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Genetic Mitochondrial Diseases Nasdaq: RPHM Corporate Presentation May 2023
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manufacturers, suppliers and distributors; our ability to obtain necessary additional capital; our ability to obtain necessary regulatory approvals for our products and, if and when approved, market acceptance of our products; the commercialization
plans and expectations for commercializing mavodelpar (REN001) in the United States and rest of world, estimates of the number of patients impacted by PMM or LC-FAOD and who are appropriate for treatment with mavodelpar, the potential benefits of
mavodelpar, the financial impact or revenues from any commercialization we undertake, the impact of competitive products and therapies; our ability to attract and retain key employees; the costs of our commercialization plans and development
programs; the design, implementation and outcomes of our clinical trials; our ability to manage the growth and complexity of our organization; our ability to maintain, protect and enhance our intellectual property; and our ability to continue to
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Disclaimer This presentation contains preliminary financial information
as of and for the three months ended March 31, 2023 and is subject to completion. The unaudited, estimated results as of and for the three months ended March 31, 2023 are preliminary and were prepared by the Company's management, based upon
estimates, a number of assumptions and currently available information, and are subject to revision based upon, among other things, quarter end closing procedures and/or adjustments, the completion of our interim financial statements and other
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principles and audited or reviewed by our auditors. 3
Investment Highlights Mavodelpar Mitochondrial Anticipated Financial
(REN001) Diseases Milestones Overview Rx Preliminary evidence of Rare diseases with high Pivotal clinical trial in $94 million cash, cash efficacy and tolerability unmet medical need primary mitochondrial equivalents,
and short- from four clinical trials myopathy (PMM) with term investments as of Myopathy and reduced topline results in 4Q23 Mar 31, 2023 Favorable guidance life expectancy common from U.S. and European Expansion into two
Fundamental investor regulatory agencies additional mitochondrial base disease populations 4
Reneo Pharmaceuticals Pipeline Reneo is initially developing mavodelpar
for patients with rare genetic mitochondrial diseases that typically present with myopathy and have a high unmet medical need Preclinical Phase 1 Phase 2/3 Approved 2023 Anticipated Milestones Completed enrollment of pivotal trial in mtDNA
PMM (1Q23) mitochondrial DNA (mtDNA) mutations/deletions PMM primary Initiate enrollment of nDNA PMM patients (2Q23) mitochondrial nuclear DNA (nDNA) mutations/deletions myopathies Topline results of pivotal trial in mtDNA PMM (4Q23)
LC-FAOD Fast Track designation (LCHAD deficiency) (1Q23) nuclear DNA (nDNA) mutations/deletions long-chain fatty acid oxidation LC-FAOD clinical strategy update (4Q23) disorders 5
Mavodelpar Overview 1. Increases transcription of Biology genes central
to mitochondrial function Potent and selective agonist of peroxisome N F proliferator-activated O receptor delta (PPAR ) PPAR EC = 31nM 50 2. Drives production of new Regulates generation of O PPAR EC > 10 M
50 mitochondria cellular energy PPAR EC > 10 M 50 Present in multiple O tissue types including CO Na 2 muscle, brain, kidney, and liver 3. Increases oxidation of fatty acids and cellular energy Activation in response
production to increased cellular energy needs 7
Nutrient Utilization by Mitochondria Phosphocreatine Carbohydrates Fatty
acids 100 0 Minutes 0 2 4 6 8 10 12 30 Fatty acid oxidation becomes the predominant nutrient source for generation of cellular energy by the mitochondria during periods of increased energy demand Patients with PMM and LC-FAOD
experience myopathy, weakness, fatigue, or deterioration of muscle due to impaired mitochondrial energy production 8 % of Total Energy
Prevalence in Key Rare Disease Markets Patients in Europe
(Northern/Western) Patients in Japan PMM: 82,500 PMM: 23,500 LC-FAOD: 6,200 LC-FAOD: 1,900 Patients in US PMM: 66,200 LC-FAOD: 5,000 Patients in China PMM: 287,900 LC-FAOD: 21,600 Patients in Brazil PMM: 42,500 LC-FAOD: 3,200 Reneo has operations
currently in U.S. and UK United Nations World Population Prospects, Rev.166200 (2019) Adult mtDNA and nDNA PMM Prevalence - Gorman G. et al., Ann Neurol. 77(5): 753-759 (2015) 9 LC-FAOD Prevalence - Merritt
J.L. et al., Ann Transl Med. 6(24): 473 (2018)
Leg Immobilization Study: Overview Randomized, blinded,
placebo-controlled clinical trial in healthy adult volunteers during and after leg immobilization Leg immobilized for 14 days Mavodelpar 100 mg BID (n=12) Baseline Follow-up Placebo (n=12) Day 1 14 29 49 Primary Objective Evaluate safety and
tolerability of 28 days of mavodelpar in healthy volunteers Secondary Objectives Changes in muscle strength and size Changes in expression of PPAR regulated genes involved in mitochondrial function and biogenesis Davies
M. et al., J Clin Trials. 12:495 (2022) 10
Leg Immobilization Study: Changes in Muscle Strength Mean Change from
Baseline in Muscle Strength Placebo Mavodelpar 50 No serious adverse events (SAEs) related to mavodelpar treatment 32.8 Treatment-emergent adverse events (TEAEs) 25 were similar between subjects treated with mavodelpar or placebo 2.7
Subjects treated with mavodelpar had 0 substantially more leg strength compared to -5.9 placebo subjects Greater preservation of muscle strength -25 following immobilization Greater increase in muscle strength one -36.2 week
after immobilization -50 1 hour post-leg brace 1 wk post-leg brace (p<0.01) (p<0.004) (p-value from a mixed model with baseline value as covariate) Davies M. et al., J Clin Trials. 12:495 (2022) 11 Muscle Strength (Pounds)
Leg Immobilization Study: Changes in Gene Expression Subjects
treated with mavodelpar showed increases in expression of PPAR -regulated genes of interest Pyruvate dehydrogenase lipoamide kinase isozyme 4 (PDK4) encodes for a protein that plays a key role in regulation of glucose and fatty acid
metabolism Angiopoietin-like 4 (ANGPTL4) encodes for a protein that is directly involved in regulating lipid metabolism Solute carrier family 25 member 34 (SLC25A34) encodes for a protein that is known to transport molecules across the
mitochondrial membrane Davies M. et al., J Clin Trials. 12:495 (2022) 12
Primary Mitochondrial Myopathies (PMM) Characteristics PMMs are
rare disorders caused by mutations within mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) Mutations hamper the ability of mitochondria to generate energy Most pronounced in tissues with high energy demand (muscle, brain, and heart)
Symptoms Prevalence* Current Treatments Debilitating fatigue All adult PMM (23:100,000) No approved therapies Myopathy Symptomatic mtDNA Over-the-counter vitamins and (9.6:100,000) supplements commonly
used Exercise intolerance Symptomatic nDNA Muscle pain (2.9:100,000) Severe lack of endurance Reduced life expectancy * Adult mtDNA and nDNA PMM Prevalence - Gorman G. et al., Ann Neurol. 77(5):
PMM Phase 1b Trial: Overview Open-label clinical trial in adult PMM
subjects with mtDNA defects and myopathy Baseline Mavodelpar 100 mg QD (n=23) Mavodelpar 100 mg QD 36-week extension (optional) Week 1 2 4 8 12 Primary Objective Evaluate safety and tolerability of 12 weeks of treatment with mavodelpar in
PMM patients Secondary Objectives Evaluate safety and tolerability of 48 weeks treatment with mavodelpar in PMM patients Explore changes in clinical outcome such as exercise tests, oxygen consumption, and symptoms 14
PMM Phase 1b Trial: Changes in 12-Minute Walk Test (12MWT) Mean
increase over baseline in 12MWT distance of 104.4 meters, 95% CI [53.1, 155.6] 13 of 17 (76%) patients had greater than a 50-meter increase 12MWT distance 15
PMM Phase 1b Trial: Changes in Walking Velocity +25% +22%
Walking velocity of PMM patients decreased at each 3-minute period during the 12MWT Following 12 weeks of treatment with mavodelpar, walking velocity increased compared to baseline The greatest increase in walking velocity occurred
during the second half of the 12MWT 16
PMM Phase 1b Trial: Changes in Peak Oxygen Consumption (VO ) 2
Mean increase over baseline in peak VO of 1.7 mL/min/kg, 95% CI [-0.3, 3.7] 2 10 patients (59%) had an increase in peak VO of 0.9 mL/min/kg or greater 2 17
PMM Phase 1b Trial: Changes in Peak VO and 12MWT by Quartile 2
Mean change over baseline in peak VO parallels mean change over baseline in 12MWT 2 18
PMM Phase 1b Trial: Changes in Symptoms Mean change in SF-36
energy/fatigue score of 11.2, 95% CI [1.2, 21.2] Mean change in Modified Fatigue Impact Scale of -10.5, 95% CI [-16.3, -4.6] Mean change in Brief Pain Inventory of -1.0, 95% CI [-0.2, -1.9] 19
PMM Phase 1b Trial: Changes in Gene Transcription Expression of
PPAR -regulated genes from muscle biopsies (PMM patients) Muscle biopsies were performed at baseline and after 12 weeks of treatment with mavodelpar PDK4 ANGPTL4 SLC25A34 Differential gene expression was performed on 3.0
biopsies from seven (7) subjects that had sufficient sample quantity and quality for analysis at baseline and week 12 2.0 A statistically significant increase over baseline was observed in the expression of PDK4, ANGPTL4, and SLC25A34 1.0
Gene expression data is consistent with the findings from the leg immobilization study 0.0 Week 12 20 Change from Baseline (Log2 Values)
Pivotal PMM Phase 2b Trial and Open-Label Extension Study RDBPC
clinical trial in adult PMM patients with mtDNA defects and myopathy, plus 2-year open-label extension study "STRIDE AHEAD" "STRIDE" Mavodelpar 100 mg QD Screening Baseline Mavodelpar 100 mg QD Placebo QD 2-year open-label
extension (ex-US) Week 2 18 24 4 12 STRIDE Primary Objective Change from baseline to week 24 in distance walked during 12MWT STRIDE Secondary/Exploratory Objectives Changes from baseline in PROMIS Short Form Fatigue 13a,
Modified Fatigue Impact Scale (MFIS), Patient Global Impression of Change (PGIC), Patient Global Impression of Severity (PGIS), 30 Second Sit-To-Stand (30STS) Test, Brief Pain Inventory (BPI), 36-Item Health Survey (SF-36), Work Productivity and
Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP), and Pedometer Step Counts STRIDE and STRIDE AHEAD Status STRIDE - Completed enrollment in March 2023 (N=213); topline results anticipated 4Q23 STRIDE AHEAD
- Over 100 patients enrolled to date (50 beyond 6 months); adding nDNA PMM patients 2Q23 21
PMM Phase 1b and 2b Studies: Baseline Characteristics PMM Phase 2b* PMM
Study PMM Phase 1b (STRIDE Study) Subjects N=17 N=213 Sex (%) Male 29.4% 29.1% Female 70.6% 70.9% Age (years) Mean 55.2 46.6 Median 55 48 SD 7.5 12.8 2 Body Mass Index (kg/mg ) Mean 24.3 24.5 Median 24.5 23.7 SD 4.0 5.7 12-Minute Walk Test (meters)
Mean 603.2 653.8 Median 525 662 SD 250.1 160.4 Modified Fatigue Impact Scale (score) Mean 50.4 43.9 Median 48 46 SD 18.6 17.9 * Preliminary data, subject to change 22
Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) Characteristics
LC-FAOD are rare disorders caused by mutations within nuclear DNA (nDNA) Inherited genetic errors of metabolism resulting in the inability to use dietary long-chain fatty acids as energy sources Mutations in genes that code
for enzymes that perform long-chain fatty acid oxidation Symptoms Prevalence* Current Treatments Young children - lethargy, liver VLCAD deficiency DOLJOVI , a fatty acid dysfunction, hypoglycemia, high (1:120,000
to 1:42,500) supplement similar to medium risk for sudden death, chain triglyceride oil (MCT) LCHAD deficiency cardiomyopathy (1:150,000 to 1:110,000) Therapy includes a fat-restricted Older patients - limited diet,
supplementing with short or endurance, muscle aches, medium chain fatty acids rhabdomyolysis * LC-FAOD Prevalence - Merritt J.L. et al., Ann Transl Med. 6(24): 473 (2018) 23
LC-FAOD Phase 1b Study: Overview Open-label clinical trial in adult
LC-FAOD subjects with mutations in LCHAD, CPTs, VLCAD, and TFP genes Baseline Mavodelpar 50 mg QD (n=3) or 100 mg QD (n=21) Week 1 2 4 8 12 Primary Objective Evaluate safety and tolerability of 12 weeks of treatment with mavodelpar in
LC-FAOD patients Secondary Objectives Explore changes in clinical outcome such as exercise tests and symptoms after 12 weeks of treatment with mavodelpar Program Status U.S. FDA Fast Track designation received (LCHAD deficiency)
LC-FAOD Phase 1b Study: 12MWT, SF-36 Energy/Fatigue, and MFIS