Praxis Precision Medicines Inc

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

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PRAXIS PRECISION MEDICINES, INC.

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Dear Praxis Stockholders:

2024 was a year of notable growth and execution for our company, underscored by the significant progress we’ve made on advancing our four late-stage assets for rare and more prevalent neurological disorders. We entered 2025 sufficiently funded and with increased confidence in our ability to expand the value proposition of our patient-guided pipeline candidates across the Cerebrum TM and Solidus TM platforms.

We are looking forward to the upcoming milestones for vormatrigine, which has the potential to be best-in-class in adult epilepsy. In the first quarter of 2024, we shared results from our Phase 2 proof of concept study in epilepsy patients with photo-paroxysmal response, which showed 100% of patients responding. We subsequently initiated our ENERGY program, aiming to support a strong registrational program for vormatrigine. The first of these studies, EMPOWER, is an ongoing observational study with over 3,000 epilepsy patients consented to date. EMPOWER has continued to highlight a significant disease burden compounded by persistent, uncontrolled, often untracked seizures alongside profound psychosocial impact. Using these learnings, we have initiated two efficacy trials for vormatrigine – RADIANT, a Phase 2 study for focal onset seizures (FOS) and generalized epilepsy, and POWER1, a Phase 2/3 registrational study for treatment resistant FOS – both expected to generate topline results this year. We intend to initiate the final study in the ENERGY program, POWER2, a Phase 2/3 registrational study, in the second half of 2025.

In our rare epilepsy programs, we are encouraged by the data generated to date for relutrigine and elsunersen as we progress towards each program’s upcoming catalysts. In 2024, we shared results from cohort 1 of the EMBOLD study assessing relutrigine in SCN2A gain-of-function (GOF) and SCN8A developmental and epileptic encephalopathies (DEEs), showing unprecedented efficacy in seizure reduction versus placebo as well as meaningful gains in alertness, communication and seizure severity. Relutrigine has received rare pediatric disease designation in three indications — SCN2A GOF DEE, SCN8A DEE and Dravet Syndrome. Encouraged by these results, we initiated a registrational cohort 2 for EMBOLD for patients with SCN2A and SCN8A DEEs, with topline results anticipated no later than the first half of 2026, followed by a potential NDA filing in 2026. Given the strong biologic rationale for relutrigine to work broadly in DEEs, we plan to initiate the EMERALD study in 2025, which will evaluate relutrigine for broader DEE diagnoses. For elsunersen, targeting SCN2A GOF DEE, we finalized the registrational trial design for EMBRAVE3 and plan to start enrolling in mid-2025. Additionally, we are continuing to enroll patients in the second cohort of EMBRAVE, with topline results expected in the first half of 2026. We have also made significant progress with multiple preclinical antisense oligonucleotides within the Solidus TM platform, and have three programs we expect to nominate candidates for during 2025.

In February 2025, we shared the recommendation of the Independent Data Monitoring Committee’s interim analysis of Study 1 of our Essential3 program evaluating ulixacaltamide for essential tremor (ET). The committee 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. This is the first Phase 3 study ever undertaken in ET, and through early 2025, we have had over 150,000 people interested in participating in the study, reflecting a substantial unmet need. 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 committee, we have decided to continue both studies to completion, with topline results expected in the third quarter of 2025. While disappointed by the preliminary outcome, we remain focused on completing both studies and delivering on our other late-stage programs this year.

The next 12-18 months are set to be the most catalyst-rich in Praxis’ history, with topline readouts across our epilepsy and essential tremor programs, the initiation of multiple registrational studies in both rare and broad epilepsies, and continued acceleration of our pipeline candidates. Thank you for your continued investment in Praxis and for your support of our patient-centric mission.

Sincerely,

Marcio Souza

President and Chief Executive Officer

NOTICE OF 2025 ANNUAL MEETING OF STOCKHOLDERS

By order of our Board of Directors,

Alex Nemiroff

Corporate Secretary

Boston, Massachusetts

IMPORTANT NOTICE REGARDING THE AVAILABILITY OF PROXY MATERIALS FOR THE 2025 ANNUAL MEETING OF STOCKHOLDERS TO BE HELD ON JUNE 26, 2025: The Notice of 2025 Annual Meeting of Stockholders, proxy statement and our Annual Report on Form 10-K for the fiscal year ended December 31, 2024 are available for viewing, printing and downloading atwww.proxyvote.com.

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