Praxis Precision Medicines, Inc. · NASDAQ:PRAX
Praxis Precision Medicines — Investor Day (October 2023)
71 slides from Praxis Precision Medicines's investor day presentation, Oct 2, 2023
Slide 1: R&D Portfolio Overview
R&D Portfolio Overview October 2, 2023
Slide 2: Forward-looking statements
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 cu
Slide 3: Overview
Overview INTRODUCTION EPILEPSY OVERVIEW Marcio Souza, President & CEO Steve Petrou, PhD, Chief Scientific Officer ULIXACALTAMIDE PRAX-628 Alex La Croix, Program Lead Karl Hansen, PhD Chief Technical Operations Officer MOVEMENT DISORDER KOL EPILEPSY KOL Professor Alberto Espay, MD Professor Jacquie F
Slide 4: Developing Treatments Inspired by the Genetics of Epilepsy
Developing Treatments Inspired by the Genetics of Epilepsy ENABLED BY TWO PLATFORMS CEREBRUM™ SOLIDUS™ SMALL MOLECULE PLATFORM ANTISENSE OLIGONUCLEOTIDE (ASO) PLATFORM Ulixacaltamide (PRAX-944) PRAX-090 PRAX-222 PRAX-020 PRAX-562 PRAX-080 PRAX-100 PRAX-628 PRAX-050 Cerebrum™ utilizes deep understand
Slide 5: Targeting movement disorders & epilepsies connected by neuronal imbalance
Targeting movement disorders & epilepsies connected by neuronal imbalance Today’s Focus 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
Slide 6: Our Four Pillars
Our Four Pillars 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
Slide 7: Essential tremor market is significantly underserved and ready for disruption
Essential tremor market is significantly underserved and ready for disruption 7M US Prevalence ~2M ET patients seeking $4B+ US ET Market treatment 7
Slide 8: Essential tremor has large market potential and limited competition
Essential tremor has large market potential and limited competition compared with other diseases INDICATION / NUMBER OF BRANDED COMPETITORS Rheumatoid Arthritis / 30 drugs $35 Multiple Sclerosis / 26 drugs $15 $6 (US 2022 PRODUCT SALES*, $BN) $5 MARKET VALUE $4 $3 Tardive Dyskinesia / 2 drugs $2 Ess
Slide 9: We aim to address unmet need in the $3B+ US common epilepsy market
We aim to address unmet need in the $3B+ US common epilepsy market 3.5M >1M $3B+ w/ Refractory US Common US Prevalence Seizures Epilepsy Market Opportunity 9
Slide 10: Delivering precision medicines for rare epilepsy patients
Delivering first and best-in-class precision medicines for 14,000+ rare epilepsy patients U.S. Diagnosed Prevalence for Rare Epilepsy Programs U.S. Market Size (patients ≤20 years of age) 14,000+ pts 2,400 3,000 2,000 2,500 2,300 1,900 $770M $1.5B 23,500 ’22 sales ’26 sales (consensus est.) LGS, SCN
Slide 11: PRAX-222 (elsunersen) Update
PRAX-222 (elsunersen) Update Revolution in ASO for Epilepsy 11
Slide 12: Patients with SCN2A-DEE have a debilitating and ultimately fatal trajectory
Patients with SCN2A-DEE have a debilitating and ultimately fatal trajectory Significant Refractory seizure epilepsy and Significant burden at or developmental risk of around birth arrest SUDEP Early mortality 12
Slide 13: We have a mission to disrupt the trajectory of SCN2A-DEE
We have a mission to disrupt the trajectory of SCN2A-DEE… ONE PATIENT AT A TIME! https://onlinelibrary.wiley.com/doi/full/10.1111/epi.12554 13
Slide 14: Very first patient to receive PRAX-222
We have a mission to disrupt the trajectory of SCN2A-DEE… Very first patient to receive PRAX-222 A preterm newborn presenting with Status Epilepticus at birth • Pre-natal exome sequencing SCN2A c.3986C>A p.(Ala1329Asp) • Medical team requested emergency access to PRAX-222 after exhausting standard o
Slide 15: Very first patient to receive PRAX-222
We have a mission to disrupt the trajectory of SCN2A-DEE… Very first patient to receive PRAX-222 PRAX-222 initiated when patient was 13 weeks old; poor prognosis due to continuous Status Epilepticus After 1 dose After 7 doses • PRAX-222 was well-tolerated • PRAX-222 was well-tolerated • Status epile
Slide 16: PRAX-222 EMBRAVE Part 1 design
PRAX-222 EMBRAVE Part 1 design SAFETY ANALYSIS GOAL: Assess preliminary safety of Baseline 4 WEEKS 4 WEEKS 4-5 WEEKS PRAX-222 monitoring monitoring monitoring 21-week study PRAX-222 PRAX-222 PRAX-222 PRAX-222 N=4 IT Dose IT Dose IT Dose IT Dose 1mg 1mg 1mg 1mg 16
Slide 17: Unprecedented efficacy after dose of PRAX-222
Unprecedented efficacy after 1 dose of PRAX-222 Preliminary results of 3 monthly doses MEDIAN CHANGE IN SEIZURES V. 28 DAY-BASELINE DOSE 1 DOSE 2 DOSE 3 Improvement -39% -44% -58% 44% Median Seizure Reduction Across 3 Doses (range 27%-80%) Data through September 26 2023 17
Slide 18: Unprecedented increase in seizure-free days
Unprecedented increase in seizure-free days Improvements observed after one dose % SEIZURE-FREE DAYS PER DOSING PERIOD 42% Median: 35% 35% Significant Increase in 33% Seizure Free Days v. Baseline 21% BASELINE DOSE 1 DOSE 2 DOSE 3 Data through September 26, 2023; calculated as number of seizures ove
Slide 19: PRAX-222 Safety profile supports program advancing
PRAX-222 Safety profile supports program advancing • As of cutoff, 4 patients evaluable through three doses each, 1 received 7 doses • Safety inclusive of 4 patients receiving 3 doses, 2 patients receiving 4 doses • No TEAEs or SAEs considered related to study drug • All TEAEs recovered/resolved • D
Slide 20: PRAX-222 Next Steps
PRAX-222 – Delivering on early safety and efficacy Next Steps Complete Compile Initiate global data package and pivotal phase collection for meet with in 2024 all patients FDA 20
Slide 21: What to expect from Praxis through 1H 2024
What to expect from Praxis through 1H 2024 PLATFORM 1Q23 2Q23 3Q23 4Q23 1H 24 Ulixacaltamide Ulixacaltamide Ulixacaltamide Ulixacaltamide Phase 3 Ph 2b Essential1 End-of-Ph 2 FDA Ph 3 Initiation Complete Enrollment Study Meeting Essential Tremor Essential Tremor Topline Results Essential Tremor Esse
Slide 22: Ulixacaltamide (PRAX-944) Essential Tremor
Ulixacaltamide (PRAX-944) Essential Tremor • Clinical insights from Essential1 (PRAX-944-222) • Phase 3 Development Plan Alex La Croix Movement Disorders Program Lead 22
Slide 23: There is a clear need for a safe, tolerable and effective treatment in Essential Tremor
There is a clear need for a safe, tolerable and effective treatment in Essential Tremor 23
Slide 24: Essential Tremor is the most common movement disorder
Essential Tremor (ET) is the most common movement disorder Up to 7 million people in the United States Action tremors significantly disrupt daily may have ET1 living for people with ET Almost all ET patients suffer from at least one Hallmark feature is action tremor that primarily comorbid condition
Slide 25: The only approved medication is not widely used by patients
The only approved medication is not widely used by patients <30% <30% of patients are eligible to receive propranolol due to other medications/health conditions Of those who start propranolol >50% discontinue after only 1 month >½ Of those who start propranolol <20% <20% still receive propranolol af
Slide 26: Ulixacaltamide: Revolutionizing the treatment of essential tremor
Ulixacaltamide: Revolutionizing the treatment of essential tremor First-in-Class • First drug specifically designed for ET patients mechanism • Easy titration and simple once-daily dosing • Continued improvement observed with longer duration on treatment Differentiated profile • Improvement in funct
Slide 27: Using Essential1 to drive innovation in our Phase 3 strategy
Using Essential1 to drive innovation in our Phase 3 strategy 27
Slide 28: Essential1 as the foundation for our Phase 3 program
Essential1 as the foundation for our Phase 3 program INNOVATION IN REGISTRATION TESTING A CLINICAL HYPOTHESIS STUDY DESIGN • Strong efficacy signal with robust • Agreement with FDA on dose and endpoint (mADL11) primary endpoint • Early clinical benefit in Week 8 results • Study design structured aro
Slide 29: Essential1 Phase 2b study design
Essential1 Phase 2b study evaluating the efficacy and safety of ulixacaltamide for essential tremor ESSENTIAL1 DESIGN Week: 1–6 7-8 Weeks 9-10 Safety Regimen Titration 100 mg 1 Follow-up Crossover sub-study Randomization Days -28 to -1 1-4 5-6 Or 3 weeks 3 weeks 1:1:1 Regimen 20 mg 40 mg 60 mg Weeks
Slide 30: Clinical effect of ulixacaltamide on functional improvement in mADL11
Compelling data demonstrates clinical effect of ulixacaltamide on functional improvement in mADL11 Modified ADL11 items Improvement in mADL11 in 1. Speaking 8. Using keys 8 weeks - Essential1 Study 2. Feeding with a spoon 9. Writing 3. Drinking from a glass 10. Working p = 0.042 4. Hygiene 11. Overa
Slide 31: Patients and investigators reported higher overall improvement with ulixacaltamide
Patients and investigators reported higher overall improvement with ulixacaltamide compared to placebo PGI-C - mITT CGI-S - mITT p < 0.005* p < 0.005** 47% improved 30% improved 42% improved 26% improved IMPROVED IMPROVED IMPROVED IMPROVED NO CHANGE NO CHANGE NO CHANGE NO CHANGE WORSENED WORSENED WO
Slide 32: Using Essential1 to define clinical meaningfulness in essential tremor
Using Essential1 to define clinical meaningfulness in essential tremor ESSENTIAL1 ANCHOR-BASED ASSESSMENT PGI-C:mADL11 8 6 4 2 0 -2 -4 -6 -8 -10 -12 -14 -16 -18 -20 MSD=Meaningful Score Difference 32
Slide 33: Clear response achieved in ulixacaltamide treated patients at Week 8
Clear response achieved in ulixacaltamide treated patients at Week 8 >3-point change in mADL11 – Week 8 70% p = 0.023 60% 50% 55% • Statistically-significant 40% difference between 30% 31% ulixacaltamide and placebo 20% groups 10% 0% ULIXACALTAMIDE PLACEBO Results from Essential1 study 33
Slide 34: Robust response to ulixacaltamide treatment through Week 14
Robust response to ulixacaltamide treatment through Week 14 >3-point change in mADL11 – Week 14 70% • Durable response in patients 69% 60% 64% who continued on 50% ulixacaltamide after Week 8 40% • Strong response from 30% placebo patients who 20% transitioned to 10% ulixacaltamide after Week 8 0% U
Slide 35: Benefit of ulixacaltamide is independent of propranolol use
Benefit of ulixacaltamide is independent of propranolol use % PROPANOLOL ACHIEVING A >3 POINT MADL11 REDUCTION BY PLACEBO AND ULIXACALTAMIDE ARMS 60% Propanolol + Placebo Propanolol + ulixacaltamide 50% 48% 40% 30% 20% 25% 10% 0% Week 8 Results from Essential1 study 35
Slide 36: Ulixacaltamide treated subjects continue to benefit after weeks on treatment
Ulixacaltamide treated subjects continue to benefit after 14 weeks on treatment ESSENTIAL1 EXTENSION: CHANGE IN mADL11 FROM BASELINE, BY STUDY WEEK 8 10 12 14 0.00 CHANGE IN MADL11 V. BASELINE (DAY 0) (1.00) • Patients on drug from Day 1 (2.00) continue to show durable effect through (3.00) 14 weeks
Slide 37: Transition of subjects from placebo to ulixacaltamide confirms treatment benefit
Transition of subjects from placebo to ulixacaltamide confirms treatment benefit ESSENTIAL1 EXTENSION: CHANGE IN mADL11 FROM BASELINE, BY STUDY WEEK 8 10 12 14 0.00 • Placebo patients switched to ulixacaltamide CHANGE IN MADL11 V. BASELINE (DAY 0) (1.00) after Week 8 3.2 point2 improvement experienc
Slide 38: Essential1 randomized withdrawal approach confirms effect of ulixacaltamide
Essential1 randomized withdrawal approach confirms effect of ulixacaltamide ESSENTIAL1 SUB-STUDY AVERAGE WEEKLY CHANGE IN mADL11 V. PRIOR WEEK OVER STUDY PERIOD FAVORABLE Placebo Ulixacaltamide 10% 6% 0% UNFAVORABLE -10% -20% -30% -40% -47% -50% Sub-study design summary: Patients were re-randomized
Slide 39: Design and execution of our Phase 3 strategy
Design and execution of our Phase 3 strategy 39
Slide 40: Essential1 as the foundation for our Phase 3 program
Essential1 as the foundation for our Phase 3 program • Established reliable endpoint in mADL11 • Observed clinical meaningful results over time • De-risked key elements of registration strategy 40
Slide 41: Moving towards Essential3 initiation
Moving towards Essential3 initiation Q1 Q2 Q3 Q4 Study Essential1 EOP2 FDA initiation topline results meeting protocol feedback Alignment on key Phase 3 elements ESSENTIAL3 START UP ACTIVITIES PRE-RECRUITMENT ENGAGEMENT FULL RECRUITMENT CAMPAIGN 41
Slide 42: Essential3: An innovative Phase 3 program
Essential3: An innovative Phase 3 program that optimizes all aspects of study conduct 1. PLACEBO-CONTROLLED PARALLEL GROUP STUDY SINGLE RECRUITING 60 mg EXPERT REVIEW Placebo SCREENING 2. RANDOMIZED WITHDRAWAL STUDY BLINDED STUDY Placebo RANDOMIZATION 60 mg Randomization 60 mg 3. LONG-TERM SAFETY ST
Slide 43: Powering the parallel design and randomized withdrawal studies
Powering the parallel design and randomized withdrawal studies STUDY STUDY 1 – PARALLEL DESIGN STUDY 2 – RANDOMIZED WITHDRAWAL Participants 400 200 mADL11 Change from Baseline to Week Difference in maintenance of response rate 12 between ulixacaltamide and placebo during the 4-week RW period between
Slide 44: Decentralized design maximizes quality and control
Decentralized design maximizes quality and control Structured video neurologic exam to confirm ET Assessment Real-time data diagnosis and done in the capture and review by patient's home quality check consistent eligibility review committee Dedicated nationwide investigators consistency in assessm
Slide 45: Streamlining recruitment and enrollment de-risks execution
Streamlining recruitment and enrollment de-risks execution Two studies Stratification under single within protocol with Blinded study studies to uniform randomization maintain inclusion/ balance of exclusion key variables criteria 45
Slide 46: Unprecedented engagement and interest in Essential3
Unprecedented engagement and interest in Essential3 Engagement campaign ~600 expanding in October to patients already engaged achieve full enrollment in since September in anticipation of E3 1H 2024 46
Slide 47: Path to success with ulixacaltamide
Path to success with ulixacaltamide AGILE WAY OF WORKING SINGLE PROTOCOL STREAMLINED DESIGN Decentralized study to Optimized screening, Focused execution expand reach and enrollment, analysis reduce study burden PATIENT-DRIVEN NDA READINESS APPROACH mADL11 as a clinically meaningful primary Clear pa
Slide 48: Epilepsy Portfolio
Epilepsy Portfolio 48
Slide 49: Developing Precision Therapies in Epilepsy
Developing Precision Therapies in Epilepsy Steve Petrou, PhD. Chief Scientific Officer 49
Slide 50: Utilizing our pillars to develop precision therapies in Epilepsy
Utilizing our pillars to develop precision therapies in Epilepsy Development Pillar Manifestation in Epilepsy Clinical Program Impacting rare and common GENETICS disorders Reversing genetic etiology => 222 (ASO) TRANSLATIONAL Clinical and preclinical data TOOLS guiding development EFFICIENT & Innova
Slide 51: SOLIDUS ASO Platform
~G SOLIDUS™ ASO PLATFORM 51
Slide 52: Tackling Developmental and Epileptic Encephalopathies
Tackling Developmental and Epileptic Encephalopathies DISEASE OVERVIEW RESEARCH APPROACH • Epilepsy and developmental impairment before • Modifying gene expression to address the age of 16 years occurs in 1 in 340 children both gain and loss of function • The majority of these cases result from diso
Slide 53: Preclinical evidence for efficacy in SCN2A-DEE GoF and PCDH19-GCE
PRAXIS preclinical evidence for efficacy in SCN2A-DEE GoF and PCDH19-GCE mosaicism PRAX-222 pre-clinical Proof of Concept PRAX-080 • Gapmer ASO that binds SCN2A mRNA and tags it for degradation • PCDH19-Girls Clustering Epilepsy is a severe DEE affecting by RNAaseH females and mosaic males • Rescue
Slide 54: CEREBRUM Small Molecule Platform
CEREBRUM™ SMALL MOLECULE PLATFORM 54
Slide 55: PRAX-628 is poised to address the Focal Epilepsy Market
PRAX-628 is poised to address the Focal Epilepsy Market CURRENT ASMs PRE-DATE EPILEPSY PRECISION MEDICINE Limitation of the current treatments Drug First reported Lamictal® Lamotrigine 1981 • Complex dosing Keppra® Levetiracetam 1985 • Long time to wait for Lyrica® Pregabalin 1993 efficacy Vimpat® L
Slide 56: Can a better side effect profile lead to better efficacy?
Can a better side effect profile lead to better efficacy? ALL standard of care with dose limits PATIENTS ACHIEVING SEIZURE FREEDOM SOME Tolerability limit FEW Efficacy range LO MED HI LO HI EFFICACY DOSE RANGE 56
Slide 57: Can a better side effect profile lead to better efficacy?
Can a better side effect profile lead to better efficacy? precision drug leaving no efficacy on the table PATIENTS ACHIEVING ALL SEIZURE FREEDOM SOME Tolerability limit FEW Efficacy range LO MED HI LO HI EFFICACY DOSE RANGE 57
Slide 58: Ideal profile by precision sodium channel modulation
Ideal profile by precision sodium channel modulation GOAL: PREFERENTIAL ACTION AGAINST NEURONAL HYPEREXCITABILITY Untreated neuron epileptic range ideal drug healthy neuron NEURAL ACTIVITY non preferring drug STIMULATION LEVEL 58
Slide 59: Actual profile of precision sodium channel modulation (PRAX-628)
Actual profile of precision sodium channel modulation (PRAX-628) BIOPHYSICAL “LEVERS” TO ACHIEVE PREFERENTIAL ACTION: ACTION AGAINST HUMAN BRAIN SODIUM CHANNEL A. Reduce pro-excitatory channel function • Inhibit pathological persistent current B. Dynamic modulation of channels during modulation high
Slide 60: Actual profile of precision sodium channel modulation (PRAX-628)
Actual profile of precision sodium channel modulation (PRAX-628) DIFFERENTIATED BINDING PROFILE FAVOURING BIOPHYSICAL “LEVERS” TO ACHIEVE PREFERENTIAL ACTION: PREFERENTIAL ACTION A. Reduce pro-excitatory channel function • Inhibit pathological persistent current Faster 10 B. Dynamic modulation of ch
Slide 61: MES is a rapidly deployed pre-clinical assay predicting efficacy in Focal Onset Seizures
MES is a rapidly deployed and efficient pre-clinical assay that predicts clinical exposure and efficacy in Focal Onset Seizures (FOS) • Drugs that work in MES work in FOS • Efficacious exposures in MES models correspond to efficacious exposures in human FOS “Maximal electroshock seizure (MES) is an
Slide 62: Combining MES and human safety studies for predictive translation
Combining MES and human safety studies for predictive translation Hi efficacy FOLD CHANGE IN EFFICACIOUS HUMAN EXPOSURE Tolerability limit Efficacy range 1X LO HI Lo efficacy Current Drugs Ideal profile to capture full efficacy before reaching tolerability limits 62
Slide 63: PRAX-628 Clinical Update
PRAX-628 Clinical Update Karl Hansen, PhD. Chief Technical Operations Officer PRAX-628 Program Lead 63
Slide 64: What would the profile of a precision ASM be?
What would the profile of a precision ASM be? Limitation of the current treatments: Ideal Treatment • On-target and off-target side effects Tolerable safety profile • Efficacy capped by tolerability Reaches the brain • Complex dosing Rapidly achieves therapeutic concentrations without titratio
Slide 65: PRAX-628 has unprecedented margins over best-in-class ASMs
PRAX-628 has unprecedented margins over best-in-class ASMs based on MES efficacy and clinical tolerability in humans Clinically Tolerated Exposures No tolerability 16 concerns 15.5 14 12 Additional tolerated 10 margin for toxicity and xMES EC50 8 PRAX-628 tolerability levels 6 4 4.8 2 2.5 0 CENOBOMA
Slide 66: Composite qEEG shows clear brain activity across all doses
Composite qEEG shows clear brain activity across all doses within hours of administration PRAX-628 SAD PLACEBO ADJUSTED • Composite endpoint from 25 qEEG showed separation of drug versus placebo in the QEEG COMPOSITIVE CHANGE 20 SAD and MAD cohorts 15 • Difference between PRAX-628 and PBO significan
Slide 67: PRAX-628 achieves nearly complete coverage on Day 1
PRAX-628 achieves nearly complete coverage on Day 1 Hours of Day 1 Drug Coverage 24 23 20 16 12 8 4 5 0 0 Cenobomate XEN1101 PRAX 628 400 mg 25 mg 30 mg Estimated based on SAD Food effect data, Praxis data on file (Ph1 study) CONFIDENTIAL | 67
Slide 68: PRAX-628 maintains higher active MES EC50 multiples at steady state
PRAX-628 maintains higher active MES EC50 multiples at steady state MES EC50 Coverage Ranges (Peak to Trough) at Steady State 16 15.5 14 12 Tolerable range provides options for xMES EC50 10 optimal dosing 8 PRAX-628 at minimum 6 6 levels already exceeds to limits for 4 4.8 competitive products 2 2.5
Slide 69: PRAX-628 has presented an ideal precision ASM profile through Phase 1
PRAX-628 has presented an ideal precision ASM profile through Phase 1 Ideal Treatment Tolerable safety profile Continuous coverage at higher therapeutic levels Reaches the brain Rapidly achieves therapeutic concentrations Ability to provide maximum efficacy 69
Slide 70: Phase 2 PRAX-628 PPR study will provide insight into efficacy
The Phase 2 PRAX-628 PPR study will provide insight into efficacy and inform dose selection for pivotal studies Ranges Which Trigger PPR Response RESPONSE 60 Hz PPR present • The PPR Photosensitivity Model has LIGHT FREQUENCY PPR eliminated been used to assess many AEDs1 18 Hz • Reduction of PPR pho
Slide 71: PRAXIS "Dare for More"
PRAXIS “DARE FOR MORE"
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