Slides
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Corporate Overview January 2026
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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, expectations and assumptions regarding the future of our business, future plans and strategies, , including statements regarding the estimated market for our product candidates, if approved, our development plans, our preclinical and clinical results and other future conditions, including our cash runway, and the safety, efficacy, and regulatory and clinical design or progress, potential regulatory submissions, approvals and timing thereof of any of our product candidates. Any forward-looking statements in this presentation are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this presentation, including, without limitation, risks relating to: (i) the success and timing of our ongoing clinical trials, (ii) the success and timing of our product development activities and initiating clinical trials, (iii) the success and timing of our collaboration partners’ product development activities, (iv) the timing of and our ability to obtain and maintain regulatory approval of any of our product candidates, (v) our plans to research, discover and develop additional product candidates, (vi) our ability to enter into collaborations for the development of new product candidates, (vii) our ability to establish manufacturing capabilities, and our collaboration partners’ abilities to manufacture our product candidates and scale production, (viii) our ability to meet any specific milestones set forth herein, and (ix) the potential addressable market sizes for product candidates. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. Although we believe the expectations reflected in such forward-looking statements are reasonable, we can give no assurance that such expectations will prove to be correct. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. For further information regarding the risks, uncertainties and other factors that may cause differences between our expectations and actual results, you should review the “Risk Factors” section of our Annual Report on Form 10-K for the year ended December 31, 2024 and as updated in our Quarterly Report on Form 10-Q for the quarter ended June 30, 2025, as well as other filings made with the Securities and Exchange Commission . Certain information contained in this presentation relates to or is based on studies, publications, surveys and other data obtained from third-party sources and our own internal estimates and research. While we believe these third-party sources to be reliable as of the date of this presentation, we have not independently verified, and make no representation as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. In addition, all of the market data included in this presentation involves a number of assumptions and limitations, and there can be no guarantee as to the accuracy or reliability of such assumptions. Finally, while we believe our own internal research is reliable, such research has not been verified by any independent source. Forward Looking Statements
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3 The needs of patients with CNS disorders are devastatingly urgent. Our mission is to help patients by delivering life-altering treatments faster and more effectively than has ever been done before — and to do it again and again. PRAXIS’ MISSION
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4 2025 2025 Success is Poised to Continue over the Next 24 Months Next 24 months Portfolio Highlights Ulixacaltamide • Positive Essential3 Study1 and Study2 • Pre-NDA meeting for ulixacaltamide • Received Breakthrough Therapy Designation (BTD) Relutrigine • Positive EMBOLD readout • Received BTD Vormatrigine • RADIANT positive in 2 cohorts • Vormatrigine POWER1 recruitment completed Elsunersen • FDA meeting approved streamlined study design Ulixacaltamide NDA Ulixacaltamide Relutrigine SCN2A/8A DEE Vormatrigine POWER2: Adjunctive focal epilepsy >$20B potential peak revenue Next 24 months ElsunersenCommercial Launches Clinical Updates Relutrigine DEEs Elsunersen EMBRAVE A Elsunersen EMBRAVE3 Relutrigine EMERALD Vormatrigine POWER3 mono- therapy focal epilepsy Vormatrigine POWER1: Adjunctive focal epilepsy Relutrigine NDA Vormatrigine NDA Elsunersen NDA
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5 Praxis is Set to Capitalize on Late-Stage Portfolio Holding Over $20bn in Commercial Potential ulixacaltamide relutrigine vormatrigine elsunersen TOTAL REVENUE Essential Tremor SCN2A/8A & Broad DEEs FOS & Generalized Epilepsy SCN2A DEE >$10B >$5B ~$1B >$4B >$20B
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6 Pricing for recent approvals reflects significant value to patients Praxis portfolio poised for similar impact • High unmet-need indications with few, if any, effective treatment modalities • Significant price potential within current market analogs SKYCLARYS® omaveloxolone EVRYSDI® risdiplam SEPHIENCE® sepiapterin STRENSIQ® asfotase alfa BRINEURA® cerliponase alfa relutrigineulixacaltamide REZDIFFRA® resmetirom NUPLAZID® pimavanserin INGREZZA® valbenazine AUSTEDO® deutetrabenazine vormatrigine elsunersen Praxis Portfolio Commercial Pricing Analogs Common indications Rare indications REXULTI® brexiprazole
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7 PROGRAM PRE CLINICAL PHASE ONE PHASE TWO PHASE THREE NDA Cerebrum SMALL MOLECULE PLATFORM Ulixacaltamide Essential Tremor1 Vormatrigine Adjunctive focal epilepsy Monotherapy focal epilepsy Relutrigine SCN2A- and SCN8A-DEE2 Broad DEEs PRAX-020 KCNT13 Solidus ASO PLATFORM Elsunersen Early Onset SCN2A 4 PRAX-080 PCDH19 PRAX-090 SYNGAP1 PRAX-100 SCN2A LoF Praxis comprehensive CNS pipeline 1. Ulixacaltamide has received Breakthrough Therapy Designation 2. Relutrigine has received Breakthrough Therapy Designation (BTD), Orphan Drug Designation (ODD) and Rare Pediatric Disease (RPD) designation from the FDA, and ODD from the European Medicines Agency (EMA) for the treatment of SCN2A and SCN8A-DEE and RPD designation for Dravet Syndrome 3. PRAX-020 (KCNT1) has been licensed to UCB 4. Elsunersen has received ODD and RPD designation from the FDA, and ODD and PRIME designations from the EMA for the treatment of SCN2A GoF DEE=developmental & epileptic encephalopathy, GoF=gain-of-function, LoF=loss-of-function, PRIME=Priority Medicines
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8 MOVEMENT DISORDERS: Ulixacaltamide for Essential Tremor
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9 • An estimated 7 million people in the U.S. live with ET • Major functional impacts affecting writing, eating, drinking and social activities • High psychosocial burden (frustration, anxiety, embarrassment, isolation) • Significant proportion receive no or inadequate treatment Essential Tremor: A Major Unmet Need No ET-specific FDA-approved therapies
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10 PRIMARY ENDPOINT % MAINTAIN RESPONSE Essential3: Two Positive Phase 3 Studies Supporting Breakthrough Therapy Designation and NDA Filing in early 2026 The first successful Phase 3 program for a drug in Essential Tremor -4.3 -1.7 p= 0.0000014 ULIXACALTAMIDE (n=199) PLACEBO (n=233) 55% 33% p=0.037 ULIXACALTAMIDE (n=40) PLACEBO (n=40) OR=2.7 (1.06-6.92) • Effect as early as 2 weeks and maintained for 12-weeks • Improvement in secondary endpoints rate of disease improvement, PGI-C and CGI-S for all timepoints • Benefit for patients on background propranolol and other ET medications, with or without intention tremor and with or without family history of ET • Demonstrates maintenance of benefit • Validates durability and robustness of response • Reinforces functional benefit observed in Study 1 Favorable tolerability with no drug-related SAEs. Majority of TEAEs were mild to moderate, occurred within 2 weeks of starting treatment and resolved quickly without intervention. mADL11: modified score derived from items 1 to 11 of the TETRAS-Activities of Daily Living; CFB: Change from Baseline; OR: Odds Ratio; TEAE: Treatment Emergent Adverse Event PRIMARY ENDPOINT mADL11 CFB TO DAY 56 Study 1: 12-week Parallel-group Design (n=432) Study 2: Blinded Stable Responder, Randomized Withdrawal Design (n=80)
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11 COMMON EPILEPSY: Vormatrigine
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12 Sources: AAN 2023 Poster - PRAX-628: A Novel Sodium Channel Blocker with Greater Potency and Activity Dependence Compared to Standard of Care; Kahlig, K., Chapman, M., Petrou, S. AAN 2024 Poster - First-in-human Phase 1 Clinical Trial Evaluating the Safety, Tolerability, Pharmacokinetics and Food Effect of Vormatrigine in Healthy Participants; Hansen, K.; Frizzo, S., Jacotin, H., Patel, D., Epstein, N., Patel, A., Sun, H., Petrou, S., Souza, M. 1. Praxis Claims Analysis on File 2024. FOS patient cohort (n = 440k) ASM: Anti-Seizure Medication • An estimated 3 million patients live with epilepsy • ~35% of patients change medications annually • 63% require two or more medications 1 • Treatments are needed which are: • Fast acting • Durable • Better tolerability • Compatible with complex regimens Vormatrigine poised to rapidly transform the epilepsy landscape • Once daily dose, fast acting • No need to be taken with food or require dietary changes Ease of Administration • Favorable safety profile • Minimal drug-drug interaction risk with common ASMs Ideal Tolerability and Limited DDIs Vormatrigine: Best-in-Disease Sodium Channel Modulator • Best-in-disease efficacy in the RADIANT study • Broad applicability across focal and generalized epilepsy • Sustained long-term effect Superior Efficacy Epilepsy is a chronic neurological disorder that affects all age groups, causing life- threatening seizures
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13 MEDIAN % REDUCTION IN FOCAL SEIZURES (Weeks 1-16) RADIANT Phase 2 study showed disease-leading efficacy 100% median seizure reduction after 10 weeks Hansen et al AES 2025 DISEASE IMPACTING CRITERIA RADIANT RESULTS Speed and durability of response • Rapid response after only 1 week of dosing • By week 10 median reduction was 100% • Generalized epilepsy patients had similar benefit of FOS patients Efficacy with other ASMs • Patients were on an average of 2.1 ASMs • >30% of patients on best approved drug (Cenobamate) Seizure freedom • 11% of patients were seizure free within the treatment period • Over 30% were seizure free for any 28-day period Safety & tolerability • Lowest rate of TEAEs and CNS AEs with modern ASMs • Most AEs were mild to moderate and transient
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14 Total Addressable Market (patients) Vormatrigine ENERGY Program: Developing for Broad, Foundational Use Pivotal Efficacy Studies Proof of Concept in Focal and Generalized epilepsy, Safety & tolerability POWER1, n= 230+ POWER2, n=400 RADIANT POWER3 Study evaluating Vormatrigine as a single agent STUDY / OBJECTIVE 2H 2025 1H 2026 2H 2026 Third Line: ~1m • Rapid, durable effect • Significant impact in seizures after 8 weeks • 100% median reduction at 10 weeks for OLE • Over 1/3 patients seizure free for any 28-day period • Improved efficacy on top of SoC • TEAEs mostly mild/moderate and transient First Line: 3+m
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15 DEVELOPMENTAL & EPILEPTIC ENCEPHALOPATHIES (DEEs) Relutrigine, Elsunersen
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16 Relutrigine: Potential for class leading efficacy and tolerability AE: adverse event, DEE: developmental & epileptic encephalopathy, NaV: voltage-gated sodium channel, SAE: serious adverse event Relutrigine Small molecule functional state modulator No titration required Once daily dosing Liquid formulation - oral or G/J tube administration Precision Mechanism: Superior selectivity for hyperactive NaV channels, a known driver of seizure activity across DEEs Clinical Profile: • Demonstrated robust seizure reduction and unprecedented seizure- free periods over 28-day intervals • Generally well-tolerated with mostly mild to moderate AEs, no drug- related SAEs and no dose reductions required Regulatory Designations: • FDA: Orphan Drug, Rare Pediatric Disease Designations for SCN2A DEE, SCN8A DEE, and Dravet syndrome, plus Breakthrough Therapy • EMA: Orphan Drug Designations for SCN2A DEE and SCN8A DEE • Planned NDA submission early 2026
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17 Kamireddy et al AES 2025 EMBOLD results: Disease modifying results in SCN2A/8A DEEs supports NDA filing • >80% of patients were on stable doses of Sodium Channel Blockers at baseline • AEs were mostly mild to moderate • No drug-related SAEs • No dose reduction of relutrigine required MARKED IMPROVEMENT IN DISEASE MODIFYING DOMAINS 78% 67% 78% 35% 78% 53% 78% 27% 0% 20% 40% 60% 80% Seizure Severity and Intensity Communication Alertness Disruptive Behavior Clinician Caregiver SEIZURE REDUCTION OVER TIME ON RELUTRIGINE COHORTS 1 and 2, COHORT 1 OLE PROPORTION OF PATIENTS IMPROVING BY DOMAINMonths of Exposure
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18 • All genetically driven DEEs result in hyperactivation of sodium channels, manifesting in epilepsy syndromes • Relutrigine’s mechanism of action targets hyperactive NaV channels addressing the neuronal hyperexcitability driving seizures • By targeting a common pathway implicated in DEE symptomology, relutrigine has the potential to be applicable across a broad range of DEEs Relutrigine’s potential for broad applicability across multiple etiologies *Illustrative etiologies, not limited by examples shown DEE=developmental & epileptic encephalopathy, NaV=voltage-gated sodium channel OtherCDKL5 KCNQ2 SCN1A SCN2A SCN8A TSC MECP2 UPSTREAMDOWNSTREAM Sodium channels KCNH1 KCNC1 KCNA1 HCN1 PCDH19SYNGAP1SEIZURE DRIVER MOST SEIZURE ETIOLOGIES CONVERGE AT SODIUM CHANNELS*
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19 Mechanistic Precision: • Selective targeting of SCN2A gain-of-function mutations, a key driver of early-onset, severe seizure activity • ASO-mediated degradation of SCN2A mRNA reduces NaV1.2 hyperactivity, normalizing neuronal excitability Clinical Profile : • Significant reduction in seizures achieved in SCN2A GoF patients • No adverse events were considered treatment-emergent or serious Regulatory Designations : • FDA: ODD and Rare Pediatric Disease designation • EMA: ODD and PRIME designation Elsunersen: First-in-Class ASO for SCN2A GoF DEE ELSUNERSEN Antisense oligonucleotide (ASO) Intrathecal administration Once every 4 weeks Designed for selective SCN2A mRNA reduction DEE=developmental & epileptic encephalopathy, GoF=gain-of-function, PRIME= Priority Medicines
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20 Key endpoints: • Incidence and severity of treatment-emergent adverse events (TEAEs) • Change from baseline in monthly (28-day) motor seizure frequency Safety: • No TEAEs or SAEs considered related to study drug • All TEAEs recovered/ resolved EMBRAVE Part 1 showed clinically meaningful seizure reduction in SCN2A GoF patients Frizzo S, et al. EEC 2024, Praxis data on file. ClinicalTrials.gov Identifier: NCT05737784. https://clinicaltrials.gov/study/NCT05737784 GoF=gain-of-function, SAE=serious adverse event -39% -43% Improvement 52% 48% MEAN MEDIAN Improvement OVERALL % REDUCTION IN SEIZURES FROM 28-DAY BASELINE (N=4) OVERALL RELATIVE % INCREASE IN SEIZURE-FREE DAYS FROM 28-DAY BASELINE (N=4) MEAN MEDIAN Upcoming EMBRAVE Part A and EMBRAVE3 create a complete, NDA-ready registrational package for elsunersen in SCN2A GoF DEE
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21 Long, multi-layered and strong IP position across the clinical portfolio 2039 2042 2046 relutrigine ulixacaltamide vormatrigine US Current Exclusivity1 US Potential Exclusivity2 ulixacaltamide relutrigine vormatrigine elsunersen elsunersen 1 based on US Patent Nos. 11,649,207; 11,427,540; 12,077,502; 11,014,931; 12,325,711;11,866,439; 11,731,976; 11,731,978; and 12,227,746 2 based on issuing of US App Nos. 17/975,457; 18/834,466; 19/312,146; 18,885,261 and others
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22 Appendix Ulixacaltamide Relutrigine Vormatrigine Elsunersen
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23 Two platforms enabling repeatable CNS innovation * Relutrigine has received Breakthrough Therapy Designation (BTD), Orphan Drug Designation (ODD) and Rare Pediatric Disease (RPD) designation from the FDA, and ODD from the European Medicines Agency (EMA) for the treatment of SCN2A and SCN8A-DEE and RPD designation for Dravet Syndrome ^ PRAX-020 (KCNT1) has been licensed to UCB ** Elsunersen has received ODD and RPD designation from the FDA, and ODD and PRIME designations from the EMA for the treatment of SCN2A GoF DEE=developmental & epileptic encephalopathy, GoF=gain-of-function, LoF=loss-of-function, PRIME=Priority Medicines 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 precision therapies Solidus ANTISENSE OLIGONUCLEOTIDE (ASO) PLATFORM Solidus is an efficient, targeted precision medicine discovery and development engine for ASOs anchored on proprietary, computational methodology MOLECULE INDICATION MECHANISM ulixacaltamide Essential Tremor T-type calcium channel modulator vormatrigine Focal Onset Seizures & Generalized Epilepsy Sodium channel functional state modulator for broad use relutrigine* DEE Sodium channel functional state modulator for pediatric use PRAX-020^ KCNT1 Epilepsy KCNT1 specific inhibitor PRAX-050 Movement Disorders Not disclosed MOLECULE INDICATION MECHANISM elsunersen** SCN2A DEE Gapmer ASO PRAX-080 PCDH19 DEE Gapmer ASO PRAX-090 SYNGAP1 DEE Splice switching ASO PRAX-100 SCN2A Autism Undisclosed mechanism ASO
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24 Ulixacaltamide: Precision Modulation of Tremor Circuits Images from Matthews et al. Ann Clin Transl Neurol. 2023 • Mechanism of Action selectively modulates T-type calcium channels within the cerebello-thalamo-cortical circuit, normalizing abnormal tremor oscillations. • Modified release formulation blunts Cmax and distributes ~70% of dose over 8-hour period Aberrant T-type calcium channel activity in the cerebello- thalamo-cortical circuit drives essential tremor Targeting T-type Ca²⁺ channels offers circuit-level normalization
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25 Surveys of >400 ET patients across the US highlight ongoing hidden burden of ET and associated challenges in managing everyday life Praxis data on file. The Essential Tremor Patient Research was conducted by Fuel Insights (www.fuelinsights.com) from June-July 2024. Two separate surveys were completed online and included 150 US adults living with ET and a further 261 US adults living with ET who were pre-screened, but did not qualify, for the Essential3 study (https://essential3study.com/) ET burden has a profound impact on daily activities Patients with ET experience high psychosocial burden ET is inadequately managed and undertreated UP TO 80% working / attending social events writing drinking from a glass frustratedworried of patients do not feel their ET symptoms are manageable with current treatments of patients are not receiving treatment for their ET of patients with ET reported needing to adjust how they complete daily tasks due to their symptoms TOP CHALLENGES: ashamed sad hopeless UP TO 77% UP TO 50% Nearly all patients with ET experience a level of psychosocial burden, with many reporting feeling:
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26 US neurologists emphasize the need for more effective treatments and the importance of patient-physician dialogue in ET of neurologists reported mental and emotional challenges among the top three challenges for their ET patients of neurologists stated their patients’ descriptions of their ET symptoms and impact on daily activities influence treatment decisions of neurologist visits are for patients seeking ET treatment of neurologists rarely refer ET patients for specialist management >90% ET burden has a profound impact on daily activities Patients with ET experience high psychosocial burden ET is inadequately managed and undertreated 60% 85% NEARLY 1/2 Praxis data on file. The Essential Tremor Patient Research was conducted by Fuel Insights (www.fuelinsights.com) from June-July 2024. Two separate surveys were completed online and included 150 US adults living with ET and a further 261 US adults living with ET who were pre-screened, but did not qualify, for the Essential3 study (https://essential3study.com/)
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27 Essential3: An ambitious and innovative Phase 3 program Blinded randomization 2:1 (Study 1: Study 2) occurred following completion of screening Blinded randomization 1:1 (Ulixacaltamide: Placebo) for treatment arm allocation in Study 1 and for treatment arm allocation of Responders into the randomized withdrawal phase in Study 2 STUDY 1: PLACEBO-CONTROLLED PARALLEL GROUP STUDY Ulixacaltamide n=199 (mITT) Placebo n=233 (mITT) STUDY 2: RANDOMIZED-WITHDRAWAL STUDY Ulixacaltamide n=147 Randomization of Responders N=80 Ulixacaltamide n=40 Placebo n=40 BLINDED LEAD-IN 8 WEEKS RW: 4 WEEKS 12 WEEKS R 2:1 N = 473 Randomized N = 238 Randomized R 1:1
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28 Study 1 Baseline demographics - mITT ULIXACALTAMIDE (N = 199) PLACEBO (N = 233) Age, Mean (SD) 67.9 (9.1) 68.9 (8.1) Gender, Male/Female % 57.3% / 42.7% 56.7% / 43.3% Race, White/Other % 98.5% / 1.5% 95.7% / 4.3% Years since ET Onset, Mean (Median) 29.8 (26.0) 31.1 (27.0) ET symptoms worsened over past 3 years, Yes % 188 (94.5%) 216 (92.7%) Currently on ET Medication, Yes % Currently on Propranolol, Yes % 44.2% 35.7% 48.1% 36.5% Family History of ET, Yes/No/Unknown % 71.9% / 20.6% / 7.5% 72.1% / 19.7% / 8.2% Presence of Intention Tremor, Yes % 65.3% 66.1% mADL11, Mean (SD) 18.5 (2.4) 18.4 (2.4) Patient Global Impression – Severity, Mean (SD) 3.0 (0.7) 2.9 (0.7) Clinician Global Impression –Severity, Mean (SD) 4.0 (0.6) 4.0 (0.6)
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29 Study 1 - Primary and all key secondary efficacy endpoints met -4.3 -1.7 ULIXACALTAMIDE (n=199) PLACEBO (n=233) LS means for the mADL11 were estimated using a mixed model for repeated measures with treatment group, visit (categorical), trea tment-by-visit interaction, randomization strata (IT status, propranolol use, family history of ET), and baseline mADL11 score as fixed effects; subject was a random effect with an unstructured covariance matrix. Sensitivity to missingness was done with a pre-specified delta-adjusted tipping-point analysis which remained statistically significant at the maximum pre-specified shift (Δ = 2.5; p = 0.0026), exceeding the ~½ SD robustness criterion of Ratitch et al. (2013) and confirming strong resilience of the primary endpoint to non- MAR assumptions. Primary Endpoint mADL11 CFB to Day 56 p= 0.0000014 Secondary Endpoint Analyses: Rate of Disease Improvement: p < 0.0001 ; PGI-C: p < 0.0001 ; CGI-S: p = 0.0007
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30 Study 1 - Rapid and consistent response over 12 weeks All Visits: p-value < 0.017
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31 Study 1 efficacy – Robust response across subgroups All subgroups: p-value < 0.05
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32 Study 1 Efficacy remains significant under extreme scenarios LS means for the mADL11 were estimated using a mixed model for repeated measures with treatment group, visit (categorical), trea tment-by-visit interaction, randomization strata (IT status, propranolol use, family history of ET), and baseline mADL11 score as fixed effects; subject was a random effect with an unstructured covariance matrix. Sensitivity to missingness was done with a pre-specified delta-adjusted tipping-point analysis which remained statistically significant at the maximum pre-specified shift (Δ = 2.5; p = 0.0026), exceeding the ~½ SD robustness criterion of Ratitch et al. (2013) and confirming strong resilience of the primary endpoint to non- MAR assumptions. Jump to reference (JTR) sensitivity conducted using the ITT population with both the MMRM and ANCOVA models (p-value < 0.001).
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33 Study 1 – Clinical meaningfulness with mADL11 and ADL -4.3 -1.7 ULIXACALTAMIDE (n=199) PLACEBO (n=233) LS means for the mADL11 were estimated using a mixed model for repeated measures with treatment group, visit (categorical), trea tment-by-visit interaction, randomization strata (IT status, propranolol use, family history of ET), and baseline mADL11 score as fixed effects; subject was a random effect with an unstructured covariance matrix. Sensitivity to missingness was done with a pre-specified delta-adjusted tipping-point analysis which remained statistically significant at the maximum pre-specified shift (Δ = 2.5; p = 0.0026), exceeding the ~½ SD robustness criterion of Ratitch et al. (2013) and confirming strong resilience of the primary endpoint to non- MAR assumptions. Primary Endpoint mADL11 CFB to Day 56 -5.5 -2.1 p < 0.0001 ULIXACALTAMIDE (n=199) PLACEBO (n=233) ADL CFB to Day 56 p= 0.0000014
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34 Study 2 – RW baseline demographics – stable-responders BLINDED LEAD-IN ULIXACALTAMIDE ULIXACALTAMIDE STABLE RESPONDERS Age, Mean (SD) 67.9 ( 7.9) 67.3 (8.4) Gender, Male/Female % 51.8% / 48.2% 55.0% / 45.0% Race, White/Other % 96.3% / 3.7% 95.0% / 5.0% Years since ET Onset, Mean (Median) 28.7 (25.0) 28.5 (24.5) ET symptoms worsened over past 3 years, Yes % 95.8% 93.8% Currently on ET Medications, Yes % Currently on Propranolol, Yes % 42.4% 34.6% 41.3% 38.8% Family History of ET, Yes/No/Unknown % 73.3% / 22.0% / 4.7% 76.3% / 18.8% / 5.0% Presence of Intention Tremor, Yes % 63.9% 53.75% mADL11, Mean (SD) 19.0 (2.5) 10.6 (4.8) Patient Global Impression – Severity, Mean (SD) 3.0 (0.7) 1.2 (0.6) Clinician Global Impression – Severity, Mean (SD) 4.0 (0.7) 3.1 (0.9)
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35 Study 2 efficacy - Primary and first secondary endpoint met 55% 33% p=0.037 ULIXACALTAMIDE (n=40) PLACEBO (n=40) OR=2.7 (1.06-6.92) For primary endpoint, odds ratio, 95% confidence interval, and p-value were obtained from a logistic regression model including treatment group as the main effect and randomization strata (IT status, propranolol use, and family history of ET) as fixed effects. Primary Endpoint % Maintain Response Secondary Endpoint Analyses: Rate of Disease Improvement: p =0.0042 ; PGI-C: p = 0.0871 ; CGI-S: p = 0.0545
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36 -4.3 -1.7 p < 0.0001 ULIXACALTAMIDE (n=390) PLACEBO (n=233) Primary Endpoint mADL11 CFB to Day 56 Hypothesis 3– Day 56 Parallel-group combined efficacy analysis All Visits: p < 0.0001
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37 -4.2 -1.7 p < 0.0001 ULIXACALTAMIDE (n=191) PLACEBO (n=233) Primary Endpoint mADL11 CFB to Day 56 Hypothesis 4– Day 56 Parallel-group combined efficacy analysis All Visits: p < 0.0004
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38 • No change in overall safety profile and no new signals identified • Most common TEAEs (≥10%) in participants treated with ulixacaltamide were constipation, dizziness, euphoric mood, brain fog, headache, paraesthesia and insomnia. • Discontinuations were primarily due to AEs, with most common due to dizziness and brain fog • Majority of TEAEs were mild to moderate in severity • No SAEs related to ulixacaltamide Safety across studies remains consistent
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39 Essential3 Program: Study 1 and Study 2 disposition Study 1 Enrolled/ITT: All randomized participants Study 2 Enrolled: All randomized participants Safety: All participants who received at least one dose of study drug Study 1 mITT: All randomized participants who received at least one dose and had at least one post-baseline efficacy assessment Study 2 mITT/Stable responders: Participants with an average improvement of three or more points in mADL11 at Days 49 –56, received at least one dose in RW and one post RW baseline efficacy assessment Non-stable responders: Participants at Day 56 who did not meet the criteria for Responders DISPOSITION STUDY 2 DISPOSITION STUDY 1 POPULATIONS OVERALL Enrolled 238 (100%) Population at Day 56 147 (61.8%) Stable Responders (mITT) 80 (54.4%) Non-stable responders 67 (45.6%) POPULATIONS ULIXACALTAMIDE PLACEBO Enrolled/ITT 236 (100%) 237 (100%) Safety 233 (98.7%) 234 (98.7%) mITT 199 (84.3%) 233 (98.3%)
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40 Safety population – Overview of AEs OVERVIEW OF ADVERSE EVENTS STUDY 1 STUDY 2 ULIXACALTAMIDE (N = 233) PLACEBO (N = 234) ULIXACALTAMIDE (N = 231) Participants with any TEAE 221 (94.9%) 177 (75.6%) 209 (90.5%) Participants with: Mild TEAEs 98 (42.0%) 89 (38.0%) 87 (37.7%) Moderate TEAEs 109 (46.8%) 78 (33.3%) 105 (45.5%) Severe TEAEs 14 (6.0%) 10 (4.3%) 17 (7.4%) Participants with any SAE* 2 (0.86%) 8 (3.4%) 4 (1.73%) Participants with drug-related TEAEs leading to discontinuation 63 (27.0%) 4 (1.7%) 65 (28.1%) Discontinued from the study 83 (35.6%) 13 (5.6%) 88 (38.1%) *none related to study drug
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41 Safety population - Most common TEAEs TREATMENT EMERGENT ADVERSE EVENTS ≥10% OF PATIENTS STUDY 1 STUDY 2 Preferred Term ULIXACALTAMIDE (N = 233) PLACEBO (N = 234) ULIXACALTAMIDE (N = 231) Constipation 57 (24.5%) 16 (6.84%) 68 (29.4%) Dizziness 56 (24.0%) 27 (11.5%) 59 (25.5%) Euphoric mood 30 (12.9%) 3 (1.28%) 15 (6.5%) Brain fog 27 (11.6%) 8 (3.42%) 44 (19.0%) Paraesthesia 23 (9.87%) 5 (2.14%) 27 (11.7%) Fatigue 22 (9.44%) 26 (11.1%) 22 (9.52%) Headache 19 (8.15%) 20 (8.55%) 29 (12.6%) Insomnia 18 (7.73%) 9 (3.85%) 27 (11.7%)
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42 Appendix Ulixacaltamide Relutrigine Vormatrigine Elsunersen
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43 Relutrigine: Mechanistic Differentiation & Superior Selectivity Praxis data on file µM = micromolar Relutrigine Carbamazepine Lamotrigine Concentration to achieve 50% inhibition, µM) .1 1 10 100 1000 Narrow margin between blocking tonic and excitability enhancing currents Wide margin between blocking tonic and excitability enhancing currents Tolerability-Supporting Current • Physiological (Tonic) Sodium Current • Maintains normal neuronal function • Inhibition leads to side effects Pathological Excitability Currents • Currents: • Persistent • Voltage • Use-dependent • Promote hyperexcitability • Inhibition drives anti-seizure efficacy potency efficacy tolerability BALANCING EFFICACY AND TOLERABILITY IN EPILEPSY: SELECTIVE SODIUM CHANNEL INHIBITION PROFILES
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44 KEY ENDPOINTS: • Change from baseline in monthly motor seizure frequency • Length of seizure freedom achieved over a 28-day period • Incidence and severity of treatment- emergent adverse events (TEAEs) • Clinical and Caregiver Global Impression of Improvement and Severity EMBOLD pivotal relutrigine study *Participants randomized (1:1) to receive relutrigine QD for 16 weeks, or relutrigine QD for 12 weeks and matching placebo QD for 4 weeks, with timing of placebo administration blinded for both participants and investigator. ClinicalTrials.gov Identifier: NCT05818553. https://clinicaltrials.gov/ct2/show/NCT05818553 Frizzo et al IEC 2025 DOUBLE -BLIND TREATMENT PERIOD (4 x 4 -week periods 16 WEEKS) Relutrigine 1:1 Randomization and Baseline N=80 (SCN2A/SCN8A) OLE TREATMENT PERIOD Relutrigine for 4 x 4 weeks* 1 mg/kg/day Placebo for 1 x 4 weeks Relutrigine for 3 x 4 weeks* 1 mg/kg/day
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45 EMERALD targets phenotypic DEEs, regardless of etiology Key Inclusion Criteria • Ages ≥2 and ≤65 years • Has a documented diagnosis of a developmental and epileptic encephalopathy in childhood • Has 4 or more countable motor seizures during the 28-day observation period Treatment • Relutrigine or matching placebo 1mg/kg/day. At day 35, the dose may be escalated to 1.5 mg/kg/day Relutrigine 1 mg/kg/day 1:1 Randomization N=160 Placebo OLE TREATMENT DOUBLE-BLIND TREATMENT PERIOD 16 WEEKS Primary Endpoint: Change from baseline in monthly motor seizure frequency ClinicalTrials.gov Identifier: NCT07010471 Kamireddy et al IEC 2025
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46 Appendix Ulixacaltamide Relutrigine Vormatrigine Elsunersen
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47 30 mg vormatrigine QD 8 weeks Observation baseline Safety Follow-up RADIANT patients represent the real-world refractory group NCT#06908356 QD = Once daily N=65 Age (Years) Mean (SD) 43 (14.45) Sex M,F 29,36 # background ASMs Mean (SD) 2.1 (0.85) Concomitant ASM Sodium Channel Blocker SV2A GABA modulators Others 77% 59% 29% 12% Baseline seizure Median (IQR) 9 (4,21)
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48 Vormatrigine Effect in RADIANT: Best-in-Disease Efficacy Hansen et al AES 2025, Wilcoxon sign test p<0.05 in all weeks and overall; LOESS: Locally weighted plot smoothing MEDIAN % SEIZURE REDUCTION BY TREATMENT WEEK
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49 AVG. DAYS ON THERAPY, BY LINE • Source: Praxis Claims Analysis on File 2024. FOS patient cohort (n = 440k) Majority of focal epilepsy patients quickly progress to multiple ASM use by trial and error 295 Days 168 Days 155 Days 129 Days 114 Days Simpler and more rational way to manage patients is needed FOS DX - PATIENTS BY LINE OF THERAPY Improvised layering of drugs does not result in better patient outcome
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50 Vormatrigine safety profile positioned to be best-in-disease ASM 1. Cenobamate Krauss, G. L., et al. The Lancet Neurology,. 2020;19(1), 38–48. https://doi.org/10.1016/S1474-4422(19)30399-0; https://www.ema.europa.eu/en/documents/assessment- report/ontozry-epar-public-assessment-report_en.pdf, 2. XEN1101: French JA, et al; JAMA Neurology. 2023;80(11):1145–1154. doi:10.1001/jamaneurol.2023.3542 3. Episode of diplopia, resolved after reduction of lamotrigine dose Not a head-to-head comparison Vormatrigine 30 mg (N = 65) Cenobamate 400 mg (N = 111) XEN1101 25 mg (N = 114) Study RADIANT Study C0171 X-TOLE2 Discontinuation 16 (25 %) 30 (27 %) 26 (23 %) Patients with ≥ 1 TEAE 44 (68 %) 100 (90 %) 97 (85 %) Patients with severe AEs 4 (6.2 %) 18 (16 %) Not reported Serious AEs (SAEs) 4 (6.2 %) 8 (7 %) 3 (2.6 %) Related SAE 1 (1.5 %)3 – Not reported CNS-related AEs (≥ 10%) 39 (60%) 80 (72.1 %) 83 (72.8 %) Dizziness 21 (32 %) 37 (33 %) 36 (31.6 %) Somnolence 8 (12 %) 41 (37 %) 17 (14.9 %) Headache 9 (14 %) 12 (11 %) 9 (7.9 %) Titration None 12-weeks None Food Effect None; Any time of day, with or without food None; Any time of day, with or without food Yes; Evening dosing with food Significant DDIs N/A Multiple CYP3A
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51 Pivotal POWER1 study topline results 1H 2026, POWER2 enrollment complete 2H 2026 6 weeks, 30mg 12 weeks placebo • Screening • Observation • Randomization Safety Follow-up • Both studies expected to support NDA submission • Range of doses in POWER2 based off PK/PD analysis to optimize efficacy opportunity 6 weeks, 20 mg, QD 6 weeks, 30 mg, QD Open Label Extension or POWER2, n= ~400 Observation period 20 mg Placebo Safety Follow-up Open-label Extension or30 mg 40 mg 12 weeks, QD POWER1, n= 230+ QD: Once-daily dosing
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52 • Key study aspects: • Refractory epilepsy with 1-2 current ASMs • Initiate vormatrigine while titrating off current regimen over 4 weeks • Details to follow after protocol finalization POWER3 designed to demonstrate the potential of vormatrigine as a stand-alone agent • Screening • Observation Vormatrigine monotherapy Monotherapy conversion Safety Follow-up Open-label Extension or Expected to initiate 1H 2026
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53 Appendix Ulixacaltamide Relutrigine Vormatrigine Elsunersen
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54 Precision targeting of SCN2A GoF patients positions elsunersen as a potential disease-modifying therapy ASO=antisense oligonucleotide, DEE=developmental & epileptic encephalopathy, NaV=voltage-gated sodium channel DISEASE STATE: EXCESSIVE SCN2A ACTIVITY ASO TREATED: NORMALIZED SCN2A ACTIVITY • SCN2A mutation leads to hyperactive NaV1.2 sodium channels • Hyperactive channels leads to an increased ion flow leading to seizure • Elsunersen selectively interacts with SCN2A mRNA causing RNase H1 mediated degradation • The number of SCN2A sodium channels is reduced, which normalizes ion flow and reduces seizure activity elsunersen
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55 • Starting dose of 1 mg with optional dose escalation up to 8 mg based on individual tolerability at each dose • Topline results expected 1H 2026 • *Option to increase to n=16 Ongoing EMBRAVE Part A supports registrational package Sham procedure every 4 weeks for 24 weeks 3:1 Randomization Ages >2-18, n=8 Elsunersen 1 mg every 4 weeks for 24 weeks Open Label Extension Key Inclusion criteria • Documented SCN2A GoF variant with seizures prior to 3 months of age • Between the ages of 2 to ≤18 years at Screening • Seizure frequency of 8 or more countable motor seizures per 28-day during Baseline Primary Endpoint • Median percent change in monthly motor seizure frequency from baseline
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56 EMBRAVE3 registrational trial Cohort 1: ages >2-18 yrs (n=30) Open Label Extension Observation Period Elsunersen 1 mg every 4 weeks for 24 weeks Key Inclusion Criteria • Documented SCN2A GoF variant with seizures prior to 3 months of age • Between the ages of 0 to ≤18 years at Screening (ages 2-18 go to Cohort 1, 1-2 to Cohort 2, 0-1 to Cohort 3) • Seizure frequency of 4 or more countable motor seizures per 28-day during baseline Primary Endpoint • Median percent change in monthly motor seizure frequency from baseline ClinicalTrials.gov Identifier: NCT07019922
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