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Genetic Mitochondrial Diseases K Ke ey y O Opi pin niio on n L Le ead ade er r an and d Man Manag age em me en nt t U Updat pdate e October 9, 2023
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Today's Speakers Welcome & Opening Remarks Gregory J. Flesher
President & CEO Reneo Pharmaceuticals, Inc. Overview of Mitochondrial Disease Amel Karaa, MD Director of the Mito Clinic Massachusetts General Hospital Harvard Medical School Mavodelpar Development Program Alejandro Dorenbaum, MD Chief Medical
Officer Reneo Pharmaceuticals, Inc. Addressable Patients (US) Michael Cruse Chief Operating Officer Reneo Pharmaceuticals, Inc. 3
Mavodelpar Overview 1. Increases transcription of Biology gen genes es
ce centra ntral l to to mito mitoch chond ondria rial l function Potent and selective agonist of peroxisome proliferator-activated receptor delta (PPAR ) PPAR EC = 31nM 50 2. May drive production of new Regulates
generation of PPARa EC > 10 M 50 mitochondria cellular energy PPAR EC > 10 M 50 Present in multiple tissue types including muscle, brain, kidney, and liver 3. Increases oxidation of fatty acids and cellular energy
Activation in response production to increased cellular energy needs 4
Mavodelpar Clinical Trials STUDY DESIGN SUBJECTS DOSE DURATION KEY
OBSERVATIONS 1 Phase 1 SAD Healthy 25-250 mg Single-dose Well tolerated Obese Well tolerated 2 Phase 1 MAD 50-200 mg 14 days (dyslipidemic) Dose-dependent decrease in lipids Well tolerated RDBPC Phase 1 3
Healthy 200 mg 28 days Increase in expression of PPAR regulated genes (leg immobilization) Increase in muscle strength Well tolerated PMM 12 weeks 4 Open-label Phase 1b 100 mg Increase in expression of
PPAR regulated genes (+36 weeks) (mtDNA) Increase in 12MWT, 30STS, and peak VO / decrease in fatigue and pain 2 Well tolerated 5 Open-label Phase 1b McArdle Disease 100 mg 12 weeks Increase in oxidation of fatty
acids Well tolerated LC-FAOD 6 Open-label Phase 1b 100 mg 12 weeks Increase in expression of PPAR regulated genes (nDNA) Increase in 12MWT / decrease in fatigue (certain genotypes) RDBPC Phase 2b PMM 7 100 mg 24
weekso Ongoing; topline data expected Dec 2023 (STRIDE Study) (mtDNA) Open-label safety PMM 8 100 mg 2 yearso Ongoing; interim data expected 2024 (STRIDE AHEAD Study) (mtDNA + nDNA) randomized
Reneo 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 2023-2024 Milestones and Anticipated Milestones STRIDE AHEAD initiated screening nDNA
PMM patients (2Q23) Adults with mitochondrial DNA (mtDNA) defects PMM STRIDE last patient last visit (Oct 2023) primary mitochondrialo STRIDE topline results with mtDNA PMM (Dec 2023) Adults with nuclear DNA (nDNA) defects myopathies o
Regulatory meetings and NDA/MAA applications (2024) LC-FAOD Fast Track designation (LCHAD deficiency) (1Q23) nuclear DNA (nDNA) mutations/deletions long-chain fatty acid oxidationo LC-FAOD clinical strategy update (4Q23) disorders
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):
Multisystem Manifestation and Burden of PMM Greater severity of myopathy
Overview of Mitochondrial Disease Amel Karaa, MD Director of the Mito
Clinic Massachusetts General Hospital Harvard Medical School STRIDE Principal Investigator
Mitochondrial Myopathy Primer AMEL KARAA, MD DIRECTOR OF THE MITO
CLINIC MASSACHUSET TS GENERAL HOSPITAL HARVARD MEDICAL SCHOOL
Disclosures & Disclaimers UMDF: fellow, SMAB Chair-Elect, Planning
committee. Mitochondrial clinical network founder and governance board member. North American Mitochondrial Disease Consortium site PI Immediate past President of the Mitochondrial Medicine Society and MitoAction medical board. Grants and research
support from Stealth BioTherapeutics, Reata pharmaceuticles, Astellas, MitoBridge, Reneo, Cyclerion, Sanofi Genzyme, Shire, Portalix, Idorsia Consulting for Sanofi Genzyme, Stealth Biotherapeutics, Alexion, Lumleian, Homology, MitoBridge,
Akros, Astellas, Neurovive, Mivovia, Reneo, Zogenix, Cyclerion, UCB, Pretzels Therapeutics, Nanna Therapeutics .
Disclaimer: The information presented are my own professional and not
that of my employer, organization, committee or other group or individual I work with.
Overview of mitochondrial disease
Vafai and Mootha, Nature 2012
Primary Mitochondrial Myopathy (Consortium of International Experts in
Mitochondrial Disease) PMM refers to a subset of primary mitochondrial disease that predominantly but not exclusively affect skeletal muscles. Neuromuscul Disord. 2017 December ; 27(12): 1126-1137.
doi:10.1016/j.nmd.2017.08.006.
Myopathy can be the only clinical feature of a mitochondrial
PMM includes a number of clinical syndromes like CPEO, CPEO +, isolated
mitochondrial myopathy Arturito, TK2 myopathy Chronic progressive external ophthalmoplegia (CPEO) https://www.fairfaxfamilyfun.com/ Gorman et al. Saudi Journal of Ophthalmology. Volume 25, Issue 4, 2011, 395-404
Myopathy can be associated with additional manifestations NEJM 2010.
Clinical Manifestations in Percent (number positive/number recorded)
Manifestation Overall Pediatric Adults Weakness 41.8 (308/737) 41.6 (138/332) 42.0 (170/405) Developmental Delay 41.2 (319/775) 72.8 (273/375) 11.5 (46/400) Exercise Intolerance 40.4 (289/716) 34.8 (110/316) 44.8 (179/400) Fatigue 35.5 (262/738)
26.2 (85/325) 42.9 (177/413) Hypotonia 35.4 (260/735) 65.1 (231/355) 7.6 (29/380) Myopathy 34.1 (255/747) 31.0 (105/339) 36.8 (150/408) Seizures 31.1 (237/763) 42.5 (151/355) 21.1 (86/408) Ataxia 28.7 (216/753) 32.5 (112/345) 25.5 (104/408) Hearing
Loss 26.3 (194/739) 16.4 (54/330) 34.2 (140/409) Ptosis 25.9 (199/769) 18.6 (65/350) 32.0 (134/419) Dysphagia 22.0 (162/738) 26.7 (90/337) 18.0 (72/401) Thinness 19.8 (144/726) 23.2 (77/332) 17.0 (67/394) Migraine Headaches 18.2 (131/720) 9.7
(31/319) 24.9 (100/401) Hearing Loss 17.3 (124/718) 13.2 (42/319) 20.6 (82/399) Growth Delay 16.0 (113/708) 27.2 (88/323) 6.5 (25/385) Depression 15.9 (111/700) 3.8 (12/316) 25.8 (99/384) Anxiety 15.3 (107/699) 10.5 (33/315) 19.3 (74/384)
Ophthalmoparesis 15.3 (111/727) 6.5 (21/324) 22.3 (90/403) Mental Retardation 13.6 (97/715) 25.1 (79/315) 4.5 (18/400) 13.1 (96/733) 23.8 (81/341) Motor Regression 3.8 (15/392) Total number 878 402 476 NAMDC Registry accessed 01/2017
PLOS ONE | https://doi.org/10.1371/journal.pone.0197513 A. Karaa et al.
/ Molecular Genetics and Metabolism 119 (2016) 100-108
The most common presentation of PMM in adults is CPEO (+) 16% 14% 12%
10% 8% 6% 4% 2% 0% Barca et al Neurol Genet 2020;6:e402. doi:10.1212/NXG.0000000000000402 Multi Systemic Other Clinical MELAS Leigh Syndrome Myopathy Encephalomyopathy LHON cPEO+ Encephalopathy KSS cPEO MERRF Alpers Syndrome
SANDO Pearson Syndrome DAD MNGIE NARP Hepatocerebral Maternal Inherited Cardiomyopathy Barth Syndrome Leukoencephalopathy RIM with COX
Primary Mitochondrial Myopathy (Consortium of International Experts in
Mitochondrial Disease) PMM refers to a subset of primary mitochondrial disease that predominantly but not exclusively affect skeletal muscles. Late-onset mild isolated mitochondrial myopathies might be difficult to diagnose
(secondary mitochondrial dysfunction) Secondary involvement of mitochondria observed in multiple neuromuscular diseases is not considered PMM. Neuromuscul Disord. 2017 December ; 27(12): 1126-1137.
doi:10.1016/j.nmd.2017.08.006.
Primary Mitochondrial Myopathy JCSM Clin Rep. Author manuscript;
available in PMC 2022 January 21 Journal of Neurology (2022) 269:6555-6565
Primary Mitochondrial Myopathy Courtesy of Reneo
Overview of the unmet needs Mitochondrial diseases remain difficult to
diagnose - Lack of diagnostic consensus - No gold standard diagnostic method
Diagnostic Evaluation Complicated genotypes mDNA (37 genes) nDNA (~400
genes) ~1500 various genes S.L. Stenton and H. Prokisch / EBioMedicine 56 (2020) 102784
S.L. Stenton and H. Prokisch / EBioMedicine 56 (2020) 102784
Diagnostic Evaluation Symptoms Family history Testing:
Diagnostic Evaluation Evaluating organ involvement
Diagnostic Evaluation Tissue pathology (muscle) EM
Histochemistry SDH COX RRF
Diagnostic Evaluation Tissue pathology (muscle)
Functional assays (EMG, PFT, Swallow, sniff test ) Biochemical tests (lactate, CPK, UOA, ) Parikh S, Karaa A, et al. J Med Genet. 2019 Mar;56(3):123-130.
Diagnostic Evaluation Montero, et al (2016). PLOS ONE. 11. e0148709.
10.1371/journal.pone.0148709. Journal of Diabetes Research Volume 2015, Article ID 490842 Neurology 2016;86:2010-2015
Other diagnostic barriers Mitochondrial Care Network - Disease
complexity - Lack of awareness - Lack of education - Insurance
Treatment and Management Optimize energy gains. Minimize energy losses
Restorative Sleep Avoid stressors Nutrition Adequate rest Exercise Symptomatic End organ survey and treatment Avoid environmental toxins: Supportive (ETOH, smoking, drugs..) Overall disease burden Supplements (CoQ10)
What is new in research and development? IW-6463 Mt DNA Gene editing
technology KL1333 Acipimox OMT-28 ASP0367 J Inherit Metab Dis. 2020;1-20.
Thank you, and any questions? For any questions: Amel Karaa, MD
Massachusetts General Hospital Harvard Medical School akaraa@mgh.Harvard.edu
Mavodelpar Development Program Alejandro Dorenbaum, MD Chief Medical