Praxis Precision Medicines, Inc. · NASDAQ:PRAX
Praxis Precision Medicines — Investor Presentation (August 2023)
45 slides from Praxis Precision Medicines's investor presentation, Aug 9, 2023
Slide 1: Corporate Overview August 2023
CORPORATE OVERVIEW August 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 across Cerebrum and Solidus platforms
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 Essential Tremor Key Upcoming Milestones
8 Q4 2023 ET Phase 3 Initiation Ulixacaltamide (PRAX-944) Essential Tremor 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: Essential tremor has large market potential and limited competition
11 Essential tremor has a large market potential and limited competition compared with other diseases Source: Evaluate Pharma US Sales by Product (#) number of drugs with branded revenue report by company *US products sales are not indication specific $0 $1 $2 $3 $4 $5 $6 - 1 2 3 M AR KE T VA LU E (
Slide 12: Active 2023 as ulixacaltamide marches towards Phase 3
12 Essential1 Phase 2 Study • Clinically meaningful effect • Well tolerated safety profile Active 2023 as ulixacaltamide marches towards Phase 3 Continue to generate supportive data and de-risk Phase 3 trial design 1mADL11 comprises 11 elements of the TETRAS Activities of Daily Living, excluding soc
Slide 13: T-type calcium channels gatekeep neuronal firing in the CTC circuit
13 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 14: Ulixacaltamide is a differentiated, selective T-type calcium channel blocker
14 Ulixacaltamide is a differentiated, selective T-type calcium channel blocker in development for movement disorders 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 a
Slide 15: Wide dosing range and modified release formulation
15 Ulixacaltamide’s wide dosing range and modified release formulation supports late-stage development and registration potential Source: Praxis Data on fil. 1. Profile for 20mg dose 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) S
Slide 16: mADL11 as Phase 3 endpoint used in Phase 2 program
16 mADL11 as Phase 3 endpoint has been successfully used in the Phase 2 program 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 10. Working 11. Overall disability with most affecte
Slide 17: Treated patients continue to benefit after 14 weeks
17 -5.00 -4.00 -3.00 -2.00 -1.00 0.00 8 10 12 14 CH AN GE IN M AD L1 1 V. B AS EL IN E (D AY 0 ) Ulixacaltamide treated patients continue to benefit after 14 weeks on treatment 1.7 point1 improvement week 8 to week 14 for patients remaining on ulixacaltamide beyond the Essential1 readout • Patients
Slide 18: Transition from placebo to ulixacaltamide supports benefit
18 5.00 4.00 3.00 2.00 1.00 0.00 8 10 12 14 CH AN GE IN M AD L1 1 V. B AS EL IN E (D AY 0 ) 3.2 point2 improvement week 8 to week 14 for patients moving from placebo to ulixacaltamide Transition from placebo to ulixacaltamide supports benefit of treatment 1.7 point1 improvement week 8 to week 14 for
Slide 19: Randomized withdrawal study supports Phase 3 design
19 Randomized withdrawal randomized study supports design of proposed Phase 3 Sub-study design summary: Patients were re-randomized in a blinded-fashion to either receive placebo or continue to receive ulixacaltamide. Twenty-one patients who completed assessments at Week 14 of the OLE were eligible
Slide 20: Phase 3 program of two complementary 12-week studies
20 Randomization Randomized Withdrawl Study Placebo-Controlled Parallel Group Study • Single dose (60 mg) • Control for intention tremor, family history and propranolol use by arm • Agreement on the size of safety database for registration to include 300 subjects for 6 months of exposure and 100 sub
Slide 21: PRAX-562 Key Upcoming Milestones
21 PRAX-562 SCN2A, SCN8A & OTHER DEEs KEY UPCOMING MILESTONES Q4 2023 Ph 2 EMBOLD Study Topline Results
Slide 22: PRAX-562 potential first- and best-in-class small molecule for DEEs
22 Preclinical and emerging clinical data demonstrate PRAX-562 has the potential to be a first- and best- in-class small molecule for DEEs Superior selectivity for disease-state NaV channel hyperexcitability Convenient auto-titration regimen with stable PK Unprecedented therapeutic window with poten
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: PRAX-562 potency and selectivity comparison
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 inhibits seizures in SCN2A and SCN8A mouse 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 1 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 design
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 2H 2023 Topline Results from Phase 2 PPR 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 hyperexcitable state of sodium channels in the brain associated with disease Favorable safety and tolerability profile across broad concentration range in healthy
Slide 32: PRAX-628: Road to Phase 2 focal epilepsy study
32 PRAX-628: Road to Phase 2 focal epilepsy study DECEMBER MAY AUGUST 2H ’23 Phase 1 Study qEEG Analysis Confirmed pharmacodynamic activity across all dose levels for study subjects who received PRAX-628 Topline results Phase 2 PPR study 1H’24 Initiate Phase 2 Focal study Phase 1 Safety Study Demons
Slide 33: Preferential action against hyperexcitability
33 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 34: PRAX-628 delivers improved potency and separation to tonic inhibition
34 C. MARGINS BETWEEN DISEASE CURRENT INHIBITION TO TONIC BLOCK OF HEALTY CURRENT 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 Cenobamat
Slide 35: PRAX-628 margins over best-in-class ASMs
35 PRAX-628 has unprecedented margins over best in class ASM’s based on MES efficacy and clinical tolerability in humans Source: Praxis data on file Cenobamate Cmax: >46,100 ng/mL, 400 mg Cmax (Vernillet et al 2020) XEN1101 Cmax: >107 ng/mL (Phase 1 data) x MES EC50 = multiple of predicted human EC5
Slide 36: Photosensitivity frequency range reduction indicates AED efficacy
36 Reduction of photosensitivity frequency range relative to baseline or PBO is ASM activity is indicative of AED efficacy 18 Hz 60 Hz 2 Hz BASELINE: PLACEBO WITH DRUG LI GH T FR EQ UE NC Y PPR present PPR eliminated PARTIAL RESPONSE 1 References: First Pub: C.D. Binnie Electroencephalography and cl
Slide 37: Solidus ASO Platform
37 SOLIDUS™ ASO PLATFORM
Slide 38: PRAX-222 SCN2A-GoF ASO Key Upcoming Milestones
38 2H 2023 EMBRAVE Study First Dose Cohort (Part 1) Topline Safety Results PRAX-222 SCN2A-GoF ASO KEY UPCOMING MILESTONES
Slide 39: PRAX-222 potential to be disease-modifying for SCN2A GoF DEE
39 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 40: PRAX-222 EMBRAVE study initial dose cohort
40 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
Slide 41: PRAX-222 down-regulates SCN2A expression
41 PRAX-222 is an ASO designed to down-regulate SCN2A expression in patients with gain-of-function mutation
Slide 42: PRAX-222 down-regulates mRNA and protein in vitro
42 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 43: PRAX-222 increases survival in SCN2A GoF mice
43 PRAX-222 increases survival in SCN2A GoF mice ***p<0.001 ****p<0.0001 All experiments conducted with SCN2A R1882Q mouse model SCN2A ASO INCREASES SURVIVAL WITH A SINGLE DOSE INJECTION 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 Postnata
Slide 44: Simulated mRNA knockdown in human cortex
44 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
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