What changed in this filing

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Item 1. Business

2025-02-28 compared with 2024-03-05 · 276 added, 158 removed, 453 unchanged (49% of the section changed)

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Cerebrum ™ (small molecule platform)

We have built a platform, Cerebrum™, which is enabled by innovative computational and experimental tools, to discover and develop first- and best-in-class CNS small molecule therapies.

We have built Cerebrum™, enabled by innovative computational and experimental tools, to discover and develop first- and best-in-class CNS small molecule therapies.

Our world-class ion channel discovery science team, along with external collaborators, accelerate our ability to create and execute novel screening cascades for our selected genetic targets.

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The precision application of our candidates is guided by genomics and informatics to identify, stratify and activate patients for trial recruitment and execution.

To date, Cerebrum™ has generated three clinical stage product candidates – ulixacaltamide (formerly known as PRAX-944), PRAX-562 and PRAX-628, and has the potential to continue delivering first- and best-in-class orally available therapies for genetic CNS targets.

To date, Cerebrum™ has generated three clinical stage product candidates, ulixacaltamide (formerly known as PRAX-944), vormatrigine (formerly known as PRAX-628) and relutrigine (formerly known as PRAX-562), as well as PRAX-020 which has been in-licensed by UCB Biopharma SRL, or UCB.

Cerebrum™ has the potential to continue delivering first- and best-in-class orally available therapies for genetic CNS targets.

Solidus ™ (ASO platform)

We have built a platform, Solidus™, to discover and develop first- and best-in-class ASOs with high probability of advancement into the clinic.

We have built Solidus™ to discover and develop first- and best-in-class ASOs with high probability of advancement into the clinic.

Solidus™ is enabled by our proprietary, computational workflow to discover ASOs with desired drug-like properties to optimize for up/down-regulation, avoidance of toxic motifs and optimization of binding affinity and specificity.

Led by our clinical-stage product candidate, elsunersen (formerly known as PRAX-222), Solidus™ has also generated novel ASOs with preclinical proof of mechanism, including PRAX-080, for which we expect to nominate a development candidate for the treatment of PCDH19 in 2024, PRAX-090, and PRAX-100.

Led by our clinical-stage product candidate, elsunersen (formerly known as PRAX-222), Solidus™ has also generated three novel ASOs with preclinical proof of mechanism that we expect to nominate development candidates for in 2025 — PRAX-080 targeting PCDH19-related developmental epilepsy;

PRAX-090 targeting SYNGAP1 loss-of-function, or LoF, mutation driven developmental epilepsy;

and PRAX-100 targeting SCN2A LoF mutations, the predominant genetic link to de novo autism spectrum disorders.

The platform is uniquely positioned to continue discovering and advancing other new ASOs for novel genetic CNS targets.

Below is a summary of our portfolio:

*PRAX-020 (KCNT1) is a research collaboration with UCB Biopharma SRL

+PRAX-080 (PCDH19), PRAX-090 (SYNGAP1) & PRAX-100 (SCN2A-LoF) ASOs are a collaboration with The Florey Institute of Neuroscience and Mental Health

^PRAX-020 (KCNT1) has been in-licensed by UCB Biopharma SRL

Our Strategy & Approach to Drug Development

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Utilize translational tools to validate the potential of our targets and product candidates.

We leverage translational tools to both confirm pharmacodynamic effects of our drug product candidates in the brain and establish on-mechanism effects.

We leverage translational tools to both confirm pharmacodynamic, or PD, effects of our drug product candidates in the brain and establish on-mechanism effects.

Our programs utilize target-specific electroencephalogram, or EEG, endpoints to serve as robust markers of pharmacological engagement of the drug target and novel transgenic animal models to assess the therapeutic activity of our molecules.

We expect these tools, along with rigorous preclinical pharmacokinetics, or PK, and pharmacodynamic characterization of our molecules will position us to more efficiently translate preclinical findings into clinical utility.

We expect these tools, along with rigorous preclinical pharmacokinetics, or PK, and PD characterization of our molecules will position us to more efficiently translate preclinical findings into clinical utility.

Pursue efficient, rigorous clinical development paths to proof-of-concept in humans .

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We pursue the development of candidates that address the treatment needs of patients, caregivers and the treating community, including targeting the underlying disease pathology versus just symptom management.

We focus on clinical endpoints that offer a clear connection between pharmacodynamic effects and clinical measures that are meaningful to patients, physicians and regulatory agencies.

We focus on clinical endpoints that offer a clear connection between PD effects and clinical measures that are meaningful to patients, physicians and regulatory agencies.

We intend to develop therapies that provide patients long-term relief from their disorders and significantly reduce the overall burden to patients and caregivers.

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Additionally, we have an exclusive collaboration and license agreement with Tenacia Biotechnology (Shanghai) Company, Ltd., a China-based portfolio company of Bain Capital, to develop and commercialize ulixacaltamide for the treatment of ET in China, Hong Kong, Macau and Taiwan.

Ulixacaltamide Phase 3 Essential3 trial

Ulixacaltamide has the potential to be developed for other indications, including Parkinson’s disease.

Ulixacaltamide Phase 3 Essential3 Program

Essential3 is a decentralized, Phase 3, multi-study, clinical trial evaluating the safety and efficacy of 60 mg of ulixacaltamide in ET.

The study includes two separate and simultaneous Phase 3 pivotal studies, of which one is a 12-week parallel design and the other a 12-week randomized withdrawal design, with all participants undergoing one screening process and a long-term safety study, or LTSS.

The trial includes two separate and simultaneous Phase 3 pivotal studies — a 12-week parallel design, placebo-controlled study (N=400), or Study 1, and a 12-week randomized withdrawal study (N=200), or Study 2 — with all participants undergoing one screening process and a long-term safety study, or LTSS.

The study uses the modified Activities of Daily Living 11, or mADL11, as the primary endpoint.

Enrollment for the Phase 3 trials is expected to be completed in the first half of 2024, with topline results expected in the second half of 2024 to support a potential New Drug Application, or NDA, submission in 2025.

A pre-planned interim analysis of Study 1 was conducted in the first quarter of 2025.

The Independent Data Monitoring Committee, or IDMC, overseeing the interim analysis of Study 1 of the Essential3 program has provided Praxis with the outcome of such analysis.

Based on the predefined decision framework for Study 1, the IDMC has recommended that the study be stopped for futility, due to the results being unlikely to meet the primary efficacy endpoint under the parameters set by the statistical model.

The committee also indicated that some underlying assumptions of the statistical model might have influenced this outcome and encouraged us to explore alternative analysis methods.

Given the advanced state of enrollment for both Study 1 and Study 2 in the Essential3 program, and in the context of the advice received by the IDMC, we have decided to continue both studies to completion, with topline results expected in the third quarter of 2025.

The decision about whether the data supports the submission of an NDA will be made after analyzing the final results for Study 1 and Study 2.

Essential1 study

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Topline results for the Phase 2b Essential1 study were announced in the first quarter of 2023.

Results of the Essential1 study informed an end-of-Phase 2 meeting with the FDA and the design of the Phase 3 Essential3 program.

Results of the Essential1 study informed the design of the Phase 3 Essential3 program.

Essential Tremor

ET is the most common movement disorder with a prevalence of approximately 7 million patients in the United States alone, including more than two million diagnosed patients, one million of whom are actively treated for their ET.

ET is the most common movement disorder with a prevalence of approximately seven million patients in the United States alone, including more than two million diagnosed patients, one million of whom are actively treated for their ET.

ET is characterized by involuntary rhythmic movements in the upper limbs that significantly disrupt ability to function and are progressive in nature.

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For these reasons, approximately 40% of patients who seek pharmacotherapy treatment discontinue within two years.

As a last line therapy, a small subset of patients will opt for invasive procedures such as gamma knife and MRI guided focused ultrasound thalamotomy, where part of the thalamus involved in the cerebello-thalamo-cortical, or CTC, circuit is ablated, or deep brain stimulation, or DBS, where an electrode is implanted to deliver therapeutic electrical stimulation to the

While these procedures are generally effective, they are associated with significant side effects and risk.

Therefore, many patients who are eligible elect not to have these procedures.

Key findings from a combined analysis of over 400 ET patients that we conducted included that up to 80% of patients adjust how they complete daily tasks due to burden of the disease, and 77% of patients do not feel their disease is adequately managed with current treatments.

In totality, there is significant unmet need for an effective and tolerable pharmacotherapy targeted for ET.

PRAX-628 for Focal Epilepsy

PRAX-628 is a next-generation, functionally selective small molecule targeting the hyperexcitable state of sodium-channels in the brain and is currently being developed as a once daily, oral treatment for adult focal onset epilepsy.

Preclinical data demonstrates PRAX-628 is differentiated from standard of care, with the potential to be best-in-class for focal epilepsy.

In vitro, PRAX-628 has demonstrated superior selectivity for disease-state NaV channel hyperexcitability.

In vivo studies of PRAX-628 have demonstrated unprecedented potency in the maximal electroshock seizure, or MES, model, a highly predictive translational model for efficacy in focal epilepsy.

Data from the PRAX-628 Phase 1 study demonstrated that PRAX-628 was well tolerated in healthy subjects at greater than 15 times the predicted human equivalent of the mouse MES,EC 50 .

We intend to initiate a Phase 2b study of PRAX-628 in focal epilepsy in the second half of 2024.

PRAX-628 Phase 2a Photo-Paroxysmal Response study

We are conducting a Phase 2a Photo-Paroxysmal Response, or PPR, study to evaluate the efficacy and safety of PRAX-628 across two cohorts, dosed at 15 mg and 45 mg.

Vormatrigine for Common Epilepsies (Focal Onset Seizures and Generalized Epilepsy)

Vormatrigine is a next-generation, functionally selective small molecule targeting the hyperexcitable state of sodium-channels in the brain and is currently being developed as a once daily, oral treatment for adult focal onset epilepsy.

Preclinical data demonstrates vormatrigine is differentiated from standard of care, with the potential to be best-in-class for focal epilepsy.

In vitro, vormatrigine has demonstrated superior selectivity for disease-state NaV channel hyperexcitability.

In vivo studies of vormatrigine have demonstrated unprecedented potency in the maximal electroshock seizure, or MES, model, a highly predictive translational model for efficacy in focal epilepsy.

Data from a Phase 1 study demonstrated that vormatrigine was well-tolerated in healthy subjects at greater than 15 times the predicted human equivalent of the mouse MES EC 50 .

We initiated our ENERGY program to advance vormatrigine through efficacy and registrational trials in focal onset seizures, or FOS, and generalized epilepsy.

ENERGY Program

Our ENERGY program for vormatrigine aims to generate efficacy, safety and PK data to serve as the basis of regulatory registrations globally.

The program consists of four studies — EMPOWER, RADIANT, POWER1 and POWER2.

EMPOWER Observational Study

EMPOWER is an observational study in partnership with the Epilepsy Study Consortium that aims to better characterize seizure burden.

We began enrolling patients in 2024 and we expect to generate standardized, longitudinal data to support planned interventional trials and deepen our understanding of patient experiences with epilepsy.

Preliminary findings from EMPOWER revealed a significant disease burden compounded by persistent, uncontrolled and often untracked seizures alongside profound psychosocial impact.

RADIANT Phase 2 Study

We have initiated RADIANT, a Phase 2 open-label study to evaluate PK, safety and efficacy of vormatrigine in up to 50 patients with FOS or generalized epilepsy.

Patients will be treated with a 30 mg dose over an 8-week period to evaluate the impact of vormatrigine on seizure burden.

We anticipate topline results by mid-year 2025.

POWER1 and POWER 2 Phase 2/3 Registrational Studies

POWER1 and POWER2 are two 12-week Phase 2/3 studies in patients with FOS to evaluate the efficacy of vormatrigine.

We have initiated and plan to enroll approximately 250 patients in POWER1, which is assessing adjunctive treatment that allows dosing of vormatrigine on top of one to three antiseizure medications.

POWER1 is a parallel-arm study, comparing a treatment arm of 20 mg for six weeks followed by 30 mg for six weeks versus a placebo arm for 12 weeks.

We anticipate topline results in the second half of 2025.

POWER2 will be a multi-arm, 12-week registrational study for vormatrigine, and we expect to begin enrollment of the study in the second half of 2025.

Phase 2a Photo-Paroxysmal Response study

We conducted a Phase 2a Photo-Paroxysmal Response, or PPR, study to evaluate the efficacy and safety of vormatrigine across two cohorts, dosed at 15 mg and 45 mg.

PPR studies measure EEG signatures after intermittent photic stimulation and are widely used as a marker of anti-seizure efficacy and to aid in dose determination.

We believe this approach has been validated with several approved and new therapies.

A preliminary analysis of the 15 mg cohort completed in January 2024 showed that this cohort exceeded our expectations in terms of drug activity.

Topline results, including data from the ongoing 45 mg cohort, are anticipated in the first quarter of 2024.

PRAX-628 Phase 1 first-in-human study

We initiated a Phase 1 healthy volunteer study of PRAX-628 in the fourth quarter of 2022 to evaluate the tolerability, pharmacokinetics, or PK, pharmacodynamics, or PD, and food effect of PRAX-628 across single and multiple ascending dose cohorts.

Topline results from the study were announced in the second quarter of 2023.

This first clinical study of PRAX-628 was a randomized, double-blind, placebo-controlled single ascending dose, or SAD, and multiple ascending dose, or MAD, trial in healthy participants aged 18-55 years.

Interim analysis from Part A (SAD, 5 to 45 mg) and Part B (MAD, 20 to 30 mg) demonstrated drug plasma exposure increases with both dose and time.

The concentrations achieved exceeded the predicted efficacious level based on the mouse MES EC 50 and were reached in all cohorts.

In the SAD cohorts, average concentrations 2-4x the MES EC 50 were maintained for 8 hours with a single dose of 15 mg.

In the MAD cohorts, concentrations in excess of 15x the MES EC 50 were achieved at C max with average C trough around 3-5x the MES EC 50 at steady-state.

PRAX-628 was well tolerated with no serious adverse events, or SAEs, observed at repeated doses up to 30 mg/day for 10 days.

We announced topline results in the first quarter of 2024, with 100% of patients responding in both cohorts.

In the 15 mg cohort (n=5), 80% of patients achieved a complete response and 20% achieved a partial response.

In the 45 mg cohort (n=3), 100% of patients achieved a complete response.

Safety results were consistent with our prior Phase 1 dose escalation study of vormatrigine and PK analysis confirmed therapeutic exposures.

Vormatrigine Phase 1 studies

We have conducted Phase 1 healthy volunteer studies of vormatrigine to evaluate the tolerability, PK, PD and food effect of vormatrigine across single and multiple ascending dose cohorts and first announced topline results in the second quarter of 2023.

This first clinical study of vormatrigine was a randomized, double-blind, placebo-controlled single ascending dose, or SAD, and multiple ascending dose, or MAD, trial in healthy participants aged 18-55 years.

Vormatrigine was generally well-tolerated at all tested doses.

PK data demonstrated dose-dependent exposure, supporting once-daily dosing without titration to achieve potentially therapeutically effective drug concentration levels.

No adverse events, or AEs, or AEs of special interest led to study drug withdrawal, and no clinically significant findings on vital signs, electrocardiogram or neurological examination were observed.

All AEs were mild, mostly transient (lasting minutes to hours), and resolved spontaneously, with the most common AEs being CNS-related.

Focal Epilepsy

Focal epilepsy is the most common type of epilepsy, accounting for approximately 60% of all cases.

In the United States alone, it is estimated that focal epilepsy affects approximately two million people.

Focal epilepsy is characterized by seizures that originate in one side or area of the brain and affects one side of the body.

Focal epilepsy patients are treated with sodium channel targeting antiepileptic drugs, or AEDs, such as Tegretol (carbamazepine), Lamictal (lamotrigine), Xcopri (cenobamate) and many others.

However, despite the plethora of marketed treatments, up to 30% of patients remain refractory to treatment.

Results from an additional 45 mg MAD cohort showed a dose proportional increase in exposure with favorable tolerability, similar to the 20 and 30 mg MAD cohorts.

In addition, a Phase 1 food effect study demonstrated that food intake did not affect vormatrigine absorption, which increases the flexibility in dosing and ease of use of vormatrigine.

Common Epilepsies (Focal Onset Seizures and Generalized Epilepsy)

An estimated 3.5 million people in the United States suffer from common epilepsies, with FOS being the most common type of epilepsy, accounting for approximately 60% of all cases.

FOS are characterized by seizures that originate in one side or area of the brain and affects one side of the body.

Sodium channel therapy is the cornerstone of treatment for patients with epilepsy yet currently approved drugs have significant safety and efficacy limitations.

Despite the plethora of marketed treatments, including sodium channel targeting antiepileptic drugs, or AEDs, such as Tegretol (carbamazepine), Lamictal (lamotrigine), Xcopri (cenobamate), at least 30% of patients remain refractory to treatment.

There are two forms of therapeutically relevant sodium current:

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Therefore, novel compounds that inhibit persistent and peak sodium channel hyperexcitability while sparing physiological levels of peak sodium current may improve clinical efficacy and tolerability.

PRAX-562 for rare, monogenic Developmental and Epileptic Encephalopathies

PRAX-562 is a first-in-class preferential inhibitor of persistent sodium current, presently in development for the treatment of rare developmental and epileptic encephalopathies, or DEEs.

In-vivo studies of PRAX-562 have demonstrated dose-dependent block of seizures up to complete inhibition of seizure activity in SCN2A, SCN8A and other DEE mouse models.

PRAX-562 has been generally well-tolerated in three Phase 1 studies and has demonstrated biomarker changes indicative of voltage-gated sodium channel, or NaV channel, blocking effects.

PRAX-562 has received Orphan Drug Designation, or ODD, and Rare Pediatric Disease Designation, or RPD, from the FDA, and ODD from the European Medicines Agency, or EMA, for the treatment of SCN2A-DEE and SCN8A-DEE, respectively.

PRAX-562 Phase 2 EMBOLD study

In the first quarter of 2023, we initiated the PRAX-562 Phase 2 EMBOLD study for the treatment of pediatric patients with DEEs, with two cohorts in early-onset SCN2A-DEE and SCN8A-DEE patients.

The EMBOLD study is a randomized, double-blind, placebo-controlled Phase 2 clinical trial to evaluate the safety, tolerability, efficacy (motor seizure frequency) and PK of PRAX-562 in pediatric participants aged 2 to 18 years with DEEs, followed by an open-label extension.

Approximately 20 participants will be enrolled initially in two distinct cohorts ([n≈10 for SCN2A-DEE and n≈10 for SCN8A-DEE]).

Topline results for both cohorts are expected in mid-year 2024.

Relutrigine for Developmental and Epileptic Encephalopathies

Relutrigine is a first-in-class preferential inhibitor of persistent sodium current, presently in development for the treatment of developmental and epileptic encephalopathies, or DEEs.

In-vivo studies of relutrigine have demonstrated dose-dependent block of seizures up to complete inhibition of seizure activity in SCN2A, SCN8A and other DEE mouse models.

Relutrigine has been generally well-tolerated in three Phase 1 studies and has demonstrated biomarker changes indicative of voltage-gated sodium channel, or NaV channel, blocking effects.

Relutrigine has received Orphan Drug Designation, or ODD, and Rare Pediatric Disease Designation, or RPD, from the FDA, and ODD from the European Medicines Agency, or EMA, for the treatment of SCN2A-DEE and SCN8A-DEE, respectively.

Relutrigine has also received RPD from the FDA for the treatment of Dravet Syndrome.

We are currently evaluating relutrigine in the EMBOLD study for SCN2A-DEE and SCN8A-DEE, with plans to initiate the EMERALD study in a broader DEE patient population by mid-year 2025.

Phase 2 EMBOLD study

The EMBOLD study is a randomized, double-blind, placebo-controlled Phase 2 clinical trial evaluating the safety, tolerability, efficacy (motor seizure frequency) and PK of relutrigine in pediatric participants aged 2 to 18 years with DEEs, followed by an open-label extension, or OLE.

We announced topline results of the first cohort of

the EMBOLD study (n=16) in the third quarter of 2024.

Relutrigine was generally safe and well-tolerated with no drug-related serious adverse events or dose reductions required.

Patients on relutrigine observed a placebo-adjusted reduction of 46% in monthly motor seizures from baseline over a 16-week period, and there were meaningful gains observed in patients' alertness, communication and seizure severity.

Patients continuing into the ongoing OLE (n=13) saw a 77% reduction in motor seizures from baseline through nine months of treatment.

Over 30% of patients (n=5) achieved seizure freedom status for a median of 46 days, inclusive of the OLE period, compared to three days at baseline.

Based on these results, we are currently enrolling 80 patients with SCN2A and SCN8A DEEs in a second, registrational cohort for the EMBOLD study and expect topline results in the first half of 2026, followed by a potential NDA filing in 2026.

Rare, monogenic DEEs

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Standard-of-care sodium channel blockers modulate neuronal activity by targeting peak sodium current, which can reverse the pathological neuronal hyperexcitability that underlies many CNS conditions, but simultaneously affects the physiological cellular action potential firing required for a functioning nervous and cardiovascular system.

While standard-of-care sodium channel blockers inhibit persistent sodium current, they also block peak sodium current at therapeutic concentrations, which can cause significant adverse events, or AEs, such as ataxia, drowsiness and dizziness, and therefore have a very narrow Therapeutic Index, or TI, resulting in subpar outcomes for patients and significant need for better therapeutic options.

While standard-of-care sodium channel blockers inhibit persistent sodium current, they also block peak sodium current at therapeutic concentrations, which can cause significant AEs, such as ataxia, drowsiness and dizziness, and therefore have a very narrow Therapeutic Index, or TI, resulting in subpar outcomes for patients and significant need for better therapeutic options.

Early onset SCN2A-DEE is a rare condition caused by a gain-of-function, or GoF, variant in the SCN2A gene.

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It is estimated that there are approximately 2,000 patients in the United States with GoF changes in SCN2A leading to epileptic encephalopathy.

SCN8A-DEE is a rare DEE caused by a gain-of-function variant in the SCN8A gene.

SCN8A-DEE is a rare DEE caused by a GoF variant in the SCN8A gene.

Similar to SCN2A-DEE, patients with SCN8A-DEE suffer from recurrent, typically drug-resistant seizures, which start as early as the first day of life.

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It is estimated that there are approximately 2,000 patients in the United States with SCN8A-DEE.

Dravet Syndrome

Dravet syndrome is a severe, progressive genetic epilepsy that typically begins within the first year of life, marked by frequent, prolonged, and treatment-resistant seizures.

Beyond seizures, the condition often leads to intellectual disability, developmental delays, movement and balance difficulties, speech and language impairments, growth abnormalities, sleep disturbances, autonomic nervous system dysfunction, and mood disorders.

Classified as a developmental and epileptic encephalopathy, Dravet syndrome is associated with significant cognitive and developmental impairments.

Patients with this condition also face an elevated risk of early mortality, including due to sudden unexpected death in epilepsy, or SUDEP.

Elsunersen for SCN2A-DEE

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Elsunersen has received ODD and RPD from the FDA, and ODD and PRIority MEdicines, or PRIME, designation from the EMA for the treatment of SCN2A-DEE.

Elsunersen EMBRAVE study

In the second quarter of 2023, we initiated the EMBRAVE study for the treatment of pediatric patients with early-onset SCN2A-DEE, after the FDA allowed us to proceed under an Investigational New Drug, or IND, application for the initial dose cohort, or Part 1 of the study.

We are continuing to evaluate elsunersen in the second cohort of the EMBRAVE study in Brazil, and plan to initiate EMBRAVE3, a Phase 3 registrational study, by mid-year 2025.

EMBRAVE study

Part 1 of the EMBRAVE study was a 21-week open label cohort, in which participants received elsunersen for up to 13 weeks, designed to determine the safety and tolerability of intrathecal delivery of elsunersen.

Dosing for Part 1 of the EMBRAVE study was completed in the fourth quarter of 2023.

No treatment related AEs or SAEs were observed.

Additionally, patients observed a marked reduction in seizures and increase in seizure-free days.

We are completing multiple global regulatory interactions in the first quarter of 2024 in anticipation of starting the pivotal phase of the program later this year.

We are enrolling patients in the second cohort of the EMBRAVE study in Brazil, in which we are evaluating the safety and efficacy of elsunersen versus sham-procedure, and anticipate topline results in the first half of 2026.

EMBRAVE3 study

We plan to initiate EMBRAVE3, a global, 24-week, double-blind, sham procedure-controlled clinical trial to assess the efficacy, safety, tolerability and PK of elsunersen by mid-year 2025.

We expect this to be a registrational trial consisting of three cohorts.

Cohort 1 will enroll approximately 40 patients between 2 and 18 years of age experiencing at least four motor seizures during a four-week baseline period.

The primary endpoint will assess the change in seizure frequency.

Patients will be randomized 1:1 to a drug arm or a sham procedure arm.

Patients in the drug arm will receive 1 mg of elsunersen intrathecally every 4 weeks for 24 weeks.

Patients in the sham procedure arm will receive no treatment or intrathecal injection.

Cohorts 2 and 3 will enroll patients from age 0 to 2 in a staggered fashion starting with patients ages 1-2 in Cohort 2.

Cohort 3 patients will be enrolled following a safety review of the Cohort 2 patients.

Patients will receive elsunersen 1.0mg and 0.5mg for Cohorts 2 and 3, respectively, for 24 weeks.

All patients will have the option to continue into an open-label extension for an additional 24 weeks.

The biopharmaceutical industry is characterized by rapidly advancing technologies, strong competition and an emphasis on proprietary products.

While we believe that our technology, knowledge, experience and scientific personnel provide us with competitive advantages, we face substantial competition from many different sources, including large and small pharmaceutical and biotechnology companies, academic research institutions, governmental agencies and public and private institutions.

While we believe that our technology, knowledge, experience and scientific personnel provide us with competitive advantages, we face substantial competition from many different sources,

including large and small pharmaceutical and biotechnology companies, academic research institutions, governmental agencies and public and private institutions.

Additionally, we may face potential challenges in the adoption or acceptance of our product candidates, if approved, by prescribers due to the unfamiliarity of new treatments for previously untreated conditions or conditions where new treatments have not been developed for an extended period of time, such as ET, or unfamiliarity with utilizing new mechanisms such as the precision approach for sodium channel modulation utilized by relutrigine and vormatrigine.

We believe continuing to develop medicines that significantly advance the standard of care for patients is the optimal strategy to differentiate us from competitors.

Any product candidates that we successfully develop and commercialize will compete with currently approved therapies and new therapies that may become available in the future.

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Our competitors fall primarily into the following groups of treatment:

• T-type calcium channel inhibitor programs in development targeting ET, including that of Jazz Pharmaceuticals, as well as other programs in clinical development targeting other mechanisms of action such as GABA by Sage Therapeutics, and approved therapies, such as propranolol, and off-label therapies, such as primidone.

• Sodium channel blocker or similar ion channel-targeting programs in development for focal epilepsy, including those of SK-Pharma, Xenon Pharmaceuticals, and Biohaven Pharmaceuticals, as well as other programs in clinical development targeting other mechanisms of action including those from Longboard Pharmaceuticals, Marinus Pharmaceuticals and Stoke Therapeutics, and approved therapies including other existing ion channel blockers.

• A pproved therapies for ET, such as propranolol, and off-label therapies, such as primidone.

• Sodium channel blocker or similar ion channel-targeting programs in development for common epilepsies, including those of SK-Pharma, Xenon Pharmaceuticals, and Biohaven Pharmaceuticals, as well as other programs in clinical development targeting other mechanisms of action including those from Lundbeck and Stoke Therapeutics, and approved therapies including other existing ion channel blockers.

Many of our competitors have substantially greater financial resources, expertise and capabilities in research and development, the regulatory approval process, manufacturing and marketing than we do.

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However, patent term restoration cannot extend the remaining term of a patent beyond a total of 14 years from the drug product’s approval date.

The patent term restoration period is generally one-half the time between the effective date of an IND and the submission date of a New Drug Application, or NDA, plus the time between the submission date of an NDA and the approval of that application.

The patent term restoration period is generally one-half the time between the effective date of an IND and the submission date of a NDA, plus the time between the submission date of an NDA and the approval of that application.

Only one patent applicable to an approved drug is eligible for the extension and the extension must be applied for prior to expiration of the patent.

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T-type Calcium channel blockers

We own twelve patent families directed to T-type Calcium channel blockers.

We own fourteen patent families directed to T-type Calcium channel blockers.

One patent family discloses and claims compositions of matter of certain T-type calcium channel modulators, including ulixacaltamide.

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A third family is directed to titration methods of using ulixacaltamide and expires in 2041.

A fourth patent family is directed to certain analog compounds of ulixacaltamide and expires in 2040.

A fourth patent family is directed to certain analog compounds

of ulixacaltamide and expires in 2040.

A fifth patent family is directed to the adjunctive use of a beta blocker and/or certain anticonvulsants with ulixacaltamide and expires in 2043.

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An eighth patent family is directed to crystalline forms of ulixacaltamide and expires in 2044.

A ninth patent family is directed to methods of treatment using ulixacaltamide and expires in 2044.The remaining patent families are directed to other TTCC blockers of various core structures and methods of use in treating diseases such as movement disorders, which expire in 2039 and 2040.

A ninth patent family is directed to methods of treatment using ulixacaltamide and expires in 2044.

A tenth patent family is directed to methods of treatment using ulixacaltamide and expires in 2044.

The remaining patent families are directed to other TTCC blockers of various core structures and methods of use in treating diseases such as movement disorders, which expire in 2039 and 2040.

Persistent sodium current blockers

We own fifteen patent families directed to persistent sodium current blockers, including a patent family that relates to PRAX-562 and PRAX-628, two additional patent families that relate to PRAX-562 program, and the remaining patent families related to other persistent sodium current blockers.

One patent family discloses and claims certain persistent sodium current blockers, including PRAX-562 and PRAX-628, and methods of use in treating diseases such as epilepsy (including pediatric epilepsy), as well as migraine and pain.

In this patent family, PRAX-562 is covered by a patent that has granted in the United States, and patent applications pending in other potentially commercially relevant jurisdictions, which expire in 2039.

In this same patent family, PRAX-628 is covered by two granted U.S.

We own fifteen patent families directed to persistent sodium current blockers, including a patent family that relates to relutrigine and vormatrigine, two additional patent families that relate to relutrigine, and the remaining patent families relate to other persistent sodium current blockers.

One patent family discloses and claims certain persistent sodium current blockers, including relutrigine and vormatrigine, and methods of use in treating diseases such as epilepsy (including pediatric epilepsy), as well as migraine and pain.

In this patent family, relutrigine is covered by a patent that has granted in the United States, and patent applications pending in other potentially commercially relevant jurisdictions, which expire in 2039.

In this same patent family, vormatrigine is covered by two granted U.S.

patents that will expire in 2039.

A second family discloses other persistent sodium current blockers and generically claims PRAX-562, as well as methods of treating diseases such as pediatric epilepsy.

A second family discloses other persistent sodium current blockers and generically claims relutrigine, as well as methods of treating diseases such as pediatric epilepsy.

This patent family is pending in multiple jurisdictions and expires in 2037.

A third family is directed to pharmaceutical formulations of PRAX-562, methods of use in treating diseases such as pediatric epilepsy, cephalgia, short-lasting unilateral neuralgiform headache attacks with conjunctival injection, or SUNCT, and tearing and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms, or SUNA, and

methods of making PRAX-562, and expires in 2040.

A third family is directed to pharmaceutical formulations of relutrigine, methods of use in treating diseases such as pediatric epilepsy, cephalgia, short-lasting unilateral neuralgiform headache attacks with conjunctival injection, or SUNCT, and tearing and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms, or SUNA, and methods of making relutrigine, and expires in 2040.

The remaining patent families are directed to other persistent sodium current blockers of various core structures and methods of use in treating diseases such as pediatric epilepsy, expiring between 2037 and 2043.

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A second patent family is directed to methods of treating SCN1A encephalopathy using ASOs targeting SCN2A and expires in 2039.

The other in-licensed patent family is owned by Ionis Pharmaceuticals, Inc., and is directed to compositions of matter of PRAX-222.

This family expires in 2041.

We own two patent families directed to our PRAX-222 program.

The other in-licensed patent family is owned by Ionis Pharmaceuticals, Inc., and is directed to compositions of matter of elsunersen.

This family expires in 2041 and one U.S.

patent has issued in this family.

We own seven patent families directed to our elsunersen program.

The first has claims directed to a method of treating SCN2A gain of function neurological diseases using certain ASOs.

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The second is directed to methods of treating SCN2A-related disorders using SCN2A inhibitors and expires in 2043.

The third is directed to methods of treating SCN2A-related disorders using SCN2A inhibitors and expires in 2044.

The fourth is directed to compositions and methods for treating SCN2A disorders and expires in 2039.

The fifth is directed to methods for detecting if a subject with an SCN2A disorder has a gain of function mutation and expires in 2039.

The sixth is directed to oligonucleotides targeting SCN2A retained introns and expires in 2039.

The seventh is directed to compositions and methods for treating disorders associated with loss-of-function mutations in SCN2A and expires in 2041.

KCNT1 blockers

We own sixteen patent families directed to KCNT1 blockers.

We own twelve patent families directed to KCNT1 blockers.

These patent families disclose and claim small molecule KCNT1 blockers and methods of use in treating diseases, such as epilepsy, including epilepsy having certain KCNT1 mutations, and expire between 2040 and 2043.

GABA A receptor positive allosteric modulators

We own five patent families directed to GABA A receptor positive allosteric modulators.

We own four patent families directed to GABA A receptor positive allosteric modulators.

One patent family discloses and claims salts and polymorphs of PRAX-114.

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A second patent family is directed to alternative salt forms of PRAX-114, and a U.S.

patent has issued, which expires in 2042.

Other patent applications cover processes for making related to PRAX-114 and methods of use in treating diseases (including the use of combination formulations), such as epilepsy, major depressive disorder, musculoskeletal conditions, motor disorder or essential tremor, which expire from 2042 to 2043.

issued, which expires in 2042.

Other patent applications cover methods of use in treating diseases (including the use of combination formulations), such as epilepsy, musculoskeletal conditions, motor disorder or essential tremor, which expire from 2042 to 2043.

We own one patent family directed to compositions and methods for the treatment of PCDH19 related disorders, which expires in 2042.

We own one patent family directed to compositions and methods for the treatment of disorders associated with loss-of-function mutations in SYNGAP1, which expires in 2041.

LICENSE AGREEMENTS

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In the second quarter of 2023, Ionis earned the Additional Milestone fee of $5.0 million, as well as the Initial Interest Amount of $1.9 million.

The $6.9 million milestone fee was paid in July of 2023.

The $6.9 million milestone fee was paid in July 2023.

The Ionis Agreement will continue in full force and effect until the expiration of all payment obligations to Ionis, unless terminated earlier by either party.

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For clinical supply, we rely on CDMOs to manufacture drug substance and drug product in accordance with the FDA’s current Good Manufacturing Practices, or cGMP.

We expect to rely on third parties for our manufacturing processes and the production of all clinical supply drug substance and drug product and currently expect to

continue to do so for commercial supplies of our product candidates, if approved.

We expect to rely on third parties for our manufacturing processes and the production of all clinical supply drug substance and drug product and currently expect to continue to do so for commercial supplies of our product candidates, if approved.

We use additional contract manufacturers to fill, label, package, store and distribute our investigational drug products and currently expect to continue to do so for commercial supplies of our product candidates, if approved.

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The FDA and comparable regulatory authorities in state and local jurisdictions and in other countries impose substantial and burdensome requirements upon companies involved in the clinical development, manufacture, marketing and distribution of prescription drugs, such as those we are developing.

These agencies regulate, among other things, the research and development, testing, manufacture, quality control, safety, effectiveness, labeling, storage, record keeping, approval, advertising and promotion, distribution, post-approval monitoring and reporting, sampling and export and import of drug products.

These agencies regulate, among other things, the research and development, testing, manufacture, quality control, safety, effectiveness, labeling,

storage, record keeping, approval, advertising and promotion, distribution, post-approval monitoring and reporting, sampling and export and import of drug products.

The process of obtaining regulatory approvals and the subsequent compliance with applicable federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources.

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The process required by the FDA before a drug may be marketed in the United States generally involves the following:

• completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice regulations;

• completion of certain preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice regulations;

• submission to the FDA of an IND, which must become effective before human clinical trials may begin;

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In such a case, the IND may be placed on clinical hold and the IND sponsor and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin.

Submission of an IND therefore may or

may not result in FDA authorization to begin a clinical trial.

Submission of an IND therefore may or may not result in FDA authorization to begin a clinical trial.

Additionally, the FDA will review any data from clinical trials conducted outside the United States when determining whether to allow an IND to proceed in the United States.

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In Phase 3, the product candidate is administered to an expanded patient population, generally at geographically dispersed clinical trial sites, in well-controlled clinical trials to generate enough data to provide substantial evidence of the efficacy and safety of the product candidate, to establish the overall risk-benefit profile of the product candidate, and to provide adequate information for the labeling of the product candidate.

In some cases, the FDA may require, or sponsors may voluntarily pursue, additional clinical trials after a product is approved to gain more information about the product.

In some cases, the FDA may require, or sponsors may voluntarily pursue, additional clinical trials after a product is approved to gain more information about the product in the approved indication.

These so-called Phase 4 studies, may be conducted after initial marketing approval, and may be used to gain additional experience from the treatment of patients in the intended therapeutic indication.

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The FDA also may require submission of a risk evaluation and mitigation strategy, or REMS, plan, if it determines that a REMS is necessary to ensure that the benefits of the drug outweigh its risks and to assure the safe use of the drug product.

A REMS is a safety strategy to manage a known or potential serious risk associated with a medicine and to enable patients to have continued access to such medicines by managing their safe use, and could include medication guides, physician communication plans, assessment plans and/or elements to assure safe use, such as restricted distribution methods, patient registries or other risk minimization tools.

A REMS is a safety strategy to manage a known or potential serious risk associated with a drug and to enable patients to have continued access to such medicines by managing their safe use, and could include medication guides, physician communication plans, assessment plans and/or elements to assure safe use, such as restricted distribution methods, patient registries or other risk minimization tools.

The FDA determines the requirement for a REMS, as well as the specific REMS provisions, on a case-by-case basis.

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In issuing the CRL, the FDA may recommend actions that the applicant might take to place the NDA in condition for approval, including requests for additional information or clarification.

If a CRL is issued, the applicant may choose to either resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application.

issued, the applicant may choose to either resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application.

If those deficiencies have been addressed to the FDA’s satisfaction, the FDA will issue an approval letter.

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and (b) rare diseases or conditions within the meaning of the Orphan Drug Act.

Congress has only authorized the Rare Pediatric

Disease Priority Review Voucher program until September 30, 2024.

Congress has only authorized the Rare Pediatric Disease Priority Review Voucher program until December 20, 2024.

Consequently, sponsors of marketing applications approved after that date will not receive the voucher unless Congress reauthorizes the program.

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A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance.

During the exclusivity period, the FDA may not accept for review an Abbreviated New Drug Application, or ANDA, or a 505(b)(2) NDA submitted by another company for a generic or follow-on version of the protected drug product, respectively, where the applicant does not own or have a legal right of reference to all the data required for approval.

During the exclusivity period, the FDA may not accept for review an Abbreviated New Drug Application, or ANDA, or a 505(b)(2) NDA submitted by another company for a

generic or follow-on version of the protected drug product, respectively, where the applicant does not own or have a legal right of reference to all the data required for approval.

However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement.

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Post-approval requirements

Following approval of a new prescription drug product, the manufacturer and the approved drug are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to monitoring and recordkeeping, periodic reporting, product sampling and distribution, advertising and promotion and reporting of adverse experiences with the product.

Following approval of a drug product, the manufacturer and the approved drug are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to monitoring and recordkeeping, periodic reporting, product sampling and distribution, advertising and promotion and reporting of adverse experiences with the product.

In addition, drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and state agencies and are subject to periodic unannounced inspections by the FDA and these state agencies for compliance with cGMP requirements.

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established annual fees and taxes on manufacturers of certain branded prescription drugs;

and created a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% (increased to 70% pursuant to the Bipartisan Budget Act of 2018, or BBA, effective as of January 2019) point-of-sale discounts off

negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D.

and created a new Medicare Part D coverage gap discount program, which was replaced by a new manufacturer discount program on January 1, 2025 (as discussed below), in which manufacturers were required to offer 50% (increased to 70% pursuant to the Bipartisan Budget Act of 2018, or BBA, effective as of January 2019) point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D.

Since its enactment, there have been judicial, administrative, executive and legislative challenges to certain aspects of the ACA.

On June 17, 2021 the U.S.

Supreme Court dismissed the most recent judicial challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA.

Supreme Court dismissed the most recent judicial challenge to the

ACA brought by several states without specifically ruling on the constitutionality of the ACA.

Thus, the ACA will remain in effect in its current form.

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On January 2, 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further reduced Medicare payments to several types of providers, including hospitals and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

Moreover, on March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminated the statutory Medicaid drug rebate cap for single source and innovator multiple source drugs, beginning January 1, 2024.

Moreover, on March 11, 2021, the American Rescue Plan Act of 2021 was signed into law, which eliminated the statutory Medicaid drug rebate cap for single source and innovator multiple source drugs, beginning January 1, 2024.

The rebate was previously capped at 100% of a drug's average manufacturer price.

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imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation (first due in 2023);

and replaces the Part D coverage gap discount program with a new discounting program (beginning in 2025).

and replaces the Part D coverage gap discount program with a new discounting program (which began on January 1, 2025).

The IRA permits the Secretary of the Department of Health and Human Services, or HHS, to implement many of these provisions through guidance, as opposed to regulation, for the initial years.

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These provisions started to take effect progressively starting in fiscal year 2023.

On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations, although the Medicare drug price negotiation program is currently subject to legal challenges.

In addition, in response to the Biden administration’s October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the Center for Medicare and Medicaid Innovation which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care.

It is unclear whether the models will be utilized in any health reform measures in the future.

On August 15, 2024, HHS announced the agreed-upon prices for the first ten drugs that will be subject to price negotiations, which take effect in January 2026.

HHS will select up to fifteen additional products covered under Part D for negotiation in 2025.

Each year thereafter, more Part B and Part D products will become subject to the HHS price negotiation program, although the program is currently subject to legal challenges.

At the state level, legislatures in the United States have also increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures and, in some cases, designed to encourage importation from other countries and bulk purchasing.

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Significant uncertainty exists as to the coverage and reimbursement status of any product candidates for which we obtain regulatory approval.

Sales of any products for which we receive regulatory approval for commercial sale

will depend, in part, on the extent to which third-party payors provide coverage and establish adequate reimbursement levels for such drug products.

Sales of any products for which we receive regulatory approval for commercial sale will depend, in part, on the extent to which third-party payors provide coverage and establish adequate reimbursement levels for such drug products.

In the United States, third-party payors include federal and state healthcare programs, government authorities, private manage care providers, private health insurers and other organizations.

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In addition to regulations in the United States, we may be subject to a variety of regulations in foreign jurisdictions that govern, among other things, preclinical and clinical studies, commercial sales and distribution of our future products.

Most countries outside of the United States, including the European Union, or the EU, require that clinical trial applications be submitted to and approved by the local regulatory authority for each clinical study.

Most countries outside of the United States, including the European Union, or the EU, require that clinical trial applications, or CTAs, be submitted to and approved by the local regulatory authority for each clinical study.

In addition, whether or not we obtain FDA approval for a product candidate, we must obtain the requisite approval from comparable regulatory authorities outside the United States before we can commence clinical studies or marketing of the product candidate in those countries.

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Non-clinical studies are performed to demonstrate the health or environmental safety of new biological substances.

Non-clinical (pharmaco-toxicological) studies must be conducted in compliance with the principles of good laboratory practice, or GLP, as set forth in EU Directive 2004/10/EC (unless otherwise justified for certain particular medical products, e.g., radio-pharmaceutical precursors for radio-labeling purposes).

Non-clinical (pharmaco-toxicological) studies must be conducted in compliance with the principles of good laboratory practice, or GLP, as set forth in EU Directive 2004/10/EC (unless otherwise justified for certain particular medicinal products, e.g., radio-pharmaceutical precursors for radio-labeling purposes).

In particular, non-clinical studies, both in vitro and in vivo, must be planned, performed, monitored, recorded, reported and archived in accordance with the GLP principles, which define a set of rules and criteria for a quality system for the organizational process and the conditions for non-clinical studies.

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If the sponsor of the clinical trial is not established within the EU, it must appoint an EU entity to act as its legal representative.

The sponsor must take out

a clinical trial insurance policy, and in most EU member states, the sponsor is liable to provide ‘no fault’ compensation to any study subject injured in the clinical trial.

The sponsor must take out a clinical trial insurance policy, and in most EU member states, the sponsor is liable to provide ‘no fault’ compensation to any study subject injured in the clinical trial.

The regulatory landscape related to clinical trials in the EU has been subject to recent changes.

The EU Clinical Trials Regulation, or CTR, which was adopted in April 2014 and repeals the EU Clinical Trials Directive, became applicable on January 31, 2022.

The EU Clinical Trials Regulation, or CTR, which was adopted in April 2014 and repeals the EU Clinical Trials Directive,

became applicable on January 31, 2022.

Unlike directives, the CTR is directly applicable in all EU member states without the need for member states to further implement it into national law.

The CTR notably harmonizes the assessment and supervision processes for clinical trials throughout the EU via a Clinical Trials Information System, which contains a centralized EU portal and database.

While the Clinical Trials Directive required a separate clinical trial application, or CTA, to be submitted in each member state in which the clinical trial takes place, to both the competent national health authority and an independent ethics committee, much like the FDA and IRB respectively, the CTR introduces a centralized process and only requires the submission of a single application for multi-center trials.

The CTR notably harmonizes the assessment and supervision processes for clinical trials throughout the EU via a Clinical Trials Information System, or CTIS, which contains a centralized EU portal and database.

While the EU Clinical Trials Directive required a separate CTA to be submitted in each member state in which the clinical trial takes place, to both the competent national health authority and an independent ethics committee, much like the FDA and IRB respectively, the CTR introduces a centralized process and only requires the submission of a single application for multi-center trials.

The CTR allows sponsors to make a single submission to both the competent authority and an ethics committee in each member state, leading to a single decision per member state.

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Once the CTA is approved, clinical study development may proceed.

The CTR foresees a three-year transition period.

The extent to which ongoing and new clinical trials will be governed by the CTR varies.

Clinical trials for which an application was submitted (i) prior to January 31, 2022 under the Clinical Trials Directive, or (ii) between January 31, 2022 and January 31, 2023 and for which the sponsor has opted for the application of the Clinical Trials Directive remain governed by said Directive until January 31, 2025.

After this date, all clinical trials (including those which are ongoing) will become subject to the provisions of the CTR.

Medicines used in clinical trials must be manufactured in accordance with good manufacturing practice.

The CTR transition period ended on January 31, 2025, and all clinical trials (and related applications) are now fully subject to the provisions of the CTR.

Medicines used in clinical trials must be manufactured in accordance with Good Manufacturing Practice, or GMP.

Other national and EU-wide regulatory requirements may also apply.

The aforementioned EU rules are generally applicable in the European Economic Area, which consists of the 27 EU member states plus Norway, Liechtenstein and Iceland.

Marketing authorization

In order to market our product candidates in the EU and many other foreign jurisdictions, we must obtain separate regulatory approvals.

More concretely, in the EU, medicinal product candidates can only be commercialized after obtaining a marketing authorization, or MA.

To obtain regulatory approval of a product candidate under EU regulatory systems, we must submit a MA application, or MAA.

The process for doing this depends, among other things, on the nature of the medicinal product.

There are two types of MAs:

• “Centralized MAs” are issued by the European Commission through the centralized procedure based on the opinion of the Committee for Medicinal Products for Human Use, or CHMP, of the European Medicines Agency, or EMA, and are valid throughout the EU.

The centralized procedure is compulsory for certain types of medicinal products such as (i) medicinal products derived from biotechnological processes, (ii) designated orphan medicinal products, (iii) advanced therapy medicinal products, or ATMPs (such as gene therapy, somatic cell therapy and tissue engineered products) and (iv) medicinal products containing a new active substance indicated for the treatment of certain diseases, such as HIV/AIDS, cancer, diabetes, neurodegenerative diseases or autoimmune diseases and other immune dysfunctions, and viral diseases.

The centralized procedure is optional for products containing a new active substance not yet authorized in the EU, or for products that constitute a significant therapeutic, scientific or technical innovation or which are in the interest of public health in the EU.

• “National MAs” are issued by the competent authorities of the EU member states, only cover their respective territory, and are available for product candidates not falling within the mandatory scope of the centralized procedure.

Where a product has already been authorized for marketing in an EU member state, this national MA can be recognized in another member state through the mutual recognition procedure.

If the product has not received a national MA in any member state at the time of application, it can be approved simultaneously in various member states through the decentralized procedure.

Under the decentralized procedure an identical dossier is submitted to the competent authorities of each of the member states in which the MA is sought, one of which is selected by the applicant as the reference member state.

Under the centralized procedure the maximum timeframe for the evaluation of an MAA by the EMA is 210 days, excluding clock stops.

In exceptional cases, the CHMP might perform an accelerated review of a MAA in no more than 150 days (not including clock stops).

Innovative products that target an unmet medical need and are expected to be of major public health interest may be eligible for a number of expedited development and review programs, such as the PRIority MEdicines, or PRIME, scheme, which provides incentives similar to the breakthrough therapy designation in the United States.

In March 2016, the European Medicines Agency, or EMA, launched the PRIME scheme, a voluntary scheme aimed at enhancing the EMA’s support for the development of medicines that target unmet medical needs.

March 2016, the EMA launched an initiative, the PRIME scheme, a voluntary scheme aimed at enhancing the EMA’s support for the development of medicines that target unmet medical needs.

It is based on increased interaction and early dialogue with companies developing promising medicines, to optimize their product development plans and speed up their evaluation to help them reach patients earlier.

Product developers that benefit from PRIME designation can expect to be eligible for accelerated assessment but this is not guaranteed.

Many benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and accelerated marketing authorization application assessment once a dossier has been submitted.

Importantly, a dedicated contact and rapporteur from the Committee for Medicinal Products for Human Use is appointed early in the PRIME scheme facilitating increased understanding of the product at EMA’s committee level.

Importantly, a dedicated contact and rapporteur from the CHMP is appointed early in the PRIME scheme facilitating increased understanding of the product at EMA’s committee level.

An initial meeting initiates these relationships and includes a team of multidisciplinary experts at the EMA to provide guidance on the overall development and regulatory strategies.

Regulation of drug products and healthcare laws and regulations outside of the United States

Our product candidates may be subject in the future to laws and regulations related to drug products and health care imposed by jurisdictions outside of the United States, including the EU which may include, for instance, applicable post-marketing requirements, including safety surveillance, anti-fraud and abuse laws and implementation of corporate compliance programs and reporting of payments or other transfers of value to healthcare professionals.

Outside of the United States, the provision of health care, including the pricing of

pharmaceutical products, is subject to governmental control in many countries, and efforts to control prices and costs, including legislative action, will likely continue as countries attempt to manage healthcare expenditures.

Under the above-described procedures, in order to grant the MA, the EMA or the competent authorities of the EU member states make an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy.

MAs have an initial duration of five years.

After these five years, the authorization may be renewed on the basis of a reevaluation of the risk-benefit balance.

Data and market protection

In the EU, new products authorized for marketing ( i.e.

, reference products) generally receive eight years of data exclusivity and an additional two years of market exclusivity upon MA.

If granted, the data exclusivity period prevents generic and biosimilar applicants from relying on the preclinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar MA in the EU during a period of eight years from the date on which the reference product was first authorized in the EU.

The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product in the EU until ten years have elapsed from the initial MA of the reference product in the EU.

The overall ten-year market exclusivity period can be extended to a maximum of eleven years if, during the first eight years of those ten years, the MA holder obtains an authorization for one or more new therapeutic indications, which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

However, there is no guarantee that a product will be considered by the EU’s regulatory authorities to be a new chemical or biological entity, and products may not qualify for data exclusivity.

Orphan medicinal products

The criteria for designating an “orphan medicinal product” in the EU are similar in principle to those in the United States.

A medicinal product can be designated as an orphan if its sponsor can establish that:

(1) the product is intended for the diagnosis, prevention or treatment of a life threatening or chronically debilitating condition, (2) either (a) such condition affects not more than five in 10,000 persons in the EU when the application is made or (b) the product, without the benefits derived from the orphan status, would not generate sufficient return in the EU to justify the necessary investment and (3) there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized for marketing in the EU or, if such method exists, the product will be of significant benefit to those affected by that condition.

Orphan designation must be requested before submitting an MAA.

An EU orphan designation entitles a party to incentives such as reduction of fees or fee waivers, protocol assistance, and access to the centralized procedure.

Upon grant of a MA, orphan medicinal products are entitled to ten years of market exclusivity for the approved indication, which means that the competent authorities cannot accept another MAA, or grant a MA, or accept an application to extend a MA for a similar medicinal product for the same indication for a period of ten years.

The period of market exclusivity is extended by two years for orphan medicinal products that have also complied with an agreed pediatric investigation plan, or PIP.

No extension to any supplementary protection certificate can be granted on the basis of pediatric studies for orphan indications.

Orphan designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

The orphan exclusivity period may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for which it received orphan destination, including where it is shown that the product is sufficiently profitable not to justify maintenance of market exclusivity or where the prevalence of the condition has increased above the threshold.

Additionally, MA may be granted to a similar product for the same indication at any time if (i) the second applicant can establish that its product, although similar, is safer, more

effective or otherwise clinically superior;

(ii) the applicant consents to a second orphan medicinal product application;

or (iii) the applicant cannot supply enough orphan medicinal product.

The aforementioned EU rules are generally applicable in the European Economic Area, or EEA, which consists of the 27 EU member states plus Norway, Liechtenstein and Iceland.

Failure to comply with EU and member state laws that apply to the conduct of clinical trials, manufacturing approval, MA of medicinal products and marketing of such products, both before and after grant of the MA, manufacturing of pharmaceutical products, statutory health insurance, bribery and anti-corruption or with other applicable regulatory requirements may result in administrative, civil or criminal penalties.

These penalties could include delays or refusal to authorize the conduct of clinical trials, or to grant MA, product withdrawals and recalls, product seizures, suspension, withdrawal or variation of the MA, total or partial suspension of production, distribution, manufacturing or clinical trials, operating restrictions, injunctions, suspension of licenses, fines and criminal penalties.

Other healthcare laws

In the EU, many EU member states have adopted specific anti-gift statutes that further limit commercial practices for medicinal products, in particular vis-à-vis healthcare professionals and organizations.

Additionally, there has been a recent trend of increased regulation of payments and transfers of value provided to healthcare professionals or entities and many EU member states have adopted national “Sunshine Acts” which impose reporting and transparency requirements (often on an annual basis), similar to the requirements in the United States, on pharmaceutical companies.

Certain countries also mandate implementation of commercial compliance programs, or require disclosure of marketing expenditures and pricing information.

Violation of any of such laws or any other governmental regulations that apply may result in penalties, including, without limitation, significant administrative, civil and criminal penalties, damages, fines, disgorgement, additional reporting obligations and oversight if a manufacturer becomes subject to a corporate integrity agreement or other agreement to resolve allegations of non-compliance with these laws, the curtailment or restructuring of operations, exclusion from participation in governmental healthcare programs and imprisonment.

Coverage, pricing and reimbursement

In addition, in many countries, the proposed pricing for a drug must be approved before it may be lawfully marketed.

The requirements governing drug pricing and reimbursement vary widely from country to country.

In the EU, governments influence the price of products through their pricing and reimbursement rules and control of national healthcare systems that fund a large part of the cost of those products to consumers.

Member states are free to restrict the range of pharmaceutical products for which their national health insurance systems provide reimbursement, and to control the prices and reimbursement levels of pharmaceutical products for human use.

Some jurisdictions operate positive and negative list systems under which products may only be marketed once a reimbursement price has been agreed to by the government.

Member states may approve a specific price or level of reimbursement for the pharmaceutical product, or alternatively adopt a system of direct or indirect controls on the profitability of the company responsible for placing the pharmaceutical product on the market, including volume-based arrangements, caps and reference pricing mechanisms.

To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost effectiveness of a particular product to currently available therapies.

Other member states allow companies to fix their own prices for medicines, but monitor and control company profits.

There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our products.

The downward pressure on healthcare costs in general, particularly prescription products, has become very intense.

As a result, increasingly high barriers are being erected to the entry of new products.

In addition, in some countries, cross border imports from low priced markets exert a commercial pressure on pricing within a country.

Healthcare Reform

The EU is also subject to political, economic and regulatory developments which may affect the ability of pharmaceutical companies to profitably commercialize their products.

In addition to continuing pressure on prices and cost containment measures, legislative developments at the EU or member state level may result in significant additional requirements or obstacles.

The delivery of healthcare in the EU, including the establishment and operation of health services and the pricing and reimbursement of medicines, is almost exclusively a matter for

national, rather than EU, law and policy.

National governments and health service providers have different priorities and approaches to the delivery of health care and the pricing and reimbursement of products in that context.

In general, however, the healthcare budgetary constraints in most EU member states have resulted in restrictions on the pricing and reimbursement of medicines by relevant health service providers.

Coupled with ever-increasing EU and national regulatory burdens on those wishing to develop and market products, this could restrict or regulate post-approval activities and affect the ability of pharmaceutical companies to commercialize their products.

In international markets, reimbursement and healthcare payment systems vary significantly by country, and many countries have instituted price ceilings on specific products and therapies.

In the EU, potential reductions in prices and changes in reimbursement levels could be the result of different factors, including reference pricing systems, parallel distribution and parallel trade.

It could also result from the application of external reference pricing mechanisms, which consist of arbitrage between low-priced and high-priced countries.

Reductions in the pricing of our medicinal products in one EU member state could affect the price in other EU member states and, thus, have a negative impact on our financial results.

Health Technology Assessment, or HTA, of medicinal products in the EU is an essential element of the pricing and reimbursement decision-making process in a number of EU member states.

The outcome of HTA has a direct impact on the pricing and reimbursement status granted to the medicinal product.

A negative HTA by a leading and recognized HTA body concerning a medicinal product could undermine the prospects to obtain reimbursement for such product not only in the EU member state in which the negative assessment was issued, but also in other EU member states.

In 2011, Directive 2011/24/EU was adopted at the EU level.

This Directive establishes a voluntary network of national authorities or bodies responsible for HTA in the individual EU member states.

The network facilitates and supports the exchange of scientific information concerning HTAs.

Further to this, on December 13, 2021, Regulation No 2021/2282 on HTA, amending Directive 2011/24/EU, was adopted.

The Regulation entered into force in January 2022 and has been applicable since January 2025, with phased implementation based on the type of product, i.e.

oncology and advanced therapy medicinal products as of 2025, orphan medicinal products as of 2028, and all other medicinal products by 2030.

The Regulation intends to boost cooperation among EU member states in assessing health technologies, including new medicinal products, and provide the basis for cooperation at the EU level for joint clinical assessments in these areas.

It will permit EU member states to use common HTA tools, methodologies, and procedures across the EU, working together in four main areas, including joint clinical assessment of the innovative health technologies with the highest potential impact for patients, joint scientific consultations whereby developers can seek advice from HTA authorities, identification of emerging health technologies to identify promising technologies early, and continuing voluntary cooperation in other areas.

Individual EU member states will continue to be responsible for assessing non-clinical (e.g., economic, social, ethical) aspects of health technology, and making decisions on pricing and reimbursement.

Data privacy and security laws

Numerous state, federal and foreign laws govern the collection, dissemination, use, access to, confidentiality, and security of personal information, including health-related information.

In the United States, numerous federal and state laws and regulations, including data breach notification laws, health information privacy and security laws, including the Health Insurance Portability and Accountability Act of 1996, or HIPAA, and federal and state consumer protection laws and regulations that govern the collection, use, disclosure, and protection of health-related and other personal information could apply now or in the future to our operations or the operations of our partners.

In the United States, numerous federal and state laws and regulations, including data breach notification laws, health information privacy and security laws, including the Health Insurance Portability and Accountability Act of 1996 and regulations promulgated thereunder, or HIPAA, and federal and state consumer protection laws and regulations that govern the collection, use, disclosure, and protection of health-related and other personal information could apply now or in the future to our operations or the operations of our partners.

In addition, certain state and non-U.S.

laws, such as the California Consumer Privacy Act of 2018, or CCPA, the California Privacy Rights Act of 2020, or CPRA, and the General Data Protection Regulation, or GDPR, and the U.K.

laws, such as the California Consumer Privacy Act of 2018, as amended by the California Privacy Rights Act of 2020, collectively, the CCPA, and the General Data Protection Regulation, or GDPR, and the U.K.

GDPR, govern the privacy and security of personal information, including health-related information in certain circumstances, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

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HUMAN CAPITAL

At Praxis, we are passionate about our mission to translate genetic insights into the development of therapies for CNS disorders characterized by neuronal imbalance.

Our culture is designed to attract, develop and retain a talent-dense team that works tirelessly to deliver treatments to positively change the lives of patients with CNS disorders.

It is the strength of our culture and our work environment that allow us to attract top talent to Praxis.

As of March 1, 2024, we have 82 employees and plan to grow as we continue to realize the potential of our pipeline.

We are dedicated to developing our culture and our employees through our company core values – Trust , Ownership , Curiosity and Results .

We Trust each other’s judgement, which is why we do not have excessively prescriptive policies.

We value transparency among team members that leads to direct, clear, and timely feedback so we can all improve together.

We commit to be one another’s checks and balances.

At Praxis, our mission is to help patients by delivering life-altering treatments faster and more effectively than has ever been done before.

Agnostic to the source of an idea, we work tirelessly to find the most practical solutions for patients as quickly and efficiently as possible.

Our people, the patient communities we serve and their caregivers and families are at the forefront of our efforts.

Our approach to building a robust clinical pipeline provides a forum for exploration and innovation where we are all involved in building the company together.

As a flat and agile organization, each employee has an impact.

Our ways of working are team-based and focused on co-creation.

We respect all opinions and encourage diversity.

Discrimination is never tolerated.

Because we trust employees to have good judgment, freedom is built into our ways of working.

We have adopted working methodologies that embrace a virtual and collaborative work environment while emphasizing Ownership for actions and outcomes.

We are a culture where employees have real accountability as we all work towards furthering achievement of ambitious goals.

Curiosity fuels innovation, and we continually challenge ourselves to better help our patients.

Learning is a passion.

We set aside one day a month known as “Curiosity Day,” in which employees are guided to step away from their day-to-day work, meetings and calls to focus on being curious.

This could mean catching up on professional articles or journals, diving deeper into a rare disease we do not currently support, exploring an area outside our comfort zone, perfecting a new skill, or taking some time to enjoy the outdoors.

These opportunities to be curious have a positive impact, and enabling our employees to bring fresh insights and learnings to the organization.

As we pursue ambitious objectives to achieve Results , we challenge ourselves daily.

By exemplifying our values of trust, ownership and curiosity, employees are positioned to propel us forward to deliver lasting results for the communities we serve.

At the end of the day, the magic we witness when employees put their minds together is what we are most proud of as a company.

In identifying our employer value proposition, we have highlighted the following aspects of working at Praxis:

Our approach to build and progress a robust clinical pipeline provides a platform for exploration and innovation.

At Praxis, we are all involved in building the company together, and as a flat and agile organization, each employee has an impact.

With our company values of Trust, Ownership, Curiosity and Results as the foundation of our efforts, we are challenged to question each other and our own assumptions to deliver treatments for patients and caregivers.

Our people, the patient communities we serve and their caregivers and families are at the forefront of our efforts.

Our ways of working are team-based and focused on co-creation, with respect for all opinions and points of view.

We show we care by giving and receiving candid feedback, and we support curiosity and ownership for all aspects of our business.

This environment fuels our growth and propels us forward.

Delivering life-altering treatments for CNS disorders is incredibly demanding, but our focus on patients with unmet needs highlights the urgency to deliver effective treatments faster and more effectively than ever before.

Our employees are passionate and persistent about transforming neuroscience because of the incredible need to positively change the lives of patients with CNS disorders.

• Dare For More TM .

We Dare For More TM in every aspect of our journey, from the patients we are working for, to the portfolio we build and advance every day, and quite importantly ourselves and our fellow team members.

People stay at Praxis to surround themselves with exceedingly motivated and passionate peers who highly value consistent excellence in their colleagues.

We are dedicated to developing our culture and our employees through our company core values – Trust , Ownership , Curiosity and Results .

Our ability to deliver life-altering treatments to patients and families affected by and living with complex brain disorders is built on the foundation of our shared core values.

More than just statements and ideas, our values provide structure for the way we work as a company and set the expectation for what we can achieve together.

By living our values, our teams drive us to deliver positive results for the communities we serve.

It is the strength of our culture and career-defining opportunities that enable us to attract and retain incredible talent to Praxis.

As of February 26, 2025, we have 116 employees and plan to grow as we continue to realize the potential of our pipeline.

In order to ambitiously deliver results based on the depth of our pipeline, we plan to grow significantly.

We provide development opportunities that will stretch and challenge employees to deliver more than they ever thought possible.

To support them we offer a world-class portfolio of compensation and benefits, including medical, dental and vision plans, a discretionary bonus program structured to pay on a quarterly basis, 401k plan with match, wellness benefits, eligibility for equity awards and an employee stock purchase plan.

AVAILABLE INFORMATION

Our Internet address is http://praxismedicines.com.

Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, including exhibits, proxy and information statements and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Exchange Act are available through the “Investors + Media” portion of our website free of charge as soon as reasonably practicable after we electronically file such material with, or furnish it to, the SEC.

file such material with, or furnish it to, the SEC.

Information on our website is not part of this Annual Report on Form 10-K or any of our other securities filings unless specifically incorporated herein by reference.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business