Praxis Precision Medicines, Inc. · NASDAQ:PRAX
Praxis Precision Medicines — Investor Presentation (November 2022)
40 slides from Praxis Precision Medicines's investor presentation, Nov 9, 2022
Slide 1: Corporate Overview November 2022
CORPORATE OVERVIEW November 2022
Slide 2: Forward-looking statements
2 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 current beliefs, expectatio
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 GABRB3 KCNT1 SCN1A CACNA1A KCNA1 SLC1A3 SETX RFC1CACNA1G GABRB3 KCN1A SCN8A SCN2A DRD3 HTT FMR1 OPA1 SYNGAP1 SHANK3 CDKL5 DNM1 UNC79 TRIM3 PCDH19 CACNA1A EPILEPSY MOVEMENT
Slide 4: Targeting movement disorders & epilepsies connected by neuronal imbalance
4SCN2A-LOF, SYNGAP1 & PCDH19 ASOs are a collaboration with The Florey Institute of Neuroscience and Mental Health Targeting movement disorders & epilepsies connected by neuronal imbalance PRECLINICAL PHASE ONE PHASE TWO REGISTRATION ENABLINGFOCUS AREA MOVEMENT DISORDERS PRAX-050 Undisclosed PRAX-944
Slide 5: Leveraging genetics to efficiently translate insights into therapies
5 Leveraging genetics to efficiently translate insights into therapies GENETICS Focus on therapeutic targets identified through human genetics TRANSLATIONAL TOOLS Translational tools validate potential of target and product candidate and can provide early proof of biology EFFICIENT & RIGOROUS Effici
Slide 6: What to expect from Praxis in 2023
6 What to expect from Praxis in 2023 Upcoming readout for late-stage program for Essential Tremor PRAX-944 PH 2B ESSENTIAL1 STUDY TOPLINE RESULTS EXPECTED IN 1Q23 Cash runway into 1Q24 to advance each clinical-stage program through value inflecting milestones $124 MILLION IN CASH & INVESTMENTS AS OF
Slide 7: Movement disorders: PRAX-944 key upcoming milestones
7 MOVEMENT DISORDERS PRAX-944 T-Type Calcium Channel Inhibitor Essential Tremor Parkinson’s Disease KEY UPCOMING MILESTONES 2H 2023 PRAX-944 Ph 2 PD Study Topline 1Q 2023 PRAX-944 Ph 2b ET Essential1 Study Topline
Slide 8: Essential tremor is the most common movement disorder
8 Essential tremor is the most common movement disorder… SOURCE: 1. GHOSH (2016) (P.231, C.1, PH.1, L.1-2), 2. Elble RJ. Curr Neurol Neurosci Rep. 2013 Jun;13(6):353. 3. Putzke JD, et al. J Neurol Neurosurg Psychiatry. 2006 Nov;77(11):1235-7. 4. Vetterick, C., Lyons, K.E., Matthews, L.G. et al. The
Slide 9: ET often remains undiagnosed, misdiagnosed, undertreated and untreated
9 Approximately 1 million people are diagnosed with ET and on treatment, while another 1 million patients are estimated to remain untreated 0 medications have been developed specifically for ET & only 1 medication was approved for ET >50 years ago Of patients who seek treatment, ~40% discontinue wit
Slide 10: PRAX-944 is a differentiated, selective T-type calcium channel blocker
10 PRAX-944 is a differentiated, selective T-type calcium channel blocker in development for ET and Parkinson’s disease Source: Praxis Data on file, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9310641/ Highly selective for T-type calcium channels Potential for effectiveness across range of neuronal
Slide 11: T-type calcium channels gatekeep neuronal firing in the CTC circuit
11 T-Type calcium channels are gatekeepers of neuronal firing patterns in the Cerebello-Thalamo-Cortical (CTC) circuit Source: Based on Milosevic 2018 figured on actual ET patient intraoperative real-time single-unit recordings of action potentials of individual neurons Mutations in T-type calcium c
Slide 12: Wide dosing range and modified release formulation for PRAX-944
12 Wide dosing range and modified release formulation for PRAX-944 may support tolerability & efficacy profile Source: Praxis Data on file 0 5 10 15 20 25 30 35 40 45 50 0 6 12 18 24 PR AX -9 44 P la sm a Co nc en tr at io n (n g/ m L) Time (h) SUSTAINED EXPOSURE WITH BLUNTED CMAX Source: Praxis Dat
Slide 13: Functional benefit observed in PRAX-944 treated patients in Ph 2a
13 MODIFIED ADLs IN RANDOMIZED WITHDRAWAL MEAN % CHANGE FROM DAY 42 Marked functional benefit observed in PRAX-944 treated patients in Ph 2a study; withdrawal of PRAX-944 results in regression to baseline severity MODIFIED ADLs IN OPEN LABEL MEAN % CHANGE FROM BASELINE *Nominal p-value based on ANCO
Slide 14: PRAX-944 Phase 2b Essential1 study design
14 Source: clinicaltrials.gov/ct2/show/NCT05021991 PRAX-944 Phase 2b Essential1 study topline results expected 1Q23 *Composite sum of items 1 to 11 of TETRAS-ADL subscale and items 6 (bilateral) and 7 of TETRAS-PS; modified ADL score is calculated as the sum of all 13 items and ranges from 0 to 42 c
Slide 15: Modified ADLs measure
15 Modified ADLs: A modified measure of TETRAS activities of daily living (ADLs) that is functionally relevant and FDA recommended 1. Speaking 2. Feeding with a spoon 3. Drinking from a glass 4. Hygiene 5. Dressing 6. Pouring 7. Carrying food trays, plates or similar items 8. Using keys 9. Writing 1
Slide 16: PRAX-944 potential non-dopaminergic therapy for Parkinson's disease
16 PRAX-944 has potential to be a non-dopaminergic therapy for motor function for people with Parkinson’s disease Dopamine promotes movement Dopamine related motor and non- motor complications
Slide 17: T-type calcium channels modulate the motor circuit in Parkinson's disease
17 T-type calcium channels modulate the motor circuit in Parkinson’s disease and overlap with target for Deep Brain Stimulation Mcgregor mm, nelson ab. Neuron. 2019. Doi:10.1016/j.Neuron.2019.03.004 Tai c-h et al. J clin invest. 2011. Doi:10.1172/jci46482 THALAMO-CORTICAL PATHWAY IMBALANCE IN PD STN
Slide 18: Blocking T-type calcium channels improves motor function in Parkinson's model
18 Blocking T-type calcium channels with Ni2+ improves motor function in burst firing model of movement deficit in Parkinson’s disease Pan et al (2016) j clin invest doi: 10.1172/jci88170 BURST FIRING IN STN OF 6-OHDA PARKINSON’S MODEL BLOCK OF BURST FIRING IMPROVES MOVEMENT IN 6-OHDA PARKINSON’S MO
Slide 19: PRAX-944 Phase 2 Parkinson's disease study design
19 PRIMARY ENDPOINT: Change from baseline to Day 77 in the International Parkinson and Movement Disorder Society (MDS) Unified Parkinson’s Disease Rating Scale (UPDRS) Part III (motor examination) score in the OFF state PRAX-944 Phase 2 Parkinson’s disease study topline data expected 2H23 Safety Fol
Slide 20: Epilepsy key upcoming milestones
20 4Q 2022 Initiate PRAX-222 EMBRAVE Study 4Q 2022 Initiate PRAX-628 Ph 1 Trial KEY UPCOMING MILESTONESEPILEPSY PRAX-562 (DEEs) PRAX-222 (SCN2A-GOF ASO) PRAX-020 (KCNT1) PRAX-628 (Focal Epilepsy) PRAX-100 (SCN2A-LOF ASO) PRAX-090 (SYNGAP1 ASO) PRAX-080 (PCDH19 ASO) PRAX-030 (Undisclosed) 1Q 2023 Ini
Slide 21: Precision medicines for 25,000+ rare epilepsy patients
21 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 22: PRAX-562 first- and best-in-class NaV blocker for DEEs
22 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 with potential for superior sa
Slide 23: Persistent sodium current drives pathological hyperexcitability
23 Persistent sodium current (INa) is a critical driver of pathological hyperexcitability in the CNS disorders
Slide 24: Comparison of potency and selectivity
24 % INHIBITION OF hNaV1.6 PERSISTENT INa 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) % In hi bi tio n Carbamazepine Lamotrigine Cenobamate PRAX-56
Slide 25: Wide therapeutic index in vivo
25 MES EFFICACY sLMA TOLERABILITY Veh 10 20 40 0 10000 20000 30000 40000 50000 60000 70000 To ta l D Is ta nc e Tr av el le d (m m ) ** ** Veh 0.3 1 3 10 0 20 40 60 M ES La te nc y (s ec ) ** ** Our mechanistic hypothesis translates to a wide therapeutic index in vivo Therapeutic Index (TI) = TC50 /
Slide 26: PRAX-562 blocks seizures in SCN2A and SCN8A GoF mouse models
26 IN VIVO POC IN SCN2A SPONTANEOUS 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/+ mi
Slide 27: PRAX-562 Phase 1 summary
27 PRAX-562 Phase 1 summary All TEAEs mild to moderate as stand-alone therapy*, with headache & dizziness most common TEAEs Significant changes observed between placebo and 90 mg of PRAX-562 on qEEG and on ASSR biomarkers PRAX-562 has been generally well tolerated in over 130 healthy volunteers Sour
Slide 28: PRAX-222 potential to be disease-modifying for SCN2A GoF DEE
28 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 anima
Slide 29: PRAX-222 ASO down-regulates SCN2A expression
29 PRAX-222 is an ASO designed to down-regulate SCN2A expression in patients with gain-of-function mutation
Slide 30: PRAX-222 down-regulates mRNA and protein in vitro
30 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 µ g ED50: 33
Slide 31: PRAX-222 increases survival in SCN2A GoF mice
31 SCN2A ASO INCREASES SURVIVAL WITH A SINGLE DOSE INJECTION RE-DOSING SIGNIFICANTLY EXTENDS SURVIVAL ADMINISTRATION POST-DISEASE ONSET ALSO EXTENDS SURVIVAL PRAX-222 increases survival in SCN2A GoF mice ***p<0.001 ****p<0.0001 All experiments conducted with SCN2A R1882Q mouse model SCN2A GOF model
Slide 32: Simulated mRNA knockdown in human cortex
32 Simulated mRNA knockdown in human cortex in pediatric patients 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 Source: Praxis data on fil
Slide 33: PRAX-222 EMBRAVE study initial dose cohort
33 PRAX-222 EMBRAVE study initial dose cohort GOAL: Assess preliminary safety of PRAX-222 21-week study Open label design screening / baseline observation UP TO 8 WEEKS 4 WEEKS 4 WEEKS 4-5 WEEKS monitoring monitoring PRAX-222 IT Dose PRAX-222 IT Dose PRAX-222 IT Dose PRAX-222 IT Dose monitoring ongo
Slide 34: Focal epilepsy affects ~2 million people in the US
34 Focal epilepsy affects ~2 million people in the US alone Most common type of epilepsy in adults and children - occurs in 60% of epilepsy cases Most common age of onset is in the first year of life and in the 6th and 7th decade~ 50% have family history but genetics is not well understood Defined a
Slide 35: PRAX-628 best-in-class NaV blocker for focal epilepsy
35 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 36: NaV blocker with high disease state dependence and wide therapeutic index
36 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 37: PRAX-628 unique pharmacological properties enable acute dosing
37 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 38: PRAX-628 protects mice from seizures with a wide therapeutic window
38 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 39: Three epilepsy drugs expected in clinic by first quarter 2023
39 PRAX-222 (SCN2A) PRAX-628 (FOCAL EPILEPSY) PRAX-562 (SCN2A, SCN8A) Three epilepsy drugs expected in clinic by first quarter 2023 Initiate EMBRAVE Study: 4Q22+ Initiate Phase 1 Study: 4Q22 Initiate Phase 2 Study: 1Q23* PRAX-222 and PRAX-562 each received Orphan Drug Designations for severe pediatr
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