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Download Presentaci£³n de PowerPoint THE PROBLEM Myotonic dystrophy (DM) is an unmet medical need, with no treatment

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  • ARTHEx Biotech S.L. is a spin-off company from the

    University of Valencia focused on the development of

    Antisense Rna THErapeutiX for genetic diseases based

    on microRNA inhibitors.

    IP and Know- how

    Non-regulatory preclinical

    Regulatory preclinical

    Phase I/IIa Phase

    IIb & III MAA

    Marketing & distribution

    Sales

    Big Pharma / Biotech Company Drug salesARTHEx Biotech

    Drug Development

    License Acquisition of

    ARTHEx: EXIT

    ARTHEx-01

    Lean Startup philosophy: Research and development activities will be

    outsourced to the University of Valencia and other collaborators

    9.Caso práctico:

  • THE PROBLEM

    Myotonic dystrophy (DM) is an unmet medical need, with no treatment available for the disease, only for some symptoms

    • Highly disabling, slow degenerative disease.

    • Genetic disease caused by abnormal DNA expansion (known as CTG repeats) in the DMPK gene on chromosome 19. This ends up sequestering MBNL proteins, causing main symptoms of the disease

    • Symptoms involve nervous system (disturbed sleep, cognitive dysfuntion), heart (arrhythmias) and skeletal musculature (atrophy and muscular weakness, including difficulty for breathing and swallowing).

    • High level of comorbidity impact on health system and social live.

    • High Economic burden: $32,236 per patient in USA.

    • Orphan and pediatric. Prevalence= 1/8000 people in Europe. 1M Patients worldwide

    MBNL

    MBNL

    https://www.mda.org/disease/myotonic-dystrophy/signs-and-symptoms/adult-onset-DM

  • • The drug ❑ Oligonucleotide inhibitors of miR-23b and miR-218

    • It is based on a newly-discovered mechanism of action: ❑ miR-23b and miR-218 silencing increase MBNL expression

    and relieve myotonic dystrophy phenotypes

    • Robust proof of concept of our therapeutic approach in in vivo (mouse model of disease) published on ❑ Chronic (long-term) treatment ❑ long-acting therapeutic potential in vivo ❑ Subcutaneous injection

    • Patent application WO2018050930

    OUR SOLUTION

    A first-in-class RNA therapy for the treatment of myotonic dystrophy

    (CTG) repeats at DMPK

    Myotonic Dystrophy context

    Cause of Symptoms of disease

    Relief of symptoms

    MBNL levels

    Therapeutic approach

    MBNL

    miR-23 and miR-218

    (CTG) repeats at DMPK

    MBNL levels

    MBNL

    MBNL

    MBNL

    AntagomiRs

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018771/

  • The model: human DM1 myoblasts

    Arandel et al. 2017

    Effect of antagomiRs on target microRNAs: 85-70% reduction

    m iR -2 3 b -3 p C N T

    m iR -2 3 b -3 p D M 1

    m iR -2 1 8- 5 p C N T

    m iR -2 1 8- 5 p D M 1

    0

    2

    4

    6 **

    **

    R e

    l a

    t i v

    e E

    x p

    r e

    s s

    i o

    n ( 2

    ^ - Δ Δ

    C t )

    miR-23 and miR-218 are

    upregulated in DM1 myoblasts

    Proof of concept in human DM1 cells

    Rescue of MBNL-

    dependent splicing

    Effect of antagomiRs on MBNL protein levels:

    2-5 fold upregulation

    AntagomiRs improve fusion index

    Cerro-Herreros et al., Nat. Commun 9, 2482 (2018)

    https://dmm.biologists.org/content/dmm/10/4/487.full.pdf https://dmm.biologists.org/content/dmm/10/4/487.full.pdf https://www.nature.com/articles/s41467-018-04892-4

  • Proof of concept in a stablished murine disease model

    Single subcutaneous injection (12,5 mg/Kg) Effects 45 days after a single subcutaneus injection (12,5 mg/Kg)

    *****

    * * *

    *****

    Untreated mice

    AntagomiR-23b

    AntagomiR-218

    AntagomiR-Sc

    In vitro screening of lead antimiR

    104 antimiRs tested in human DM1 cells with different chemistries and cojugates

    TC50 Viability (up to 17 fold reduction in

    toxicity)

    EC50 MBNL1 levels (up to 3 fold increased efficacy)

    Selection of 15 antimiRs to test in murine model

  • Proof of concept in a stablished murine disease model

    Single subcutaneous (12,5 mg/Kg) Effects 45 days after a single subcutaneous injection (12,5 mg/Kg)

    *****

    * * *

    *****

    Untreated mice

    AntagomiR-23b

    AntagomiR-218

    AntagomiR-Sc

    In vitro screening of lead antimiR

    104 antimiRs tested in human DM1 cells with different chemistries and cojugates

    TC50 Viability (up to 17 fold reduction in toxicity)

    EC50 MBNL1 levels (up to 3 fold increased efficacy)

    Selection of 15 antimiRs to test in murine model

    Long-acting subcutaneus efficacy

  • THE COMPETITORS Chemistry Stage of development Efficacy results

    Antibody-oligonucleotide

    conjugates (AOC). Preclinical Highly potent siRNAs that reduce the expression of the

    DMPK target gene in mice model.

    Small molecules. Antagonist of

    GSK3β

    Phase IIa clinical trial with Tideglusib Improvements in cognitive functioning, fatigue, as well

    as in certain neuromuscular symptoms.

    CRISPR technology Discovery and proof of concept stages.

    Technology still in development.

    Increased MBNL1 expression and rescued characteristic

    DM features in mice.

    RNA-motif-small-molecule. Preclinical Restoration of MBNL function reverses DM1-related

    deficits in mouse models of DM1.

    Phosphorothioate, 2’-O-

    methoxyethyl (2’MOE),

    constrained ethyl (cET). Improving

    in LICA chemistry. Preclinical

    Effective reductions of toxic RNA led to a reversal of

    the disease symptoms, mainly myotonia in mice.

    Small Molecule to Inhibit DMPK Preclinical Not published

    Cannabinoids as the Active

    Pharmaceutical Ingredients (APIs)

    to develop synthetic

    pharmaceuticals

    Preclinical Non-psychoactive, advanced sublingual synthetic

    cannabinoid formulations to help and reduce the

    symptoms of myotonic dystrophy.

    l

    Antibody-oligonucleotide

    conjugates (AOC).

    Preclinical Antibody-driven delivery of ASO against DMPK

  • ARTHEx: The team

    Beatriz Llamusí

    Observers

    Lluis ParerasAlbert Ferrer

    Arturo López Secretario: Xavier Foz

    Laura Rodríguez

    Independent member: Mano Manoharan

    Board of Directors

    Rubén artero

    Board of Directors

    Scientific Advisory board (SAB) CEO

    Beatriz Llamusi

    Operations

    Officer

    Pedro Fernández

    CMC Project Manager:

    Thomas Rupp Toxicology Project Manager:

    Eduardo Cunchillos

    Clinical Project Manager: to be determined

    Regulatory advice

    Asphalion

    Research institution (UV, Rubén Artero)

    Head Scientist (Estefanía Cerro)

    Financial Director

    Jordi Petit

    Vantum Corporate

    Business advisor

    IPP: Gustavo Fuster

    Hoffmann-Eitle

    Ramón Eritja Nicholas Johnson

    Eric Marcusson

    SAB

    Technical advisors

    Thomas Rupp

    Charles Thornton

  • DEVELOPMENT PLAN

    Lead Optimization

    Candidate Confirmation

    CTA/IND obtention

    FIH Start

    2020 2021 2022 2023 2024

    Preclinical Non-GLP

    development

    Preclinical GLP

    Animal testing Phase I FIH Phase II

    MILESTONES

    RESOURCES

    0

    €1M

    €2.5M

    €0.5M

    €3.7M

    €13.5M

    Current Sought

    Local VC (InVivo Capital) commitment of €1.5M

    secured upon milestone accomplishment

    Phase II Start

    €5.5M

    CDTI-INNVIERTE commited 1,2 million

  • Reto 1: Encontrar financiación privada

    Due Diligence

    Data room

    Pre-money/post-money: Company valuation

    Business plan/Budget

    Non-confidential deck/teaser

    NDA/CDA

    Term-sheet (cap table) FEBRERO 2019

    Tu mensaje debe resultar atrayente sin necesidad de compartir información confidencial

    La suele proponer el inversor El inversor te hará la

    propuesta pero necesitas tener pensados los números

  • Reto 2: Creación de la empresa

    Denominación negativa del nombre en el registro civil

    Logo/página web/dominio

    Escrituras de constitución

    Alta en RETA (seguridad social)/modelo 036 (agencia tributaria)

    Depósito de capital social y apertura de cuenta

    Esto lo puedes hacer solo pero un asesor te ahorrará tiempo y no es necesario que sea especialista en start-ups

    Septiembre 2019

  • Reto 4: Acuerdo de licencia con la universidad

    Comunicación oficial

    Solicitud de reconocimiento como spin-off

    Acuerdo de licencia

    Acuerdos de I+D

    Contrato de servicios

    Contrato de asesoramiento

    17 de Diciembre 2019

    Vigilar aquí IP de la empresa o compartida

    El procedimiento depende del centro y las ventajas suelen ser rebaja de precios en servicios o alquiler de espacios

  • Reto 5: Pacto de socios y acuerdo de inversión 23 de Diciembre 2019

    ANTI-DILUTION RIGHT

    AMOUNT, DESTINATION AND DISBURSEMENT OF THE INVESTMENT

    GOVERNING BODIES / GENERAL SHAREHOLDERS’ MEETING

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