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Drugs for Orphan Mitochondrial Disease

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Drugs for Orphan Mitochondrial Disease Drugs for Orphan Mitochondrial Disease Gino Cortopassi, CEO Ixchel:Mayan goddess of health www.ixchelpharma.com Davis, CA Executive Summary • Ixchel is a clinical stage company focused on developing IXC-109 as therapeutic for mitochondrial diseases: 109 increases mitochondrial activities in cells & mice. • XC-109 is an NCE prodrug of the active moiety Mono-methylfumarate (MMF) upon which a Composition-of-Matter patent has been applied for. • IP: rights to 5 patent families, including composition of matter, method of use, formulation and 2 granted orphan drug designations. • Efficacy: demonstrated efficacy in preclinical mouse models with IXC-109 in Leigh’s Syndrome, Friedreich’s ataxia cardiac defects. • Patient advocacy groups & KOLs: Ixchel developed a 10-year relationship with patient advocacy groups FARA, Ataxia UK, UMDF & MDA, and networks with 8 Key Opinion Leaders in Mitochondrial Research and Mitochondrial Disease clinical development • Proven path and comps – Valuation of other MMF prodrugs: Vumerity/Alkermes 8700, Xenoport/Dr. Reddy’s – Valuation of Reata FA – IXC-109 is pharmacokinetically superior to Biogen’s DMF and Vumerity 2 Ixchel’s pipeline in orphan mitochondrial disease Benefits in Benefits in Patient Cells Target Identified Orphan Mitochondrial: Mouse models POC clinical trial Friedreich’s Ataxia, IXC103 Leigh’s Syndrome, LHON Mitochondrial Myopathy, IXC109 Duchenne’s Muscular Dystrophy 3 Defects of mitochondria are inherited and cause disease Neurodegeneration Friedreich’s ataxia Mitochondrial defect Genetics Leber’s (LHON) Myopathy Leigh Syndrome Muscle Wasting MELAS 4 Friedreich’s Ataxia as mitochondrial disease target for therapy FA as an orphan therapeutic target: § FA is the most prevalent inherited ataxia: ~6000 in North America, 15,000 Europe. § Well understood, monogenic disease based on frataxin deficiency. § Extensive natural history database and excellent patient advocacy group (FARA). § We have established relationships with clinical opinion leaders. § Crippling neurodegenerative and cardiodegenerative ultimately lethal disease. § No approved therapy in US or EU. § $800M/yr peak sales potential at supportable orphan drug prices. 5 Leigh Syndrome as a disease target for therapy Leigh Syndrome (LS) is the most common pediatric mitochondrial disease: § MELAS prevalence: 10,000 in USA, most common pediatric mitochondrial disease § Progressive muscle weakness, and pediatric death. § No approved therapy in US or EU. § Increasing mitochondrial activity will benefit these patients. § $1B peak orphan sales potential at supportable orphan drug pricing. Mitochondrial Leigh Syndrome defect Muscle Wasting 6 High IP-dosage of DMF on C57Bl6 Mice Increase Screening Protocol Mitochondrial Protein Expression Screening Identifies Fumarates Liver • Diamide, a specific thiol oxidant that result in cell death, shows DMF Dosage (mg/kg) great effectiveness in killing FXN-deficient DRG neural cells as Effective in MitoDisease 1600 Drugs • Test 1600 drugs for their abililty to protect DRG neural cells from Vehicle 10 20 40 80 160 diamide-mediated cell death DMF and the other drugs 9 Frataxin 3 Cox4 8 2.5 7 • Drugs are tested for their ability to increase mitochondrial gene 6 2 40 Protective expression and protein expression in human fibroblasts 5 • DMF is selected due to its effectiveness in increasing mitochondrial 1.5 4 Drugs gene expression and mitochondrial protein expression FC Expression FC Expression 3 1 2 0.5 1 0 0 0 10 20 40 80 160 0 10 20 40 80 160 DMF Dose (mg/kg) DMF Dose (mg/kg) DMF increases mitochondrial DNA copy number as well as multiple electron transport chain mitochondrial subunits • In vivo study on C57Bl6 mice to test the drugs effectiveness in vivo 10 Drugs • DMF treated mice and MS patients shows an increase in mitochondrial gene and protein expression Increased: Activity, Expression, Function, Discussion Biogenesis v From a 1600 FDA-approved drug library we have identified DMF that can increase mitochondrial copy number and protein expression DMF increases mitochondrial DNA copy number in vivo in both C57Bl6 mice and MS patients v DMF is approved in Europe in treating MS patients, so its safe dosage profile combining with the potential therapeutic effect on mitochondria may suggest DMF to be the first FDA approved drug 103=Dimethyl Fumarate for multiple mitochondrial diseases v Further study will focus on showing the therapeutic effect of DMF 7 on multiple mitochondrial-deficit animal models v The relationship between increase mitochondrial copy number and mitochondrial function will be studied to elucidate the beneficial Can DMF provides a effect of DMF therapeutic effect on References mitochondrial-deficit animal models? Novel Prodrug Strategy: IXC-109 is an NCE prodrug with a 505b2 Regulatory path • IXC-103 is a prodrug for Monomethyl Fumarate (MMF). • IXC-109 is Ixchel’s new MMF prodrug, which is cleaved in the gut and delivers MMF • IXC-109 is a Novel Chemical Entity with an improved PK profile for the delivery of MMF • IXC-109 releases MMF in the gut, a 505b2 regulatory approval is possible. • Composition of matter and use patents protect IXC-109, and it has a simple regulatory path. Esterase RR-O cleavage Mitochondrial Effects R= CH3 = dimethyl fumarate=103 Monomethyl Fumarate R= dioxopyrrolidin = Vumerity (Bioactive) R= NAD = IMF=109 8 Friedreich’s Ataxia (FA) • Decrease in the mitochondrial protein frataxin is the only cause of FA • Thus therapies that increase frataxin or mitochondria should benefit FA Normal Phenotype Inherited IXC-103 Mitochondrial FRATAXIN defect IXC-109 Friedreich’s ataxia 9 Leigh Syndrome (LS) • Decrease in mitochondrial proteins such as Ndufs4 has been identified as a cause of LS • Hence, approaches that increase mitochondrial proteins such as Ndufs4 should have therapeutic benefit Normal Phenotype INHERITED MITOCHONDRIAL NDUFS4 IXC-103 DEFECT IXC-109 Leigh Syndrome 10 85% Decrease of Frataxin causes Friedreich’s ataxia, Disability and Death MITOCHONDRIA Healthy Normal 100% Frataxin 50% Healthy Carrier FeS: Iron/Sulfur Clusters 15% Sick nrf2 Friedreich’s Mitochondrial Antioxidant EFFECT OF Biogenesis genes IXC103/IXC109 Y"Y" Y" InflammationInflammation DEATH Neuro- and cardiodegeneration 11 IXC-103 & IXC-109 dose dependently increase Frataxin in Friedreich’s patient cells and mouse models Friedreich’s Patient Cells Brain, Frataxin protein Friedreich’s mouse model IXC-103 IXC-103 Frataxin Protein BOTH IXC-103 AND IXC-109 ARE PRODRUGS THAT DELIVER MONOMETHYL FUMARATE (MMF) – THE BIOACTIVE MOEITY IXC-109 IXC-109 raises frataxin At a lower dose 12 IXC-103 increases Mitochondria in multiple tissues of lab animals Mitochondria increase ~40% in muscle, brain Mitochondria gene expression up ~100% in muscle, brain IXC1103-103 IXC-103 Mice dosed IXC-103 13 IXC-103 increases mitochondrial number and Frataxin protein in mouse brains IXC-103 mg/Kg Mice dosed IXC-103 IXC-103 mg/Kg IXC-103 mg/Kg 14 IXC-109 improves mitochondrial function in liver more than 103-DMF IXC-103 IXC-109 15 IXC-109 has delivers more MMF to brain than IXC-103-DMF Brain Fumarate levels IXC-103-DMF IXC-109 500 Vehicle 500 P<0.05 Vehicle 110 mg/kg DMF P<0.05 400 400 30 mg/kg IMF 60 mg/kg IMF 300 300 N.S. 200 200 100 100 Fumarate (% of control) Fumarate (% of control) 0 0 Fumarate is the breakdown product of both 103 and 109 16 IXC-109 increases Median and Maximum Longevity in Ndufs4 mouse model of Leigh’s Syndrome 100 90 80 70 60 50 NoVehicle, TX/Veh n=22 N=22 40 % Alive (% Survival) % Alive DMFIXC -110mpk103, 110mpk n=11 N=11 IXC-109, 60mpk N=15 30 IMFpd 60mpk n=15 20 10 0 20 25 30 35 40 45 50 55 60 65 Days Alive, Weaned at 21 days 17 IXC-109 promotes longevity in cardiac frataxin Knockout mouse better than IXC-103 Vehicle, N=10 IXC-103, 110mpk, N=10 IXC-109, 60mpk, N=10 18 IXC-109 promotes longevity in cardiac frataxin Knockout mouse better than IXC-103 Vehicle, N=10 IXC-103, 110mpk, N=10 IXC-109, 60mpk, N=10 19 IXC-103-DMF in human proof of concept clinical trial Increases mitochondrial number, expression & frataxin Mittal Jasoliya Mitochondrial gene Frataxin Expression Expression Baseline 103, 3 months Francesco Sacca’, MD Mittal Jasoliya Humans dosed U. Naples, IT IXC-103 Baseline +3 months Baseline 103, +3mo IXC-103 is the only drug ever show an increase in Mitochondria and Frataxin in humans Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans. Hayashi G, Jasoliya M, Sahdeo S, Saccà F, Pane C, Filla A, Marsili A, Puorro G, Lanzillo R, Brescia Morra V, Cortopassi G. Hum Mol Genet. 2017 Aug 1;26(15):2864-2873. doi: 10.1093/hmg/ddx167. Francesco Sacca20’, MD U. Naples, IT IXC-103-DMF phase 2 clinical trial for Friedreich’s ataxia • Ixchel recently received funding for a phase 2 clinical trial from Friedreich’s ataxia research alliance -FARA • Trial design – Placebo-controlled, randomized, single center – Molecular (frataxin & mitochondria) and clinical endpoints of IXC-103 will be studied in 40 Friedreich’s ataxia patients. – Core phase: treatment with IXC-103 15wks, 15wk extension • Trial in collaboration with experienced neurological KOL in Naples, Italy • POC data will – set up pivotal/registration for IXC-103 or IXC-109 – result in value inflection of Ixchel’s assets 21 Intellectual Property around Fumarates in Mitochondrial disease 22 Executive Summary • Ixchel is a clinical stage company focused on developing IXC-109 as therapeutic for mitochondrial diseases: 109 increases mitochondrial activities in cells & mice. • XC-109 is an NCE prodrug of the active moiety Mono-methylfumarate (MMF) upon which a Composition-of-Matter patent has been applied for. • IP: rights to 5 patent families, including composition of matter, method of use, formulation and 2 granted orphan drug designations. • Efficacy: demonstrated efficacy in preclinical mouse models with IXC-109 in Leigh’s Syndrome, Friedreich’s ataxia. • Patient advocacy groups & KOLs: Ixchel developed a 10-year relationship with patient advocacy groups FARA, Ataxia UK, UMDF & MDA, and networks with 8 Key Opinion Leaders in Mitochondrial Research and Mitochondrial Disease clinical development • Proven path and comps – Valuation of other MMF prodrugs: Vumerity/Alkermes 8700, Xenoport/Dr.
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