Slide 1: PYC's VP-002 program: Life-changing science for ADOA
For personal use only PYC’s VP-002 program Life-changing for Autosomal science dominant optic atrophy June 2021
Slide 2: Disclaimer
Disclaimer For personal use only The purpose of this presentation is to provide an update of the business of PYC Therapeutics Limited (ASX:PYC) [‘PYC’]. These slides have been prepared as a presentation aid only and the information they contain may require further explanation and/or clarification. A
Slide 3: PYC Highlights
PYC Highlights For personal use only PYC is an RNA therapeutics company developing drugs for a range of genetic conditions Novel Technology Platform built on Cell Penetrating Peptide- Leading-edge RNA PMO technology. PPMOs solve delivery challenge and get Therapeutics more drug safely into cells Pro
Slide 4: Core therapeutic technology brings together two distinctive components
PYC’s core therapeutic technology brings together two distinctive components For personal use only PYC’s library of Cell- PMO (Phosphorodiamidate penetrating peptides Morpholino Oligomer) Latest generation anti-sense Naturally-derived peptide library oligonucleotide chemistry, neutral (500M sequence
Slide 5: Applying our technology to create life changing treatments, focus on eye and CNS
PYC is applying our technology to create life changing treatments, with an initial focus on diseases of the eye and CNS For personal use only PYC is a multi-asset drug development company Estimated addressable Program overview Indication and stage of development patients in Western World Organ Progr
Slide 6: VP-002 program for Autosomal Dominant Optic Atrophy
PYC’s VP-002 program for Autosomal Dominant Optic Atrophy For personal use only • Treating an important unmet need: PYC’s VP-002 program is directed towards a rare inherited retinal disease called Autosomal Dominant Optic Atrophy (ADOA) that causes progressive blindness in patients. VP-002 addresses
Slide 7: Autosomal dominant optic atrophy
Autosomal dominant optic atrophy For personal use only Autosomal dominant optic atrophy (ADOA) is a genetic disease causing progressive blindness The majority of ADOA cases are caused by mutations in the OPA1 gene leading to haploinsufficiency of the OPA1 protein1 Characteristics of OPA1 ADOA ar
Slide 8: ADOA is most frequently caused by mutations in the OPA1 gene
ADOA is most frequently caused by mutations in the OPA1 gene affecting the retinal ganglion cells For personal use only ADOA is caused by the loss of the retinal ganglion cells (RGCs) that make up the optic nerve This causes severe vision loss in the patient Vision loss often starts before the a
Slide 9: PPMOs increase the translation rate of the healthy OPA1 allele
PYC’s PPMOs increase the translation rate of the healthy OPA1 allele to increase OPA1 protein levels For personal use only Example of translations rate strategy Effect on mRNA Protein levels mRNA forms secondary structures due to Watson-Crick base pairing. Translation This can inhibit the translatio
Slide 10: Preclinical data support PYC's PPMOs as a differentiated approach
Preclinical data support PYC’s PPMOs as a differentiated disease-modifying approach to treat OPA1 ADOA For personal use only There is strong preclinical support for the VP-002 VP-002 benefits from the inherent program (data broken out in subsequent slides) advantages of PYC’s PPMO technology Can eff
Slide 11: PPMOs can reach the target cell in vivo
PYC’s PPMOs can reach the target cell in vivo For personal use only PYC’s PPMOs demonstrate dose dependant uptake and PYC’s PPMOs demonstrate broad and deep distribution across long duration in the mouse neural retina the mouse retina Exon-skipping in mouse neural retina, single IVT injection1 PPMO
Slide 12: PPMOs can increase the critical OPA1 protein in a dose-dependent manner
PYC’s PPMOs can increase the critical OPA1 protein in a dose- dependent and mutation agnostic manner For personal use only Change in OPA1 protein levels, day 7 post PPMO treatment, patient fibroblasts Patient 1, n=3 3 Patients (pooled), n=3 per patient Statistical differences were analysed using one
Slide 13: Further optimized PMO candidates increase OPA1 protein further
Further optimized PMO candidates have shown an ability to even further increase the OPA1 protein For personal use only Change in OPA1 protein levels, day 2 post PMO transfection, patient fibroblasts (n=3) Two further optimized PMO candidates showing even greater potency Untreated 50µM 100µM 50µM 100
Slide 14: PPMOs can increase mitochondrial ATP production
PYC’s PPMOs can increase mitochondrial ATP production in a mutation agnostic manner For personal use only Change in mitochondrial ATP levels, day 7 post PPMO treatment, patient fibroblasts Patient 1 and 3 harbour c.2708_2711delTTAG deletion, Patient 2 harbours the c985-1G>A mutation. Patient fibrobl
Slide 15: PPMOs can protect cells against Apoptosis
PYC’s PPMOs can protect cells against Apoptosis in a mutation agnostic manner For personal use only Apoptosis, relative to healthy cells day 7 post PPMO treatment, patient fibroblasts Patient fibroblasts were pre-treated with PPMO at 5 and 10 µM for 7 days and were subsequently treated with apoptoti
Slide 16: Improvements in functional outcomes increase chance of improving clinical symptoms
These demonstrated improvements in functional outcomes increase the chance of improving clinical symptoms in patients For personal use only Improvements in functional outcomes (increased bioenergetics and protection against apoptosis) have been linked to maintenance of visual acuity in OPA1 mutation
Slide 17: Preclinical data support PYC's PPMOs as a differentiated approach
Preclinical data support PYC’s PPMOs as a differentiated disease-modifying approach to treat OPA1 ADOA For personal use only Can effectively reach the target neural retina cells in vivo, compared to alternative ASO approaches that show limited ability to reach these cells at much higher doses Can up
Slide 18: Path forward for the VP-002 program
Path forward for the VP-002 program For personal use only Key Steps Target timing Additional preclinical efficacy and safety assessments in Late 2021 patient-derived retinal models and animal models Conclude lead selection and optimization of target PPMO Early 2022 molecule through multiple