TREATING NEURODEGENERATION BY IMPROVING MITOCHONDRIAL HEALTH 1 - - PowerPoint PPT Presentation

TREATING NEURODEGENERATION BY IMPROVING MITOCHONDRIAL HEALTH

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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)

Mitoconix Bio Ltd

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MITOCHONDRIAL DYNAMICS AND NEURODEGENERATIVE DISEASES

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Mitochondria is Central in Health and Disease

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Mitochondria

ATP generation, Ca++ buffering, synthesis of neurotransmitters, apoptosis control ….

Mitochondrial Dynamics

Maintains healthy robust mitochondria = healthier cells/patients

Aug 2017

Mitochondrial Dynamics and Neurodegenerative Diseases

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Fission (Drp1) Fusion (Mfn1/2)

Unbalanced mitochondria dynamic = Neurodegeneration

Due to fragmentation, lower ATP, high ROS, aberrant autophagy, etc.

Neurodegenerative Diseases associated with Defects in Mitochondrial Dynamics

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Chen et al. 2009

Our Strategy: Inhibition of Drp1 Activity in Order to

Restore Normal Mitochondria Homeostasis

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P110

Drp1 Fis 1 Drp1 Fis 1

• P110 is a rationally designed inhibitor of pathological mitochondrial fission

based on Drp1 homology to Fis1

P110 specifically inhibits Fis1 / Drp1 interaction

Disease

Mitochondrial dysfunction: ATP ROS

Drp1

Huntington’s Disease Mitoconix First Clinical Indication

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Orphan disease; mean onset at 30- 40 ; Prevalence 1:10,000

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No available disease-modifying treatment

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Genetic dominant caused mHtt poly-Q repeats

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Market projected to reach $2.4B by 2024 (Global Data 2016)

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mHtt leads to excessive fission in HD

Healthy Huntington’s Disease

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P110-TAT Efficacy in HD Mouse Model

cont TAT P110 TAT P110

P110-TAT Treatment prolongs HD Mouse Survival and improves Motor Function

10 Disatnik JEM, 2016

All experiments were terminated at week 13 P110-TAT promotes longer survival.

• 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

Guo et al J Clin Inv , 2013

Reduces Inactivity Period

cont

TAT P110 TAT P110

Increases rearing activity

Aug 2017

P110-TAT is Efficacious in Huntington’s Disease Model

Huntington’s Disease Huntington's Disease Healthy P110-TAT

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P110 in vivo benefits due to Neuroprotection, reduced Neuroinflammation & decreased mHtt Aggregates

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Reduces loss of dopaminergic neurons

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Decreases burden of mHtt aggregates, the cause of HD pathology

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Reduces neuro-inflammation

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R6/2 TAT R6/2 P110

• + -

+ P110 WT R6/2

P110

N=6

R6/2 TAT R6/2 P110

Number Size

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Translation from Animals to Patients

P110 Reduces Drp1 Association with Mitochondria in Fibroblasts of HD Patients

Guo et al J Clin Inv 2013

P110 P110 P110 P110

P110 P110 P110 P110

Human fibroblasts

DRP1 Fis 1

P110 14

P110-TAT Reduces Mitochondrial Fragmentation in Neurons Derived from HD Patients

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mitochondria nuclei

Guo et al. J Clin Inv 2013

P110 P110

HD Patient iPSC-derived spiny neurons

Control P110-TAT (1 μM for 3 days) Enlarged Enlarged

P110-TAT Corrects Mitochondrial Dysfunction in Neurons Derived from HD Patients

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P110-TAT: 1μM for 5 days

Mitochondria Membrane Potential Reactive Oxygen Species ATP Production

HD Patient iPSC-derived spiny neurons

P110-TAT Improves HD Neurite’s Length

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Healthy subject iPSC-derived spiny neurons P110-TAT

1mM 5 days

TuJ1 mature neuron DARPP-32 striatal medium spiny neur

HD iPSC-derived spiny neurons

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P110-TAT is Efficacious in Other Neurodegenerative Diseases

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Inhibits aberrant mitochondrial fission and improves mitochondrial function in culture models, neurons from patients with and in a mouse models for:

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Parkinson’s disease

(Qi et al , J Cell Science 2013; Su and Qi, Human Hum Mol Gen, 2013; Filichia et al, Nature Report, 2016)

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ALS, Alzheimer‘s (Joshi and Mochly- Rosen ; in preparation)

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Reduced demyelination and ameliorates disease symptoms in models of Multiple Sclerosis (Luo et al, Exp Neurol, 2017)

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Reduces infarct size and neurological dysfunction in MCAO stroke model in rats (Guo et al, Biochem J., 2014)

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Inhibits aberrant mitochondrial fission and mitochondrial function in post-MI cardiac disease (Distanik et al., JAHA 2014)

P110-TAT Effective in Additional Disease Models

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P110-TAT Protects Fibroblast and Neurons Derived from Parkinson’s Disease Patients

Su and Qi Hum Mol Gen, 2013

PD patient fibroblasts carrying LRRK G2019S mutant

• No effect observed in control healthy cells

PD patient iPSC-derived dopaminergic neurons

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P110-TAT Corrects Excessive Mitochondrial Fission in Alzheimer's Disease Patient Fibroblasts

Joshi and Mochly-Rosen, In preparation

Healthy control

Control

P110 Alzheimer’s disease with different etiologies APOE mut

Control

P110 PS2 mut

Control

P110 PS1 mut

Control

P110 Sporadic AD

Control

P110

n=3 in duplicate 120 cells per condition

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P110

Endpoint

P110 P110

P110-TAT Decreases Mitochondrial Fragmentation in ALS Patients Fibroblasts

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P110-TAT Mechanism of Action

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Selective Inhibitor of Drp1-Fis1 interaction

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Prevents pathological mitochondrial fission and fragmentation

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Does not affect normal (physiological) mitochondrial dynamics and function

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Efficacious in vivo in HD Genetic Model

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Efficacy demonstrated in multiple additional disease models

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Secured $20M Series A funding

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Remiges Ventures, OrbiMed, Dementia Discovery Fund, Arix Bioscience, RMGP Bio-Pharma investment Fund

Summary of Data and Achievements

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DRP1 Fis 1

P110

Aug 2017

PROGRAM 2018-19 ANTICAPTED MILESTONES

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P110-TAT for HD

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

Preclinical Pharmacology Biomarkers Safety Assessment Toxicology and Safety Pharm Regulatory and Clinical

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MitoConix Pipeline Expansion

Additional Indication P110-TAT

2017 2018 2019

GLP tox in two species Pre-IND IND Non US Phase 1 Source HD samples and qulify biomarkers In-vitro / In-vivo/Ex-Vivo POC Chronic tox Dose range Phase 2-3 IND Phase 1b-2a

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

Mitoconix Management Team

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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.

Mitoconix Board of Directors

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