Dyne Therapeutics, Inc. · NASDAQ:DYN
Dyne Therapeutics — American Society of Gene & Cell Therapy 2022
15 slides from Dyne Therapeutics's conference presentation, May 16, 2022
Slide 1: Repeat dosing with DYNE-101 is well tolerated and leads to sustained reduction of DMPK RNA expression
Repeat dosing with DYNE-101 is well tolerated and leads to a sustained reduction of DMPK RNA expression in key muscles for DM1 pathology in hTfR1/DMSXL mice and NHPs Stefano Zanotti, Ph.D. Joachim, living with DM1 American Society of Gene & Cell Therapy | 16 May 2022
Slide 2: Forward-looking statements
Forward-looking statements This presentation contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, including statements regarding Dyne’s strategy, future operations, prospects a
Slide 3: Dyne FORCE platform: Modern oligo therapeutics for muscle diseases
Dyne FORCETM platform: Modern oligo therapeutics for muscle diseases ANTIBODY Proprietary Fab targets TfR1 to enable muscle delivery PAYLOAD Modularity enables rational selection of payload to target the genetic basis of disease ASO siRNA LINKER Nuclear Cytoplasmic Clinically validated, enables loca
Slide 4: FORCE targets the genetic basis of DM1 to correct splicing
FORCE targets the genetic basis of DM1 to correct splicing DNA Triplet Toxic RNA RNA Binds Clinical Repeats Forms Foci Splicing Proteins Presentation Cytoplasm 449bp 479bp DMWD DMPK SIX5 Toxic DMPK mRNA MBNL Sequestered • Myotonia proteins Sequestered MBNL Toxic RNA is unable • Muscle weakness to le
Slide 5: hTfR1/DMSXL: Innovative model developed by Dyne to evaluate PD
hTfR1/DMSXL: Innovative model developed by Dyne to evaluate PD by measuring toxic human nuclear DMPK KD Fully human FORCE conjugate Uptakes human TfR1 Expresses human toxic (DYNE-101) targeting Fabs DMPK mDMPK ASO 1,000+ CUG hTfR1 repeats ASO hDMPK hTfR1 DMSXL Nucleus mDMPK Cytoplasm • Expresses hum
Slide 6: Toxic human DMPK is trapped in nuclei in hTfR1/DMSXL mice
Toxic human DMPK is trapped in nuclei in hTfR1/DMSXL mice Human mutant DMPK Malat1 Gapdh enrichment in the nucleus nuclear control cytoplasmic control DYNE-101 Mouse DMPK ASO 1,000+ CUG repeats hTfR1 Human DMPK ASO Nucleus Mouse DMPK Cytoplasm Note: fractions from gastrocnemius of vehicle-treated hT
Slide 7: DYNE-101 achieved robust toxic human DMPK KD in nuclei of hTfR1/DMSXL mice
DYNE-101 achieved robust toxic human DMPK KD in nuclei of hTfR1/DMSXL mice PBS DYNE-101 Note: hTfR1/DMSXL hemizygous mice. 10 mg/kg IV dose on d0, samples from gastrocnemius analyzed d28; Data are means ±SD; n = 2 7
Slide 8: DYNE-101 demonstrated DMPK KD, foci reduction, and splicing correction in heart
DYNE-101 demonstrated significant toxic human DMPK KD, foci reduction, and splicing correction in heart of hTfR1/DMSXL mice 0 1 2 3 4 Weeks IV dose 10 mg/kg Toxic human DMPK Toxic human DMPK foci reduction Splicing correction expression (%KD) DMPK Foci Nuclei Myofibers hTfR1 - PBS PBS DYNE-101 hTfR1
Slide 9: DYNE-101 demonstrated toxic human DMPK KD and splicing correction in skeletal muscle
DYNE-101 demonstrated toxic human DMPK KD and splicing correction in skeletal muscle of hTfR1/DMSXL mice Diaphragm Tibialis anterior Gastrocnemius Toxic human DMPK expression (% KD) hTfR1/DMSXL - PBS hTfR1/DMSXL – DYNE-101 Splicing correction hTfR1 - PBS hTfR1/DMSXL - PBS hTfR1/DMSXL – DYNE-101 Note
Slide 10: Low monthly dosing of DYNE-101 enhanced toxic human DMPK KD in cardiac and skeletal muscle
Low monthly dosing of DYNE-101 in hTfR1/DMSXL mice enhanced toxic human DMPK KD in cardiac and skeletal muscle 0 1 2 3 4 Months IV dose 5 mg/kg Single Dose (SD) 5 mg/kg Repeat Dose (RD) Toxic human DMPK expression (% KD) Heart Diaphragm Gastrocnemius Tibialis anterior Note: hTfR1/DMSXL hemizygous mi
Slide 11: DYNE-101 repeat monthly dosing in NHPs enhanced DMPK KD in skeletal muscle
DYNE-101 repeat monthly dosing in NHPs enhanced DMPK KD in skeletal muscle 0 1 2 Months IV dose 10 mg/kg Single dose (SD) 10 mg/kg Repeat dose (RD) WT DMPK expression (% KD) Gastrocnemius Tibialis anterior Note: Male cynomolgus monkeys. Data are means ± SD; n = 3 - 4 per arm; **p< 0.01 significant b
Slide 12: Repeat monthly dosing of DYNE-101 in NHPs achieved significant WT DMPK KD
Repeat monthly dosing of DYNE-101 in NHPs achieved significant WT DMPK KD demonstrating translatability to higher species 0 1 2 Months IV dose 10 mg/kg WT DMPK expression (% KD) Heart Diaphragm Gastrocnemius Tibialis anterior Masseter Esophagus Duodenum Note: Male cynomolgus monkeys. Data are means
Slide 13: DYNE-101 was well-tolerated in an NHP 13-week GLP toxicology study
DYNE-101 was well-tolerated in an NHP 13-week GLP toxicology study1 • No dose limiting toxicity observed up to a maximally feasible dose2 • No changes in cardiac, respiratory, neurologic, or ophthalmic endpoints • No effect on kidney function • No effect on liver function • No effect on coagulation
Slide 14: Conclusions
Conclusions • DYNE-101 demonstrated ability to target toxic human DMPK RNA in the nucleus, reduce DMPK foci, and correct splicing in the hTfR1/DMSXL mouse model of DM1 • DYNE-101 monthly dosing in hTfR1/DMSXL mice and NHPs achieved significant DMPK RNA KD in different muscle types affected by DM1 pa
Slide 15: Acknowledgements
Acknowledgements Dyne Research Dyne CMC Collaborators ▪ Tyler Picariello ▪ Scott Hildebrand ▪ Genevieve Gourdon ▪ Jin Cui ▪ John Najim Institute de Myologie ▪ Ryan Russo Paris, France ▪ Lydia Schlaefke ▪ Ann Chang ▪ John Harrell ▪ Qifeng Qiu ▪ Pei-Yi Shen ▪ Sean Spring ▪ Timothy Weeden ▪ John Davis
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