Design Therapeutics, Inc. · NASDAQ:DSGN

Design Therapeutics — Corporate Update (April 2026)

44 slides from Design Therapeutics's corporate update, Apr 28, 2026

Slide 1: Designing a novel class of genomic medicines for genetic disorders
2Q2026 DES GIN THERAPEUTICS DESIGNING A NOVEL CLASS OF GENOMIC MEDICINES FOR GENETIC DISORDERS
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 no
Slide 3: Changing the status quo of genomic medicines with GeneTAC molecules
ng the status quo of genomic medicines with molecules (GeneTAC® molecules) that ial 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 THERAPEUTICS
Slide 4: Advancing four GeneTAC molecule programs
Advancing four GeneTAC® molecule programs CLINICAL a = S = — s) w rg a Friedreich Ataxia Huntington’s Disease Gene FRATAXIN (FXN) TCF4 DMPK HUNTINGTIN (HTT) Monogenic disease GAA repeat expansion leads to reduced transcription CTG repeat expansion causes corneal endothelial cell dysfunction CTG repe
Slide 5: 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 6,000- 50,000- 4,000,000- (Dalton) © 1,000-3000 15,000 100,000 O 5,000,000 Broad distribution LIMITED LIMITED K LIMIT
Slide 7: FA: Debilitating disease with limited treatment options today
FA: Debilitating disease with limited treatment options today Monogenic disease caused by GAA- repeat expansion in 1st intron of frataxin (FXN) gene Mutation leads to reduced FXN transcription, which is necessary for mitochondrial and cellular function Unmet need in FA remains significant ® Biogen F
Slide 8: 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 Therapeutic goal: increase FXN Ligand Linker DNA-targeting moiety moiety TRANSCRIPTION FACTOR & yy “> NUCLEOSOME FA patients, carriers and controls have different average FXN levels Carriers
Slide 9: Low concentrations of DT-216 restored endogenous FXN levels in iPS-neurons
Low concentrations of DT-216 molecule restored endogenous FXN levels in FA patient iPS-neurons FXN mRNA FXN Protein @™ Vehicle 7 95. mm 10nM WT neuron FXN protein levels mm 100nM FXN mRNA (fold change relative to DMSO) FXN protein (pg/ug protein) 3 7 10 14 3 7 10 14 Days of treatment Days of treatme
Slide 10: Prior DT-216 Phase 1 MAD study revealed transient plasma PK and tissue distribution
Prior DT-216 drug product Phase 1 MAD study revealed plasma PK and tissue distribution were 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 11: 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 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 Muscle FXN mRNA (mean % change from baseline) ° n p< 0.05% 407 NS 204 -
Slide 12: DT-216P2 well-tolerated with improved exposure over prior formulation
DT-216P2 generally well-tolerated and has exhibited improved exposure over the prior formulation (DT-216P1) at comparable doses 10000 -—@® DT-216P2 intravenous (~40mg) -&- = DT-216P2 subcutaneous (~50mg) —t- DT-216P1 intravenous (50mg) 1000 = So —) i Plasma DT-216 (nM) r=) l = 1 0.17 T T T T T T 1 0
Slide 13: RESTORE-FA
RESTORE-FA Single Ascending Dose Multiple Ascending Dose study in healthy volunteers study in FA patients Additional IV cohorts + Evaluate route of _ . doses administration in FA patients to be determined Cohort 1 - IV Cohort 1 - SC FA MAD cohorts * Evaluate PK, tolerability in healthy volunteers af
Slide 14: RESTORE-FA MAD dosing and biomarker endpoints
Weekly Dosing duration IV infusion (target cohort size 2 4) weeks 12 weeks Biomarker endpoints SC infusion Endogenous FXN biomarkers Exploratory clinical endpoints 1. Whole blood mRNA and protein 2. Muscle biopsy mRNA and protein 1. mFARS? 2. Upright Stability Score (USS) 3. PROMIS Fatigue Scale 4.
Slide 15: RESTORE FA results intended to support clinical POC and inform probability of approval
RESTORE FA results intended to support clinical POC and inform probability of future approval Potential approval frameworks based on Accelerated Traditional Initial approval based on surrogate marker reasonably likely to predict clinical benefit Followed by clinical confirmatory study Approval based
Slide 16: Pathogenic Cascade in Friedreich Ataxia and Clinical Biomarker Strategy
Pathogenic Cascade in Friedreich Ataxia and Clinical Biomarker Friedreich Ataxia Healthy Strategy [oN EXON eee e [Intro G-8 © Fxn pna oe Mn \ TRANSCRIPTION mm /, TRANSCRIPTION (GAA) ~300/1000+ (GAA) <34 ge since ° oeee vwetatarata, SPLICING FXN mRNA Same endogenous spliced __ _ Measured i in ° mRNA
Slide 17: Biomarker overview
Biomarker overview Patients and Natural Endogenous FXN biomarkers reasonably i : . . . Variability! healthy carrier likely to predict clinical benefit history overlap? Protein Extensive Low Moderate WHOLE @) BIOOP (2) mRNA Limited Low Least overlap MUSCLE (3) mRNA None Medium Minimal BIOPSY (4) Prot
Slide 18: Therapeutic level, readout questions and biomarker data
Therapeutic level Readout questions Biomarker data Does DT216P2 increase Any significant increase EXN mRNA? ya or x (either blood or muscle) Natural history: “FRATAXIN LEVELS directly correlate , Does DT-216P2 increase with al! major clinical outcomes in FA [patients] ... such as age FXN protein? of
Slide 19: Observations in mFARS across FA landscape
Observations in mFARS across FA landscape (modified Friedreich Ataxia Rating Scale) * The mFARS is a clinician-administered tool to measure neurologic dysfunction and disease progression in FA * Omaveloxolone (SKYCLARYS™) pivotal trial (MOXIE study) used mFARS as the primary endpoint * Omaveloxolone
Slide 20: What is PROMIS Fatigue Scale?
What is PROMIS Fatigue Scale? The PROMIS Fatigue Scale assesses a range of self-reported symptoms, from mild feelings of tiredness to debilitating exhaustion that likely decreases one’s ability to execute daily activities and function normally in family or social roles * Scale is an 8-item, patient-
Slide 22: FECD is a progressive corneal disease caused by a single gene mutation
FECD is a progressive corneal disease caused by a single gene mutation in a majority of cases Increasing Endothelial Cell Dysfunction — Loss of cells, pump function, corneal edema Diagnosed by community optometrist Loss of visual Patient can’t Corneal transplant quality stand symptoms surgery ~2M di
Slide 23: DT-168 reduction of nuclear foci in primary CECs from FECD patients
DT-168 reduction of nuclear foci observed in primary CECs isolated from patients with FECD with high potency (<5nM foci IC50) CECs treated daily for Nuclei Foci Merge 6 or 14 days with DT-168 Cells taken from w 7 discarded FECD Foci per nucleus corneal endothelium Percent of untreated used to evalua
Slide 24: DT-168 left wild-type TCF4 transcripts unaffected while improving spliceopathy
Treatment with DT-168 left wild-type TCF4 transcripts unaffected in primary control and FECD CECs while improving spliceopathy TCF4 mRNA Percent of untreated @™ Healthy CECs donor 1 tI FECD CECs donor 2 0 2 7 2267200 0 2 7 2267200 DT-168 (nM) Patient-derived FECD CECs + DT-168 6d treatment; percent
Slide 25: DT-168 Phase 1 SAD/MAD study in healthy participants
DT-168 Phase 1 SAD/MAD study in healthy participants assessed safety, tolerability, and systemic PK ¢ DT-168 eye drops were well-tolerated in all subjects ¢ There were no serious adverse events, no ocular adverse events, or participant discontinuations due to adverse events! « All observed adverse e
Slide 26: Splicing biomarker is measurable in surgically removed corneal endothelial cells
Splicing biomarker is measurable in surgically removed corneal endothelial cells « Design conducted reference range studies showing consistently different splicing between unaffected eyes and mutant TCF4 FECD surgical samples « Design has developed RNA biomarker measurements potentially suitable we
Slide 27: DT-168 Phase 2 biomarker study with data in 2H 2026
DT-168 Phase 2 biomarker study with data in 2H 2026 Objectives: Safety and tolerability; corneal endothelial biomarkers : TCF4+ FECD patients F FECD corneal endothelium scheduled for surgery Unaffected corneal endothelium Corneal — , Corneal endothelium ee endothelium Tissues removed during Tissue f
Slide 29: DT-818 summary
DT-818 summary * DT-818 nominated as development + Begin dosing DM1 patients in a Phase 1 MAD candidate for the treatment of DM1 with trial of DT-818 in Australia in 1H 2026 potential best-in-disease profile; designed to + Injectable (initially once weekly IV, selectively target mutant DMPK explorin
Slide 30: Mechanism of disease and preclinical models in DM1
@ Mechanism of disease e@ Preclinical human cells Longer DMPK CTG repeats in affected tissues cause disease Myoblasts Myocytes = Myotubes DM1 patient myotube model CTG repeat number Foci = mutant Ep. ad . DMPK RNA Sequestered MBNL protein + Similar spliceopathy and repeat length as affected muscle +
Slide 31: DM1 clinical stage programs
DM1 clinical stage programs Approach’ Stage of development Distribution Preclinical human myotube foci Preclinical animal model Note: Patient cell data refers a DM1 patient cell line containing ~2600 repeats; Source: 1. Company materials, INN structures where available, Anand P, et, al, Metabolic St
Slide 32: Designing a better DM1 approach
Designing a better DM1 approach Design hypothesis We believe reduction of toxic foci in human myotubes is a better predictor of clinical splicing biomarker observations — Animal preclinical models (e.g. HSA-LR or wild- type NHPs) are supportive but have not been predictive of clinical splicing resul
Slide 33: DT-818 reduces toxic foci and corrects splicing regardless of repeat length
splicing, regardless of repeat length or patient genetics DT-818 reduces toxic RNA DT-818 corrects splicing in DM1 nuclear foci in DM1 myotubes myotubes Foci per nucleus Splice index Percent change relative to untreated (FISH) Index relative to healthy control myotubes 1.2: Healthy control 0.8: ¢. D
Slide 34: DT-818 reduces toxic RNA foci and liberates MBNL1 protein
DT-818 treatment reduces toxic RNA foci and liberates MBNL1 protein in DM1 patient myotubes Nuclei MBNL41 Foci
Slide 35: DT-818 shows best-in-disease potential for foci reduction
DT-818 treatment shows best-in-disease potential for foci reduction in patient cell line with 2,600 repeats 9 AVIDITY Estimated"t ~55% 5 4 3 2 Foci per nucleus (mean) 1 0. Mock siDMPK VDyne Estimated’? ~30% Foci Area/Nuclear Area % & 45 150 500 FORCE (nM ASO) bd PepGen’ 54% foci reduction? 54% reduc
Slide 36: DT-818 selectively targets mutant DMPK
DT-818 selectively targets mutant DMPK Allele-specific mechanism spares DMPK protein DM1 patients have two DMPK alleles Mutant allele Healthy allele ¥ ¥ CTG expansion No CTG expansion ¥ ¥ RNA retained in RNA exported to nucleus, forms foci cytoplasm No protein (RNA RNA translated trapped in nucleus)
Slide 37: Splicing and myotonia improved in HSA-LR mice treated with DT-818
Splicing and myotonia improved in actin repeat (HSA“®) mice treated with DT-818 Vehicle Myotonia Foci ‘Copyright © 2026 by Design Therepeutics, Inc. Allrights reserved. 37.
Slide 38: DT-818 shows good exposure and long half-life
DT-818 shows good exposure and long half-life Single IV dose nM DT-818 in plasma 100000 —® Higher dose 10000 Lower dose 1000 100 10 144 T T T T T T 1 0 24 48 72 96 120 144 168 Time (hr) ‘Copyright © 2026 by Design Therepeutics, Inc.All rights reserved. 38
Slide 39: DT-818 summary and next steps
DT-818 summary and next steps * DT-818 nominated as development + Begin dosing DM1 patients in a Phase 1 MAD candidate for the treatment of DM1 with trial of DT-818 in Australia in 1H 2026 potential best-in-disease profile; designed to + Injectable (initially once weekly IV, selectively target mutan
Slide 41: 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 * Causes brain atrophy due to death of neurons wtHTT [iy
Slide 42: Allele-specific reductions of RNA and protein in zQ175DN HD mouse brain
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 me wt HTT mm Total HTT mm mt HTT me mt HTT 3 507 os 507 2 2 oO oO g g e ec <s ott ez ot LI 25 c+ 20 Lot ["ano
Slide 43: GeneTAC HD candidates have advantages over other HTT lowering approaches
GeneTAC® HD candidates have significant advantages over other HTT lowering therapeutic approaches Allele-selective Non-selective Reduce mutant Huntingtin and spare the normal Huntingtin Reduce both normal and mutant Huntingtin GeneTAC® HD candidates WAVE WVE-003 LIFE scl | Small molecule uniQure Mod
Slide 44: 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 * Three clinical-stage programs (FA, FECD, and DM’1) in 2026 o DT-216 restores endogenous frat

Design Therapeutics — Corporate Update (April 2026) on 6ix

Design Therapeutics — Corporate Update (April 2026)

Slide 1: Designing a novel class of genomic medicines for genetic disorders

Slide 2: Disclaimers

Slide 3: Changing the status quo of genomic medicines with GeneTAC molecules

Slide 4: Advancing four GeneTAC molecule programs

Slide 5: GeneTAC molecules can distribute widely, overcoming a central challenge

Slide 6: Friedreich Ataxia

Slide 7: FA: Debilitating disease with limited treatment options today

Slide 8: FA GeneTAC molecules normalized FXN levels in FA patient cells

Slide 9: Low concentrations of DT-216 restored endogenous FXN levels in iPS-neurons

Slide 10: Prior DT-216 Phase 1 MAD study revealed transient plasma PK and tissue distribution

Slide 11: Prior DT-216 MAD study showed FXN expression dialed up with drug exposure

Slide 12: DT-216P2 well-tolerated with improved exposure over prior formulation

Slide 13: RESTORE-FA

Slide 14: RESTORE-FA MAD dosing and biomarker endpoints

Slide 15: RESTORE FA results intended to support clinical POC and inform probability of approval

Slide 16: Pathogenic Cascade in Friedreich Ataxia and Clinical Biomarker Strategy

Slide 17: Biomarker overview

Slide 18: Therapeutic level, readout questions and biomarker data

Slide 19: Observations in mFARS across FA landscape

Slide 20: What is PROMIS Fatigue Scale?

Slide 21: Fuchs Endothelial Corneal Dystrophy

Slide 22: FECD is a progressive corneal disease caused by a single gene mutation

Slide 23: DT-168 reduction of nuclear foci in primary CECs from FECD patients

Slide 24: DT-168 left wild-type TCF4 transcripts unaffected while improving spliceopathy

Slide 25: DT-168 Phase 1 SAD/MAD study in healthy participants

Slide 26: Splicing biomarker is measurable in surgically removed corneal endothelial cells

Slide 27: DT-168 Phase 2 biomarker study with data in 2H 2026

Slide 28: Myotonic Dystrophy Type 1 (DM1)

Slide 29: DT-818 summary

Slide 30: Mechanism of disease and preclinical models in DM1

Slide 31: DM1 clinical stage programs

Slide 32: Designing a better DM1 approach

Slide 33: DT-818 reduces toxic foci and corrects splicing regardless of repeat length

Slide 34: DT-818 reduces toxic RNA foci and liberates MBNL1 protein

Slide 35: DT-818 shows best-in-disease potential for foci reduction

Slide 36: DT-818 selectively targets mutant DMPK

Slide 37: Splicing and myotonia improved in HSA-LR mice treated with DT-818

Slide 38: DT-818 shows good exposure and long half-life

Slide 39: DT-818 summary and next steps

Slide 40: Huntington's Disease (HD)

Slide 41: GeneTAC molecules selectively reduce mutant Huntingtin and spare normal allele

Slide 42: Allele-specific reductions of RNA and protein in zQ175DN HD mouse brain

Slide 43: GeneTAC HD candidates have advantages over other HTT lowering approaches

Slide 44: Strong financial position to enable programs and platform