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1. www.valentiabiopharma.com info@valentiabiopharma.com

2. Valentia Biopharma - In vivo DrugDiscovery Research and development of new drugs for human diseases Currently focused on finding lead compounds to achieve an effective treatment on Myotonic Dystrophy Type 1 (DM1) disease

3. Valentia Biopharma - In vivo DrugDiscovery Drosophila melanogaster, a new technology for Drug Discovery Valentia Biopharma R&D

4. Why Drosophila? • 75% of humandiseasecausing genes are conserved in • Drosophila • Short time frame from drug dosing to results • No ethical issues. • Large number of genetic tools available • Low variability at low costs • (Flies are CHEAP) Not only Drosophila: Drug delivery can be problematic and not all human systems can be easily modeled. (pulmonary disease…) So we always validate any positive result with mouse models and human cell lines

5. Drosophilamodels. Screening experimental approaches • Phenotypic assay (viability) • Biochemical assay (gene-reporter) by fusing known human genes involved in DM1 pathologies to a reporter DM1 fly TRANSGENIC FLY PROMOTER-CONSTRUCT Viability model Gene Reporter FLY INJECTION Toxic in mushroombodies (neuronal cells) n=191 n=67 Control

6. In vivo automated HTS platform Our high-throughput screen (HTS) platform allows testing thousands of compounds per week with the advantage of working in in vivo conditions. TOXICITY AND ACTIVITY EVALUATION IN THE SAME EXPERIMENTAL APPROACH

7. In vivo automated HTS platform By genetic modification we have been able to develop transgenic flies models that reproduces some aspects of the genetic human disease Myotonic Dystrophy. This has been the first model we developed in and now it is being used with our High Throughput Screening (HTS) technology. Our HTS platform allows the testing of thousands of compounds per week, with the differential advantage of working with in vivo models. Large scale in vivo compound testing on Drosophila provides important early information on multiple key parameters of drug discovery Screening platform - Steps in red are automated 5. READING (Envision Reader /Scanner) 1. FLY CROSSES 3. SEEDING (SorterCytometry) 4. HOMOGENIZATION (Robot with stackers) 2. DRUG PLATES PREPARATION (Robot with stackers) 6. ANALYSIS F1:Adults F1:Embryo/Larvae F0:Adults

8. DM1 Drug Discovery Pipeline > 15,000 small molecules screening >8,000 screening analyisis and validation 30 candidates Secondary assays validation 4 hits *ABP1 was discovered by an academic group performing manual screening in the DM1 Drosophila model

9. The disease: Myotonic Dystrophy Type 1 (Steiner disease) Rare Disease. Overall worldwide prevalence: 1 / 8,000. Higher in some populations like in Quebec (Canada). High penetrance Multifactorial disease. Mainly a muscular disorder: Myotonia, progressive muscular wasting and weakness. • But also cataracts, hypogonadism, ECG changes, infertility, cognitive dysfunction, mental retardation… Source:http://omim.org/entry/160900 Harper 2001

10. DM1 DNA mutation: repeat expansion (A) (B) (C) Size of CUG repeat 50 - 400 DM1 Phenotype 38 - 49 “Premutation” Asymptomatic 5 - 37 Normal (A) In DM1, the repeat involved is a CTG tract located in the 3´UTR region of the DMPK gene. In normal population we have two alleles between 5-37 CTG repeats. In patients the length of one allele is expanded from more than 50 repeats up to even thousands of repeats. (B) Mutant transcripts form stable CUG hairpins that avoid their normal transportation to cytoplasm, with the ability of forming nuclear aggregates and sequester RNA-binding factors such as Muscleblind-like-1 protein (MBLN1), which plays an important role in alternative splicing and gene expression regulation. (C) Thus, in DM1 patients several aberrant splicing events in many genes (spliceopathy) have been characterized, most of them dependent of MBLN1. A few of these aberrant splicing event have already been linked to distinct DM1 clinical symptoms. CAP (AAA)n (CUG)n 5’ 3’ 5’ UTR 3’ UTR DMPK Gene (Coding region)

11. VLT001 (ABP1) active compound In vivo discovery of a peptide that prevents CUG–RNA hairpin formation and reverses RNA toxicity in myotonic dystrophy models Amparo García-López, Beatriz Llamusía Mar Orzáez, Enrique Pérez-Payá, and Ruben D. Artero PNASU S A. 2011 Jul 19;108(29):11866-71. SummaryResults: 1. Orally administered ABP1 increased adult viability and reversed muscle degeneration phenotypes in DM model flies in a dose-dependent manner. 2. Aberrantribonuclear CUG foci diminished and Muscleblind (the Drosophila functional homolog of human MBNL1) misdistribution in CUG foci was improved in model flies taking ABP1 orally. 3. Intramuscular administration of ABP1 suppressed muscle histopathology signs and reversed missplicing events in DM model mice up to one month after administration. Expression of Clcn1, which is low in DM1 model mice, recovered in ABP1 injected muscle. 4.Binding and destabilizing CUG repeat RNA hairpins in vitro suggest a mechanism of action of ABP1 located very upstream of the disease pathway suggesting the molecule should be therapeutically active against many of the clinical signs.

12. ABP1 suggested mechanism of action MBNL1 MBNL1 sequestration U U C G G G C C G C U U C C G G ABP1 C U G C U G C G C U G C U G G G C C C C G G G G MBNL1 released C C G G C C U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U G C C G Splicingmisregulation C G C C C C C C C C C C C C C C C G G G G G G G G G G G G G G G U U G G G G G G G G G G G G G G G C C C C C C C C C C C C C C C G C C G U U Normal Splicing A)n DMPK 3’ UTR DMPK 3’ UTR ABP1 binds to CUG repeat RNA and induce a switch to a single-stranded conformation, releasing MBLN1 and decreasing CUG toxicity.

13. Business case for DM • Among rare diseases, Myotonic Dystrophy presents an attractive commercial opportunity on multiple fronts: • Clinical state (urgent unmet medical need, lack of suitable treatments) • Scientific rationale (solid understanding of disease pathology, druggable targets, and proof of concept for therapeutic intervention leading to clinically meaningful benefit in animal models) • Logistics/marketing considerations (significant disease prevalence/potential market size, accessibility of patients, well-organized global research community) Source: 2010 Marigold therapeutic strategies for myotonic dystrophy