TREATING NEURODEGENERATION BY IMPROVING MITOCHONDRIAL HEALTH 1 - PowerPoint PPT Presentation

TREATING NEURODEGENERATION BY IMPROVING MITOCHONDRIAL HEALTH 1

Mitoconix Bio Ltd Mission: Develop disease-modifying therapies for neurodegenerative diseases by improving mitochondrial health Lead Product: P110-TAT (MTC-1203 ) a selective peptide inhibitor of pathological Drp1 activation to reduce excess mitochondria fission and dysfunction Indications: Huntington ’ s Disease (primary), Parkinson ’ s Disease (secondary) Funding: $20M Series A investment (July 2017) – Remiges Ventures, OrbiMed, Dementia Discovery Fund, Arix Biosciences, RMPG. FutuRx provided seed funding (J&J, Takeda, OrbiMed) 2

MITOCHONDRIAL DYNAMICS AND NEURODEGENERATIVE DISEASES 3

Mitochondria is Central in Health and Disease Mitochondria Mitochondrial Dynamics ATP generation, Ca ++ buffering, synthesis of Maintains healthy robust mitochondria = neurotransmitters , apoptosis control … . healthier cells/patients 4 Aug 2017

Mitochondrial Dynamics and Neurodegenerative Diseases Unbalanced mitochondria dynamic = Neurodegeneration Due to fragmentation, lower ATP, high ROS, aberrant autophagy, etc . Fission Fusion (Drp1) (Mfn1/2) 5

Neurodegenerative Diseases associated with Defects in Mitochondrial Dynamics Chen et al. 2009 6

Our Strategy: Inhibition of Drp1 Activity in Order to Restore Normal Mitochondria Homeostasis Mitochondrial dysfunction: Drp1 Disease ATP ROS • P110 is a rationally designed inhibitor of pathological mitochondrial fission based on Drp1 homology to Fis1 P110 specifically inhibits Fis1 / Drp1 interaction Drp1 P110 Drp1 Fis 1 Fis 1 7

Huntington ’ s Disease Mitoconix First Clinical Indication Orphan disease; mean onset at 30- 40 ; Prevalence 1:10,000 ▪ No available disease-modifying treatment ▪ Genetic dominant caused mHtt poly-Q repeats ▪ ▪ Market projected to reach $2.4B by 2024 (Global Data 2016) mHtt leads to excessive fission in HD ▪ Healthy Huntington ’ s Disease 8

P110-TAT Efficacy in HD Mouse Model JP Morgan 2017 9

P110-TAT Treatment prolongs HD Mouse Survival and improves Motor Function R6/2 mice express exon 1 of the human mHtt gene with 120 Q repeats • Exhibit progressive neurological phenotype mimicking features of human HD • P110-TAT is delivered by continuous SC infusion 3mg/kg/day • All experiments were terminated at week 13 Disatnik JEM, 2016 P110-TAT promotes longer survival. Increases rearing Reduces Inactivity activity Period cont cont TAT P110 TAT P110 TAT P110 TAT P110 Guo et al J Clin Inv , 2013 10 Aug 2017

P110-TAT is Efficacious in Huntington ’ s Disease Model Huntington ’ s Disease Huntington's Disease Healthy P110-TAT Aug 2017 11

P110 in vivo benefits due to Neuroprotection, reduced Neuroinflammation & decreased mHtt Aggregates R6/2 TAT R6/2 P110 Reduces loss of dopaminergic ▪ neurons R6/2 TAT R6/2 P110 Number Size Decreases burden of mHtt ▪ aggregates, the cause of HD pathology Reduces neuro-inflammation ▪ - + - + P110 P110 WT R6/2 N=6 12

Translation from Animals to Patients JP Morgan 2017 13

P110 Reduces Drp1 Association with Mitochondria in Fibroblasts of HD Patients Human fibroblasts P110 P110 P110 P110 DRP1 P110 Fis 1 P110 P110 P110 P110 14 Guo et al J Clin Inv 2013

P110-TAT Reduces Mitochondrial Fragmentation in Neurons Derived from HD Patients HD Patient iPSC-derived spiny neurons P110-TAT (1 μ M for 3 days) Control mitochondria nuclei Enlarged Enlarged P110 P110 15 Guo et al. J Clin Inv 2013

P110-TAT Corrects Mitochondrial Dysfunction in Neurons Derived from HD Patients HD Patient iPSC-derived spiny neurons Mitochondria Membrane Potential Reactive Oxygen Species ATP Production P110-TAT: 1 μ M for 5 days 16 Guo et al. J Clin Inv 2013

P110-TAT Improves HD Neurite ’ s Length Healthy subject iPSC-derived spiny neurons TuJ1 mature neuron DARPP-32 striatal medium spiny neur P110-TAT 1 m M 5 days HD iPSC-derived spiny neurons 17 Guo et al. J Clin Inv 2013

P110-TAT is Efficacious in Other Neurodegenerative Diseases JP Morgan 2017 18

P110-TAT Effective in Additional Disease Models ▪ Inhibits aberrant mitochondrial fission and improves mitochondrial function in culture models, neurons from patients with and in a mouse models for: Parkinson ’ s disease ▪ (Qi et al , J Cell Science 2013; Su and Qi, Human Hum Mol Gen, 2013; Filichia et al, Nature Report, 2016) ALS, Alzheimer ‘ s (Joshi and Mochly- Rosen ; in preparation) ▪ Reduced demyelination and ameliorates disease symptoms in ▪ models of Multiple Sclerosis (Luo et al, Exp Neurol, 2017) Reduces infarct size and neurological dysfunction in MCAO stroke model ▪ in rats (Guo et al, Biochem J., 2014) Inhibits aberrant mitochondrial fission and mitochondrial function in ▪ post-MI cardiac disease (Distanik et al., JAHA 2014) 19

P110-TAT Protects Fibroblast and Neurons Derived from Parkinson ’ s Disease Patients PD patient fibroblasts carrying LRRK G2019S mutant PD patient iPSC-derived dopaminergic neurons No effect observed in control healthy cells • 20 Su and Qi Hum Mol Gen, 2013

P110-TAT Corrects Excessive Mitochondrial Fission in Alzheimer's Disease Patient Fibroblasts 72 0 Healthy control P110 Control Endpoint P110 P110 P110 n=3 in duplicate 120 cells per condition Alzheimer ’ s disease with different etiologies P110 P110 Control Control PS2 mut APOE mut Sporadic AD PS1 mut P110 Control P110 Control Joshi and Mochly-Rosen, In preparation

P110-TAT Decreases Mitochondrial Fragmentation in ALS Patients Fibroblasts 22 Joshi and Mochly-Rosen, Unpublished

Summary of Data and Achievements P110-TAT Mechanism of Action ✓ DRP1 P110 Fis 1 Selective Inhibitor of Drp1-Fis1 interaction ✓ Prevents pathological mitochondrial fission and fragmentation ✓ Does not affect normal (physiological) mitochondrial dynamics and ✓ function ✓ Efficacious in vivo in HD Genetic Model Efficacy demonstrated in multiple additional disease models ✓ Secured $20M Series A funding ✓ Remiges Ventures, OrbiMed, Dementia Discovery Fund, Arix ✓ Bioscience, RMGP Bio-Pharma investment Fund 23 Aug 2017

PROGRAM 2018-19 ANTICAPTED MILESTONES 2017 2018 2019 P110-TAT for HD Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Preclinical Pharmacology Source HD samples and qulify biomarkers Biomarkers Safety Assessment GLP tox in two species Chronic tox Dose range Toxicology and Safety Pharm Non US Phase 1 Phase 2-3 Pre-IND Regulatory and Clinical IND \ MitoConix Pipeline Expansion IND Phase 1b-2a In-vitro / In-vivo/Ex-Vivo POC Additional Indication P110-TAT 24 Confidential | 5 January 2018

Mitoconix Management Team Gili Hart, PhD: CEO • PhD and postdoc in Immunology, Weizmann Inst of Science • Previously General Manager, OPKO Biologics (Opko Health ), leading drug discovery and development from bench to clinic ( global phase 3 studies ) Eyal Neria, PhD: COO • PhD in Chemical Physics (Tel Aviv U); Postdoc protein modeling (Harvard) • Previously VP Therapeutics Development at Compugen Ltd Lior Weissman, PhD: VP R&D • PhD in Biochemistry, Tel-Aviv University, NIA postodoc on neurodegeneration Previously, Senior Principal Scientist & Projects Leader, Omrix (J&J Company) • Building a strong team to accelerate development and novel drug discovery 25

Mitoconix Board of Directors Erez Chimovits (Chairman)- Senior Managing Director at OrbiMed – world leading healthcare investment fund Daria Mochly-Rosen, PhD – Mitoconix Founder and SAB Chairperson. The George D Smith Professor in Translational Medicine, Stanford Univ. USA Taro Inaba – Remiges Ventures founder and chairman. A US/Japan investment fund with special interest in mitochondria targeted therapeutics Tetsu Maruyama , PhD - CSO of the Dementia discovery fund (DDF). DDF is dedicated to innovative dementia drug discovery and development. Previously, Takeda ’ s Head of Global Drug Discovery. 26

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