EX-99.2 5 tm2233262d2_ex99-2.htm EXHIBIT 99.2
Exhibit 99.2

 

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For precision medicinesAXIOMER®RNA BASE EDITING TECHNOLOGY PLATFORM Ticker: PRQR December 22, 2022

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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 Scientific Officer René Beukema Chief Corporate Development OfficerSpeakers IP OverviewRené BeukemaQ&ADaniel de BoerGerard Platenburg René Beukema

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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," "expect," "goal," "intend," "look forward to", "may," "plan," "potential," "predict," "project," "should," "will," "would" and similar expressions. Such forward-looking statements include, but are not limited to, statements regarding our strategy and future operations, statements regarding the potential of and our plans with respect to our technologies and platforms (including Axiomer®), our other programs and business operations, our current and planned partnerships and collaborators and the intended benefits thereof, including the collaboration with Lilly and the intended benefits thereof, including the upfront payment, equity investment, and milestone and royalty payments from commercial product sales, if any, from the products covered by the collaboration, as well as the potential of our technologies and product candidates; our updated strategic plans and the intended benefits thereof, our plans to seek strategic partnerships for our ophthalmology assets, and our financial position and cash runway. Forward-looking statements are based on management's beliefs and assumptions and on information available to management only as of the date of this presentation. Our actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including, without limitation, the risks, uncertainties and other factors in our filings made with the Securities and Exchange Commission, including certain sections of our annual report filed on Form 20-F. These risks and uncertainties include, among others, the cost, timing and results of preclinical studies and other development activities by us and our collaborative partners whose operations and activities may be slowed or halted due to shortage and pressure on supply and logistics on the global market; our reliance on contract manufacturers to supply materials for research and development and the risk of supply interruption from a contract manufacturer; the ability to secure, maintain and realize the intended benefits of collaborations with partners, including the collaboration with Lilly; the possible impairment of, inability to obtain, and costs to obtain intellectual property rights; possible safety or efficacy concerns that could emerge as new data are generated in research and development; general business, operational, financial and accounting risks; and risks related to litigation and disputes with third parties. Given these risks, uncertainties and other factors, you should not place undue reliance on these forward-looking statements, and we assume no obligation to update these forward-looking statements, even if new information becomes available in the future, except as required by law.3

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Daniel de Boer, Founder & CEOStrategic Overview and Lilly Partnership ExpansionProQR Therapeutics -Partnership Expansion4

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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 uses well-proven modality of oligonucleotides to recruit a novel mechanism of actionValidated across multiple genes Preclinical data demonstrate Axiomer® is broadly validated across multiple genesADARAxiomer® is ADAR-mediated RNA editing, recruiting endogenous adenosine deaminase acting on RNA (ADAR)Two pillars underly strategy •ProQR developing wholly owned pipeline: Initial targets to be disclosed in early 2023 •Selectively enter into partnerships: initial partnership with Lilly in Sept 2021, expansion announced Dec 2022Ophthalmology partnerSeeking strategic partner for ophthalmologyassets

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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 correctionCorrection of genetic disease-causing mutation to a wild-type sequence (>20,000 disease causing G>A mutations described)Missing or disease causing protein A I Sequence modificationModification of a wild-type protein to prevent or treat disease (modify characteristics, caspase sites, post translational modifications Wild-type protein A I •Can correct or change an Adenosine (A) to an Inosine (I), which is translated as a Guanine (G)•Broad therapeutic potential: common, rare diseases, wide variety of organs, and so-far undruggable targets

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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 and selectively enterpartnershipsProQR Therapeutics -Partnership Expansion7 •Lilly partnership expansion announced December 2022 –total partnership includes up to 15 targets and potential value of ~$3.9 B•ProQR may selectively enter additional partnerships Axiomer®

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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 consisting of an upfront payment and equity investment; additional $50 million to be paid to ProQR if Lilly exercises option for five additional targets•ProQR eligible to receive up to $2.5 billion in milestones, plus royalties based on expanded collaboration •Collaboration with Lilly now includes a total of up to 15 targets, with the potential for ProQR to receive up to $3.75 billion in research, development, and commercialization milestones, plus royalties•ProQR to access Lilly delivery technology to use in its wholly-owned pipelineProQR Therapeutics -Partnership Expansion8

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Gerard Platenburg, Chief Scientific OfficerAxiomer®OverviewProQR Therapeutics -Partnership Expansion9

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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 I*RNADouble stranded A •ADAR normally binds to double stranded structuresin RNA to perform A-to-I editing •Later, during the translation process, the ‘I’ in the RNA is read as a ‘G’ (guanosine) by the cellA = AdenosineI=Inosine*Will be read as G(Guanosine) Natural ADAR editing (A-to-I) Inosine (I)* Adenosine (A) *Inosine will be read as Guanosine (G)

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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•Uses short strands of synthetic RNA, called EONs(Editing Oligonucleotides)•EONs bind to the target (single stranded) RNA and mimics double stranded structure that attracts ADAR•EONs attract ADAR to specific location in RNA to make A-to-I editResults•RNA with disease-causing mutation is corrected back to normal RNA•Function of protein is changed to help prevent or treat diseaseEON

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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 altered protein4The EON is periodically delivered to the targeted organ or tissue 2 RNAProtein I (G) RNAADAREONA→I

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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 stabilityEON total lengthBetween ~25 -30 nt Optimized sequence and chemistry define functionalityBring metabolic stability Prevent off-target (‘bystander’) editing Ensure bioavailability (cell and tissue uptake) Offer safety and tolerability at therapeutic dosesIncrease editing efficacy

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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 of hCEP290 K1575X in human LCA retinal organoidsGymnosis, 10µM single dose, N=8, 4 weeksEditing of USH2A WT RNAin human retinal organoidsGymnosis, 15µM single dose + 40µM CQ, N=4, 4 weeksUp to 4x APP dC APP dZ 01234 Editing % (ddPCR)fold change relative to dC Editing of APP WT RNAin human retinal organoidsGymnosis, 10µM single dose + 40µM CQ, N=6, 4 weeksUp to 3xUp to 6x APP dCAPP dZ 012 3 Editing % (ddPCR)fold change relative to dC hA1AD dChA1AD dZ 0246810 Editing % (ddPCR)fold change relative to dC Editing of WT APP RNA in human ARPE-19Transfection of 100nM EON, N=3, 48 hoursEditing of SERPINA1 E366K in A1AD patient hepatocytesTransfection of 100nM EON, n=2, 48 hoursUp to 2.5xUp to 9xProQR –UC DAVIS Collaboration

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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, dPCR) 0204060 80NTACTB-5ACTB-6ACTB-3Editing (%)Up to 40%increasedediting Editing of ACTB in human retinal pigment epithelium cells(Transfection, 100nM, single dose, N=1, 48 hours, dPCR) 020 40 60 80NTACTB-5ACTB-6ACTB-3Editing (%)Up to 30%Increasedediting •Chemical optimization greatly increases EON editing in positions within ABR region•SAR screen of 2nd backbone modification for best position within ABR region ongoing

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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; PS; PN; MeP; UNA; PAcImproved PK and PD EON A7 6 5 4 3 2 1 0 -1 -2 -3 -4 This work led to a portfolio of 13 foundational platform patents C G U

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ProQR Therapeutics -Partnership ExpansionAxiomer®platform over timeOptimization is yielding stability improvements and efficacy increase in cells and in vivo17

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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 frontier Model targets PoC therapeutic targets Tool targets used for optimization Pipeline targets

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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, single dose, N=1, 48 hours, Sanger sequencing) NTACTB-5ACTB-6ACTB-3 020406080 Editing (% ) NTMockActB S3-3 020406080 Editing (%) •Similar levels of editing of ACTB achieved in mouse and human models of retinal origin•High confidence of translatability of the approach

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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) 50 30 40 20 10 0 ActB - 3 ActB - 6 Scr Editing % ( ddPCR ) RNA+EONDoublestrandedAEON RNA+EONDouble stranded IEON ADAR •Each chemical modification improves EON editing efficacy•The highest editing efficacy increase is obtained for EONs with multiples modification combined•Over 40% editing was observed after gymnosis

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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 with all modification combined•Over 40% editing was observed after gymnosis for ACTB and over 20% editing observed after gymnosis for CEP290 NTCEP290-1CEP290-3CEP290-6 CEP290-9 01020 30 Editing % ScrACTB-6ACTB-3 010203040 50 Editing % Editing of CEP290 in LCA human retinal organoids(Gymnosis, 10uM, single dose, N=8, 2 weeks, ddPCR)Editing of ACTB in human retinal organoids(Gymnosis, 20 uM, single dose, N=6, 7 days, ddPCR)

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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 UntreatedhCEP290-6hCEP290-9 020406080 %CEP290-positive basal bodies ✱✱✱ ✱✱✱✱ Significant increase in CEP290 protein levels and intensity was detected at the basal body of LCA07-3 organoids treated with hCEP290-6 and-9 after 2-weeks treatment

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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 GymnoticuptakeDAY 0D3D5 Washout regimenW1W210 µM EON Assembloidcollection Editing quantification using ddPCR

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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 binding or efficient RNA editing >50% Editing of SERPINA1 E366K in human A1AD patient hepatocytes 0204060 02040 6080 Editing (%)EON5 GalNac EON5 Editing of ACTB in human primary hepatocytesGymnosis, 10uM, single dose, N=1, 48 hours, dPCRTime in minGalNacdoes not interfere A-to-I editing in vitroN=1, BEA assay 020406080NTACTB-5ACTB-6ACTB-3Editing (%)Editing of SERPINA1 E366K in human A1AD patient hepatocytesTransfection, 100 nM, single dose, N=2, 47 hours, dPCR NTMockScrA1AD-54 0204060 Editing (%)

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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 Days of treatmentEditing (%) Treatment of LMTs with 5µM EON for 7 days results in up to 40% of edited ACTB. Live image of Day 7 LMTStained with 5-CFDA (green), PI (red) and Hoescht(nuclei; blue) Presence of bile channels in LMTs by day 7 Fluorescent dye 5-CFDA secreted from healthy cells into bile channels (canaliculi) BSEP Bile Canaliculi (InSpherodata)25

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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 autocleavage site reduces protein in bloodstream•Less PCSK9 leads to increase of LDL-R on cells, decrease of ‘bad’ LDL in bloodstream•Loss-of-function PCSK9 variant Q152H is associated with low plasma LDL cholesterol in a French-Canadian family and with impaired processing and secretion in cell culture >40% Editing of PCSK9 mRNA in transfected HeLa cellsFEH patients Axiomer®edit PCSK9Q152 PCSK9Q152REON ↓PCSK9 ↓LDL ↑LDL ↑PCSK9

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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 using ddPCR assays•EONs treated HeLa cells produce lower levels and more uncleaved PCSK9 protein •Up to 80% reduction of total PCSK9 protein measured in treated samples•Shift in the ratio cleaved to uncleaved PCSK9 observed; 70%:30% to 25%:75% MockPCSK9-18PCSK9-19PCSK9-23 0102030 Editing (%) PCSK9 protein expression in HeLa cellsTransfection, 100nM, single dose, N=2, 48 hours, western blot MockPCSK9-18PCSK9-19PCSK9-23 0.00.51.0 Relative Total PCSK9 expressionPro-PCSK9 PCSK9

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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, changes localization, folding, preventimmune escape and slows down degradation Change protein-protein interactionsChangeslocalization, folding and protein function and preventimmune escape of glycosylatedtumor antigensCreate new proteinsNew proteins achieving loss or gain of functions that helps address diseaseInclude protective variantsAt the RNA level, to develop new functions that help prevent disease Broad therapeutic potential√Common diseases√Rare diseases√Target a wide variety of organs√Treat so-far undruggabletargets

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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

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René Beukema, Chief Corporate Development Officer and General CounselIP OverviewProQR Therapeutics -Partnership Expansion30

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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 KR NZ US ZA4 (0016)19JAN2017EONs + protecting sense oligonucleotidesGranted US 5 (0023)18MAY2018EONs with phosphorothioate linkages, EONs with chiral linkages (e.g.,PS, PN)Published 6 (0026)11FEB2019EONs with phosphonacetate linkages and UNA modificationsPublished 7 (0029)03APR2019EONswith methylphosponate linkagesPublished 8 (0031)24APR2019Targeted editing inhibitionPublished 9 (0032)13JUN2019EONs with cytidine analogs for increased catalytic activityPublished 10 (0039)23JUL2020Split EONsPublished ProQR Therapeutics -Partnership Expansion31In addition to the above, numerous patent applications are pending but have not yet been published.ProQR expands its Axiomer®IP portfolio continuously.

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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 deep RNA expertise Strategic-partnership strategy for Axiomer®as evidenced by Lilly collaboration, provides optionality and multiple value-creation opportunities Strong balance sheetas of September 30, 2022, cash runway into 2026, now upside with potential for additional BD-related upside €

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Q&A

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IT’S INOUR RNA