Slides
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1 Analyst Day 2026 KRRO-121: A Potential First-in-Class Treatment for Ammonia Control January 27th, 2026
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2 Forward-Looking Statements and Disclaimers Forward-Looking Statements Certain statements in this presentation may constitute “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements include, but are not limited to, express or implied statements regarding expectations, hopes, beliefs, intentions or strategies of Korro Bio, Inc. (Korro) regarding the future including, without limitation, express or implied statements regarding: the timing of the regulatory filing for KRRO-121; KRRO-121’s pan-urea cycle disorder (UCD) potential; KRRO-121’s first in class potential as a treatment for ammonia control; KRRO-121’s ability to drive strong patient engagement and recruitment in clinical trials; KRRO-121’s pipeline-in-a-product, blockbuster potential; KRRO-121’s differentiation and potential impact for patients; among others. In addition, any statements that refer to projections, forecasts, or other characterizations of future events or circumstances, including any underlying assumptions, are forward-looking statements. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “plan,” “possible,” “potential,” “predict,” “project,” “should,” “strive,” “would,” “aim,” “target,” “commit,” and similar expressions may identify forward-looking statements, but the absence of these words does not mean that statement is not forward looking. Forward-looking statements are based on current expectations and assumptions that, while considered reasonable are inherently uncertain. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Factors that may cause actual results to differ materially from current expectations include, but are not limited to, various factors beyond management’s control including risks inherent in biopharmaceutical development; risks associated with pre-clinical studies and clinical studies; risks associated with validating in clinical trials observations from pre-clinical studies; along with other risks inherent in biopharmaceutical development; and other risks associated with obtaining regulatory approvals and protecting intellectual property; as well as risks associated with general economic conditions (including recent geopolitical uncertainty and potential supply chain disruptions due to changes in economic policy); and other risks and uncertainties indicated from time to time in Korro’s filings with the SEC, including “Risk Factors” in Korro’s most recent Quarterly Report on Form 10-K or Form 10-Q filed with the SEC, as such may be amended or supplemented by its other filings with the SEC. Nothing in this presentation should be regarded as a representation by any person that the forward-looking statements set forth herein will be achieved or that any of the contemplated results of such forward-looking statements will be achieved. You should not place undue reliance on forward- looking statements in this presentation, which speak only as of the date they are made and are qualified in their entirety by reference to the cautionary statements herein. Except as required by law, Korro does not undertake or accept any duty to release publicly any updates or revisions to any forward-looking statements to reflect any change in their expectations or in the events, conditions or circumstances on which any such statement is based. This presentation does not purport to summarize all of the conditions, risks and other attributes of an investment in Korro. Industry and Market Data Certain information contained in this presentation relates to or is based on studies, publications, surveys and Korro’s own internal estimates and research. In this presentation, Korro relies on, and refers to, publicly available information and statistics regarding market participants in the sector in which Korro competes and other industry data. Any comparison of Korro to any other entity assumes the reliability of the information available to Korro. Korro obtained this information and statistics from third-party sources, including reports by market research firms and company filings. In addition, all of the market data included in this presentation involve a number of assumptions and limitations, and there can be no guarantee as to the accuracy or reliability of such assumptions. Finally, while Korro believes its internal research is reliable, such research has not been verified by any independent source and Korro has not independently verified the information. Trademarks This presentation may contain trademarks, service marks, trade names and copyrights of Korro or other third parties, which are the property of their respective owners. Solely for convenience, some of the trademarks, service marks, trade names and copyrights referred to in this presentation may be listed without the TM, SM © or ® symbols, but Korro will assert, to the fullest extent under applicable law, the rights of the applicable owners, if any, to its trademarks, service marks, trade names and copyrights.
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3 Today’s Speakers Ram Aiyar CEO Todd Chappell COO Loïc Vincent CSO Michelle Dinon UCD Parent Bruce Scharschmidt Clinician
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4 Agenda Expanding to New Biological Frontiers with RNA Editing Ram Aiyar, CEO Living with UCD: A Mother’s Perspective Michelle Dinon, UCD Parent Ammonia-driven Diseases: Urea Cycle Disorders and Hepatic Encephalopathy Dr. Bruce Scharschmidt, Clinician KRRO-121 Scientific Overview and Preclinical Data Loïc Vincent, CSO KRRO-121 Target Product Profile & Market Opportunity Todd Chappell, COO Closing Remarks Ram Aiyar, CEO Q&A All Presenters
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5 Expanding to New Biological Frontiers with RNA Editing Ram Aiyar, PhD, MBA Chief Executive Officer
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6 Modulate Protein Function (Activate pathway) Examplesof Modulate = Hyperammonemia, ALS, MASH, Fibrosis… RNA TRANSLATION Normal Protein TRANSLATION Protein Variant Edited RNA Editing RNA Without permanently modifying DNA Modular Delivery Potential to deliver to multiple cell types Learning from Genetics To support predictable biological impact Developing Transformative Genetic Medicines for Rare and Highly Prevalent Diseases
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7 Living with UCD: A Mother’s Perspective Michelle Dinon UCD Mother
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8 Ammonia-driven Diseases: Urea Cycle Disorders and Hepatic Encephalopathy Bruce Scharschmidt, MD Hepatologist, Former CMO of Hyperion Therapeutics
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Professional Background / Bruce F . Scharschmidt, MD UCSF Faculty from 1977-1996: Professor of Medicine & Chief of GI • Helped start the UCSF liver transplant program with colleagues in surgery & medicine • Editor-in-Chief of the J. Clinical Investigation & President of the Am Society for Clin Invest 1996-2006: Head of Chiron Clinical Development (Vaccines & Therapeutics) • 1st Cancer immunotherapeutic; Influenza, pandemic influenza & meningococcal vaccines 2008-2015: Chief Medical & Development Officer, Hyperion Therapeutics • Development/launch of glycerol phenylbutyrate (GPB, aka Ravicti®) for UCDs; ph2 trial of GPB for HE • Initial public offering in 2012 and acquisition in 2015 2015-present: Board of Directors, Founder/Co-Founder, Consultant, Patient Advocacy, Children’s Book Author (visit: brucescharschmidt.com) Disclosures: Consultant to Korro, others; Board Member Saccharo, Umecrine Don’t hesitate to ask questions / I have sensorineural hearing loss 9
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Ammonia (NH3): Most People’s First Thoughts Ammonia is in household cleaners Surprised to learn that ammonia is in our bloodstream Imagine: You / your child are / is diagnosed with a urea cycle disorder 10
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Urea Cycle Disorders (UCDs) are Cruel & Unforgiving You/your child becomes severely and acutely ill Your physician/pediatrician orders blood NH3, refers to a metabolic geneticist Metabolic geneticist confirms UCD Dx; advises: • Severely protein-restricted diet; perhaps with supplements • A short acting tablet or liquid ≤3-4x/day • Non-compliance may trigger a hyperammonemic crisis (HAC) • HACs may require hospitalization, cause disability / death • HACs may happen anyway; have no apparent cause • The disorder is lifelong; you/your child won’t outgrow it • Severely affected patients may require a liver transplant 11 (You’re among the fortunate ones whose physician thought to check blood NH3)
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Ammonia Production & Disorders of Hyperammonemia • Humans have no nitrogen/protein ‘depot’; protein not utilized is broken down, releases ammonia. • Ammonia is produced in our body/intestines as a byproduct of protein catabolism. • Ammonia is normally detoxified in the liver through a series of enzymatic steps: the urea cycle. • Two major disorders of hyperammonemia: liver disease & enzymatic defects in the urea cycle Our Liver is Strategically Positioned The Urea Cycle Resides in the Liver Triage & Cleansing • Blood from the intestines passes first through the liver • The liver triages nutrients and clears NH3 & other toxins Normal UCD NH3urine urea cycle NH3urine urea cycle urine ‘Alternate Pathway’ Drugs • Sodium phenylbutyrate (NaPBA, Buphenyl®) • Glycerol phenylbutyrate (GPB, Ravicti®) • Both are prodrugs of phenylacetic acid, which is converted to phenylacetyl glutamine (PAGN) 12
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UCDs: Overview • Urea Cycle: enzymatic steps NH3 → urea • All autosomal recessive except X-linked OTCD • Genetically heterogeneous • HACs particularly a problem with proximal UCDs • The more severe the defect, the earlier the onset • Severity assessed clinically; measuring urea cycle activity involves stable isotopes (research tool) • Not all UCD subtypes detected by NBS • Incidence ~ 1:35,000 births; prevalence uncertain • Dedicated physician (UCD Consortium; UCDC), patient advocacy groups (National Urea Cycle Disorders Foundation; NUCDF) Demographics in Hyperion’s GPB Trials* • 49% peds; 51% adult (≥18) • 67% female; 33% male • OTC (69%); ASL (13%); ASS (12%) *Lee, Diaz, Rhead…Scharschmidt, Genet Med 2014 13
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Ammonia Control: Lessons from the GPB Trials Berry et al (J Ped 2001): “The goal of treatment is to maintain normal levels of plasma ammonia through the use of the low-protein diet and medication while allowing for normal growth. ” But • No consensus among investigators regarding ammonia control • 24-hr monitoring NH3 increases up to severalfold after meals What is meant by keeping NH3 normal, and does it benefit patients? • So, we analyzed our unique data set 14 →
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UCD Patients Benefit from Tight Ammonia Control Time-to-event (HAC) ‘survival type’ analysis < 0.5x ULN 0.5 – 1x ULN > 1x ULN Genetics in Medicine; 2014 Methods: • Post-hoc analysis: > 1000 samples, 114 UCD pts • Examined NH3 exposure (24-hour AUC) vs. HAC Results • HAC risk, frequency correlates with NH3 exposure • NH3 AUC correlates with fasting/morning level • Patients benefit by fasting/morning NH3 < ½ ULN 15
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Urea Cycle Disorders (UCDs): Unmet Need • UCD patients benefit from ‘tight’ ammonia control, but… • Treatment is tough • Particularly for school age children & adolescents • Severely restricted diets sometimes don’t resemble food • Sodium phenylbutyrate is unpleasant and causes body odor • Glycerol phenylbutyrate is easier to take and more slowly absorbed, but both drugs… • are short acting and may require multiple times / day dosing • may decrease serum levels of BCAA, requiring monitoring, dietary supplements1 • have a narrow therapeutic index, potential for phenylacetic toxicity (PAA)2 • We explored the role of compliance/other factors as contributors to HACs 16 1. Branched-chain amino acids (BCAA): Burrage et al., Mol Genet Metab, 2014; Batshaw et al., Mol Genet Metab, 2014 2. PAA & Safety: Mokhtarani et al., Mol Genet Metab, 2013; Monteleone et al., J. Clin Pharm, 2013; Glinton et al., Mol Genet Metab, 2023
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* Berry et al., Glycerol Phenylbutyrate Treatment in Children with Urea Cycle Disorders: Pooled Analysis of Short and Long- term Ammonia Control and Outcomes. Mol Genet Metab, 2014 Trigger % Intercurrent illness 26.3% Infection 15.8% Drug non-compliance 10.5% Diet non-compliance 10.5% Other or ‘none’ 55.2% CLINICAL TRIAL DATA: HAC Triggers Among 49 Pediatric Patients on NaPBA in the Year Prior to Enrollment* *Batshaw et al., A longitudinal study of urea cycle disorders. Mol Genet Metab, 2014 What We Learned About HACs 17 Additional Considerations • Role of infection/intercurrent illness consistent with data from UCDC sponsored Longitudinal Study (33%) * • Role of non-compliance likely understated • Infection/illness may cause nausea/vomiting • HACs decreased by > 50% after patients enrolled in GPB studies, where compliance is monitored • Most UCD patients with crises experience several • A substantial fraction of the ~62% of patients not taking alternate pathway drugs likely also experience HACs
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Some “Asymptomatic” Female OTCD Patients are Not Well • Most common subtype, X-linked • It was believed most females were asymptomatic • Dr. Andrea Gropman’s work has shown that ‘asymptomatic’ female patients exhibit subtle cognitive (executive, fine motor) and functional brain imaging abnormalities • Among >100 pts in the UCDC Longitudinal Study classified as asymptomatic at baseline, 38% developed neuropsychiatric diagnoses (average age 17); 4% HAC (average age 50 years) Gropman et al., Altered Neural Activation in Ornithine Transcarbamylase Deficiency During Executive Cognition: An fMRI Study. Human Brain Mapping, 2013. Gropman et al., Urea cycle defects and hyperammonemia: effects on functional imaging; Met Brain Dis, 2013 Sprouse et al., Investigating Neurological Deficits in Carriers and Affected Patients with Ornithine Transcarbamylase Deficiency, Mol Genet Metab, 2014 Sen et al., Are asymptomatic carriers of OTC deficiency always asymptomatic? A multicentric retrospective study of risk using the UCDC longitudinal study database, Mol Gen Metab, 2024 “New research shows female OTC carriers (heterozygous females) face more symptoms, risks than expected. ” NUCDF news, June 2024 18
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Decompensated Cirrhosis and Hepatic Encephalopathy (HE) • Scarred liver impedes portal blood flow → portal hypertension & portal-systemic shunting (PSS) (i.e., shunting of blood around the liver) • 3 major manifestations of liver failure/PSS : HE, variceal bleeding, fluid retention with ascites/kidney failure • Liver transplantation is the only ‘cure’ , but • Severely donor limited -> long wait times • Patients may live years • Can cause brain damage, sometimes death • Strong pharmaco-economics • US prevalence likely > 200,000 • Big question when Hyperion started its trial: Is elevated ammonia a correlate or a cause? Cirrhosis with PS Shunting 19
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Ammonia Lowering is Effective in Secondary Prophylaxis of HE Methods: • RDBPC multi-national trial of GPB • 178 patients with ≥2 prior HE episodes in ≤ 6 mos • Cochran-Mantel-Haenszel analysis stratified by country Results • GPB lowered ammonia • GPB lowered HE risk, HE frequency, HE hospitalizations Time-to-event (HE event) ‘survival type’ analysis placebo GPB 2012 AASLD Plenary / Hepatology; 2014 But… Might the effect of GPB be due to something other than its effect on ammonia? Hazard ratio: 0.56 95% CI: (0.32, 0.99) P = 0.047 20
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GPB Works by Ammonia Lowering Methods: • Post-hoc analysis: > 1000 ammonia samples from 178 pts • Examined fasting ammonia vs. risk, frequency of HE events • Binary logistic regression & Cox proportional hazard Results • Morning/fasting ammonia correlates with HE risk, frequency • GPB effect explained by ammonia lowering • Patients benefit by keeping fasting / morning ammonia ≤1.5 x ULN Clinical Gastroenterology & Hepatology; 2016 HE Risk & Frequency vs. Fasting Ammonia 21
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HE is Still a Big and Expensive Problem HE Observational Study • 265 pts; 30 sites; ≥1 HE event ≤30 days; 72d mean F/U • 72 (27%) pts experienced a total of 122 HE events • 23 (9%) / 13 (5%) had ≥ 2 / ≥ 3 HE events • 82% of patients with HE were on rifaximin • 85% of events resulted in hospitalization • No difference related to rifaximin use at baseline Big Healthcare Burden; Strong Pharmacoeconomics • Impacts cognition, HRQoL, outcome • HE hospitalizations (>>$10K/hospitalization) • Total US costs: $B’s Landis, Ghabril, Rustgi, … Scharschmidt: Prospective Multicenter Observational Study of Overt Hepatic Encephalopathy, Dig Dis Sci, 2016 Hirode et al., Increasing Burden of Hepatic Encephalopathy Among Hospitalized Adults: An Analysis of the 2010-2014 National Inpatient Sample, Dig Dis Sci, 2019 Bajaj et al. The Burden of Hepatic Encephalopathy use of Albumin as a Potential treatment, Ann Hep, 2025 22 From Landis, 2016
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HE Final Thoughts Why is HE still such a big problem? • Drug compliance almost certainly an issue • Other complications better treated • HE not prioritized for liver transplant • Ammonia may not be the only cause, and/or • Current Rx doesn’t lower ammonia enough Minimal/Covert HE • Conceptually analogous to ‘asymptomatic’ OTCD • Subtle/subclinical cognitive & imaging abnormalities • Difficulty with executive function, driving • No consensus: Whether to test, how to diagnose and no approved Rx. • Consensus: It is an important problem and more common than overt HE (~50% of cirrhotics) As a hepatologist: I’m hoping we can do more for these patients! “Hepatic encephalopathy (HE) is … one of the most debilitating manifestations of liver disease, severely affecting the lives of patients and their caregivers….. results in utilization of more health care resources in adults than other manifestations of liver disease” Hendrik, AASLD/EASL HE practice guidelines, 2014 23
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THANK YOU 24
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25 KRRO-121 Scientific Overview and Preclinical Data Loïc Vincent, PhD Chief Scientific Officer
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26 Glutamine Synthetase (GS)is a critical ammonia clearing mechanism ▪ Genetic evidence uncovers a key amino acid modification that can augment GS protein stability ▪ Ammonia-lowering benefits of stabilized GS activity may address substantial unmet need in patients with poor ammonia control, including UCD and hepatic encephalopathy ▪ KRRO-121 is a GalNAc-conjugated ASO that edits GS mRNA to generate a stable, de novo GS variant specifically in the liver ▪ KRRO-121 demonstrates potential to enable robust ammonia clearance, supporting a pan-UCD approach that may enable dietary liberalization as well as clinical activity in other ammonia-driven diseases, such as HE Mechanism: Stabilizing Glutamine Synthetase to Clear Ammonia KRRO-121 regulatory submission to enable commencement of FIH trial is anticipated in the 2nd half of 2026
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27 Two Complementary Pathways for Ammonia Clearance: Urea Cycle and Glutamine Synthetase (GS) Source: Inoue at al., Seizure (2015); Bennet et al., Child Neurology Open (2020); Jones et al., The American Journal of Human Genetics (2024); Soria et al., J Inherit Metab Dis (2019); KOL interviews Glutamine Glutamine synthetase Glutamine Synthetase Glutamate Ammonia Expressed in many tissues, including liver, brain, and muscle Urea Cycle Expressed primarily in liver Ammonia Urea Urea Cycle OTC ASL ARG ASS CPS-1
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28 Degradation of GS Controlled by Levels of Glutamine Source: Van Nguyen et al., Mol Cell (2017) GS degraded when glutamine rises, reducing ammonia clearance capacity Glutamine Drives Degradation of GS Degradation Mechanism: Acetylation of Key N-terminal Residues Glutamine Glutamine synthetase Glutamate Ammonia GS Degradation High glutamine Acetylation of lysine residues, leading to ubiquitination and protein degradation Ubiquitination signal Glutamine synthetase N Lys Lys AcAc Low glutamine No lysine acetylation, GS is stable N Glutamine synthetase Degradation
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29 9 patients with start-loss variants, stabilizing GS due to loss of N-terminal Lys residues GS stability Stable activity Patient with Lys14Asn mutation (mimicking acetyl- lysine) resulted in GS deficiency, hyperammonemia GS StabilityAmmonia Acetylation mimic prone to degradation Human Genetic Evidence Supports Stabilization of GSby Preventing Degradation Source: Bennet et al., Child Neurology Open (2020); Jones et al., The American Journal of Human Genetics (2024); Van Nguyen et al., Mol Cell (2017) N Asn Lys Glutamine synthetase No N-terminal degron Glutamine synthetase Gain of FunctionLoss of Function Ammonia
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30 Hypothesis: Preventing GS Degradation Will Stabilize the Protein and Enable Increased Ammonia Clearance Liver-specific GS modification may prevent degradation, increase ammonia clearance Glutamine Glutamine synthetase N Arg Lys Glutamate Ammonia GS degradation prevented
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31 Our Approach: Liver-specific, GalNAc-ASO to Generate a Stable GS Variant De novo GS variant Liver directed editing (GalNAc delivery) KRRO-121 GS mRNA + I (G) A Edited GS mRNA De novo GS variant N Arg Lys Glutamine synthetase Designed to maintain consistent ammonia clearance capacity GalNAc KRRO-121: GalNAc-conjugated oligonucleotide designed for liver-specific RNA editing of GS to enhance ammonia clearance capacity
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32 KRRO-121 Stabilized GS in OTC-Deficient iPSC-Derived Hepatocytes Vehicle KRRO-121 (10 μM) 0 1 2 3 0.4 0.91.0 1.0 Fold Change to Vehicle non treated 10 mM NH4Cl ✱✱✱ GS degradation GS remained stable upon oligo treatment Similar results in ASS1-deficient iPSC-derived hepatocytes 20–25% editing observed in oligo-treated cells Note: OTC D175V human iPSC-derived hepatocytes differentiated for 14 days, then treated with oligo for 48 hours where indicated (10 mM NH4Cl added after 24 hours where indicated). GS concentration measured at conclusion of 48-hour incubation. KRRO-121 Stabilized GS in UCD-derived Human Cell Models KRRO-121 OTC iPSC
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33 Improved Clearance in Ammonia Challenge Supports Potential to Increase Protein Intake Note: Vehicle or Mouse-optimized oligo dosed at 10 mg/kg-SC daily on Days 0-4. Ammonia and glutamine measured following ammonia challenge (150 mg/kg) on Day 14 Ammonia challenge designed to model patient protein consumption Nonsignificant Increase in Plasma Glutamine Levels 0 500 1000 1500 2000 2500 Blood Gln (μM) Fasted ammonia ULN: 450 M (human range 75 g/dL) Ammonia (µM) 0 200 400 600 800 1000 Day 14 Day 14 Vehicle Mouse-optimized oligo Ammonia Reduction in OTC-DeficientMice Challenged with Ammonia Supports Clinical Activity, Diet Liberalization OTCspf/ash
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34 De Novo GS Variant Enabled Ammonia Control in OTC Mice Under Protein Load, with Stable Isotope Tracer Validating MOA Note: Vehicle or Mouse-optimized oligo dosed at 10 mg/kg-SC daily on Days 0-4. Glutamine, ammonia, and GS concentration measured following challenge with 100 mg/kg glutamine + N-15 glutamate on Day 11 Demonstrated GS target engagement in OTC-deficient mice; similar results observed in wild-type mice (not shown) Min Ammonia (µM) Min AUC Glutamine Conc (µM) x Minutes Min 0 20 40 60 80 100 0.5 1.0 1.5 ✱✱ 30 45 90 200 400 600 800 1000 ✱✱ 0 20 40 60 80 100 0 1000 2000 3000 4000 ✱✱ Decreased Plasma Ammonia Increased Plasma N-15 Glutamine Increased Total Liver GS Concentration N-15 glutamate used as target engagement tracer Fasted ammonia ULN: 450 µM (75 µg/dL) Vehicle Mouse-optimized oligo Fold Change to Control OTCspf/ash
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35 Ammonia Reduction in CPS-1 DeficientMice Further Validates Potential Pan-UCD Applicability and Diet Liberalization Note: Vehicle or Mouse-optimized oligo dosed at 10 mg/kg-SC daily on Days 0-4. Ammonia and glutamine measured following ammonia challenge (150 mg/kg) on Day 8 “… Korro’s RNA editing approach targeting glutamine synthetase in hepatocytes has been proven to effectively redirect excess toxic ammonia towards the synthesis of glutamine in UCD animal models …” – Nicola Brunetti-Pierri MD and Leandro R. Soria PhD 0 500 1000 1500 2000 Ammonia (μM) ns Baseline Post Challenge p < 0.05 0 500 1000 1500 Blood Gln (μM) Baseline Post Challenge ns ns Reduction in Ammonia Following Ammonia Challenge Nonsignificant Increase in Plasma Glutamine Levels Vehicle Mouse-optimized oligo CPS-1
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36 Note: Vehicle or KRRO-121 dosed at 50 mg/kg-SC on Days 0, 14 and 28. Mice challenged with 350 mg/kg ammonia on Day 21. GS levels measured on Day 31. PXB mice retain zonal GS expression. Source: J Toxicol Pathol 2025; 38: 183–189 KRRO-121 Significantly Reduced Ammonia Levels in Basal State and Following Ammonia Challenge in Humanized Liver Mouse Model KRRO-121 stabilized GS levels, providing robust ammonia control in a humanized mouse model Vehicle Control KRRO-121 Treated 0 50 100 150 Predose ammonia levels Ammonia (M) ✱✱✱ Vehicle Control KRRO-121 Treated 0 500 1000 1500 2000 Post-challenge ammonia levels Ammonia (M) ✱✱✱ ULN Vehicle Control KRRO-121 Treated 0 200 400 600 800 Protein (nM, in liver) Native GS protein De novo GS variant Vehicle Control KRRO-121 Treated 0.0 0.5 1.0 1.5 2.0 Glutamine mM ns Stabilized GS Variant and Normal GS Protein Levels Reduction in Basal Ammonia Enhanced Ammonia Clearance in Challenge Steady Glutamine Post-Challenge Ammonia (µM) Ammonia (µM) Protein (nM, in liver) Glutamine (mM) Potent ammonia lowering through a minimal amount of de novo GS KRRO-121 PXB
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37 KRRO-121 OTCspf/ash KRRO-121 Showed No Increase in Astrocyte Activation in Brain Note: Vehicle or KRRO-121 dosed at 20 mg/kg-SC daily on Days 0-4. Editing and GFAP measured following ammonia challenge (150 mg/kg) on Day 14 GFAP+ cells represented as brown dots 1 mm 5 mm 5 mm 1 mm
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38 KRRO-121 Displayed Strong Liver Uptake and No Adverse Findings in Non-Human Primates KRRO-121 Note: Vehicle or KRRO-121 dosed to cynomolgus monkeys (n=3 male/group) QWx3 (10 or 30 mg/kg), samples collected for biodistribution and histopathology 48h post third dose and clinical chemistries and hematology 6 and 48h post first and last dose >90% Delivery of KRRO-121 to Liver No Changes in Liver or Kidney Function Confirmed Liver Localization of KRRO-121 with Pericentral GS ALT AST TBIL Creatinine BUN Prothrombin time Platelets Complement Bb 0.0 0.5 1.0 1.5 2.0 KRRO-121 (QWx3, Monkey) - 6h post 3rd dose Fold change to Vehicle Control 10 mg/kg 30 mg/kg Cy5 (purple) = KRRO-121 Cy7 (teal) = GS DAPI (blue) = nuclei Injection Site Kidney Liver: 90%+ Spleen Liver <0.05% delivery to bone marrow, brain, heart, lymph nodes and muscle
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39 KRRO-121: A Potential First-in-class Treatment For Ammonia Control ▪ Pan-UCD potential impacting multiple UCD subtypes ▪ Robust ammonia control in OTC and CPS-1 mice challenged with ammonia1 ▪ Diet liberalization potential demonstrated by ammonia reduction during protein challenge Preclinical Activity ▪ NHP: No adverse safety signals in repeat QWx3 dose range finding tox studies ▪ NHP: No impact on coagulation, complement, platelets, cytokines ▪ No evidence of editing observed in mouse brain tissue ▪ No increase in mouse astrocyte staining in KRRO-121 treated mice relative to vehicle treatment Preclinical Safety ▪ Production of stable, de novo GS variant which increased ammonia clearance and maintained normal glutamine levels ▪ Scaled from mouse to monkey and showed targeted liver delivery Demonstrated Translation Strong preclinical data support KRRO-121’s anticipated regulatory submission Note: 1. As demonstrated using a surrogate mouse-optimized oligo
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40 KRRO-121: Anticipated Regulatory Filing in Second Half of 2026 Compelling product profile for controlling ammonia expected to drive strong patient engagement and recruitment 2025 2026 H2 H1 H2 Regulatory Filing for FIH Trial DC Nominated KRRO-121 ✓ Analyst Day✓
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41 KRRO-121 Market Opportunity Todd Chappell, MBA Chief Operating Officer
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42 Urea Cycle Disorders Hepatic Encephalopathy KRRO-121 Has Blockbuster Potential in Multiple Indications Note: 1. Severe late-onset UCD patients; 2. Patients prescribed rifaximin +/- lactulose with ≥1.5x normal ammonia and satisfactory liver function as assessed by laboratory values; 3. EU + UK estimate applies U.S. epidemiology assumptions to estimated EU + UK cirrhosis population Source: 3rd party primary market research study (April 2025); KOL interviews; GlobalData; Electronic medical records analysis (data from 2022). All figures approximate. Addressable Patients 4,200 U.S. 1 5,100 EU + UK 1 80,000 U.S. 2 150,000 EU + UK3 Market Opportunity $1.5B $2B+
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43 Plasma Ammonia Significantly Impacts Pathology Across Multiple Diseases ▪ High ammonia leads to: ‒ Neurological impairment, potentially permanent ‒ Frequent hospitalization ‒ Highly restricted diet ‒ Elevated infection risk ‒ Additional non-neurological complications ▪ Can be caused by cirrhosis or urea cycle dysfunction ▪ Clinical studies have shown benefit of lowering ammonia in multiple indications Ammonia Diet & metabolism Normal Clearance Diminished Clearance Normal excretion through kidneys Hyperammonemia Ammonia Pathology ! Source: 3rd party primary market research study and analysis (April 2025); KOL interviews
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44 Uncontrolled Ammonia is a Persistent Danger for UCD Patients UCD 35 µmol/L 1x ULN 52.5 µmol/L 1.5x ULN 0 25 50 75 100 125 150 175 200 Ammonia (µmol/L) Healthy adult range Ammonia Frequently >1.5x ULN in UCD, Leading to Increased Hyperammonemia Risk Ammonia control is highly challenging in UCD patients today, often requiring nitrogen scavengers + strict diet that can lead to malnutrition Note: 1. ~150 measurements in 16 patients with confirmed SNPs associated with urea cycle enzymes. ULN – Upper limit of normal Source: Electronic medical records analysis (data from 2022)
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45 KRRO-121 is Designed to Have a Compelling Product Profile to Potentially Address UCD Patients with Substantial Unmet Need UCD De novo hepatic GS variant with enhanced stability, designed to enable robust ammonia clearance capacity via chronic maintenance therapy Differentiated Ammonia-Lowering Approach Pan-UCD approach Convenient SC delivery Diet liberalization Reduction in HACs
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46 KRRO-121 Can Potentially Address Patients Across All UCD subtypes Note: 1. Onset of symptoms at age >1 month; 2. Severe defined as symptomatic patients expected to benefit from pharmacological therapy Source: 3rd party primary market research study (April 2025); KOL interviews; GlobalData. All figures approximate. U.S. UCD Epidemiology UCD Subtypes UCD OTC ASL ASS CPS1 ARG1 + HHH + NAGS + Citrin 6,500 UCD patients 4,600 post-neonatal onset1 4,200 severe2 5,100 additional addressable patients in EU + UK
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47 Ammonia Measurements in Uncontrolled HE Patients Are Frequently Above Normal, Correlating with Higher HE Risk HE HE Events Correlate with Ammonia Ammonia Elevated in Many Severe / Recurring HE Patients 1 Note: 1. 523 measurements from HE patients with rifaximin exposure in 2022 (27 outliers excluded from graph as defined by Q3 + 1.5 x IQR or Q1 – 1.5 x IQR); 2. Cirrhosis patients with exposure to rifaximin (+/- lactulose); 3. Excluding patients with no available ammonia data. ULN – Upper limit of normal Source: Rockey et al., Hepatology (2014); Electronic medical records analysis (data from 2022) ~38% ~40% ~62% ~13% ~47% No data available Controlled HE Severe / recurring HE2 High ammonia (≥1.5x ULN) Normal ammonia 35 µmol/L 1x ULN 52.5 µmol/L 1.5x ULN 0 25 50 75 100 125 150 175 200 Ammonia (µmol/L) Healthy adult range Ammonia Measurements: Severe / Recurring HE HE Patient Segmentation ~70 µM median ammonia ~76% of severe/ recurring HE patients with available ammonia data have an elevation ≥1.5x ULN3 Glycerol Phenylbutyrate Phase 2 HALT-HE Study
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48 Elevated Ammonia Levels Are Associated with a Greater Healthcare Burden in HE HE Clear shift towards greater healthcare utilization in HE underscores strong pharmacoeconomic case for treatments that can reduce this burden High Ammonia Significantly Increases Hospitalization Risk 1 2 3 4 Severe / recurring HE w/ high ammonia and stable MELD All severe / recurring HE Note: 1. HE-related hospitalization defined as an inpatient visit with a concurrent lactulose prescription; 2. Addressable HE defined as HE patients prescribed rifaximin +/- lactulose with ≥1.5x normal ammonia and MELD ≤20; 3. Average payer costs for HE hospitalization in 2020 based on commercial claims database analysis; ** p <0.01; *** p <0.001 Source: Harris et al., Clinics in Liver Disease (2024); Wong et al., Clin Transl Gastroenterol (2025); Electronic medical records analysis (data from 2022) Severe / recurring HE w/ high ammonia and stable MELD All severe / recurring HE HE-related1 All-cause 1 2 3 4 Mean annual hospitalizations / patient *** ** ▪ >2-fold increase in HE-related hospitalization for addressable HE patients2 vs all severe / recurring HE ▪ >$10B inpatient charges for HE in the U.S. each year; average cost per hospitalization over $75K3
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49 KRR O-121 Also Has an Opportunity to Potentially Address Significant Unmet need in HE HE De novo hepatic GS variant with enhanced stability , designed to enable robust ammonia clearance capacity via chronic maintenance therapy Differentiated Ammonia-Lowering Approach Direct ammonia control Convenient SC delivery Improved survival and quality of life Reduction in HE events
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50 Up to ~80K Addressable Patients in the U.S. with Severe / Recurring HE May Benefit from Ammonia-Lowering Treatment Note: 1. U.S. cirrhosis prevalence as estimated by Tapper et al (2023); 2. Cirrhosis patients with exposure to rifaximin (+/- lactulose); 3. Ammonia measurement ≥52.5 µM (1.5x upper limit of normal) and average MELD score below 20 (excluding patients where no ammonia data was available) Source: Tapper et al., JAMA (2023); Electronic medical records analysis (data from 2022). All figures approximate. HE Additional opportunity can be unlocked in prevention of initial HE episode U.S. HE Epidemiology Up to 80,000 High ammonia and sufficient liver function3 150,000 Additional patients in EU + UK 2,200,000 Patients with cirrhosis1 140,000 Severe / recurring HE2
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51 Ram Aiyar, PhD, MBA Chief Executive Officer Closing remarks
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52 K ey T akeaways from KRRO-121 Significant unmet medical need for controlling ammonia Robust scientific / geneticevidence supporting GS stabilization approach Transformative potential to impact patients Vision for the future as a leader in modulating disease biology
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53 Q&A Ram Aiyar CEO Loïc Vincent CSO Todd Chappell COO Bruce Scharschmidt Clinician
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54 Edit the message. Rewrite the future.