Design Therapeutics, Inc. · NASDAQ:DSGN
Design Therapeutics — Investor Presentation (January 2025)
47 slides from Design Therapeutics's investor presentation, Jan 13, 2025
Slide 1: Designing a Novel Class of Genomic Medicines for Genetic Disorders
7SOCC— ~~ DESIGNING A NOVEL CLASS OF GENOMIC MEDICINES FOR GENETIC DISORDERS 1Q2025
Slide 2: Disclaimers
Disclaimers This presentation contains forward-looking statements. All statements other than statements of historical facts contained in this presentation are “forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements include, but are not
Slide 3: GeneTAC Molecules dial up or dial down transcription to treat monogenic disorders
cules (GeneTAC® Molecules) that up or dial down transcription... ...to treat significant monogenic disorders BECAUSE WE BELIEVE YOUR FATE DOESN'T HAVE TO BE WRITTEN IN YOUR GENES DESIGN THERAP. gutics
Slide 4: Advancing four GeneTAC molecule programs
Advancing four GeneTAC® molecule programs Differentiated profile Significant market FRATAXIN (FXN) TCF4 DMPK HUNTINGTIN (HTT) GAA repeat expansion leads to reduced transcription CTG repeat expansion causes nuclear foci & corneal endothelial cell dysfunction CTG repeat expansion causes nuclear foci &
Slide 5: GeneTAC Molecules have several advantages over traditional genomic medicine approaches
GeneTAC® Molecules have several advantages over traditional genomic medicine approaches Simple drug Working with Annual R&D spend delivery natural genome Gene editing/ 130-460M' gene therapy $ Oligo : , nucleotide $50-150M $60 - 80M? platform 41, Estimates derived from analysis of R&D spend of selec
Slide 6: GeneTAC Molecules can distribute widely overcoming a central challenge
GeneTAC® Molecules can distribute widely overcoming a central challenge for traditional genomic medicines GeneTAC® Small Molecule Oligonucleotide Protein Gene Therapy MOLECULAR SIZE om 6,000- 50,000- 4,000,000- (Datton) © 1,000-3000 © 15,000 100,000 O 5,000,000 Broad distribution LIMITED LIMITED LIM
Slide 7: Differentiated mode of action of GeneTAC molecules
OEE Ligand | inker DNA-targeting moiety moiety wn TRANSCRIPTION ; FACTOR NUCLEOSOME Differentiated mode of action of GeneTAC® molecules DIAL UP EXPRESSION Recruited complex Drug Cw 1 Sidi onesie Designed to facilitate transcription through the locus DIAL DOWN EXPRESSION Recruited complex jai cTG —e
Slide 8: Friedreich Ataxia
or Friedreich Ataxia DESIGN
Slide 9: Friedreich ataxia: debilitating disease with limited treatment options
Monogenic Ma disease caused by GAA-repeat expansion in 15t a intron of frataxin ZEB) pm (FXN) gene Protein Mutation leads 2. to reduced FXN transcription, which is necessary for Function mitochondrial and cellular function CY) 47 Cellular Function FA: Debilitating disease with limited treatment opti
Slide 10: Therapeutic goal: increase FXN protein
Therapeutic goal: : FXN prote lymphoblastoid cells increase FXN p < 0.0001 4 — p= 0.003 — FA patients, carriers and qq £00 P —p=0.005— controls have different od average FXN protein levels = 500 7 fe) Carriers are free of FA 5 oO. symptoms = 4007 2 Oo ~2X increase of FXN 3 | A protein could potentia
Slide 11: FA GeneTAC molecules normalized FXN levels in FA patient cells
FA GeneTAC® molecules normalized FXN levels in FA patient cells but did not alter FXN levels in healthy cells FA PATIENT (two expanded copies) | Expression a " ~300 to >1,000 REPEATS | petuced é H — gi GaAGAAGARGANGAAGANGHEG REGAN. an | FRATAXIN i : le INTRON 1 zo =i Drug candidate | HEALTHY INDIVID
Slide 12: Low concentrations of DT-216 restored endogenous FXN levels in FA iPS-neurons
Low concentrations of DT-216 molecule restored endogenous FXN levels in FA patient iPS-neurons mM Vehicle 25 mm 100M WT neuron FXN protein levels = 1000 20 t FXN mRNA FXN protein (pg/ug protein) (fold change relative to DMSO) 3 7 10 14 3 7 10 14 Days of treatment Days of treatment Note: Bars represe
Slide 13: Prior DT-216 Phase 1 MAD study design
« Primary and secondary objectives: evaluate safety, tolerability and pharmacokinetics (PK) « Exploratory objective: evaluate FXN gene expression Selection of MAD doses was based upon anticipated: Study Population s . | 2 + Tissue exposures in therapeutic ‘ i) range at 200-300mg dose levels oe 182 >
Slide 14: Prior DT-216 Phase 1 MAD study revealed plasma PK and tissue distribution
Prior DT-216 drug product Phase 1 MAD study revealed plasma PK and tissue distribution are both transient with QW IV dosing Plasma DT-216 PK after 3rd Dose Muscle DT-216 PK after 3rd Dose » Average DT-216 levels in skeletal muscle at both 200mg and 300mg cohorts were ~8-10nM two days 10000 ~® +300 m
Slide 15: Prior DT-216 MAD study showed FXN expression dialed up with drug exposure
Prior DT-216 drug product Phase 1 MAD study showed FXN expression is dialed up in response to drug exposure in FA Patients Muscle FXN mRNA response correlated with dose and muscle DT-216 exposure, p < 0.05* Cohorts: 200mg and 300mg Individual FA Patients 405 Lower quartile in healthy Carrierst Upper
Slide 16: Injection site thrombophlebitis and new drug product DT-216P2
Injection site thrombophlebitis new drug product DT-216P2 Prior DT-216 drug product Phase 1 MAD safety + No serious or severe adverse events (AEs) and no treatment-related discontinuations (1 unrelated study withdrawal due to COVID infection) * 5AEs of injection site thrombophlebitis on DT-216 arm —
Slide 17: DT-216P2 demonstrates superior product profile in NHPs
DT-216P2 demonstrates superior product profile in NHPs using a proprietary and novel excipient NHP Intravenous @ ~1/4 reference dose DT-216P2 New -@ ~1/10 reference dose DT-216P2New 4 Prior DT-216 drug product Plasma DT-216 (nM) 0 24 48 72 96 Time post dose (hours) 120 144 168 192 Note: Bars represe
Slide 18: Daily or weekly administration of DT-216P2 reaches steady state plasma exposure
Daily or weekly administration of DT-216P2 reaches steady state plasma exposure @ Subcutaneous 10000 -- ~1/8 reference dose DT-216P2 SC QW ~~ ~1/80 reference dose DT-216P2 SC QD Plasma DT-216 (nM) Note: Bars represent standard deviation
Slide 19: DT-216P2 achieved comparable drug levels in tissue and plasma
DT-216P2 achieved comparable drug levels in tissue and plasma Clinical MAD study NHP prior DT-216 drug product QW IV DT-216P2 QW IV -& 300mg cohort plasma PK after 3rd dose | -e ~1/4 reference dose plasma PK after 4th dose x 300mg cohort muscle biopsy after 3rd dose * ~1/4 reference dose muscle biop
Slide 20: Biodistribution of DT-216P2 IV compared with the prior drug product
Biodistribution of DT-216P2 IV compared with the prior drug product 62 _ = 10000. mm DT-216P2 New l@™ Prior DT-216 drug product 10: Tissue DT-216 (nM) 2 Note: Bars represent standard deviation. Rats received three weekly IV injections of DT 216P2 or prior DT-216 drug product at the same dose level a
Slide 21: FA program next steps
FA program next steps » Repeat administration of DT-216P2 in rats + Initiate Phase 1 SAD in 1H 2025 to assess PK and NHPs well-tolerated at doses that in healthy volunteers by multiple routes of achieved higher and more durable exposure administration, IV (infusion) and subcutaneous than prior DT-21
Slide 22: Unmet need in FA remains significant
Unmet need in FA remains significant Ss Biogen Skyclarys® does not address the genetic root cause of FA or change FXN level Skyclarys® slows disease progression on neurological end point (mFARS) but only during the 15 year Estimated peak sales of $1.6B/yr 10 © Natural History -@- Omaveloxolone Basel
Slide 23: Activity of FA GeneTAC molecules compared with other compounds
Activity of FA GeneTAC® molecules compared with other compounds that have purportedly increased FXN in FA patient LCLs FXN mRNA (24 hours) FXN Protein (3 days) 150 ° 100 50 + 42 0 2 4 6 Log Concentration (uM) 3 a Percent of Healthy Control FXN MRNA(%) a g 2 £ rs 3 & 5 2 2 > £ rs 2 Ey z Fe z “© FAGen
Slide 24: Fuchs Endothelial Corneal Dystrophy
-uchs Endothelial Corneal DESIGN
Slide 25: FECD patients quietly suffer declining visual function
patients quietly suffer declining visual function 18 to 30K ae ~5M US FECD patients comeal transplant surgeries annually Vision with FECD* (0.5% of all FECD)' t I Increasing Endothelial Dysfuncti Diagnosis by Loss of visual Patient can’t optometrist function stand symptoms 4.6-5.3M US FECD patients
Slide 26: Treatment goal: restore endothelial function and visual function
Treatment goal: Restore endothelial function and visual function out of the stroma to ensure proper dehydration of collagen fibrils for corneal transparency * CEC loss or dysfunction leads to excess hydration of corneal stroma, resulting in loss of corneal transparency, and visual dysfunction + As C
Slide 27: FECD GeneTAC molecules designed to suppress transcription of TCF4 with expanded CTG repeats
FECD GeneTAC® Molecules are designed to suppress transcription of TCF4 DNA that contains expanded CTG repeats Mutant TCF4 RNA induces \ es | INTRON 3 EI \\ FECD molecular pathology: TCF4 La. Hairpin formation J Mutant Nuclear foci TCF4 RNA J MBNL sequestration 1 Spliceopathy J ieee ORK — VII =! CEC
Slide 28: DT-168 reduces nuclear foci in FECD CECs
Vehicle DT-168 2 e @ ® 2 Note: Bars represent stan g & CECs treated daily for 6 or 14 days with DT-168 Foci per nucleus Percent of untreated Ty 6d IC80 =4nM i © 14d 01 4 10 100 1000 DT-168 (nM) 28
Slide 29: Wild-type TCF4 transcripts unaffected following treatment with DT-168
Wild-type TCF4 transcripts are unaffected in primary control and FECD CECs following treatment with DT-168 TCF4 mRNA RT-qPCR; normalized to RPLPO 125 100 aS m™ control CECs donor 1 50 GI FECDCECs donor 2 | 25 0 0 2 7 2267200 0 2 7 2267200 DT-168 (nM) Notes: Control CECs fom donor 1 and patient-deriv
Slide 30: DT-168 improves spliceopathy in primary FECD CECs
DT-168 improves spliceopathy in primary FECD CECs Top 7 improved genes for FECD CECs derived from donor 2 Patient-derived FECD CECs + DT-168 6d treatment 1205 100-- + control CECs DT-168 (nM) 80- 0 605 25 mm 7.4 40- mm 22 20- mm 67 o+ FECD CECs mm 200 -20-— T T T T T T a * 4 ay A, 0 att ort cart ohh
Slide 31: DT-168 eye-drops were well-tolerated and readily distributed to CECs
DT-168 eye-drops were well-tolerated and readily distributed to CECs Key observations from no: ical studies Well-tolerated after single and multiple doses per day for 14 days with clean histology DT-168 distributed throughout cornea after topical delivery, measurable levels of drug in aqueous humor
Slide 32: FECD Observational Study aims to increase probability of DT-168 success
OBSERVATIONAL STUDY * Targeting recruitment of 200 patients (~400 eyes) with genetically confirmed TCF4 mutations 2-year follow-up * Confirm disease characteristics and deterioration in context of running a trial + Identify characteristics for FECD patients at risk of more rapid disease progression
Slide 33: Myotonic Dystrophy Type 1 (DM1)
Ytonic Dystrophy Type 1 (DM1) DESIGN THERAPEUTICS
Slide 34: Dominant repeat expansion drives DM1 disease
Symptoms intellectual impairment and excessive daytime sleepiness Dominant repeat expansion drive disease DM1 patients have expanded CTG repeat in the 3’ UTR of one copy of their DMPK gene cataracts heart problems DMPK _ CTCCTG.,. e digestive problems causing stomach pain 3’UTR Diseased (one copy) D
Slide 35: GeneTAC molecules for DM1 have several advantages
GeneTAC® molecules for DM1 have several advantages GeneTAC® DM1 candidates AVIDITY AOC 1004 DYNE-101 Non-selective Non-selective Allele selectivity Allele-selective 7 siRNA conjugated to ASO conjugated to TfR1 | Modality Soudhinowete TfR1 targeting mAb targeting Fab Target tissue Dies ibutss widely
Slide 36: DM1 GeneTAC molecule reduces nuclear foci in patient-derived cells
Nuclei DMSO GeneTAC® Molecule Note: Bars represent standard deviation Foci Merge DM1-patient derived cells treated with DM1 GeneTAC® Molecule Average foci per nucleus tol f IC50= ~6 nM 8 6 a 4 t 7 2 t 1 10 100 GeneTAC® Molecule (nM) 36
Slide 37: GeneTAC Molecule leads to robust correction of mis-spliced transcripts
GeneTAC® Molecule leads to robust correction of mis-spliced transcripts in patient-derived cells DM1 patient-derived cells 7d treatment with DM1 Gene TAC® Molecule 1 ee eee ; aaa WT splicing index 0.5: Splicing Index ECgo= ~8nM “0.01 0.4 1 10 100 1000 GeneTAC® molecule (nM) Note: Bars represent stan
Slide 38: Huntington's Disease (HD)
1’s Disease (HD) DESIGN
Slide 39: GeneTAC molecules selectively reduce mutant Huntingtin and spare normal allele
Huntington’s Disease (HD) GeneTAC® molecules selectively reduce mutant Huntingtin and spare the normal Huntingtin allele Normal HTT gene — thought to be important to normal state GeneTAC® molecules preserve transcription at the wild type locus on gays HTT gene with expansion » Causes brain atrophy d
Slide 40: Allele-selective reduction of mtHTT mRNA in HD fibroblasts (Candidate 1)
GeneTAC® Molecule treatment causes potent, allele-selective reduction of mtHTT mRNA in HD patient fibroblasts Candidate 1 Normal onset HD patient-derived fibroblasts Early onset HD patient-derived fibroblasts CAG 18/44 CAG 18/180 150 ° wtHTT os : e mtHTT <t gt? 8 yey Z2 100; ® af “5 3 : ee r 5 ° eo
Slide 41: Allele-selective reduction of mtHTT protein in HD fibroblasts (Candidate 1)
GeneTAC® Molecule treatment causes potent, allele-selective reduction of mtHTT protein in HD patient fibroblasts Candidate 1 Normal onset HD patient-derived fibroblasts Early onset HD patient-derived fibroblasts CAG 18/44 CAG 18/180 Western blot Western blot mM: UIC. Ot 04 25 8 21 mM: UTC 01 04 15 6
Slide 42: Allele-selective reduction of mtHTT mRNA in HD fibroblasts (Candidate 2)
GeneTAC® Molecule treatment causes potent, allele-selective reduction of mtHTT mRNA in HD patient-derived fibroblasts Candidate 2 Normal onset HD patient-derived fibroblasts Early onset HD patient-derived fibroblasts CAG 18/44 CAG 18/180 150 = wtHTT = mt HTT 2 3 a ao 100) 7 i! Ze aa "a eS aa = re fa
Slide 43: Allele-selective reduction of mtHTT protein in HD fibroblasts (Candidate 2)
GeneTAC® Molecule treatment causes potent, allele-selective reduction of mtHTT protein in HD patient-derived fibroblasts Candidate 2 Normal onset HD patient-derived fibroblasts Early onset HD patient-derived fibroblasts CAG 18/44 CAG 18/180 Western blot Western blot nM UTC 01 04 15 6 21 72 nM: UTC 0
Slide 44: Candidates well-tolerated in both rodents and NHPs
Candidates well-tolerated in both rodents and NHPs Rodents NHP Tested in wild-type rats and mice: » Well-tolerated in ongoing studies: - Weekly doses for three weeks in rats - Daily doses for one week in mice * Tolerability assessed across all macroscopic measures including weight, blood chemistry a
Slide 45: Allele-specific reductions of RNA and protein in brain of HD mouse model
Allele-specific reductions of RNA and protein observed in the brain in zQ175DN HD mouse model after 8 weeks of systemic administration HTT RNA level in striatum HTT protein level in striatum mm Total HTT mm mt HTT mm wt HTT mm mt HTT on So HTT mRNA Percentage change to untreated i—} & So a So So Veh
Slide 46: GeneTAC HD candidates have significant advantages over other HTT lowering approaches
GeneTAC® HD candidates have significant advantages over other HTT lowering therapeutic approaches Allele-selective Non-selective Reduce both normal and Reduce mutant Huntingtin and spare the normal Huntingtin mutant Huntingtin GeneTAC® HD candidates WWE WVE-003 . - Small molecule uniQure Modality Fa
Slide 47: Strong financial position to enable programs and platform
Strong financial position to enable programs and platform PLATFORM » Proprietary GeneTAC® platform designed to generate blockbuster products with first/best-in-class profiles for severe monogenic disorders PROGRAMS. * Two clinical-stage programs in 2025 — FA and FECD * Active research pipeline led b
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