Proqr Therapeutics N.v. · NASDAQ:PRQR
Proqr Therapeutics — Corporate Update (December 2022)
34 slides from Proqr Therapeutics's corporate update, Dec 23, 2022
Slide 1: Axiomer RNA Base Editing Technology Platform
For precision medicinesAXIOMER®RNA BASE EDITING TECHNOLOGY PLATFORM Ticker: PRQR December 22, 2022
Slide 2: Agenda and Speakers
WelcomeSarah KielyStrategic Overview, Lilly Partnership ExpansionDaniel de BoerAxiomer®RNA Editing Platform TechnologyGerard PlatenburgProQR Therapeutics -Partnership Expansion2Agenda Sarah KielyVP Investor Relations & Corporate Communications Daniel de BoerFounder & CEO Gerard Platenburg Chief Scie
Slide 3: Forward looking statements
ProQR Therapeutics -Partnership ExpansionForward looking statementsThis presentation contains forward-looking statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as "anticipate," "believe," "could," "estimate," "
Slide 4: Strategic Overview and Lilly Partnership Expansion
Daniel de Boer, Founder & CEOStrategic Overview and Lilly Partnership ExpansionProQR Therapeutics -Partnership Expansion4
Slide 5: About ProQR: Focus on Axiomer
ProQR Therapeutics -Partnership Expansion5About ProQR Focus on Axiomer® Exclusively focused on the development of proprietary Axiomer® RNA editing platform across multiple therapeutic areas; initial focus on liver and CNS diseasesNovel Mechanism of ActionAxiomer® discovered in ProQR labs in 2014 and
Slide 6: Axiomer platform and use cases
ProQR Therapeutics -Partnership Expansion6Axiomer®platform and use casesProQR discovery of EONs guiding endogenous ADAR•Highly specific and targeted platform •Natural and endogenously expressed adenosine deaminases acting on RNA (ADARs)•Modified synthetic editing oligonucleotides (EONs) Sequence cor
Slide 7: Diversified value creation strategy
Diversified value creation strategy•ProQR to build in-house pipeline based on Axiomer® RNA editing technology platform. •Initial focus on liver and CNSapplications•Largely unencumbered platform, great potential for additional Axiomer® partnershipsAxiomer® StrategyProQR will develop its own pipeline
Slide 8: Expansion of Axiomer RNA licensing and research collaboration to $3.9B
Expansion of Axiomer®RNA licensing and research collaboration to $3.9B•Companies to develop editing oligonucleotides for five new targets and an option for an additional five targets using ProQR’s proprietary Axiomer® RNA editing platform, for a total of 15 targets•ProQR to receive $75 million consi
Slide 9: Axiomer Overview
Gerard Platenburg, Chief Scientific OfficerAxiomer®OverviewProQR Therapeutics -Partnership Expansion9
Slide 10: What is ADAR editing?
ProQR Therapeutics -Partnership Expansion10What is ADAR editing?ADAR (Adenosine Deaminase Acting on RNA) Enzyme that performs specific form of natural RNA editing, called A-to-I editing. During A-to-I editing an A nucleotide (adenosine) is changed into an I nucleotide (inosine)RNADoublestrandedADAR
Slide 11: What is Axiomer?
ProQR Therapeutics -Partnership Expansion11What is Axiomer®?Natural ADAR editing (A-to-I)RNADoublestrandedADAR I*RNADouble stranded A A = AdenosineI=Inosine*Will be read as G(Guanosine) EON-directed therapeutic editing (A-to-I)RNASingle strandedA RNA+EONDouble strandedADARI*EON How Axiomer®works•Use
Slide 12: How does Axiomer work? Step by step
How does Axiomer®work?Step by stepProQR Therapeutics -Partnership Expansion12We identify where an A-to-I edit could treat disease, and design an EON1The EON binds to the target RNA and attracts ADAR to make an A-to-I edit3During translation, the ‘I’ is read as a ‘G’, resulting in a corrected or alte
Slide 13: ProQR expertise driving optimized EONs
ProQR Therapeutics -Partnership Expansion A>I EON ProQRexpertise driving the development of optimized EONs fortherapeutic use13ADAR-binding region (ABR)Backbone modifications enable ADAR binding, and disable off-target editingEditing EnablingRegion (EER)Sequencedefinestarget RNA binding and provides
Slide 14: Improved editing obtained for several targets
ProQR Therapeutics -Partnership ExpansionImproved editing obtained for several targetsdZmodification on EER improves editing in different cell types14 CEP290 dCCEP290 dZ 0123 45 Editing % (ddPCR)fold change relative to dC USH2A dC USH2A dZ 024 68 Editing % (ddPCR)fold change relative to dC Editing o
Slide 15: EON backbone modifications enable ADAR binding and improve stability
ProQR Therapeutics -Partnership Expansion A>I EON Backbone modifications enable ADAR binding, and improvestability ADAR-binding region (ABR)(EER)15ADAR-binding region (ABR) modification greatly enhances editing Editing of ACTB in human primary hepatocytes(Gymnosis, 10uM, single dose,N=1, 48 hours, d
Slide 16: Focus on the EON design principles
ProQR Therapeutics -Partnership Expansion16Focus on the EON design principles AspectDetermined byModificationsEffectsBase Target RNAMismatches and analogsImproved PDRibose modificationADAR structure2’-H; 2’-OMe; 2’-MOE; 2’-F; 2’-NH2, LNA, TNA, diF, 2’-FANAImproved PK and PDLinkageADAR structurePO; P
Slide 17: Axiomer platform over time
ProQR Therapeutics -Partnership ExpansionAxiomer®platform over timeOptimization is yielding stability improvements and efficacy increase in cells and in vivo17
Slide 18: Optimization of Axiomer in multiple models, targets and organs
Optimization of Axiomer®in multiple models, targets and organsOpening the pathway for new class of medicines targeting diverse types of diseases ProQR Therapeutics -Partnership Expansion18The retina as early proof of concept The liver as a promising area of development The CNS The CNS as the next fr
Slide 19: Retina as early proof-of-concept: ACTB editing
ProQR Therapeutics -Partnership ExpansionThe retina as early proof-of-conceptEfficient editing of ACTB in mouse and human retinal cells19Editing of ACTB in mouse RPE cells(Transfection, 100nM, single dose, N=2, 24 hours, Sanger sequencing)Editing of ACTB in human RPE cells(Transfection, 100nM, singl
Slide 20: Efficiency confirmed in human retinal organoids
ProQR Therapeutics -Partnership ExpansionThe retina as early proof-of-conceptEfficiency confirmed in human retinal organoids with >40% editing achieved 20Retinal organoid225 daysEON-directed therapeutic editingEditing of ACTB in iPSChuman retinal organoids(Gymnosis, 20 uM, single dose, N=6, 7 days)
Slide 21: From model target to PoC therapeutic targets
ProQR Therapeutics -Partnership ExpansionFrom model target to PoC therapeutic targets21Approx. 20% editing was observed after gymnosisfor CEP290, a tool targets used for optimization •Each chemical modification improves EON editing efficacy•The highest editing efficacy increase is obtained for EONs
Slide 22: Editing increases CEP290 protein levels
ProQR Therapeutics -Partnership Expansion22Editing results in significant increase in CEP290 protein levels and intensity at the basal bodyMean ±SEM. Statistical significance was determined using Brown-Forsythe and Welch ANOVA testUntreatedhCEP290-6hCEP290-9 CEP290PCN 2 weeks CEP290 protein 2 weeks
Slide 23: The CNS as the next frontier
ProQR Therapeutics -Partnership ExpansionThe CNS as the next frontier>30% editing was achieved in IPSC derived brain organoids23 Editing of ACTB in IPSC derived brain organoids(Gymnosis, 10uM, single dose, n=7, 6 days, ddPCR) NTACTB 010203040 Editing (%) D6Human brain organoid130 days Gymnoticuptake
Slide 24: The liver as a promising area of development
ProQR Therapeutics -Partnership ExpansionThe liver as a promising area of developmentHigh potential of EONs editing in the liver24 •Similar levels of editing of ACTB achieved in several models of liver origin•High confidence of translatability of the approach GalNAcappears not to interfere with ADAR
Slide 25: Editing in InSphero human liver microtissues
ProQR Therapeutics -Partnership ExpansionEditing in InSpheroHuman Liver microtissues (LMTs)Primary hepatocytes, Kupffer cells and liver endothelial cells in 3D spheroidEditing of ACTB in human LMTs(Gymnosis, 5µM, single dose, 3 pools of 6 LMTs per condition, 7 days, dPCR) Day 3Day 5Day 7 01020304050
Slide 26: Liver targeted editing of PCSK9
Liver targeted editing of PSCK9De novo generation of a loss-of-function variant to lower PCSK9ProQR Therapeutics -Partnership Expansion26 0102030 4050 Editing (%)Percentage A→G editing of PCSK9 in transfected HeLa cellsTransfection, 100 nM, single dose, N=2, 48 hours, ddPCR Disruption of PCSK9 autoc
Slide 27: PCSK9 mRNA editing leads to reduced PCSK9 protein levels
PCSK9 mRNA editing leads to reduced PCSK9 protein levelsEditing of PCSK9 mRNA results in a loss-of-function phenotypeProQR Therapeutics -Partnership Expansion27Editing of PCSK9 in HeLa cellsTransfection, 100nM, single dose, N=2, 48 hours, dPCR •Up to 25% precent A-to-I editing of PCSK9 mRNA detected
Slide 28: Axiomer technology potential
ProQR Therapeutics -Partnership Expansion28Axiomer®technology potential CorrectionModulation / RegulationModificationRepairing G-to-A mutationsThousands of G-to-A mutations described in literatureEdit >400 different types of PTMs (Post-translational modifications)To regulate protein activity, change
Slide 29: RNA editing expert advisory board
ProQR Therapeutics -Partnership Expansion29RNA editing expert advisory board Phillip D. ZamorePhD Art Levin PhD Martin Maier PhDPeter A. Beal PhD Yi-Tao YuPhD Scientific Advisory Board
Slide 30: IP Overview
René Beukema, Chief Corporate Development Officer and General CounselIP OverviewProQR Therapeutics -Partnership Expansion30
Slide 31: Overview of Axiomer related patents
Overview of Axiomer®related patents DocketPriorityFeatureStatus1 (0004)17DEC2014Targeted RNA Editing using endogenous ADARsGranted CA CN EP IL JP NZ RU US ZA2 (0013)22JUN2016Short EONs with wobble and/or mismatch base pairsGranted IL JP KR US 3 (0014)01SEP2016Chemically modified short EONsGranted EP
Slide 32: Investment Highlights
ProQR TherapeuticsInvestment HighlightsProQR Therapeutics -Partnership Expansion32Quickly advancing toward the clinicand a large number of potential therapeutic applications Dominant and blocking IP positionAxiomer®platform protected by >10 granted patents families Experienced Management Teamwith de
Slide 33: Q&A
Q&A
Slide 34: \ IT’S IN
\ IT’S IN ProQR) ouR RNA
ProQR Therapeutics — Corporate Update (December 2022) on 6ix