Praxis Precision Medicines, Inc. · NASDAQ:PRAX
Praxis Precision Medicines — Investor Day (April 2022)
135 slides from Praxis Precision Medicines's investor day presentation, Apr 27, 2022
Slide 1: Epilepsy Day April 27, 2022
© EPILEPSY DAY APRIL 27, 2022
Slide 2: Forward-looking statements
2 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, operations, and financial conditions, including but not limited to express or implied statements regarding the
Slide 3: Developing New Classes of Treatments Inspired by the Genetics of Epilepsy
3 Developing New Classes of Treatments INSPIRED BY THE GENETICS OF EPILEPSY PSYCHIATRY GABRB3 KCNT1 SCN1A CACNA1A KCNA1 SLC1A3 SETX RFC1 CACNA1G GABRB3 KCN1A SCN8A SCN2A DRD3 HTT FMR1 OPA1 SYNGAP1 SHANK3 TPH2 FKBP2 HTR2A CDKL5 DNM1 UNC79 TRIM3 PCDH19 CACNA1A EPILEPSY MOVEMENT
Slide 4: Praxis is built on four key pillars
4 Praxis is built on four key pillars DEVELOPMENT INFORMED BY TRANSLATIONAL TOOLS TARGETS IDENTIFIED THROUGH GENETICS CLINICAL DEVELOPMENT PATHS TO POC ARE RIGOROUS & EFFICIENT DEVELOPMENT STRATEGIES ARE PATIENT-GUIDED
Slide 5: Unmet need in the $3B+ US common epilepsy market
5 >1M w/ Refractory Seizures We aim to address unmet need in the $3B+ US common epilepsy market Source: CDC, EvaluatePharma; Tang F. et al. Front. Neurol. (2017) 3.5M US Prevalence $3B+ US Common Epilepsy Market Opportunity
Slide 6: Precision medicines for 25,000+ rare epilepsy patients
6 Delivering first and best-in-class precision medicines for 25,000+ rare epilepsy patients LGS: Lennox-Gastaut Syndrome; TSC: Tuberous Sclerosis Complex Source: Ambit Genetic Testing and Claims Data Analysis; EvaluatePharma; Sanders S. J. et al. Trends Neurosci. (2018); Wolff M. et al Brain (2017);
Slide 7: Largest targeted epilepsy pipeline in development
7 MOVEMENT DISORDERS EPILEPSY PSYCHIATRY PRECLINICAL IND / PHASE ONE PHASE TWO REGISTRATION ENABLING PRAX-562 DEEs PRAX-020 KCNT1 PRAX-628 Focal Epilepsy PRAX-080 (ASO) PCDH19 PRAX-090 (ASO) SYNGAP1 PRAX-100 (ASO) SCN2A LoF PRAX-030 Undisclosed PRAX-050 Undisclosed PRAX-114 Essential Tremor PRAX-944
Slide 8: Introductions
8 DANIEL FRIEDMAN, M.D., MSc. Professor of Neurology at NYU Grossman School of Medicine and Co-director of the Video-EEG laboratory at NYU Langone Medical Center • MD from Case Western Reserve University School of Medicine; neurology residency training at the Hospital of the University of Pennsylvan
Slide 9: Today's Agenda
9 • Unmet Needs in Epilepsy Management: Challenges with clinical management of epilepsy today and possibility for precision-based therapies tomorrow Today’s Agenda JACQUELINE FRENCH, M.D. STEVE PETROU, Ph.D. DANIEL FRIEDMAN, M.D., MSc. • Praxis Epilepsy Innovation Strategy: Using genetics to elucida
Slide 10: Unmet Needs in Epilepsy Management
10 Unmet Needs in Epilepsy Management Jacqueline French, MD NYU School of Medicine Unmet Needs in Epilepsy Management Jacqueline French, M.D. NYU School of Medicine
Slide 11: Disclosures
11 Disclosures • I receive salary support from the Epilepsy Foundation and for consulting work and/or attending Scientific Advisory Boards on behalf of the Epilepsy Study Consortium for Adamas, Aeonian/Aeovian, Alterity Therapeutics Limited, Anavex, Arkin Holdings, Arvelle Therapeutics, Inc., Athene
Slide 12: Incidence of epilepsy
12 Incidence of epilepsy • By a conservative estimate, 50 million people worldwide have epilepsy1 • The annual incidence ranges from 20-70 cases per 100,000 • Overall, 5% of persons report a seizure at some time in their lives (excluding febrile seizures) • Incidence rates are highest in childhood,
Slide 13: Antiseizure medicine: 2022
13 Antiseizure medicine: 2022 1st Generation • Phenytoin • Carbamazepine • Sodium Valproate • Phenobarbital • Primidone 2nd Generation • Felbamate • Gabapentin • Lamotrigine • Topiramate/ • Tiagabine • Oxcarbazepine • Levetiracetam 3rd Generation • Zonisamide • Pregabalin • Lacosamide • Rufinamide •
Slide 14: Outcome with initial drug therapy as of 2000
14 Outcome with initial drug therapy-all comers as of 2000 Kwan P and Brodie MJ. N Engl J Med. 2000;342(5):314-319. Seizure Free First drug monotherapy 47% Second drug monotherapy 13% Third drug monotherapy 1% Duotherapy 3% Total seizure free 64%
Slide 15: How far have we advanced?
15 How far have we advanced? • Studies in the 1980’s established the critical ratio of treatment response in both adults and children: - 60-70% respond to ASM - 30-40% are “treatment resistant” • With 20 new ASMs in the last few decades, we would anticipate a change in the ratio • Unfortunately, the
Slide 16: Outcome with initial drug therapy
16 Seizure Free 20001 Seizure free 20122 First drug monotherapy 47% 49.5 Second drug monotherapy 13% Third drug monotherapy 1% Duotherapy 3% 6% Total seizure free 64% 68% Outcome with initial drug therapy 1. Kwan P and Brodie MJ. N Engl J Med. 2000;342(5):314-319. 2. Brodie et al, Neurology. 2012 ;7
Slide 17: We have treatment for two thirds of patients
17 We Have Treatment for two thirds of patients AED Therapy: Current status and unmet needs We Need • Treatment for the one third of adult patients who are refractory • Treatment for difficult pediatric syndromes – Many now identified as monogenetic • Ability to predict efficacy/tolerability • Impro
Slide 18: Adherence burden
18 Adherence burden • About 2/3 of patients can have seizures controlled with a new ASM • But these people are burdened by a daily requirement to take ASM, with dire consequences if even a single day is missed • This can be a lifetime obligation!
Slide 19: We have no problem finding new drugs with novel mechanisms
19 We have no problem finding new drugs with novel mechanisms* • Brivaracetam - binds SV2A & blocks voltage-gated Na+ channels • 2-deoxy-glucose inhibits glycolysis • Ganaxolone - GABAA-PAM tonic inhibition • Huperzine A - NMDA antagonist • Cenobamate - inhibits voltage gated sodium channels and pos
Slide 20: Novel mechanisms
20 Novel mechanisms • To date, novel mechanisms have not translated into better efficacy or tolerability
Slide 21: Antiepileptic drug?
21 Antiepileptic drug? • ILAE is considering an “official” name change for the venerable Antiepileptic Drug, dividing drugs into: - Anti-seizure medication (ASM) - Disease modifying Epilepsy Medication (DMEM) • This is to highlight that most medications do not alter the course of epilepsy and are es
Slide 22: Can we predict a better drug?
22 Can we predict a better drug? • A drug could differentiate in a number of important ways: - Disease modifying - Targeted at a specific population - Clear and indisputable advance in treating resistant epilepsy - Seizure freedom - Better tolerability - Less issues for women of childbearing potenti
Slide 23: Seizure freedom is important
23 Seizure freedom is important • In add-on studies, less than 5% of subjects are able to obtain seizure freedom, even for the 3 months of randomization • There is a great opportunity to develop a new therapy that increases rate of seizure freedom, or even 75-90% seizure reduction
Slide 24: But it all comes down to risk vs benefit
24 But it all comes down to risk vs benefit • Don’t forget that the balance of adverse effects/risk of harm to benefit is important, even to individuals with treatment resistant epilepsy Source: h.fraimow
Slide 25: Can better side effect profile lead to better efficacy?
25 Can better side effect profile lead to better efficacy? % achieving Seizure Freedom Dose Toxicity 10 40 20 50 30 Maximum Benefit
Slide 26: Precision therapy?
26 Precision therapy? • Recent studies of emerging anti-seizure drugs in orphan diseases - Dravet syndrome • Fenfluramine • Cannabidiol - Lennox-Gastaut syndrome • Clobazam (US) • Rufinamide • Cannabidiol • Fenfluramine • Is this “precision medicine”? - To date, these studies have only determined th
Slide 27: Precision therapy with Disease Modifying Epilepsy Medications
27 Precision therapy with Disease Modifying Epilepsy Medications (DMEM) • Targeted drugs (The hope for the future) - Correct pathology caused by a specific mutation or mutations - Everolimus and Tuberous sclerosis complex (TSC) • A mutation in TSC1 or TSC2 causes hyperactivity of the mammalian targe
Slide 28: Do epilepsy patients represent a satisfied market?
28 Do epilepsy patients represent a satisfied market? • In one word, No! • Many issues with existing ASMs • 1/3 continue to have seizures • 1/3 (by estimation) have dose-related side effects • No disease modifying treatments
Slide 29: Do neurologists represent a satisfied market?
29 Do neurologists treating epilepsy patients represent a satisfied market? • In a word, No! • All but 3 of the new ASMs either: - require long titration with complex instructions or - Have complicated pharmacokinetic interactions • Many patients continue to have seizures • Many ASMs have potential
Slide 30: Praxis Epilepsy Innovation Strategy
30 Praxis Epilepsy Innovation Strategy Steve Petrou, Co-founder and CSO
Slide 31: Why Epilepsy? Why Now?
WHY EPILEPSY? WHY NOW? 4 2)
Slide 32: Understanding of the genetics of epilepsy has come a long way
32 Carolyn • 16 yrs – early morning tonic clonic seizures, myoclonus • 23 yrs-psychosis Our understanding of the genetics of epilepsy has come a long way in the eighty years since Lennox Lennox series (studied 1941) Eleanor • 17 yrs – early morning tonic clonic seizures, myoclonus • 22 yrs-psychosis
Slide 33: What distinguishes epilepsy, if anything?
33 What distinguishes epilepsy, if anything? Very common Migraine, Depression Common Epilepsy, Autism, Schizophrenia, Alzheimer’s Disease Not common Multiple Sclerosis, Motor Neuron Disease etc. Essentially all neurological disorders have complex genetic inheritance
Slide 34: Outsized understanding of epilepsy genetics
34 Today, the field has an outsized understanding of epilepsy genetics relative to other CNS (and non-CNS) diseases Perucca et al. Annu Rev Genomics Hum Genet 2020 OMIM: Online Mendelian Inheritance in Man ; a catalog of human genes and genetic disorders
Slide 35: Outsized understanding of epilepsy genetics
35 Today, the field has an outsized understanding of epilepsy genetics relative to other CNS (and non-CNS) diseases Perucca et al. Annu Rev Genomics Hum Genet 2020 OMIM: Online Mendelian Inheritance in Man ; a catalog of human genes and genetic disorders
Slide 36: Classes of genes identified in genetic epilepsy
36 Classes of genes identified in genetic epilepsy are critical to other neurological disorders Adapted from Ellis CA, Petrovski S, Berkovic SF. Epilepsy genetics: clinical impacts and biological insights, The Lancet Neurology, Volume 19, Issue 1, 2020, Pages 93-100 Ion channels mTOR pathway Synapti
Slide 37: Framework for evaluating each epilepsy gene
37 Framework for evaluating each epilepsy gene and new opportunities for therapy development EF FE C T S IZ E (O D D S R A T IO ) ALLELE FREQUENCY Rare Large effect size Common Small effect size Rare Small effect size Common Large effect size
Slide 38: Epilepsy-causing variants fall within two quadrants
38 The majority of epilepsy-causing variants fall within these two quadrants EF FE C T S IZ E (O D D S R A T IO ) ALLELE FREQUENCY Rare Large effect size Common Small effect size 1 2 Rare Small effect size Common Large effect size Rare monogenic epilepsies Common polygenic epilepsies
Slide 39: Landscape of genetic and acquired epilepsies
39 Current understanding of the landscape of genetic and acquired epilepsies P R E V A L E N C E RARE MONOGENIC EPILEPSIES COMMON POLYGENIC EPILEPSIES ACQUIRED EPILEPSIES
Slide 40: Epilepsy genetics guiding the Praxis portfolio build
40 Non-Epilepsy Epilepsy genetics guiding the Praxis portfolio build Prevalence relative; not plotted to scale P R E V A L E N C E RARE MONOGENIC EPILEPSIES COMMON POLYGENIC EPILEPSIES ACQUIRED EPILEPSIES GABAergic system genetically implicated in both epilepsy and mood disorders with separate roles
Slide 41: Epilepsy genetics guiding the Praxis portfolio build
41 Non-Epilepsy Epilepsy genetics guiding the Praxis portfolio build Prevalence relative; not plotted to scale P R E V A L E N C E RARE MONOGENIC EPILEPSIES COMMON POLYGENIC EPILEPSIES ACQUIRED EPILEPSIES CACNA1G genetically implicated in epilepsy and tremor and ataxia due to involvement in neurophy
Slide 42: Epilepsy genetics guiding the Praxis portfolio build
42 Non-Epilepsy Epilepsy genetics guiding the Praxis portfolio build Prevalence relative; not plotted to scale P R E V A L E N C E RARE MONOGENIC EPILEPSIES COMMON POLYGENIC EPILEPSIES ACQUIRED EPILEPSIES PRAX-222 PRAX-562 PRAX-020 PRAX-030 PRAX-080 PRAX-090 PRAX-100 RARE EPILEPSIES Epilepsy PRAX-94
Slide 43: Epilepsy genetics guiding the Praxis portfolio build
43 Non-Epilepsy Epilepsy genetics guiding the Praxis portfolio build Prevalence relative; not plotted to scale P R E V A L E N C E RARE MONOGENIC EPILEPSIES COMMON POLYGENIC EPILEPSIES ACQUIRED EPILEPSIES PRAX-222 PRAX-562 PRAX-020 PRAX-030 PRAX-080 PRAX-090 PRAX-100 PRAX-944 PRAX-114 Treatment of f
Slide 44: Praxis targeting the largest and untapped segment
44 Non-Epilepsy Praxis targeting the largest and untapped segment Prevalence relative; not plotted to scale P R E V A L E N C E RARE MONOGENIC EPILEPSIES COMMON POLYGENIC EPILEPSIES ACQUIRED EPILEPSIES PRAX-944 PRAX-114 Praxis future pipeline exploiting new genetics of common epilepsy Epilepsy PRAX-
Slide 45: Three imperatives guide our epilepsy portfolio build
45 TARGET ID BY POLYGENIC RISK VARIANTS SMALL MOLECULE TARGETS IDENTIFIED THROUGH GENETICS These three imperatives guide our epilepsy portfolio build PRAX-562 SMALL MOLECULE PRAX-628 SMALL MOLECULE PRAX-944 SMALL MOLECULE PRAX-114 SMALL MOLECULE Focus on nodes of pathophysiological convergence infor
Slide 46: Our Science in Action
46 Our Science in Action Steve Petrou, Co-founder and CSO
Slide 47: Leveraging genetics with a translational toolkit and collaborations
47 Leveraging our understanding of genetics to discover and develop therapies enabled by a translational toolkit and strategic collaborations DEVELOPMENT INFORMED BY TRANSLATIONAL TOOLS MULTISCALE DISEASE MODELS: Molecular, Neuronal, Network, Brain, Behavior BIOMARKERS: qEEG, Biofluids, Endophenotyp
Slide 48: Focus on nodes of pathological convergence informed by genetics
48 Focus on nodes of pathological convergence informed by genetics
Slide 49: Voltage-gated sodium channels are key arbiters of neuronal excitability
49 Voltage-gated sodium channels (NaV) are the key arbiters of neuronal excitability in the CNS Debanne, D., Campanac, E., Bialowas, A., Carlier, E. and Alcaraz, G., 2011. Axon physiology. Physiological reviews, 91(2), pp.555-602. Nav1.1 Nav1.1
Slide 50: Persistent sodium current drives pathological hyperexcitability
50 Persistent sodium current (INa) is a critical driver of pathological hyperexcitability in the CNS disorders
Slide 51: SCN8A GoF DEE patients have elevated persistent INa
51 SCN8A GoF DEE patients have elevated persistent INa Increased persistent INa in patient neurons (P1, P2) relative to control (C2)
Slide 52: SCN2A GoF DEE patients have elevated persistent INa
52 SCN2A GoF DEE patients have elevated persistent INa Increased persistent INa in disease neurons relative to WT
Slide 53: Next generation sodium channel blocker program at Praxis
53 • Praxis sodium channel “functional” selectivity drug discovery program • Design molecules with in vitro profile including • preference for persistent current • rapid binding and unbinding kinetics • Goal is to selectively dampen hyperexcitable neuronal activity sparing physiological activity to
Slide 54: PRAX-562 in DEEs
54 PRAX-562 SMALL MOLECULE PRAX-628 SMALL MOLECULE Genetics SCN8A gain-of-function SCN2A gain-of-function TSC +other DEEs US Diagnosed Prevalence >10,000 patients* Symptoms Early-onset seizures Developmental delay Intellectual disability Treatment Refractory to symptomatic agents *Lead indications o
Slide 55: Standard NaV blockers do not preferentially target disease-state hyperexcitability
55 Standard NaV blockers do not preferentially target disease-state hyperexcitability, driving limiting side effect profile Source: Praxis data on file “NaV Fingerprint” Persistent INa Inhibition Peak INa, UDV-10Hz (Disease-State Dependence) Inhibition Peak INa, Tonic Block Inhibition 0.01 0.1 1 10
Slide 56: PRAX-562 more potent and selective persistent INa blocker
56 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 Concentration, M % I n h ib it io n o f h N a V 1 .6 Carbamazepine (CBZ) We discovered PRAX-562 as a more potent and selective persistent INa blocker, more disease-state selective, with a wider therapeutic window Source: Praxis data on file 0.01 0.1 1 10
Slide 57: PRAX-562 has best-in-class preferences
57 % INHIBITION OF hNaV1.6 PERSISTENT INa (SAME DATA AS ON PRIOR SLIDE) COMPARISON OF POTENCY AND SELECTIVITY Broader in vitro panel indicates PRAX-562 has best-in-class preferences *solubility concerns 0.01 0.1 1 10 100 1000 10000 0 20 40 60 80 100 Concentration (µM) % I n h ib it io n Carbamazepin
Slide 58: Wide therapeutic index in vivo
58 MES EFFICACY sLMA TOLERABILITY Veh 10 20 40 0 10000 20000 30000 40000 50000 60000 70000 T o ta l D Is ta n c e T ra v e ll e d ( m m ) ** ** Veh 0.3 1 3 10 0 20 40 60 M E S L a te n c y ( s e c ) ** ** Our mechanistic hypothesis translates to a wide therapeutic index in vivo Therapeutic Index (TI
Slide 59: PRAX-562 blocks seizures in SCN2A and SCN8A GoF mouse models
59 IN VIVO POC IN SCN2A SPONTAEOUS SEIZURES1 IN VIVO POC IN SCN8A AUDIOGENIC EVOKED SEIZURES2 PRAX-562 completely blocks seizures in SCN2A and SCN8A GoF mutation mouse models 1 PRAX-562 inhibition of spontaneous seizures in Q54 GoF mice. 2 PRAX-562 inhibition of audiogenic seizures in N1768D D/+ mic
Slide 60: Modulating persistent current increases survival
60 IMPROVES SCN2A GoF SURVIVAL1 IMPROVES SCN8A GoF SURVIVAL2 0 100 200 300 0 50 100 Age (days) % S u rv iv a l Control Tool compound 0 20 40 60 80 100 0 10 20 30 40 50 60 70 80 90 100 Age (days) % S u rv iv a l Control Tool compound Modulating persistent current increases survival in the same geneti
Slide 61: PRAX-562 efficacious in KCNQ2 and KCNC1 DEE models
61 PRAX-562 is highly efficacious in KCNQ2 and KCNC1 DEE models 1WT and KCNQ2 +/K556E mice were treated with PRAX-562 at 10 mg/kg or vehicle 1-hr prior to PTZ injection (100 mg/kg s.c.); N=10 per group 2N=10-14 per group Source: Praxis data on file. KCNQ2 K556E PTZ SEIZURE MODEL1 KCNC1 R320H PTZ SEI
Slide 62: PRAX-628 in adult focal epilepsy
62 PRAX-562 SMALL MOLECULE PRAX-628 SMALL MOLECULE Disease Adult focal epilepsy US Diagnosed Prevalence ~2,000,000 patients (most common type of epilepsy) Symptoms Focal motor and non-motor seizures Treatment Anti-epileptic drugs (AEDs) >30% refractory to available AEDs
Slide 63: NaV blocker with high disease state dependence and wide therapeutic index
63 LOW DISEASE-STATE DEPENDENCE THIN THERAPEUTIC INDEX HIGH DISEASE-STATE DEPENDENCE WIDE THERAPEUTIC INDEX Our internal discovery effort focused on developing a NaV blocker with high disease state dependence and wide therapeutic index Source: Praxis data on file 0.01 0.1 1 10 100 1000 0 20 40 60 80
Slide 64: PRAX-628 unique pharmacological properties enable acute dosing
64 PRAX-628 has unique pharmacological properties that enable acute dosing in a broader patient population Modeling 90mg, single dose of PRAX-628 or PRAX-562. Preclinical simulation recapitulates PRAX-562 clinical data. 0 4 8 9 6 1 4 4 0 .1 1 1 0 Preclinical Simulation of Human PK 90 mg Single Dose
Slide 65: PRAX-628 protects mice from seizures with wide therapeutic window
65 Molecule Plasma Therapeutic Index PRAX-628 16.7x MES EFFICACY sLMA TOLERABILITY PRAX-628 protects mice from seizures with a wide therapeutic window Therapeutic Index (TI) = TC50 / EC50 CD-1 mice; (n=8/group veh, n=10 PRAX) ANOVA/Dunnett (PRAX) **p<0.01 vs. Veh ED50: 0.67 mg/kg PRAX-628 (mg/kg, PO
Slide 66: Focus directly on underlying genetic defects in rare epilepsy
66 Focus directly on underlying genetic defects in rare epilepsy
Slide 67: PRAX-222 in SCN2A gain-of-function
67 PRAX-080 ASO PRAX-100 ASO PRAX-020 SMALL MOLECULE PRAX-090 ASO PRAX-030 SMALL MOLECULE PRAX-222 ASO Note: PRAX-222 in collaboration with Ionis. PCDH19 (PRAX-080), SYNGAP1(PRAX-090), SCN2A-LOF(PRAX-100) ASOs are a collaboration with The Florey Institute of Neuroscience and Mental Health. Genetics
Slide 68: PRAX-222 ASO down-regulates SCN2A expression
68 PRAX-222 is an ASO designed to down-regulate SCN2A expression in patients with gain-of-function mutation
Slide 69: PRAX-222 down-regulates mRNA and protein in vitro
69 SCN2A mRNA KNOCKDOWN SCN2A PROTEIN KNOCKDOWN In vitro, PRAX-222 down-regulates both mRNA and protein ASOs were administered at P30 and brains were collected 14 days post-ICV for qPCR analysis D o s e (µ g ) % c o n tr o ls 1 1 0 1 0 0 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 A S O -C tr l 2 0 0 g ED50: 33
Slide 70: SCN2A ASO increases survival with a single dose
70 SCN2A ASO INCREASES SURVIVAL WITH A SINGLE DOSE INJECTION A single dose of PRAX-222 increases survival well beyond standard of care in SCN2A GoF mice ***p<0.001 ****p<0.0001 All experiments conducted with SCN2A R1882Q mouse model SCN2A GOF model ASO-Ctrl (n=39) ASO-SCN2A ED80 (n=49) ASO-SCN2A ED5
Slide 71: Re-dosing significantly extends survival
71 SCN2A ASO INCREASES SURVIVAL WITH A SINGLE DOSE INJECTION RE-DOSING SIGNIFICANTLY EXTENDS SURVIVAL A second dose of PRAX-222 significantly extends survival of SCN2A GoF mice SCN2A GOF model ASO-Ctrl (n=39) ASO-SCN2A ED80 (n=49) ASO-SCN2A ED50 (n=22) 0 20 40 60 80 0 25 50 75 100 Postnatal day % s
Slide 72: Post-disease onset administration also extends survival
72 SCN2A ASO INCREASES SURVIVAL WITH A SINGLE DOSE INJECTION RE-DOSING SIGNIFICANTLY EXTENDS SURVIVAL ADMINISTRATION POST-DISEASE ONSET ALSO EXTENDS SURVIVAL PRAX-222 also extends survival of SCN2A GoF mice if first administered later in life, well after disease onset SCN2A GOF model ASO-Ctrl (n=39)
Slide 73: PRAX-020 in KCNT1 gain-of-function
73 PRAX-080 ASO PRAX-100 ASO PRAX-020 SMALL MOLECULE PRAX-090 ASO PRAX-030 SMALL MOLECULE PRAX-222 ASO Note: PRAX-222 in collaboration with Ionis. PCDH19 (PRAX-080), SYNGAP1(PRAX-090), SCN2A-LOF(PRAX-100) ASOs are a collaboration with The Florey Institute of Neuroscience and Mental Health. Genetics
Slide 74: PRAX-020 selectively inhibits KCNT1 GoF variants
74 PRAX-020 is a small molecule designed to selectively inhibit KCNT1 GoF variants Source: Praxis data on file. -4 -3 -2 -1 0 1 2 0 50 100 PRAX-020 Inhibition of KCNT1 GoF Variants Concentration (M) % I n h ib it io n
Slide 75: PRAX-020 eliminates seizures in KCNT1 transgenic mice
75 PRAX-020 REDUCES SEIZURES* …AND DECREASES INTERICTAL SPIKE FREQUENCY PRAX-020 eliminates seizures in KCNT1 transgenic mice and suppresses interictal spikes *In 24 hours Source: Praxis data on file. PRAX-020 Dose (mg/kg, PO) Veh Low dose High dose -100 -50 0 50 100 M e a n % C h a n g e f ro m B L
Slide 76: PRAX-020 may rescue behavioral and cognitive phenotype
76 PRAX-020 KCNT1 inhibition may translate to rescue of behavioral and cognitive phenotype Source: Praxis data on file. 24 48 0 2 4 6 Nesting score Time (hrs) N e s ti n g S c o re Vehicle (n=7) PRAX-020 (n=9) ns ✱✱ No nesting Nesting
Slide 77: PRAX-080 in PCDH19
77 PRAX-080 ASO PRAX-100 ASO PRAX-020 SMALL MOLECULE PRAX-090 ASO PRAX-030 SMALL MOLECULE PRAX-222 ASO Note: PRAX-222 in collaboration with Ionis. PCDH19 (PRAX-080), SYNGAP1(PRAX-090), SCN2A-LOF(PRAX-100) ASOs are a collaboration with The Florey Institute of Neuroscience and Mental Health. Genetics
Slide 78: PCDH19 mosaic expression and disease mechanism
78 In PCDH19, hemizygous null patients and hemizygous non-mosaic male carriers are asymptomatic and preserve ability to form normal neuron networks Source: Beyond the Ion Channel; Depienne C. et al PLOS Genetics (2009) Wild-type PCDH19 Variant PCDH19 Normal sorting Same adhesion properties Unaffecte
Slide 79: Knock down PCDH19 to restore cell-cell adhesion
79 We aim to knock down PCDH19 to restore cell-cell adhesion and rescue phenotype Source: Beyond the Ion Channel; Depienne C. et al PLOS Genetics (2009) Wild-type PCDH19 Variant PCDH19 Normal sorting Healthy HealthyNo PCDH19 Normal sorting Healthy Abnormal sorting PCDH19 Disease PCDH19 ASO therapy t
Slide 80: PCDH19 ASO mRNA knockdown
80 PCDH19 ASO MRNA KNOCKDOWN Hits identified achieve >90% in vitro knockdown PCDH19 mRNA Source: Data on file. On track to deliver lead candidate in 2023 0 20 40 60 80 100 0 20 40 60 80 100 % B a s e lin e P C D H 1 9 m R N A Low dose High dose >90% knockdown
Slide 81: PRAX-090 in SYNGAP1
81 PRAX-080 ASO PRAX-100 ASO PRAX-020 SMALL MOLECULE PRAX-090 ASO PRAX-030 SMALL MOLECULE PRAX-222 ASO Note: PRAX-222 in collaboration with Ionis. PCDH19 (PRAX-080), SYNGAP1(PRAX-090), SCN2A-LOF(PRAX-100) ASOs are a collaboration with The Florey Institute of Neuroscience and Mental Health. Genetics
Slide 82: SYNGAP1 is a synaptic RAS GTPase activating protein
82 SYNGAP1 is a synaptic RAS GTPase activating protein Source: Weldon, M. et al . Journal of Neurodevelopmental Disorders. (2018)
Slide 83: Re-expression of SYNGAP1 improves seizure and memory measures
83 Re-expression of SYNGAP1 in adult mice improves measures of seizure and memory Source: Creson et al., eLife (2019) Improvements in: SYNGAP1 restoration EEG ✓ Seizures ✓ Memory ✓ SYNGAP1 haploinsufficiency is the cause of disease, so ASO-mediated up-regulation could rescue disease phenotype
Slide 84: Approx. 3-fold improvement in SYNGAP1 expression
84 Hits identified achieve approx. 3-fold improvement in SYNGAP1 expression Source: Data on file. SYNGAP1 ASO MRNA UP-REGULATION On track to deliver lead candidate in 2023 1.5x 2.5x 0.5x 2.0x 1.0x 3.0x Top ASOs Avg. fold change in SYNGAP1 expression Up-regulation Down-regulation
Slide 85: Focus on implicated genes in common diseases
85 Focus on implicated genes in common diseases
Slide 86: PRAX-114 and PRAX-944 target ID by polygenic risk variants
86 PRAX-114 SMALL MOLECULE PRAX-944 SMALL MOLECULE TARGET ID BY POLYGENIC RISK VARIANTS SMALL MOLECULE Imputed - Current Direct - Future
Slide 87: Inspired by the role of the GABAA receptor in epilepsy
87 PRAX-114 SMALL MOLECULE PRAX-944 SMALL MOLECULE TARGET ID BY POLYGENIC RISK VARIANTS SMALL MOLECULE In development for MDD, PTSD, and ET, but inspired by the role of the GABAA receptor in epilepsy
Slide 88: GABAA receptors with delta subunit dysfunction give rise to epilepsy
88 GABAA receptors with delta (δ) subunit dysfunction give rise to epilepsy Source: Dibbens, L.M. et al. Human Mol Genet. (2004)
Slide 89: PRAX-114 preferentially potentiates extrasynaptic GABAA receptor
89 PRAX-114 preferentially potentiates the delta (δ) subunit of the GABAA receptor, which sits in the extrasynaptic space Source: Dibbens, L.M. et al. Human Mol Genet. (2004); Praxis data on file GABA: Gamma-aminobutyric acid; GABAA PAMs: GABAA receptor positive allosteric modulators Potentiation Fo
Slide 90: PRAX-114 anti-seizure effect in preclinical models
90 PTZ-INDUCED TONIC SEIZURES PTZ-INDUCED CLONIC SEIZURES PRAX-114 protects 100% of animals from PTZ-induced tonic and clonic seizures PRAX-114 has demonstrated anti-seizure effect in preclinical epilepsy models Source: Praxis data on file. Veh1 VPA Veh2 3 10 30 0.0 0.2 0.4 0.6 0.8 1.0 N u m b e r o
Slide 91: Target ID by polygenic risk variants: direct, future
91 PRAX-114 SMALL MOLECULE PRAX-944 SMALL MOLECULE TARGET ID BY POLYGENIC RISK VARIANTS SMALL MOLECULE Direct - Future
Slide 92: GWAS elucidates polygenic risk variants in genetic generalized epilepsy
92 GWAS studies have elucidated common polygenic risk variants among genetic generalized epilepsy patients (N=15,212 epilepsy cases; 3,769 GGE) Polygenic risk variants are those above the line • SCN1A • KCNN2 • GABRA2 • PCDH7 • PNPO • GRIK1 MANHATTAN PLOT FOR GWAS ANALYSIS OF GENETIC GENERALIZED EPI
Slide 93: Disruption potential comparable to polyspecific antibodies
93 Disruption potential comparable to bi- and tri-specific antibodies in immuno-oncology space Source: Suurs, F. V. et al. Pharmacology & Therapeutics. (2019); Ma, J., et al. Front Immunol. (2021) Dozens of bispecific antibodies in clinical development Emerging clinical data show polyspecific antibo
Slide 94: Three imperatives guide our epilepsy portfolio build
94 TARGET ID BY POLYGENIC RISK VARIANTS SMALL MOLECULE TARGETS IDENTIFIED THROUGH GENETICS These three imperatives guide our epilepsy portfolio build PRAX-562 SMALL MOLECULE PRAX-628 SMALL MOLECULE PRAX-944 SMALL MOLECULE PRAX-114 SMALL MOLECULE Focus on nodes of pathophysiological convergence infor
Slide 95: Perspectives from Clinical Practice
95 Unmet Needs in Epilepsy Management Jacqueline French, MD NYU School of Medicine Perspectives from Clinical Practice: Shortcomings of existing treatment landscape provide opportunities for differentiation Daniel Friedman, M.D., MSc.
Slide 96: Disclosures
96 Disclosures • Receive salary support from the Epilepsy Study Consortium (which has received funding from multiple pharmaceutical companies including Biogen, Cerivell, Crossject, Eisai, Engage, SK Lifesciences, Xenon, Zynerba) • Consultant for Eisai, Neurelis • Research support from Empatica, Epit
Slide 97: Case presentation
97 Case presentation • 28 year old woman with a history of depression presents to the office after an ER visit for a witnessed convulsive seizure. • Evaluation in the emergency room was unremarkable. • Upon careful history taking, for several years she has had rare episodes where she hears a “buzzin
Slide 98: Case presentation
98 Case presentation Focal cortical dysplasia Left temporal spikes
Slide 99: Navigating therapeutic choices
99 Navigating therapeutic choices • Patient is diagnosed with epilepsy • Next step is symptomatic treatment – prevention of recurrent seizures − To reduce risks of mortality from seizures- accidents, drownings, SUDEP − To reduce risks of morbidity from seizures- fractures, burns, long term cognitive
Slide 100: ASMs for common epilepsies: where are we now?
100 ASMs for common epilepsies – Where are we now? Adapted from Loscher & Schmidt Epilepsia 2011 GEN1 GEN2 1. Kwan P and Brodie MJ. N Engl J Med. 2000 2. Brodie et al , Neurology, 2012 64% sz-free1 68% sz-free2
Slide 101: Despite many marketed ASMs, more choices are needed
101 Despite the high number of marketed ASMs, more choices are needed 28 yr old woman with depression and new onset focal epilepsy Phenobarbital Phenytoin Carbamazepine Valproate Gabapentin Felbamate Lamotrigine Vigabatrin Topiramate Oxcarbazepine Leviteracetam Zonisamide Pregabalin Lacosamide Cloba
Slide 102: More choices needed: oral contraceptives and weight gain
102 Who is on oral contraceptives and is concerned about weight gain 28 yr old woman with depression and new onset focal epilepsy Phenobarbital Phenytoin Carbamazepine Valproate Gabapentin Felbamate Lamotrigine Vigabatrin Topiramate Oxcarbazepine Leviteracetam Zonisamide Pregabalin Lacosamide Clobaz
Slide 103: More choices needed: desire for children
103 Who is on oral contraceptives and is concerned about weight gain 28 yr old woman with depression and new onset focal epilepsy Phenobarbital Phenytoin Carbamazepine Valproate Gabapentin Felbamate Lamotrigine Vigabatrin Topiramate Oxcarbazepine Leviteracetam Zonisamide Pregabalin Lacosamide Clobaz
Slide 104: Where is there room for improvement?
104 Where is there room for improvement? Outcome of interest Target of current therapy Kerr Acta Neurologica 2012
Slide 105: Where is there room for improvement?
105 Where is there room for improvement? Kerr Acta Neurologica 2012
Slide 106: Efficacy: seizures and QOL in DRE
106 Efficacy -2 -1 0 1 2 3 4 5 6 7 8 seizure free 75-99% reduction 50-74% reduction 0-50% reduction Seizures and QOL in DRE change in QOLIE31 change in QOLIE89 Seizure freedom is perhaps the largest single driver of QOL in patients with DRE focal epilepsy From Birbeck et al, Epilepsia 2002
Slide 107: Where is there room for improvement?
107 Where is there room for improvement? Kerr Acta Neurologica 2012
Slide 108: Tolerability
108 Tolerability Type Examples Acute, predictable (related to mechanisms of action), serum concentration dependent, common Fatigue, vertigo, ataxia, CNS depression, cognitive changes, diplopia, tremor, mood changes Acute, unpredictable (related to individual vulnerability), rare Rash, immunological
Slide 109: Teratogenicity and neurodevelopmental outcomes
109 Teratogenicity & neurodevelopmental outcomes Rates of major congenital malformations for ASMs in monotherapy from 3 prospective registriesInsufficient data for newer ASMs like lacosamide, perampanel, brivaracetam Tomson et al, Curr Opinion Neurol 2019
Slide 110: Where is there room for improvement?
110 Where is there room for improvement? Kerr Acta Neurologica 2012
Slide 111: Comorbidities
111 Comorbidities • Depression, anxiety, memory disturbance are common focal/IGE epilepsy comorbidities • More common among drug- resistant patients • Causes include: • Seizures • Medication effects • Underlying biological abnormalities leading to epilepsy Keezer et al Lancet Neurol 2016
Slide 112: Where is there room for improvement?
112 Where is there room for improvement? Kerr Acta Neurologica 2012
Slide 113: Disease modification
113 Disease modification Current therapies are symptomatic – treat seizures & not underlying disorder • Do not address the underlying mechanisms that lead to altered seizure thresholds, comorbid symptoms • Need to be taken chronically No treatments: • Alter the underlying mechanism leading to increa
Slide 114: Promise of identifying novel targets for therapy
114 Promise of identifying novel targets for therapy • Improved efficacy • Disease modification - remittance of epilepsy, change DRE -> treatment responsive • Modify comorbidities • Improve tolerability • Limit off target effects and neurodevelopmental outcomes
Slide 115: Conclusions
115 Conclusions Despite 18+ marketed ASMs for focal and generalized seizures, options fall short for many patients with common epilepsies, too • Lack of efficacy • Intolerable side effects • Limited choices for women who may become pregnant • Burden of daily of medication taking Shortcomings of avai
Slide 116: Accelerating Path towards Registration
116 Accelerating Path towards Registration Bernard Ravina, CMO
Slide 117: Advancing best-in-class therapies for epilepsies
117 PRAX-222 (SCN2A) PRAX-562 (SCN2A, SCN8A, TSC, +other DEEs) PRAX-628 (FOCAL EPILEPSY) Advancing best-in-class therapies for epilepsies
Slide 118: PRAX-222 potential to be disease-modifying for early onset SCN2A DEE
118 Preclinical data suggest PRAX-222 has potential to be disease- modifying for early onset SCN2A gain-of-function DEE Dose-dependent reduction in interictal spikes, seizures and increased survival Survival benefit extended with repeat dosing Improvement in behavioral and locomotor activity in anim
Slide 119: Patients experience significant seizure burden from birth
119 Patients experience significant seizure burden from birth Note: each horizontal line corresponds to a unique patient identifier. Patient record demographics (N=15): 7 males, 8 females. Average age of seizure onset at 5.1 days (range: 1-44 days). Source: Praxis data on file. EARLY ONSET SCN2A SEI
Slide 120: Significant burden of disease in early onset SCN2A patients
120 Significant burden of disease through lifetime of early onset SCN2A patients ASM: Antiseizure Medications Note: Hospital Duration is the mean total days in hospital for all patients over the duration of the medical records. Source: Praxis data on file. MEDICATIONS DIAGNOSTIC & THERAPEUTIC PROCED
Slide 121: Patient-guided insights: EEG measure of IEDs
121 IEDS DETECTED IN 11-YEAR-OLD WITH EARLY ONSET SCN2A MEDIAN IED BURDEN PER EEG Patient-guided insights drive development, such as EEG measure of interictal epileptiform discharges (IEDs) 0- 2m 2m -6 m 6m -1 y 1y -2 y 2- 4y 4- 8y 8- 16 y 0 10 20 30 40 50 60 Age IE D b u rd e n Early Onset SCN2A DE
Slide 122: Design principles for the PRAX-222 seamless trial
122 Design principles for the PRAX-222 seamless trial submitted to FDA Seamless Placebo-controlled Patient Population Statistical considerations Endpoints Dose Multiple parts to identify and confirm a safe, efficacious dose and optimize dosing schedule Placebo controlled, with confirmatory phase des
Slide 123: Simulated mRNA knockdown in human cortex
123 Simulated mRNA knockdown in human cortex in pediatric patients Safely achieves distribution in key areas of brain based on NHP data PK/PD modeling informs starting dose and proposed escalation based on level of knockdown anticipated to achieve clinical benefit and tolerability Median and 95% pre
Slide 124: Next steps for PRAX-222 Clinical Program
124 Next steps for PRAX-222 Clinical Program • Further characterize the population • Quantify EEG seizure burden, IED, variability in seizure frequency as potential biomarker Enroll observational study Ongoing Initiate PRAX-222 Seamless Study Mid-2022 • Assess safety, tolerability, PK and efficacy o
Slide 125: PRAX-562 first- and best-in-class NaV blocker for DEEs
125 Preclinical and emerging clinical data demonstrate PRAX-562 will be a first- and best-in-class NaV blocker for DEEs Superior selectivity for disease-state NaV channel hyperexcitability Convenient auto-titration regimen with stable PK Unprecedented therapeutic window translating to superior safet
Slide 126: PRAX-562 path to rapid clinical proof of concept in DEEs
126 PRAX-562 path to rapid clinical proof of concept in DEEs PHASE 1 HEALTHY VOLUNTEERS SAD/MAD, ASSR Biomarker w/ 14-day Treatment Duration PHASE 2 DEEs (SCN2A, SCN8A, and TSC) Seizure Reduction, Safety PHASE 1 HEALTHY VOLUNTEERS PK, ASSR Biomarker w/ 28-day Treatment Duration TO BE INITIATED 2H22T
Slide 127: PRAX-562 in healthy volunteers exceeds projected therapeutic exposure
127 PRAX-562 EXPOSURES ON DAY 1 EXPOSURES AT 28 DAYS, WELL ABOVE PREDICTED THERAPEUTIC EXPOSURE* PRAX-562 in healthy volunteers safely exceeds projected therapeutic exposure 0 2 4 6 8 10 12 14 16 18 20 22 24 10 10,000 100 1,000 120mg 90mg 45mg 30mg Mean PRAX-562 Concentration (ng/mL) Time Post-Dose,
Slide 128: SCN8A DEE patients experience significant disease burden
128 SCN8A DEE patients experience significant disease burden SCN8A SEIZURE HISTORY PER PATIENT Source: Praxis data on file.
Slide 129: SCN8A DEE patients experience significant disease burden
129 SCN8A DEE patients experience significant disease burden MEDICATIONS DIAGNOSTIC & THERAPEUTIC PROCEDURES HOSPITALIZATIONS HOSPITALIZATION DURATION (DAYS) 6.6 17.6 LifetimeFirst Year of Life 9.3 27.6 First Year of Life Lifetime 3.3 9.9 First Year of Life Lifetime 27.6 62.8 First Year of Life Life
Slide 130: PRAX-562 in DEEs: path to clinical proof of concept
130 PRAX-562 in DEEs: Path to clinical proof of concept Rapid proof of concept Endpoints Initial patient population Open-label to identify a safe, efficacious dose and optimize dosing schedule in patients Collect data on seizure frequency and neurodevelopment, cognition assessments Pediatric patient
Slide 131: PRAX-628 best-in-class NaV blocker for focal epilepsy
131 Preclinical data demonstrates PRAX-628 will be a best-in-class NaV blocker for focal epilepsy Superior selectivity for disease-state NaV channel hyperexcitability PK differentiated for broad epilepsy population Unprecedented therapeutic window translating to superior safety and efficacy PRAX-628
Slide 132: PRAX-628 clinical development program for focal epilepsy
132 PRAX-628 clinical development program for focal epilepsy IND-ENABLING TOX 28-day GLP Tox PHASE 2 FOCAL EPILEPSY Seizure Reduction, Safety PHASE 1 HEALTHY VOLUNTEERS SAD/MAD, ASSR Biomarker w/14-day Treatment Duration ONGOING TO BE INITIATED 4Q22 TO BE INITIATED 2023
Slide 133: Three epilepsy drugs in clinic by end of 2022
133 PRAX-222 (SCN2A) PRAX-562 (SCN2A, SCN8A, TSC) PRAX-628 (FOCAL EPILEPSY) Three epilepsy drugs in clinic by end of 2022 Initiate Seamless Study: Mid-2022 Initiate Phase 2 Study: 2H22 Initiate Phase 1 Study: 4Q22 PRAX-222 and PRAX-562 received Orphan Drug Designations for severe pediatric epilepsy
Slide 134: Developing New Classes of Treatments Inspired by the Genetics of Epilepsy
134 Developing New Classes of Treatments INSPIRED BY THE GENETICS OF EPILEPSY PSYCHIATRY GABRB3 KCNT1 SCN1A CACNA1A KCNA1 SLC1A3 SETX RFC1 CACNA1G GABRB3 KCN1A SCN8A SCN2A DRD3 HTT FMR1 OPA1 SYNGAP1 SHANK3 TPH2 FKBP2 HTR2A CDKL5 DNM1 UNC79 TRIM3 PCDH19 CACNA1A EPILEPSY MOVEMENT
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Praxis Precision Medicines — Investor Day (April 2022) on 6ix