Praxis Precision Medicines, Inc. · NASDAQ:PRAX
Praxis Precision Medicines — Technical Presentation (December 2023)
19 slides from Praxis Precision Medicines's technical presentation, December 2023
Slide 1: Progress Toward the Discovery of an ASO for Therapeutic Upregulation of SYNGAP1
Progress Toward the Discovery of an ASO for Therapeutic Upregulation of SYNGAP1 Kris Kahlig, Ph.D. VP of Biology, Praxis Precision Medicines Steven Petrou, Ph.D. CSO, Praxis Precision Medicines The Florey Institute of Neuroscience and Mental Health Kris Kahlig and Steven Petrou are current employees
Slide 2: Forward-looking statements
SYNGAP1 Background Forward-looking statements This presentation may contain “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 relating to our business and operations, including but not limited to express or implied statements regarding the curren
Slide 3: Our mission at Praxis
Our mission at Praxis To help patients by delivering life-altering treatments faster and more effectively than has ever been done before — and to do it again and again. 3
Slide 4: Leveraging genetics to efficiently translate insights into therapies
Leveraging genetics to efficiently translate insights into therapies TRANSLATIONAL EFFICIENT & GENETICS TOOLS RIGOROUS Focus on therapeutic Translational tools validate Efficient, rigorous clinical targets identified through potential of target and development paths to proof- human genetics product
Slide 5: Targeting epilepsies & movement disorders connected by neuronal imbalance
Targeting epilepsies & movement disorders connected by neuronal imbalance REGISTRATION PLATFORM PRECLINICAL PHASE ONE PHASE TWO ENABLING PRAX-020* Ulixacaltamide CEREBRUM™ KCNT1 Essential Tremor SMALL MOLECULE PLATFORM PRAX-050 PRAX-628 Undisclosed Focal Epilepsy PRAX-562 DEEs PRAX-090+ SOLIDUS™ SYN
Slide 6: SYNGAP1 ASO Background
SYNGAP1 ASO Background Genetics SYNGAP1 loss-of-function US Diagnosed Approximately 2000 patients1,2 Prevalence PRAX-090 ASO Intellectual disability Symptoms Early onset, refractory seizures Behavioral deficits No therapies approved Treatment Refractory to symptomatic agents SYNGAP1 (PRAX-090) ASO i
Slide 7: Pathway from ASO Discovery to Approval
Pathway from ASO Discovery to Approval EARLY PRECLINICAL DISCOVERY CLINICAL STUDIES APPROVAL STUDIES • Program to discover an ASO to therapeutically upregulate SYNGAP1 mRNA and protein PPRAX-222 PRAX-090 • An antisense oligonucleotide • Potential • ASO tocandidates be the first disease-modifying hav
Slide 8: From Early Discovery to Efficacy Studies: Critical Steps for ASO Discovery
From Early Discovery to Efficacy Studies: Critical Steps for ASO Discovery Simple Cells ARPE19 Cells iPSC-derived Isolated Neurons Complex Cells iPSC-derived Neuronal Organoids SYNGAP1 Mouse Humanized Target Animals SYNGAP1 Mouse Disease Model 8
Slide 9: Recent Progress
Recent Progress 9
Slide 10: Upregulation of SYNGAP1 mRNA in Cultured ARPE19 Neurons
Upregulation of SYNGAP1 mRNA in Cultured ARPE19 Neurons Region A Region B 400 400 350 350 SYNGAP1 mRNA 300 SYNGAP1 mRNA 300 (% Vehicle) 250 (% Vehicle) 250 200 200 150 150 100 100 50 50 0 0 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81
Slide 11: Development of Patient iPSC-derived Neurons and CRISPR corrected Isogenic Controls
Development of Patient iPSC-derived Neurons and CRISPR corrected Isogenic Controls NGN2 Differentiation Protocol1 Ctrl (n=15) Replate Virus Puromycin Neuron RNA Sample DOX Patch Clamping iPSCs Addition Selection Replating Collection Day -2 -1 0 1-3 4 21 27 E8 + Y27 Neural Medium MAP2 • Neuronal expr
Slide 12: Upregulation of SYNGAP1 mRNA and Protein in Control iPSC-derived Neurons
Upregulation of SYNGAP1 mRNA and Protein in Control iPSC-derived Neurons 250 mRNA Protein 200 SYNGAP1 mRNA (% Vehicle) 150 100 50 0 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 ASO # • Identified ASOs capable of increasing SYNGAP1
Slide 13: Development of Patient iPSC-derived Organoids to Study 3D Architecture
Development of Patient iPSC-derived Organoids to Study 3D Architecture Protocol for Producing Organoids1 Molecular analysis • Morphological analysis • RNA sequencing and analysis • Whole proteome sequencing 1Velasco, S.. et al. Nature 570 523-527 (2019) Neuronal organoids allow for the study of syna
Slide 14: Cytoarchitecture Exploration in SYNGAP1 Organoids
Cytoarchitecture Exploration in SYNGAP1 Organoids Imaging of Organoid Macrostructure Imaging of Organoid Microstructure CONTROL SYNGAP1 DEE MAP2 (Neuron) DAPI (Nuclei) Exploration of organoid cytoarchitectural pathology provides opportunity to assess potential for ASO mediated reversal of structural
Slide 15: The Potential of ASOs in Rare Genetic Epilepsies: Praxis Proof of Concept
The Potential of ASOs in Case Study: Elsunersen Rare Genetic Epilepsies INTRATHECALLY- ADMINISTERED ASO for Praxis Proof of Concept SCN2A GoF DEE
Slide 16: Potential to be First Disease-Modifying Treatment for SCN2A-DEE
Potential to be First Disease-Modifying Treatment for SCN2A-DEE Precision targeting “Knocked down” mRNA and protein in animal studies Elsunersen Benefit potential INTRATHECALLY- Showed significant seizure reduction in ADMINISTERED animal studies ASO for SCN2A GoF DEE Disease-modifying potential Norm
Slide 17: Early Clinical Experience: Unprecedented Clinical Efficacy and Tolerability
Early Clinical Experience: Unprecedented Clinical Efficacy and Tolerability PRIME Designation from Significant and sustained seizure EMA for treatment of SCN2A GoF reduction at 1 mg dose levels Developmental Elsunersen Epilepsies INTRATHECALLY- Unexpected benefits across all ADMINISTERED treated par
Slide 18: Summary
Summary • Screening prospective ASOs for the upregulation of SYNGAP1 mRNA in cell culture • Promising ASOs upregulate SYNGAP1 mRNA and protein in iPSC-derived neurons • Establishing platform for measuring potential therapeutic normalization of SYNGAP1 expression in response to ASO treatment in funct
Slide 19: Acknowledgements
Acknowledgements The Florey Institute of Neuroscience and Mental Health • Snezana Maljevic How you can stay informed about • Brett Bennetts PRAX-090 for SYNGAP1? • Montanna Waters • Pamela Kairath Sign up for Praxis communications • Sannu Thomas so we can update you • Alicia Sedo • Svetlana Paskas •
Praxis Precision Medicines — Technical Presentation (December 2023) on 6ix