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

Regulatorypreclinical

Phase I/IIaPhase

IIb & IIIMAA

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 forthe 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 MBNLproteins, causing main symptoms of the disease

• Symptoms involve nervous system (disturbed sleep, cognitive dysfuntion),heart (arrhythmias) and skeletal musculature (atrophy and muscularweakness, 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 Patientsworldwide

MBNL

MBNL

• 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

The model: human DM1 myoblasts

Arandel et al. 2017

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

miR-23b-3p CNT

miR-23b-3p DM1

miR-218-5p CNT

miR-218-5p DM1

0

2

4

6 **

**

Re

la

tiv

e E

xp

re

ss

io

n (2

^-ΔΔ

Ct)

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)

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 differentchemistries and cojugates

TC50 Viability

(up to 17 fold reduction in toxicity)

EC50 MBNL1 levels

(up to 3 fold increased efficacy)

Selection of 15 antimiRsto 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 withdifferent 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 murinemodel

Long-acting subcutaneus efficacy

THE COMPETITORSChemistry 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 technologyDiscovery and proof of concept stages.

Technology still in development.

Increased MBNL1 expression and rescued characteristic

DM features in mice.

RNA-motif-small-molecule. PreclinicalRestoration 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

PreclinicalNon-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 RuppToxicology 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

CandidateConfirmation

CTA/IND obtention

FIH Start

2020 2021 2022 2023 2024

Preclinical Non-GLP

development

Preclinical GLP

Animal testingPhase 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-INNVIERTEcommited 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

BOARD OF DIRECTORS: matters reserved to the board

LIMITATIONS ON THE TRANSFER OF SHARES/TERMS AND CONDITIONS OF TRANSFER OF COMPANY’S SHARES

PRE-EMPTIVE RIGHT/TAG-ALONG RIGHT /DRAG-ALONG RIGHT

LIQUIDITY EVENTS AND PREFERRED LIQUIDATION

COMMITMENTS OF KEY TEAM / EMPLOYEE STOCK OPTION POOL

NON-COMPETE OBLIGATION/EXCLUSIVITY

LIFE INSURANCE /NON-DISCLOSURE AGREEMENT

Derecho de compra/ de acompañamiento/ de arrastre

Reto 6: Organización interna

Asesor legal, RRH, financiero y contable

Asesor de IP

Secretaría técnica

Director financiero

Asesor de Toxicología

Temas regulatorios

Diseño del ensayo clinico

CRO= Contracted research organization

Asesor de CMC CMO= contracted manufacturer organization

Chief executive officer

Chief financial officer

Chief scientific officer

CMOCOOCTO

Chief medical officerChief operating officerChief Technology officer

Chief comercial/communications

Chief innovation/information

Chief knowledge officer

General structure

Reto 7: Estructura de inversión futura

Lead Optimization

CandidateConfirmation

CTA/IND obtention

FIH Start

2020 2021 2022 2023 2024

Preclinical Non-GLP

development

Preclinical GLP

Animal testingPhase 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

Ronda A: 2x minimo

Ronda B: 5x minimo

Ronda A de 10 millones: 2x minimo

Inversión pública