Praxis Precision Medicines, Inc. · NASDAQ:PRAX
Praxis Precision Medicines — Investor Presentation (May 2023)
43 slides from Praxis Precision Medicines's investor presentation, May 11, 2023
Slide 1: Corporate Overview May 2023
© CORPORATE OVERVIEW May 2023
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 Treatments Inspired By The Genetics of Epilepsy
3 Developing Treatments Inspired By The Genetics of Epilepsy ENABLED BY TWO PLATFORMS CEREBRUM™ SMALL MOLECULE PLATFORM Cerebrum™ utilizes deep understanding of neuronal excitability and neuronal networks and applies a series of computational and experimental tools to develop orally available precis
Slide 4: Pipeline
4 PHASE TWO Targeting movement disorders & epilepsies connected by neuronal imbalance *PRAX-020 (KCNT1) is a research collaboration with UCB +PRAX-080 (PCDH19 ), PRAX-090 (SYNGAP1) & PRAX-100 (SCN2A-LoF) ASOs are a collaboration with The Florey Institute of Neuroscience and Mental Health PRECLINICAL
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 1Q23 2Q23 3Q23PLATFORM 4Q23 CEREBRUM™ SMALL MOLECULE PLATFORM SOLIDUS™ ASO PLATFORM PRAX-628 Ph 1 Topline Results PRAX-562 Ph 2 EMBOLD Study Topline Results DEEs PRAX-222 EMBRAVE Study First Dose Cohort (Part 1) Topline Safety Results SCN2A GoF DEE Ulixacaltamide
Slide 7: Cerebrum Small Molecule Platform
7 CEREBRUM™ SMALL MOLECULE PLATFORM
Slide 8: Ulixacaltamide Key Upcoming Milestones
8 2H 2023 ET Phase 3 Initiation June 2023 ET End-of-Phase 2 FDA Meeting Ulixacaltamide (PRAX-944) Essential Tremor and Parkinson’s Disease KEY UPCOMING MILESTONES
Slide 9: Essential Tremor is the most common movement disorder
9 Essential Tremor (ET) 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.
Slide 10: ET often remains undiagnosed, misdiagnosed, undertreated and untreated
10 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 wi
Slide 11: Ulixacaltamide is a differentiated, selective T-type calcium channel blocker
11 Ulixacaltamide 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 ne
Slide 12: T-Type calcium channels gatekeepers of neuronal firing in CTC circuit
12 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 13: Ulixacaltamide dosing range and modified release formulation
13 Ulixacaltamide’s wide dosing range and modified release formulation 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 Ul ix ac al ta m id e Pl as m a Co nc en tr at io n (n g/ m L) Time (h) SUSTAINED EXPOSURE WITH BLUNTED CMAX Sour
Slide 14: Breaking ground with Essential1 - path forward toward registration
14 • Clinically meaningful effect observed in functional outcomes • Improvement or stabilization in all TETRAS ADL* measurements • Therapeutic drug levels achieved, suggesting individualized exposure response curve consistent with translational data • Well tolerated safety profile, no new safety sig
Slide 15: Essential1 topline results show mADL and ADL improvement
15 Essential1 topline results show mADL* and ADL improvement over placebo at Day 56 in Phase 2b ET study *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 MMRM, Adjust
Slide 16: More patients on ulixacaltamide showed improvements in ADL scores
16 -30 -25 -20 -15 -10 -5 0 5 10 15 More patients taking ulixacaltamide showed improvements in ADL scores compared to patients on placebo in Essential1 study Observed ADL Change - mITTObserved mADL Change - mITT -30 -25 -20 -15 -10 -5 0 5 10 15 CH AN GE IN M AD L SC OR E AT D AY 5 6 More daily funct
Slide 17: Consistent effect relative to placebo across ADL items
17 Ulixacaltamide demonstrated consistent effect relative to placebo across ADL scored items in Essential1 study IM PR OV EM EN T TETRAS-PS items Fold-change difference between placebo and ulixacaltamide at Day 56 for mADL individual Item scores adjusted by placebo MMRM, Adjusted by baseline value,
Slide 18: Improvement over placebo in mADL excluding PS
18 Ulixacaltamide demonstrated improvement over placebo in the mADL excluding PS at Day 56 in Essential1 study MMRM, Adjusted by baseline value, propranolol use and familial history of ET, all p values are nominal -3.01 -1.44 -2.69 -0.88 -3.6 -1.07 p=0.126 ULIXACALTAMIDE (n=78) ULIXACALTAMIDE (n=78)
Slide 19: Results excluding patients with intention tremor
19 mADL and mADL excluding PS improvement over placebo at Day 56 mITT Excluding ET Patients with Intention Tremor MMRM, Adjusted by baseline value, propranolol use and familial history of ET, all p values are nominal -3.12 -0.41 -2.86 -0.01 p=0.032 ULIXACALTAMIDE (n=60) ULIXACALTAMIDE (n=60) PLACEBO
Slide 20: Essential1 next steps toward registration
20 • End of Phase 2 meeting with the FDA scheduled for June 2023 • Preliminary elements of Phase 3 program planned to start in 2H23: • Parallel design with 60 mg and placebo treatment arms • Primary endpoint of mADL excluding PS • 6-week treatment duration NEXT STEPS • Clinically meaningful effect o
Slide 21: PRAX-562 Key Upcoming Milestones
21 PRAX-562 SCN2A, SCN8A & OTHER DEEs KEY UPCOMING MILESTONES 4Q 2023 Ph 2 EMBOLD Study Topline Results
Slide 22: PRAX-562 potential first- and best-in-class NaV blocker for DEEs
22 Preclinical and emerging clinical data demonstrate PRAX-562 has the potential to 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 potentia
Slide 23: Persistent sodium current drives pathological hyperexcitability
23 Persistent sodium current (INa) is a critical driver of pathological hyperexcitability in 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 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-562 Persistent INa IC50
Slide 25: Wide therapeutic index in vivo for PRAX-562
25 MES EFFICACY sLMA TOLERABILITY Our mechanistic hypothesis translates to a wide therapeutic index in vivo for PRAX-562 Therapeutic Index (TI) = TC50 / EC50 CD-1 mice; (n=12/group) **p<0.01 vs. Veh ED50: 2 mg/kg Molecule Plasma Therapeutic Index PRAX-562 17.2x PRAX-562 (mg/kg, PO) PRAX-562 (mg/kg,
Slide 26: PRAX-562 completely inhibits seizures in SCN2A and SCN8A GoF models
26 IN VIVO POC IN SCN2A SPONTANEOUS SEIZURES1 IN VIVO POC IN SCN8A AUDIOGENIC EVOKED SEIZURES2 PRAX-562 completely inhibits 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/+
Slide 27: PRAX-562 Phase summary
27 PRAX-562 Phase 1 summary Source: Praxis data on file; https://investors.praxismedicines.com/news-releases/news-release-details/praxis-precision-medicines-provides-corporate-update-and-5 * Co-administration of supra-therapeutic doses of PRAX-562 and oxcarbazepine led to additive sodium blocking ef
Slide 28: PRAX-562 Phase 2 EMBOLD Study
28 PRIMARY ENDPOINT: Incidence and severity of treatment- emergent adverse events (TEAEs) KEY SECONDARY: Change from baseline in monthly (28 day) motor seizure frequency PRAX-562 Phase 2 EMBOLD Study topline data expected 4Q23 * Two distinct cohorts in early-onset SCN2A-DEE and SCN8A-DEE patients +
Slide 29: PRAX-628 Focal Epilepsy Key Upcoming Milestones
29 PRAX-628 Focal Epilepsy KEY UPCOMING MILESTONES 4Q 2023 Initiate Focal Epilepsy Study
Slide 30: Focal epilepsy affects ~2 million people in the US
30 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 31: PRAX-628 potential best-in-class treatment for focal epilepsy
31 Preclinical and Phase 1 data demonstrate potential of PRAX-628 as best-in-class treatment for focal epilepsy Superior selectivity for functional-state NaV channel hyperexcitability Favorable safety and tolerability profile across broad concentration range in healthy volunteers Unprecedented thera
Slide 32: Preferential action against hyperexcitability
32 PREFERENTIAL ACTION AGAINST HYPEREXCITABILITY BIOPHYSICAL “LEVERS” TO ACHIEVE PREFERENTIAL ACTION Restoring physiological neural activity by precisely modulating biophysics A. Reduce pro-excitatory channel function • Inhibit persistent current B. Dynamic block of channels during high activity • I
Slide 33: PRAX-628 improved potency and separation to tonic inhibition
33 C. MAINTAIN CHANNEL AVAILABILITY DURING LOW ACTIVITY BY SPARING TONIC BLOCK INHIBITION PRAX-628 delivers improved potency and separation to tonic (toxic) inhibition 0.001 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 Concentration (µM) P er si st en t I N a In hi bi tio n (% ) hNaV1.6 Persistent INa C
Slide 34: PRAX-628 wider potential therapeutic range compared to Cenobamate
34 0 2 4 6 8 10 12 14 16 x MES EC50 Cenobamate Approved Regimen TOX PRAX-628 MAD * # Human Equivalent of Mouse MES EC50, ng/mL Cenobamate 9,600 PRAX-628 24 PRAX-628 was generally well-tolerated in humans at concentrations that provide a wider potential therapeutic range compared to Cenobamate # Cmax
Slide 35: Solidus ASO Platform
35 SOLIDUS™ ASO PLATFORM
Slide 36: PRAX-222 Key Upcoming Milestones
36 2H 2023 EMBRAVE Study First Dose Cohort (Part 1) Topline Safety Results PRAX-222 SCN2A-GoF ASO KEY UPCOMING MILESTONES
Slide 37: PRAX-222 potential to be disease-modifying
37 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 PRAX-222
Slide 38: PRAX-222 ASO designed to down-regulate SCN2A expression
38 PRAX-222 is an ASO designed to down-regulate SCN2A expression in patients with gain-of-function mutation
Slide 39: PRAX-222 down-regulates mRNA and protein
39 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 40: PRAX-222 increases survival in SCN2A GoF mice
40 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 41: Simulated mRNA knockdown in human cortex
41 Simulated mRNA knockdown in human cortex in pediatric patients Achieves distribution in key areas of brain based on NHP data PRAX-222 PK/PD modeling informs starting dose and proposed escalation based on level of knockdown anticipated to achieve clinical benefit and tolerability Source: Praxis da
Slide 42: PRAX-222 EMBRAVE study initial dose cohort
42 PRAX-222 EMBRAVE study initial dose cohort (Part 1) results expected 2H23 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 P
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