Design Therapeutics, Inc. · NASDAQ:DSGN
Design Therapeutics — Q3 2025 Earnings Presentation
42 slides from Design Therapeutics's earnings presentation, Aug 7, 2025
Slide 1: Designing a Novel Class of Genomic Medicines for Genetic Disorders
7SOSC— DESIGNING A NOVEL CLASS OF GENOMIC MEDICINES FOR GENETIC DISORDERS 3Q2025
Slide 2: Disclaimers
Disclaimers This presentation contains forward-ooking 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: Changing the status quo of genomic medicines with GeneTAC molecules
jing the status quo of genomic medicines with ll 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
Slide 4: Advancing four GeneTAC molecule programs
Advancing four GeneTAC® molecule programs Differentiated profile Status Significant market FRATAXIN (FXN) TCF4 DMPK HUNTINGTIN (HTT) GAA repeat expansion leads to reduced transcription CTG repeat expansion causes corneal endothelial cell dysfunction CTG repeat expansion causes nuclear foci & cellula
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 delivery natural genome Gene editing/ $130-460M1 gene therapy Oligo ; $50-150M" nucleotide GeneTAC® $60 - 80M? platform 1. Estimates derived from analysis of R&D spend of select peers in
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 a 6,000- 50,000- 4,000,000- (Datton) © 1,000-3000 O 15,000 100,000 O 5,000,000 Broad distribution LIMITED LIMITED i LI
Slide 7: Differentiated mode of action of GeneTAC molecules
OO Ligand | inker DNA-targeting moiety moiety 7 TRANSCRIPTIO FACTOR NUCLEOSOME Differentiated mode of action of GeneTAC® molecules DIAL UP EXPRESSION Recruited complex Designed to facilitate transcription through the locus DIAL DOWN EXPRESSION Recruited complex Cu negli ciao cTG —e Designed to block
Slide 8: Friedreich Ataxia
for Friedreich Ataxia DESIGN
Slide 9: FA: Debilitating disease with limited treatment options today
FA: Debilitating disease with limited treatment options today , FXN Monogenic an disease caused by GAA-repeat expansion in 1st intron of frataxin ZOE on (FXN) gene Protein Mutation leads to reduced FXN transcription, S which is Mitochondrial necessary for Function mitochondrial and cellular function
Slide 10: Therapeutic goal: increase FXN
Therapeutic goal: increase FXN FA patients, carriers and controls have different average FXN protein levels Carriers are free of FA symptoms ~2X increase of FXN protein could potentially bring patients’ levels into asymptomatic carrier range FXN prote lymphoblastoid cells p< 0.0001 4 — p= 0.003 — <q
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) ~300 to >1,000 REPEATS} Expression Reduced gi cAAGAACAAGAAGAAGAAGIMIERECAR. FRATAXIN H INTRON 1 | HEALTHY INDIVIDUAL (two normal copies) Normal FRATAXIN INTR
Slide 12: 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 mm Vehicle 25. mm 100M WT neuron FXN protein levels mm 100nM 15: 10: 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 t
Slide 13: 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 14: Prior DT-216 MAD study showed FXN expression dialed up
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 Individual FA Patients 1254 s Lower quartile in healthy Carrierst 25% C
Slide 15: DT216P2 generally well-tolerated with improved exposure over prior formulation
DT216P2 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) = 1000 . < —t- DT-216P1 intravenous (50mg) © y 100- E a © 10-5 = o & oa 17 01-7 T T T T T T 1 0 24 48
Slide 16: Observed human plasma PK profile of DT-216P2 consistent with NHPs
Observed human plasma PK profile of DT-216P2 consistent with NHPs Human/NHP PK Intravenous 4H Human subcutaneous (P2) 4@ NHP subcutaneous (P2) 10000. 10000- 4 Human intravenous (P2) = 4@ NHP intravenous (P2) = = 1000 = 10004 o o 5 5 5 100 5 1005 i oC € € 8 & | = 10 z= 10 14 T T T T T T 1 1 T 0 24 #4
Slide 17: DT-216P2 clinical plan
DT-216P2 clinical plan Single Ascending Dose study in healthy volunteers A + Escalate single doses + Evaluate route of administration Cohort 1-IV_ § Cohort 1 - SC + Evaluate PK, tolerability in healthy volunteers after a single dose + Evaluate both IV (infusion) and SC (injection and infusion) admin
Slide 18: Unmet need in FA remains significant
Unmet need in FA remains significant S 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 -@- Omaveloxoione Basel
Slide 19: 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 a 3 50: Percent of Healthy Control FXN mRNA(%) a 4 2 0 2 4 6 Log Concentration (uM) g 2 £ s 3 & 5 2 2 > £ s 2 Ey z Fe z “© FAGeneTAC® Mo
Slide 20: Fuchs Endothelial Corneal Dystrophy
, uchs Endothelial Corneal DESIGN
Slide 21: FECD is a progressive corneal disease caused by a single gene mutation
mutation in a majority of cases FECD is a progressive corneal disease caused by a single gene Increasing Endothelial Cell Dysfunction — Loss of cells, pump function, corneal edema Diagnosed by community optometrist ~2M diagnosed patients (U.S.)' quality Most cases are caused by a CTG repeat expansio
Slide 22: 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 6 or 14 days DT-168 Foci Merge Foci per nucleus Percent of untreated © 6d ee 14d \ 1C50 ~24nM o1 14 10 100 1000 I 2 « c 8 as Cells taken from discarded
Slide 23: 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 Patient-derived FECD CECs + DT-168 Percent of untreated 6d treatment; percent spliced Cells taken from discarded FECD corneal endothelium used to evaluate efficacy
Slide 24: DT-168 Phase 1 SAD/MAD First-In-Human Study in Healthy Participants
DT-168 Phase 1 SAD/MAD First-In-Human Study in Healthy Participants to Assess the Safety, Tolerability, and Systemic PK of DT-168 Twenty-four (24) healthy participants received single and multiple dose administration of DT-168 eye drops (or placebo) twice daily for seven days in three ascending dose
Slide 25: Phase 1 study data takeaways
Phase 1 study data takeaways ee - 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 events were non-ocular and were considered not related to drug produc
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 for
Slide 27: DT-168 Phase 2 Biomarker Study with Data in 2026
DT-168 Phase 2 Biomarker Study with Data in 2026 Objectives: Safety and tolerability; corneal endothelial biomarkers a TCF4+ FECD patients 5 FECD cornealendothelium oo auied ier ona Ea Unaffected corneal endothelium Corneal Corneal endothelium E> endothelium Tissues removed during Tissue from cornea
Slide 28: FECD Observational Study aims to increase probability of DT-168 success
FECD Observational Study aims to increase probability of DT-168 programmatic success OBSERVATIONAL STUDY + Recruited and completed baseline assessments on ~250 patients + Based on the baseline data, ~100 patients chosen for future follow-up visits characteristics and evaluate deterioration in contex
Slide 29: Myotonic Dystrophy Type 1 (DM1)
c Dystrophy Type 1 (DM1) DESIGN THERAPEUTICS
Slide 30: Dominant repeat expansion drives disease
Dominant repeat expansion drive disease DM1 patients have expanded CTG repeat in the 3’ UTR of one copy of their DMPK gene 50 repea DMPK CCC. 3’ UTR Diseased (one copy) 10 to 1000+ repeal DMPK TOXIC GAIN OF FUNCTION CTGCTGCTGCTGCTGCTGCTGCT... I 3’ UTR Symptoms intellectual impairment and excessive d
Slide 31: 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 . siRNA conjugated to ASO conjugated to TfR1 | Modality Small molecule TfR1 targeting mAb targeting Fab Target tissue Distributes widel
Slide 32: DM1 GeneTAC molecule reduced 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 cr f IC50= ~6 nM 8 6 + 4 i + 2 i 1 10 100 GeneTAC® Molecule (nM) 32
Slide 33: Correction of mis-spliced transcripts in patient-derived cells
mis-spliced transcripts in patient-derived cells DM1 patient-derived cells 7d treatment with DM1 Gene TAC® molecule ee ; ne WT splicing index 0.54 Splicing Index ECgo= ~8nM 0.0 . + 7 . ; 1 0.01 0.1 1 10 100 1000 GeneTAC® molecule (nM) GeneTAC® molecule led to robust correction of Note: Bars represen
Slide 34: Huntington's Disease (HD)
ton’s Disease (HD) DESIGN
Slide 35: Huntington's Disease (HD)
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 > wHTT FL
Slide 36: Allele-selective reduction of mtHTT mRNA in HD fibroblasts (Candidate 1)
GeneTAC® molecule observed to cause 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 e@ wtHTT e@ mtHTT 150 e wtHTT e@ mtHTT petaegt HTT mRNA 50 "bee, 50 P
Slide 37: Allele-selective reduction of mtHTT protein in HD fibroblasts (Candidate 1)
GeneTAC® molecule observed to cause potent, allele-selective reduction of mtHTT protein in HD patient fibroblasts Candidate 1 Normal onset HD patient-derived fibroblasts CAG 18/44 Western blot nM: MW ture DIF Total art Vinculin UTC 01 04 15 6 21 72 E 7 ahs ee ee Note: Cells were treated for 7 days T
Slide 38: Allele-selective reduction of mtHTT mRNA in HD fibroblasts (Candidate 2)
GeneTAC® molecule observed to cause 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 = mtHTT 3 3 a a © 100 i! Ze ia "a @S a ES fae é S
Slide 39: Allele-selective reduction of mtHTT protein in HD fibroblasts (Candidate 2)
GeneTAC® molecule observed to cause 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 mM UIC 01 04 nM: UTC 01 04 15 6
Slide 40: 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 wt HTT mm Total HTT mE mt HTT mm mt HTT 505 a o n HTT mRNA Percentage change to untreated HTT protein (per
Slide 41: GeneTAC HD candidates have significant advantages over other HTT lowering approaches
lowering therapeutic approaches Non-selective Allele-selective Reduce mutant Huntingtin and spare the normal Huntingtin (eclnes (nein mstarrel etre mutant Huntingtin GeneTAC® HD candidates WWE WVE-003 uniQure AMT-130 Small molecule Facilitate drug biodistribution to the whole brain Modality Parenter
Slide 42: Proprietary GeneTAC platform designed to generate blockbuster products
° Proprietary Gene TAC® platform designed to generate blockbuster products with first/best-in-class profiles for severe monogenic disorders * Two clinical-stage programs in FA and FECD with data in 2026 o DT-216 restores endogenous frataxin with broad tissue distribution o DT-168 eye drop targeting