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Item 1. Business

2026-02-19 compared with 2025-02-28 · 200 added, 163 removed, 566 unchanged (39% of the section changed)

COMPANY OVERVIEW

We are a clinical-stage biopharmaceutical company translating insights from genetic epilepsies into the development of therapies for central nervous system, or CNS, disorders characterized by neuronal excitation-inhibition imbalance.

We are a fully integrated, leading central nervous system, or CNS, precision neuroscience biopharmaceutical company translating insights from genetic epilepsies into the development of therapies for CNS disorders characterized by neuronal excitation-inhibition imbalance.

Normal brain function requires a delicate balance of excitation and inhibition in neuronal circuits, which, when dysregulated, can lead to abnormal function and both rare and more prevalent neurological disorders.

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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), 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.

To date, Cerebrum™ has generated three clinical stage product candidates, ulixacaltamide, vormatrigine and relutrigine, 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.

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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 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;

Led by our clinical-stage product candidate, elsunersen, for SCN2A early-onset DEE, Solidus™ has also generated three novel ASOs with preclinical proof of mechanism that we expect to nominate development candidates for in the first half of 2026 — PRAX-080 targeting PCDH19 mosaic expression disorders;

PRAX-090 targeting SYNGAP1 loss-of-function, or LoF, mutations, a leading cause of severe intellectual disability and epilepsy in developmental and epileptic encephalopathies, or DEEs;

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

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Below is a summary of our portfolio:

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

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

Our Strategy & Approach to Drug Development

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Ulixacaltamide for Essential Tremor

Our most advanced program, ulixacaltamide, is a differentiated and highly selective small molecule inhibitor of T-type calcium channels currently in Phase 3 clinical development for the treatment of Essential Tremor, or ET.

Our most advanced program, ulixacaltamide, is a differentiated and highly selective small molecule inhibitor of T-type calcium channels in development for the treatment of essential tremor, or ET.

Food and Drug Administration, or the FDA, granted Breakthrough Therapy Designation, or BTD, for ulixacaltamide for the treatment of patients with ET based on the positive topline data from the Essential3 program, as described below.

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

In addition to ET, ulixacaltamide has the potential to be developed for other indications.

We submitted a New Drug Application, or NDA, for ulixacaltamide for the treatment of ET to the FDA, and have commenced commercial preparations and pre-launch activities.

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 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.

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.

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

The program included two separate and simultaneous Phase 3 pivotal studies:

• Study 1 was a double-blind, parallel design, placebo-controlled study that enrolled 473 patients randomized 1:1 to receive either ulixacaltamide or placebo for 12 weeks.

The primary endpoint was the change from baseline in the modified Activities of Daily Living 11, or mADL11, at Week 8.

• Study 2 was a stable-responder randomized withdrawal study that enrolled 238 patients to receive ulixacaltamide for 8 weeks.

Patients who improved by 3 points in the mADL11 from baseline were then randomized to receive either placebo or to continue receiving ulixacaltamide for an additional 4 weeks.

The primary endpoint evaluated the proportion of patients who maintained response while receiving ulixacaltamide versus placebo.

There were two additional pre-specified hypotheses evaluating combinations of arms in Study 1 and Study 2 using the change in mADL11 at Week 8.

Hypothesis 3 compared the ulixacaltamide arms of Study 1 and Study 2 with the placebo arm of Study 1, and Hypothesis 4 compared the ulixacaltamide arm of Study 2 with the placebo arm of Study 1.

Key secondary endpoints in Studies 1 and 2 assessed the rate of disease improvement (slope of mADL11 change), the Patient Global Impression of change, or PGI-C, and Clinical Global Impression of severity, or CGI-S.

We announced positive topline results for the Essential3 program in the fourth quarter of 2025.

Placebo-controlled Parallel Group Study

Study 1 met its primary and all key secondary endpoints.

Patients treated with ulixacaltamide showed a mean improvement from baseline in the mADL11 at Week 8 of 4.3 points (p<0.0001).

The improvement in mADL11 was observed as early as Week 2 and was sustained through Week 12.

All key secondary endpoints were met, including rate of disease improvement, PGI-C and CGI-S at Week 8 showing statistically significant improvement with ulixacaltamide versus placebo (p<0.001).

Randomized Withdrawal Study

Study 2 met its primary endpoint and first secondary endpoint.

The primary endpoint of percentage of patients maintaining response was met with 55% of patients on ulixacaltamide vs 33% of patients on placebo maintaining their response (p=0.037).

The first key secondary endpoint of rate of disease improvement during the randomized withdrawal period also demonstrated superior effect in patients on ulixacaltamide versus placebo (p=0.0042).

Combined Study 1 and Study 2 Hypotheses

Hypothesis 3 and 4 further supported the consistency of the effect of ulixacaltamide versus placebo.

For Hypothesis 3, there was a 4.3 point improvement in mADL11 at Week 8 for the combined Studies 1 and 2 ulixacaltamide groups versus Study 1 placebo (p<0.0001).

For Hypothesis 4, there was a 4.2 point improvement in mADL11 at Week 8 for the Study 2 ulixacaltamide group versus Study 1 placebo (p<0.0001), respectively.

Ulixacaltamide was generally well tolerated over 12 weeks of treatment with a safety profile consistent with previous trials and no drug-related serious adverse events.

Essential1 study

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Essential Tremor

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.

There is only one approved pharmacotherapy for ET, a beta blocker (propranolol), approved by the FDA for ET in 1986, that offers limited efficacy and poor tolerability and is contraindicated for comorbidities that affect a significant share of the ET population.

Other CNS drugs are used off-label, though similarly are characterized by limited efficacy and poor tolerability.

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 thalamus.

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.

ET is one of the most common movement disorders, affecting roughly seven million people in the United States alone, representing a multi-billion dollar commercial opportunity.

ET is characterized by involuntary rhythmic movements in the upper limbs, with or without tremor in other body locations such as the head, vocal cords, or legs.

These tremors significantly disrupt daily living and are progressive in nature, with increases in tremor severity commonly observed over the course of the disease.

Propranolol, a beta-blocker, is the only approved pharmacotherapy for ET offering limited efficacy and poor tolerability and is contraindicated for comorbidities that affect a significant share of the ET population.

Other beta blockers and anti-convulsants are used off-label, though similarly are characterized by limited efficacy and tolerability.

The vast majority of patients are left without a treatment option, with an estimated minimum of two million patients currently seeking treatment.

In a patient survey, up to 77% of patients felt their ET is inadequately controlled.

neurologists surveyed indicated that 85% of their visits are for patients seeking ET treatment.

We believe these findings underscore the need for more effective treatments for ET.

Relutrigine for Developmental and Epileptic Encephalopathies

Relutrigine is a first-in-class small molecule in development for the treatment of DEEs as a preferential inhibitor of persistent sodium current, shown to be a key driver of seizure symptoms in severe DEEs.

Relutrigine's mechanism of precision sodium channel, or NaV, modulation is consistent with superior selectivity for disease-state NaV channel hyperexcitability.

In-vivo studies of relutrigine have demonstrated dose-dependent inhibition of seizures up to complete control 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 NaV channel modulation.

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

We have submitted an NDA for relutrigine for the treatment of SCN2A-DEE and SCN8A-DEE to the FDA based on data from the EMBOLD study, and commercial preparations and pre-launch activities are underway.

Assuming successful initial NDA approval for relutrigine, we believe the EMERALD study evaluating relutrigine in patients with broad DEEs, if positive, could serve as the basis for a supplemental NDA, or sNDA, submission in 2027.

Phase 2 EMBOLD study

The EMBOLD study was 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.

Data from cohort 1 of the Phase 2 EMBOLD study demonstrated a well-tolerated, robust, short- and long-term improvement in motor seizures in a heavily pre-treated population, alongside maintained seizure freedom in some patients with SCN2A-DEE and SCN8A-DEE.

In the fourth quarter of 2025, we announced positive results from the registrational cohort of the EMBOLD study after receiving a recommendation from the Data Monitoring Committee to stop the study early for efficacy.

Relutrigine was well-tolerated with rapid, significant and increasing seizure reduction over time with broad functional improvements across behavior, alertness, communication and overall status.

Patients receiving relutrigine (n=51) experienced a 53% placebo-adjusted reduction in seizures over 16-weeks (p<0.0002) and achieved a 66% increase in motor seizure-free days (p=0.034).

Both clinician and caregiver global impression scores showed statistically significant improvements, with most patients improving across both scales in alertness, communication, and seizure severity.

There were no drug-related serious adverse events and treatment-related adverse events were predominantly mild and moderate.

Phase 3 EMERALD Study

The EMERALD study is a randomized, double-blind, placebo-controlled Phase 3 clinical trial evaluating the efficacy, safety, tolerability and PK of relutrigine in patients with broad DEEs regardless of etiology.

We have initiated the study and expect to be fully enrolled in the second half of 2026.

Assuming approval of the NDA for relutrigine, the EMERALD study, if positive, could serve as the basis for an sNDA submission in 2027.

Rare, monogenic DEEs

Epilepsies are common neurological disorders characterized by brain excitation-inhibition, or E/I, imbalance.

Hyperexcitability can lead to abnormal synchronization of neurons and neuronal circuits, which is the electrical basis of a seizure.

Fundamentals of brain electrophysiology and mechanisms dictating seizure genesis are conserved across species and, consequently, animal models of seizures and epilepsy enable a clinically predictive and therefore efficient drug development path.

A subset of epilepsies are rare, monogenic DEEs characterized by early onset (less than 2 years of age), frequent seizures, abnormal epileptiform EEG activity, developmental impairment and resistance to available AEDs.

Furthermore, these DEEs are associated with a high mortality rate and comorbidities such as developmental delay in addition to behavioral disorders, movement disorders, pain and sensory dysfunction and sleep disruptions.

Collectively, DEEs represent a broader, heterogeneous group of severe epilepsies that impose a profound burden on patients and caregivers and can include autonomic dysfunction in addition to the comorbidities described above.

The understanding of the etiology of DEEs has been revolutionized by recent whole-exome sequencing initiatives that revealed over 60 genetic causes of epilepsy.

Even when an identifiable genetic etiology is present, clinical presentation and severity can vary widely across patients and etiologies.

We estimate there are approximately 200,000 patients in the United States living with a DEE.

An underlying pathologic feature of many DEEs is dysregulated neuronal activity leading to hyperexcitability, seizures and associated comorbidities.

This phenomenon is observed in many pediatric DEEs with an identified genetic cause, such as PCDH19, SCN8A, SCN2A, KCNT1, KCNQ2, KCNQ1, STXBP1 and SYNGAP1, as well as epilepsies in which a genetic cause remains unclear, such as Lennox Gastaut Syndrome, or Doose Syndrome.

Up to 40% of DEEs are caused by single gene mutations, enabling precision medicine approaches.

Given the overlapping biology, phenotypic presentation and clinical execution considerations, we believe that developing a portfolio of drugs to treat DEEs will create a distinct body of knowledge that can be leveraged within our operating ecosystem to develop meaningful therapies for this group of patients with devastating unmet clinical needs.

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 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.

SCN2A-DEE is a rare condition caused by a mutation in the SCN2A gene.

The SCN2A gene encodes the NaV1.2 subunit of brain sodium channels, which control neuronal excitability by regulating the flow of sodium ions into neurons.

This movement of sodium ions is a major component of generating electrical signals called action potentials, the way in which the cells communicate.

SCN2A-DEE is associated with profound impact on patients, including drug-resistant seizures, significant cognitive impairment, movement disorders such as dystonia or ataxia, and problems in other body systems such as the gastrointestinal or ocular systems.

Currently, there are no approved treatments for SCN2A-DEE, and the standard-of-care typically involves a regimen of many concurrent anti-seizure medications as well as medications for comorbidities.

Despite these interventions, it is estimated that more than 80% of SCN2A-DEE patients live with uncontrolled seizures, and approximately 75% live with severe intellectual disability.

It is estimated that there are approximately 4,000 patients in the United States with gain-of-function changes in SCN2A leading to epileptic encephalopathy.

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.

The seizures can be of multiple different types, up to dozens per day, with poor response to current treatment options.

Patients with SCN8A-DEE have significant cognitive disabilities, ranging from moderate to severe, often have movement disorders, such as dystonia or ataxia, and have problems in other body systems such as the gastrointestinal or ocular systems.

SCN8A-DEE patients also may experience autonomic features such as increases or decreases in heart rate, abnormal breathing and cyanosis.

It is estimated that there are approximately 5,000 patients in the United States with SCN8A-DEE.

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.

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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

Data from patients in the RADIANT study demonstrated a robust seizure reduction, with vormatrigine being generally well tolerated.

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.

ENERGY Program

The ENERGY program consists of five studies — EMPOWER, RADIANT, POWER1, POWER2 and POWER3.

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.

EMPOWER is an observational study that aims to better characterize seizure burden.

We initiated the study in the third quarter of 2024 and continue to generate standardized, longitudinal data to support planned interventional trials and deepen our understanding of patient experiences with epilepsy.

Findings to date from EMPOWER revealed that few patients are cared for by epileptologists, with epilepsy patient burden compounded by uncontrolled seizures that affect quality of life.

Despite being on multiple antiseizure medications, patients continue to report seizures, reinforcing the urgent need for targeted and innovative therapies.

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.

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

We announced positive topline results from RADIANT in the second half of 2025.

Patients with FOS (n=62) taking vormatrigine for eight weeks on background anti-seizure medications saw a 54%

median reduction in seizures.

In week 1, 58% of patients achieved at least a 50% reduction in seizures, which increased to 61% by week 8.

Patients continuing to the open-label extension observed an increasing and sustained effect, reaching 100% median weekly seizure reduction after 8 weeks and maintained through 16 weeks.

Over 11% of patients experienced seizure freedom for the entire 8-week period and roughly one third of patients experienced seizure freedom for a consecutive 28-day period.

Patients with generalized epilepsy (n=3) also demonstrated rapid, durable seizure reduction, supporting the broad potential of vormatrigine across seizure types.

Vormatrigine was generally well-tolerated and demonstrated a favorable safety profile.

POWER1 and POWER2 Registrational Studies

POWER1 is a Phase 2/3 double-blind, placebo-controlled, 12-week study to evaluate the efficacy and safety of vormatrigine in patients with FOS (n=~230).

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, followed by an open-label extension.

The primary endpoint is change in seizure frequency.

We expect to announce topline results in the second quarter of 2026.

POWER2 is a Phase 3 double-blind, placebo-controlled 12-week study to evaluate the efficacy and safety of vormatrigine in patients with FOS (n=~400).

POWER2 is a multi-arm study, comparing treatment arms of 20 mg, 30 mg and 40 mg versus placebo for 12 weeks.

POWER2 is enrolling patients, with completion expected in the second half of 2026 and topline results expected in 2027.

If the POWER1 and POWER2 studies are positive, we plan to submit an NDA for vormatrigine in 2027.

We intend to initiate POWER3, a clinical trial evaluating vormatrigine as a single-agent treatment for FOS, in the first half of 2026.

Phase 2a Photo-Paroxysmal Response Study

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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.

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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.

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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)

Common Epilepsies (FOS 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.

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Standard of care sodium channel targeting AEDs can produce severe toxicity at therapeutic doses from excessive inhibition of peak sodium current, as physiological levels of peak sodium current are required for normal neuronal function.

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.

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

Epilepsies are common neurological disorders characterized by brain excitation-inhibition, or E/I, imbalance.

Hyperexcitability can lead to abnormal synchronization of neurons and neuronal circuits, which is the electrical basis of a seizure.

The understanding of the etiology of DEEs has been revolutionized by recent whole-exome sequencing initiatives that revealed over 60 genetic causes of epilepsy.

An underlying pathologic feature of many DEEs is dysregulated neuronal activity leading to hyperexcitability, seizures and associated comorbidities.

Up to 40% of DEEs are caused by single gene mutations, enabling precision medicine approaches.

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

The SCN2A gene encodes the NaV1.2 subunit of brain sodium channels, which control neuronal excitability by regulating the flow of sodium ions into neurons.

This movement of sodium ions is a major component of generating electrical signals called action potentials, the way in which the cells communicate.

Early-onset SCN2A-DEE presents before three months of life and can lead to profound impact on patients, including drug-resistant seizures, significant cognitive impairment, movement disorders such as dystonia or ataxia, and problems in other body systems such as the gastrointestinal or ocular systems.

Currently, there are no approved treatments for SCN2A-DEE, and the standard-of-care typically involves a regimen of many concurrent anti-seizure medications as well as medications for comorbidities.

Despite these interventions, it is estimated that more than 80% of early-onset SCN2A-DEE patients live with uncontrolled seizures, and approximately 75% live with severe intellectual disability.

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 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.

The seizures can be of multiple different types, up to dozens per day, with poor response to current treatment options.

SCN8A-DEE patients also may experience autonomic features such as increases or decreases in heart rate, abnormal breathing and cyanosis.

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.

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

Elsunersen for SCN2A-DEE

Elsunersen is a clinical-stage ASO designed to down-regulate Na V 1.2 expression, an effect that has demonstrated disease-modifying activity in animal models of SCN2A epileptic encephalopathy.

In transgenic mice carrying a human SCN2A GoF mutation, we observed a significant, dose-dependent reduction in seizures and increased survival of mice treated with a mouse ASO that is designed to down-regulate SCN2A.

The survival benefit from the ASO was maintained with repeat dosing.

We also observed survival benefits following administration of a mouse ASO to a group of mice after onset of disease and around the time of onset of mortality.

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.

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.

Elsunersen is a clinical-stage ASO designed to selectively decrease SCN2A gene expression, directly targeting the underlying cause of early seizure-onset SCN2A-DEE to treat seizures and other symptoms in patients with gain-of-function SCN2A mutations.

In vitro studies of elsunersen have demonstrated reduction in both SCN2A gene expression and protein levels.

In vivo, elsunersen has demonstrated significant, dose-dependent reduction in seizures, improvement in behavioral and locomotor activity and increased survival in SCN2A mouse models, with potential to be the first disease-modifying treatment for SCN2A-DEE.

Elsunersen has received ODD and RPDD from the FDA, and ODD and PRIority MEdicines, or PRIME, designations from the European Medicines Agency for the treatment of SCN2A-DEE.

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.

Part 1 of the EMBRAVE study was a 21-week open label cohort, in which participants received elsunersen for 16 weeks, designed to determine the safety and tolerability of intrathecal delivery of elsunersen.

No treatment related AEs or SAEs were observed.

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

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 EMBRAVE Study Part A is evaluating the safety and efficacy of elsunersen versus sham-procedure.

We have enrolled 9 patients randomized 3:1 to elsunersen or placebo/sham for 20 weeks, followed by a blinded transition to elsunersen for up to two years in an open-label extension.

We expect to disclose the topline results in the first half of 2026.

EMBRAVE3 Phase 3 study

We have initiated EMBRAVE3, a Phase 3 registrational study evaluating the efficacy, safety, tolerability and PK of elsunersen in early-onset SCN2A-DEE, and expect to announce topline results in 2027.

EMBRAVE3 is a single-arm study where all patients will receive elsunersen for 24 weeks.

This study consists of three cohorts and will enroll approximately 30 patients.

Cohort 1 will enroll 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.

Patients will receive 1 mg of elsunersen intrathecally every 4 weeks for 24 weeks.

Cohorts 2 and 3 will enroll patients from age 0 to 2 years in a staggered fashion, starting with patients ages 1-2 in Cohort 2 following a safety review of a subset of patients from Cohort 1.

Cohort 3 patients (ages 0-1 years) will be enrolled following a safety review of a subset of the Cohort 2 patients.

Patients will receive elsunersen at starting doses of 1.0 mg for Cohort 2, and 0.5 mg for Cohort 3, every 4 weeks 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.

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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.

Key product features that would affect our ability to effectively compete with other therapeutics include the efficacy, safety, convenience, cost, effectiveness of promotional support and intellectual property protection of our products.

Key product features that would affect our ability to effectively compete with other therapeutics include the efficacy, safety, convenience, cost, effectiveness of

promotional support and intellectual property protection of our products.

Our competitors fall primarily into the following groups of treatment:

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

• Approved 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.

Many of our competitors have sufficient financial resources, expertise and capabilities in research and development, the regulatory approval process, manufacturing and marketing to advance their portfolios.

Smaller or early-stage companies may also prove to be significant competitors, particularly through merger and acquisition activity and sizeable collaborative arrangements with established companies.

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T-type Calcium channel blockers

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

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

An eleventh family is directed to methods of treatment using ulixacaltamide and expires in 2045.

A twelfth family is directed to methods of treating Parkinson’s disease with ulixacaltamide and expires in 2045.

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 relutrigine and vormatrigine, two additional patent families that relate to relutrigine, and the remaining patent families relate to other persistent sodium current blockers.

We own sixteen 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 patent family, relutrigine is covered by two patents that have granted in the United States, one that covers the composition of matter and one that covers a method of use.

These patents both expire in 2039.

The family also has patents and pending patent applications that cover relutrigine in other potentially commercially relevant jurisdictions, which expire in 2039.

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

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

Two patents are granted in the United States, which expire in 2039.

Three patents are granted in the United States, which expire in 2039.

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

issued, which expires in 2042.

patent has 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.

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Ionis will be entitled to receive an additional one-time milestone payment of $5.0 million, or the Additional Milestone, upon the earliest to occur of the following (each, a Payment Trigger):

(i) the first acceptance of an NDA filing for a product by the regulatory authority in a major market, (ii) we have both (a) received, in the aggregate, $300.0 million in cash since September 11, 2019 and (b) initiated the first clinical study with respect to a product or (iii) the closing of a change of control event affecting Praxis.

(i) the first acceptance of an NDA filing for a product by the regulatory authority

in a major market, (ii) we have both (a) received, in the aggregate, $300.0 million in cash since September 11, 2019 and (b) initiated the first clinical study with respect to a product or (iii) the closing of a change of control event affecting Praxis.

In addition, upon the occurrence of a Payment Trigger, Ionis is also entitled to certain interest payments equal to (i) 10% simple interest per annum calculated from the effective date of the agreement on the Additional Milestone, or the Initial Interest Amount, plus (ii) 10% simple interest per annum calculated from the date the Additional Milestone is paid on the initial Interest Amount, or the Second Interest Amount, until the earliest to occur of the following:

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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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Furthermore, an independent IRB for each site proposing to conduct the clinical trial must review and approve the plan for any clinical trial and its informed consent form before the clinical trial begins at that site, and must monitor the study until completed.

Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board, which provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study, and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy.

grounds, such as no demonstration of efficacy.

Similarly, the FDA or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health risk.

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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.

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

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.

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

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Orphan drug designation and exclusivity

Under the Orphan Drug Act, the FDA may designate a drug product as an “orphan drug” if it is intended to treat a rare disease or condition (generally meaning that it affects fewer than 200,000 individuals in the United States, or more in cases in which there is no reasonable expectation that the cost of developing and making a drug product available in the United States for treatment of the disease or condition will be recovered from sales of the product).

product available in the United States for treatment of the disease or condition will be recovered from sales of the product).

A sponsor must request orphan drug designation before submitting an NDA.

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If a product with orphan status receives the first FDA approval for the disease or condition for which it has such designation or for a select indication or use within the rare disease or condition for which it was designated, the product generally will receive orphan product exclusivity.

Orphan product exclusivity means that the FDA may not approve any other applications for the same product for the same disease or condition for seven years.

Orphan product exclusivity means that the FDA may not approve any other applications for the same product for the same approved use or indication within the relevant rare disease or condition for seven years.

If a drug or drug product designated as an orphan product ultimately receives marketing approval for a disease or condition broader than what was designated in its orphan product application, it may not be entitled exclusivity.

Orphan exclusivity will not bar approval of another product under certain circumstances, including if a subsequent product with the same active ingredient for the same disease or condition is shown to be clinically superior to the approved product on the basis of greater efficacy or safety, or to provide a major contribution to patient care, or if the company with orphan drug exclusivity is not able to meet market demand.

Orphan exclusivity will not bar approval of another product under certain circumstances, including if a subsequent product with the same active ingredient is shown to be clinically superior to the approved product with respect to the same indication or use on the basis of greater efficacy or safety, or to provide a major contribution to patient care, or if the company with orphan drug exclusivity is not able to meet the needs relating to the approved indication or use of the patients with the relevant disease or condition.

Among the other benefits of orphan drug designation are tax credits for certain research and a waiver of the NDA application user fee.

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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 December 20, 2024.

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

If the program is not reauthorized, if a drug candidate receives Rare Pediatric Disease Designation before October 1, 2024, the sponsor of the marketing application for such drug will only be eligible to receive a voucher if the application for the designated drug is approved by the FDA before October 1, 2026.

Congress has only authorized the Rare Pediatric Disease Priority Review Voucher program until September 30, 2029.

Consequently, unless Congress reauthorizes the program, the sponsor of the marketing application for a drug that receives Rare Pediatric Disease Designation will only be eligible to receive a voucher if the FDA grants the voucher on or before September 30, 2029.

Fast track, breakthrough therapy and priority review designations

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The designation includes all of the fast track program features, as well as more intensive FDA interaction and guidance beginning as early as Phase 1 and an organizational commitment to expedite the development and review of the product candidate, including involvement of senior managers.

Praxis has two programs which have received breakthrough therapy designation:

ulixacaltamide for treatment of Essential tremor and relutrigine for the treatment of seizure associated with SCN2A and SCN8A DEEs.

Finally, the FDA may designate an NDA for priority review if the product candidate treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness.

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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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Pediatric exclusivity, if granted, adds six months to existing regulatory exclusivity periods or patent terms.

This six-month exclusivity may be granted based on the voluntary completion of a pediatric trial in accordance with an FDA-issued “Written Request” for such a trial.

This six-month exclusivity may be granted based on the voluntary completion of a pediatric trial in accordance with an FDA-issued “Written

Request” for such a trial.

The FDA's issuance of a written request does not obligate the sponsor to complete the requested pediatric studies.

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increased the minimum Medicaid rebates owed by manufacturers under the Medicaid Drug Rebate Program and extended the rebate program to individuals enrolled in Medicaid managed care organizations;

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

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.

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

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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By way of example, in August 2022, the Inflation Reduction Act of 2022, or the IRA, was signed into law.

Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), with prices that can be negotiated subject to a cap;

Among other things, the IRA requires manufacturers of certain drugs to

engage in price negotiations with Medicare (beginning in 2026), with prices that can be negotiated subject to a cap;

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

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

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.

HHS has announced the agreed-upon prices for the first ten drugs that were subject to price negotiations, which took effect in January 2026, and the subsequent fifteen additional drugs, which will first take effect in January 2027.

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.

More recently, the One Big Beautiful Bill Act, which was enacted in July 2025, imposes significant reductions in the funding of the Medicaid program.

Such reductions are expected to decrease the number of persons enrolled in Medicaid and reduce the services covered by Medicaid, which could adversely affect our sales of any product candidate that we commercialize.

The current presidential administration is pursuing a two-fold strategy to reduce drug costs in the United States.

While it is unclear whether and how such policies will be implemented, the proposed policies are likely to have a negative impact on the pharmaceutical industry and on our ability to receive adequate revenues for any product candidates we develop, if approved.

As part of this strategy, President Trump has proposed imposing significant tariffs on pharmaceutical manufacturers that do not adopt pricing policies such as most favored nation pricing, which would tie the price for drugs in the United States to the lowest price in a group of other countries.

In response, multiple manufacturers have reportedly entered into confidential pricing agreements with the federal government.

In addition, the Trump administration is pursuing traditional regulatory pathways to impose drug pricing policies, although final regulations have not yet been published.

In addition, pharmaceutical pricing and marketing has long been the subject of considerable discussion in Congress and among policymakers, and it is possible that Congress could enact additional laws that negatively affect the pharmaceutical industry.

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, drug price reporting and other transparency measures and, in some cases, designed to encourage importation from other countries and bulk purchasing.

Some states have also enacted legislation creating so-called prescription drug affordability boards, which ultimately may attempt to impose price limits on certain drugs in these states.

In addition, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs.

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We may need to conduct expensive pharmaco-economic studies in order to demonstrate the medical necessity and cost-effectiveness of our product candidates, if approved, in addition to the costs required to obtain the FDA approvals.

Nonetheless, our product candidates may not be considered medically necessary or cost-effective.

Nonetheless, our

product candidates may not be considered medically necessary or cost-effective.

Moreover, the process for determining whether a third-party payor will provide coverage for a drug product may be separate from the process for setting the price of a drug product or for establishing the reimbursement rate that such a payor will pay for the drug product.

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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.

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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.

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.

In 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.

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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;

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;

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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.

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.

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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.

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.

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individual or business from paying, offering, authorizing payment or offering of anything of value, directly or indirectly, to any foreign official, political party or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or retaining business.

The FCPA also obligates companies whose securities are listed in the United States to comply with certain accounting provisions requiring the company to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations.

reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations.

Compliance with the FCPA is expensive and difficult, particularly in countries in which corruption is a recognized problem.

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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.

As of February 16, 2026, we have 168 employees and plan to continue to grow as we advance the potential of our pipeline.

In order to ambitiously deliver results based on the depth of our programs and prepare for potential commercialization, we expect to expand our workforce, with the majority of anticipated hiring focused on building commercial capabilities.

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.

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 including a monthly allowance that employees may apply toward a broad range of health and well-being expenses, 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.

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.

In addition, our filings with the SEC may be accessed through the SEC’s Interactive Data Electronic Applications system at http://www.sec.gov.

All statements made in any of our securities filings, including all forward-looking statements or information, are made as of the date of the document in which the statement is included, and we do not assume or undertake any obligation to update any of those statements or documents unless we are required to do so by law.

All statements made in any of our securities filings, including all forward-looking statements or

information, are made as of the date of the document in which the statement is included, and we do not assume or undertake any obligation to update any of those statements or documents unless we are required to do so by law.

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