-seq) hKu80 (rilparencel) ROI = Region of Interest ROI Differential lipid metabolite & protein enrichment (MSI)
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34 Translational studies suggest multifactorial MoA for rilparencel Whole-kidney multi-omics following rilparencel injection show signatures of (ASN talk FR-OR044): • Preserved vascular integrity & ECM remodeling • Improved lipid & glucose metabolic programs • Reduced pro-inflammatory signaling Human CKD biopsy & rilparencel co-culture studies revealed (ASN poster TH-PO1129): • Treatment-based transcriptional changes in ferroptosis pathway (also validated in vitro, see ASN poster SA-PO0013) Primary kidney cells Kidney-on-chip Kidney biopsy explant culture Rodent models of CKD In vitroEx vivoIn vivo (rodent) Rilparencel Transcriptomic analyses of REGEN-007 pre-formulation cell retains & patient biopsies, using the KPMP database (ASN poster SA-PO0014): • Cells of proximal & distal tubule origin exhibiting a reparative, plasticity- associated transcriptional signature with partial retention of native lineage identity MoA Hypothesis Rilparencel attenuates oxidative damage, metabolic dysregulation, & pro-inflammatory signaling to support cellular resilience, preserved vascular integrity & functional stabilization under chronic kidney disease-relevant conditions In vivo (human) Clinic (Phase 2) Plasma & urine proteomic analysis from baseline & correlation studies show signatures of (unpublished): • Basement membrane remodeling & vascular preservation Human decedent study upcoming: • Longitudinal 39-day post-dose tissue, urine, & plasma multiomic analysis Decedent Publications Human proximal tubule epithelial cell & glomerular vascular endothelial cell models of metabolic & inflammatory stress cultured with rilparencel showed (ASN poster TH-PO1128): • Lowered oxidative damage • Improved redox balance & mitochondrial fitness • Reduced pro-inflammatory signaling • Improved barrier integrity How rilparencel may be able to preserve kidney function in patients with advanced CKD
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Katherine R. Tuttle, MD, FASN, FACP , FNKF Executive Director for Research Providence Inland Northwest Health Professor of Medicine Nephrology Division and Kidney Research Institute University of Washington School of Medicine In the spirit of honoring the composition of place, I acknowledge that I live and work on the homelands of the Spokane, Palouse, Nez Perce, Coeur d’Alene, and Kootenai Tribal People. I am grateful to be on this land and ask for its support as we work to create an equitable, diverse, and inclusive community. The Quest to Save Kidneys, Hearts, and Lives Mechanisms Matter
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CKD Is A Global Public Health Crisis K o v e s d y C P. Kidney Int Suppl 2022;12:7–11 Global Burden of Disease, Chronic Kidney Disease Collaboration. Lancet 2025;406:2461-2482 Global Burden of Disease, Causes of Death Collaborators. Lancet 2024;403:2100-2132 Worldwide Increasing death rate 19th 13th 9th 5th 2013 2016 2019-2025 2040 (predicted) Rank in cause of death 850 Extremely common MILLION 2017- 2023 people in the general population have CKD 1 10in 41.5% from 1990 to 2017 Western Europe USA 44 MILLION 40 MILLION in 2023 144,000 147,000 deaths and caused in 2023
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What Problem are We Trying to Solve? Tuttle KR et al. CJASN 2022;17:1092-1103 International Diabetes Federation Atlas 11th edition, 2025 589 million 2024 and 850 million 2050
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Cardiovascular-Kidney-Metabolic Syndrome Kidney in the Middle Tuttle KR et al. Clin J Am Soc Nephrol 2026; online ahead of print Ndumele CE et al. Circulation 2023; 148:1636-1664
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GOAL: MITIGATE HIGH KIDNEY & CARDIOVASCULAR RISK Grams ME et al. JAMA 2023;330:1266-1277.
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Neuen B et al. Nephrol Dial Transplant 2025:40 (S1):i59-i69 Combination Therapy and the 4-Pillars Diabetic and Non-Diabetic CKD
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Alicic RZ, Neumiller JJ, Tuttle KR. Nephrol Dial Transplant 2025; 40 (S1):i3–i17 Complementary Mechanisms for CKM Therapies
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Neuen BL et al. Circulation 2024;149:450–462 Combination Therapy and Kidney Outcomes Added to RAS Blockade
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Neuen BL et al. Circulation 2024;149:450–462 Combination Therapy and Cardiovascular Outcomes Added to RAS Blockade
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Time to Events for Survival and Kidney Function in CKD Population Level and Person Level Tuttle KR et al. Clin J Am Soc Nephrol 2026; online ahead of print
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Residual Risks with Current CKD Therapies Questions and Potential Roles for Rilparencel • Who are treatment responders and non-responders? • TBD • What therapy or combination will work best? • TBD • When is the right time to deploy therapy? • Rilparencel as a reparative tool • Why does a therapy work or not work? • Rilparencel as rescue treatment • Where can therapies be sourced? • Rilparencel from a person’s own body • How to make treatment fit-for-purpose? • Rilparencel is designed for CKD 45
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What Can We Learn from Mechanistic Studies?
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Reduced Albuminuria and Stabilized eGFR Tuttle KR, Bjornstad P… Kretzler M et al. Nat Med 2026 Oct 1. Online ahead of print. PMID: 42823485 Semaglutide treatment compared to placebo after 52 weeks: • UACR reduced 40% (ETR 0.60, 95% CI 0.41;0.88, p=0.008) • eGFR differences • Creatinine-based: ETD 3.4 mL/min/1.73 m2 (95% CI -0.2;6.9, p=0.063) • Cystatin C-based: ETD 2.3 mL/min/1.73 m2 (95% CI -0.4;5.0, p=0.096) • Creatinine-cystatin C-based: ETD 2.9 mL/min/1.73 m2 (95% CI -0.2;6.1, p=0.069) 0 10 20 30 40 50 -6 -4 -2 0 2 4 Change in eGFR Creatinine-cystatin C-based Time since randomization (weeks) C hange from baseline (mL/min/1.73 m 2) Semaglutide 1.0 mg Placebo 0 10 20 30 40 50 0.0 0.5 1.0 1.5 2.0 UACR Time since randomization (weeks) R atio to baseline
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Reduced Kidney Fat and Renal Arterial Resistance with Stabilized Cortical Fibrosis Semaglutide treatment compared to placebo after 52 weeks: • 25% and 13% lower perirenal and sinus fat volumes, respectively • Reduced renal arterial resistive index (RARI) reflecting lower renal vascular resistance • No decrease in cortical apparent diffusion coefficient (ADC) reflecting stabilized fibrosis in the kidney cortex S emaglutide 1.0 mg Placebo 0.90 0.95 1.00 1.05 1.10 0.95 1.00 Cortical ADC R atio to baseline E TR 1.05 [95% CI 1.01;1.09] p = 0.005 S emaglutide 1.0 mg Placebo 0.94 0.96 0.98 1.00 1.02 1.04 1.06 1.01 0.97 Renal arterial resistive index R atio to baseline E TR 0.96 [95% CI 0.93;0.99] p = 0.008 S emaglutide 1.0 mg Placebo S emaglutide 1.0 mg Placebo 0.50 0.75 1.00 1.25 1.50 1.75 1.13 1.02 0.84 0.89 Kidney fat R atio to baseline E TR 0.87 [95% CI 0.78;0.97] p = 0.012 E TR 0.75 [95% CI 0.58;0.97] p = 0.027 Perirenal Si n u s Tuttle KR, Bjornstad P… Kretzler M et al. Nat Med 2026 Oct 1. Online ahead of print. PMID: 42823485
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Indicators of Improved Glomerular Filtration and Barrier Function Semaglutide treatment compared to placebo after 52 weeks: • 24-hour creatinine clearance was higher by a mean ETD of 12 mL/min • Filtration fraction was numerically higher by 19% S emaglutide 1.0 mg Placebo -16 -12 -8 -4 0 4 8 12 16 -9.0 3.0 Creatinine clearance Change from baseline (mL/min) E TD 12.0 (95% CI 0.7;23.3) p = 0.038 S emaglutide 1.0 mg Placebo 0.75 1.00 1.25 1.50 0.9 1.1 Filtration fraction R atio to baseline E TR 1.19 [95% CI 0.98;1.45] p = 0.086 Tuttle KR, Bjornstad P… Kretzler M et al. ASN Kidney Week 2025; Late Breaking Abstract: FR-OR089
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Transcriptomic Reprogramming in Glomerular Endothelial Cells Fifty-five kidney-biopsy samples (794,000 nuclei) underwent snRNAseq with 31 canonical cell clusters, representing all major cell types in the nephron (identified using reference markers) Glomerular endothelial cells were the most semaglutide- responsive cell type: • 63% of metabolic stress genes down-regulated • 60% of fibro-inflammatory genes down-regulated C onnecting nephron - immune C onnecting nephron Proximal tubule cells 2 Natural killer T cell Glomerular endothelial cells 2 Glomerular endothelial cells 1 Regulation Down Up -75 -50 -25 0 25 50 75 Number of genes 25 75 50 UMAP dimension 2 UMAP dimension 1 Tuttle KR, Bjornstad P… Kretzler M et al. Nat Med 2026 Oct 1. Online ahead of print. PMID: 42823485
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Ligand-Receptor Interactions between Glomerular Endothelial Cells and Immune Cells – snRNAseq Semaglutide promotes glomerular endothelial repair and remodeling programs: Type 4 collagen, integrins, PECAM1 (CD31), CDH5 (VE cadherin) Tuttle KR, Bjornstad P… Kretzler M et al. Nat Med 2026 Oct 1. Online ahead of print. PMID: 42823485
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Spatial Transcriptomics Glomerular Endothelial and Natural Killer T Cells, Monocytes/Macrophages Tuttle KR, Bjornstad P… Kretzler M et al. Nat Med 2026 Oct 1. Online ahead of print. PMID: 42823485
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Reduced Fractional Intimal Area of Most Diseased Arterioles and Periglomerular Immune Cells Semaglutide Pre Post Tuttle KR, Bjornstad P… Kretzler M et al. Nat Med 2026 Oct 1. Online ahead of print. PMID: 42823485
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Pathophysiological Interpretation of Semaglutide’s Mechanisms-of-Action in CKD and T2D Improved glomerular hemodynamics Attenuated metabolic and fibro-inflammatory signaling Semaglutide Reduced albuminuria Preserved glomerular filtration Reduced intrarenal and perirenal fat Endothelial transcriptional reprogramming Better microvascular function Stabilized fibrosis Relieved glomerular endothelial stress at the filtration barrier Functional MRI Clinical/biochemical measures Histological measures Transcriptome profiling Tuttle KR, Bjornstad P… Kretzler M et al. Nat Med 2026 Oct 1. Online ahead of print. PMID: 42823485
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55 Q&A