Daybue (trofinetide) / Neuren, Acadia Pharma - LARVOL DELTA

Design, synthesis and evaluation of trofinetide prodrug based on diketopiperazine strategy. (PubMed, Bioorg Med Chem) - "Compared to oral administration of trofinetide, subcutaneous injection of TFD 10 markedly prolonged the half-life (6-fold) and substantially increased systemic exposure (40-fold), successfully achieving the design objectives. This study validates the feasibility of this strategy, and TFD 10, as a proof-of-concept lead compound, demonstrates significant potential for further development."

Journal • Developmental Disorders • Movement Disorders • Pediatrics

Modulating alternative splicing of MECP2 is a potential therapeutic strategy for Rett syndrome. (PubMed, Sci Transl Med) - "The current US Food and Drug Administration-approved treatment for RTT, trofinetide, mildly alleviates some symptoms...Last, an exon 2-skipping morpholino up-regulated MeCP2-E1 in vivo in mice. These data set the stage for a potential therapeutic strategy using antisense oligonucleotides to promote isoform switching in patients with RTT who carry partially functioning alleles of MECP2."

Journal • CNS Disorders • Developmental Disorders • Movement Disorders

858106: Advancements in Rett Syndrome (RTT) Care: Caregiver and Expert Panel Discussion (This activity is supported by an independent educational grant from Acadia Pharmaceuticals, Inc.) (ACMG 2026) - "These sessions focus on highlighting new developments, generating interest in innovative products or services, and sharing the latest insights with meeting participants. These activities are not part of the official ACMG meeting programming and are not accredited by ACMG.Learning Objectives:• Review RTT diagnostic criteria and multisystem impact• Examine clinical trial data from LAVENDER, LILAC-1, and LILAC-2, and real-world observations from the LOTUS post approval study• Discover caregiver insights based on their experiences with RTT and DAYBUE"

Grant • CNS Disorders • Developmental Disorders • Movement Disorders

Impact of Real-World, Case-Driven CME Learning on Diagnostic and Therapeutic Practice in Rett Syndrome (AAN 2026) - "Objective: To characterize the impact of a continuing medical education initiative that incorporated real-world patient scenarios in addressing diagnostic and treatment challenges in Rett syndrome (RTT).Background: The approval of trofinetide, the first therapy for RTT, requires greater clinician preparedness in treatment selection, caregiver counseling, and team-based management.Design/ A multidisciplinary expert faculty panel developed a multicomponent CME curriculum (a 60-minute foundational module and a three-part, case-based series) centered on practical strategies to facilitate early diagnosis, therapy selection, AE management through neurology–gastroenterology collaboration, and integration of rehabilitation therapy... The initiative produced measurable gains in clinician knowledge, competence, and confidence in RTT care, supporting improved diagnostic and management practices."

Clinical • Real-world • Real-world evidence • Developmental Disorders • Movement Disorders

Severe Hyperventilation Apnea Spells in Pitt Hopkins Syndrome and Beyond: A Remarkable Response to IV Diamox in the ICU (AAN 2026) - "These mice show reduced hyperventilation and improved behavior after administration of promyelinating drugs such as clemastine and sobetirome. There are several suspected mechanisms underlying PTHS, each with a promising therapeutic approach. Carbonic anhydrase inhibitors like acetazolamide have demonstrated clinical effectiveness in preventing HVAS, likely through blood acidification and direct action on the chemoreceptors in the retrotrapezoid nucleus (RTN), the primary respiratory drive center. In TCF4 knockout mice, diffuse hypomyelination occurs due to incomplete oligodendrocyte precursor cell (OPC) differentiation."

Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Mental Retardation • Respiratory Diseases • Solid Tumor • IGF1 • NAV1 • TCF4

Real-world Benefits and Tolerability of Trofinetide for the Treatment of Adults with Rett Syndrome: the LOTUS Study (AAN 2026) - "The real-world benefits and tolerability of trofinetide in adults with RTT in LOTUS followed similar trends to the overall LOTUS population."

Clinical • Real-world • Real-world evidence • Constipation • Developmental Disorders • Movement Disorders

ACAD Plans Re-Examination After CHMP Rejects Rett Syndrome Drug in EU (Yahoo Finance) - "Following the formal adoption of the opinion, Acadia reviewed the CHMP’s grounds for refusal in detail and plans to request a re-examination. The regulatory setback has delayed the potential approval of trofinetide in the EU. Although the pivotal LAVENDER study met its co-primary and key secondary endpoints, the CHMP issued the refusal, citing several perceived limitations."

European regulatory • Rare Diseases

The European Medicines Agency has recommended the refusal of the marketing authorisation for Daybu, a medicine intended for the treatment of Rett syndrome, a rare inherited condition that affects the brain and nervous system. (European Medicines Agency) - "The Agency issued its opinion on 26 February 2026. The company that applied for authorisation, Acadia Pharmaceuticals, may ask for re-examination of the opinion within 15 days of receiving the opinion."

CHMP • Rare Diseases

A Phase 1, Randomized, Open-Label Study to Assess the Bioequivalence of Trofinetide as a Ready-to-Use Oral Solution and Constituted Powder for Oral Solution in Healthy Adults. (PubMed, Adv Ther) - "The bioequivalence demonstrated in this study supports the clinical interchangeability of TPOS and TOS and shows that TPOS can be constituted using adjustable volumes of water without affecting bioavailability. There were no unexpected adverse events reported with trofinetide when administered as TPOS and TOS."

Journal • P1 data • Developmental Disorders • Movement Disorders

Real-World Benefits and Tolerability of Trofinetide for the Treatment of Male Patients With Rett Syndrome: LOTUS Study Interim Results (ACMG 2026) - "The results of the 7 males with RTT included in this follow-up suggest that the real-world benefits and tolerability of trofinetide in males follow similar trends with the general population of LOTUS."

Clinical • Real-world • Real-world evidence • CNS Disorders • Developmental Disorders • Infectious Disease • Movement Disorders • Pneumonia • Respiratory Diseases

Dual Diagnosis of Klinefelter Syndrome and Rett Syndrome in a Male Patient: A Rare Co-occurrence with Diagnostic and Phenotypic Implications (ACMG 2026) - "Treatment and Management This patient is a candidate for trofinetide, a treatment for Rett syndrome shown to provide subtle behavioral benefits...Understanding how XCI modifies disease severity has important implications for prognosis and therapeutic development. Larger cohorts and systematic evaluation of XCI patterns will be critical for defining natural history, refining management, and guiding emerging targeted therapies."

Clinical • Cardiovascular • CNS Disorders • Developmental Disorders • Endocrine Disorders • Genetic Disorders • Mental Retardation • Movement Disorders • Obstructive Sleep Apnea • Ophthalmology • Respiratory Diseases • Sleep Apnea • Sleep Disorder

IGF1 peptide targets Rett Syndrome astrocytes to degrade IGF binding protein, rescue synaptogenesis and restore mitochondrial function. (PubMed, bioRxiv) - "Our data define a molecular mechanism by which astrocyte dysfunction in RTT can be rescued and provide a mechanistic basis for the therapeutic efficacy of IGF1(1-3) peptide, including Trofinetide, an FDA-approved IGF1 peptide mimetic, in RTT...This restores IGF1 bioavailability and rescues synaptic function in a non-cell-autonomous manner. These findings provide a mechanistic explanation for the clinical efficacy of IGF1 peptide and its mimetics in Rett syndrome, and highlight astrocytes as rational therapeutic targets in neurodevelopmental and other disorders."

Journal • CNS Disorders • Developmental Disorders • Movement Disorders • Psychiatry • IGF1 • IGFBP2

Disease-modifying therapies for Rett syndrome: a review for neurologists. (PubMed, Front Neurol) - "Until the recent approval of trofinetide, management relied exclusively on symptomatic treatment and multidisciplinary supportive care...TSHA-102 uses an intrathecally delivered miniMECP2 transgene regulated by a microRNA-based autoregulatory system, whereas NGN-401 delivers full-length MECP2 via intracerebroventricular administration using a synthetic expression-feedback circuit...Finally, we address key translational considerations such as optimal timing of intervention, dosing constraints, outcome measurement in severely impaired populations, long-term safety surveillance, and barriers to broad and equitable access. The RTT gene therapy experience serves as a model for precision medicine in other monogenic neurodevelopmental disorders, illustrating both the transformative promise and the substantial complexities of translating genetic science into meaningful clinical benefit."

Journal • Review • CNS Disorders • Developmental Disorders • Gene Therapies • Movement Disorders • Pediatrics • Psychiatry • ADAR

Acadia provides update on regulatory submission for trofinetide for the treatment of Rett syndrome in the European Union (Neuren Pharma Press Release) - "Neuren Pharmaceuticals (ASX: NEU) advised that its licensee Acadia Pharmaceuticals...has today provided an update on its marketing authorization application (MAA) for trofinetide for the treatment of Rett syndrome in the European Union (EU). Acadia was informed by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) of a negative trend vote on its MAA for trofinetide for the treatment of Rett syndrome, following its recent CHMP oral explanation. Subject to the outcome of the CHMP vote in February, Acadia intends to request a re-examination of the opinion by the CHMP upon its formal adoption."

CHMP • Genetic Disorders

Post-marketing safety concerns with trofinetide: a disproportionality analysis of the first therapeutic agent for Rett syndrome based on the FDA adverse event reporting system (FAERS). (PubMed, Front Pharmacol) - "This study unveils certain potential risks associated with trofinetide in real-world applications. Medical staffs should pay more attention to AEs of patients on the first month."

Adverse events • Journal • P4 data • Autism Spectrum Disorder • Developmental Disorders • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Infectious Disease • Influenza • Movement Disorders • Respiratory Diseases

Trofinetide-Induced Enterocolitis Syndrome in a Child with Rett Syndrome. (PubMed, J Child Neurol) - "The concept of drug-induced enterocolitis syndrome (DIES) has been reported with other agents; however, to our knowledge, this represents the first reported case of FPIES/DIES triggered by trofinetide. This case expands the spectrum of trofinetide-related adverse reactions and emphasizes the need to distinguish immune-mediated enterocolitis from dose-dependent osmotic diarrhea and highlights the importance of clinician vigilance when initiating similar therapies in children with complex neurodevelopmental disorders."

Journal • CNS Disorders • Developmental Disorders • Gastrointestinal Disorder • Movement Disorders • Psychiatry

Neuren Pharmaceuticals…announced that its partner, Acadia Pharmaceuticals, has received US Food and Drug Administration (FDA) approval of DAYBUE STIX (trofinetide) for oral solution, a dye- and preservative-free powder formulation of trofinetide for the treatment of Rett syndrome in adult and pediatric patients two years of age and older (Neuren Pharma Press Release) - "The approval of this new formulation was informed by the results of a bioequivalence study, which demonstrated that both original DAYBUE (trofonetide) oral solution and the new DAYBUE STIX (trofinetide) for oral solution powder formulation provide comparable exposure....Acadia expects DAYBUE STIX to be available on a limited basis starting in the first quarter of 2026 and more broadly early in the second quarter of 2026."

FDA approval • Launch US • CNS Disorders • Developmental Disorders • Genetic Disorders

Epilepsy Rates Among Individuals with Rett Syndrome Treated with Trofinetide versus Untreated in the United States (AES 2025) - "In this real-world analysis of RTT individuals, the TROF vs. NO-TROF groups exhibited similar rates of epilepsy during the 12-month post-index period. Among individuals with post-index epilepsy, there were similar rates of pre-index epilepsy across both groups."

Clinical • Late-breaking abstract • CNS Disorders • Developmental Disorders • Epilepsy • Mood Disorders • Movement Disorders • Vascular Neurology

Demographic and Clinical Characteristics among Adult Individuals with Rett Syndrome Treated with Trofinetide vs Untreated (AES 2025) - "Data on adult RTT individuals >20 years is scarce, especially for those initiating TROF. In this real-world analysis, only 16% of eligible adult RTT individuals were initiated on TROF, while 84% remain untreated. After matching, the treated group had higher rates of baseline comorbidities; potentially suggesting individuals with higher severity initiate TROF."

Clinical • Late-breaking abstract • CNS Disorders • Developmental Disorders • Epilepsy • Gastrointestinal Disorder • Mood Disorders • Movement Disorders • Vascular Neurology

Compatibility of Trofinetide with Ketogenic Diets in Patients with Rett Syndrome: Case Reports (AES 2025) - "In these anecdotal cases, patients with RTT treated with trofinetide were successfully started and maintained on ketogenic diets to further optimize seizure control. All patients achieved ketosis, as evidenced by optimal β-hydroxybutyrate levels, and all patients experienced improved seizure control."

Case report • Clinical • Late-breaking abstract • CNS Disorders • Developmental Disorders • Epilepsy • Movement Disorders • Psychiatry

Real-World Behavioral Improvements in Patients With Rett Syndrome Treated With Trofinetide: Interim Results of the LOTUS Study (AES 2025) - "The results of LOTUS show that caregivers observe the impact of trofinetide on meaningful functions and behaviors, such as nonverbal communication. The caregiver-reported behavioral improvements expand on the behavioral improvements observed in trofinetide clinical trials."

Clinical • Late-breaking abstract • Real-world • Real-world evidence • CNS Disorders • Developmental Disorders • Movement Disorders • Psychiatry

An Evaluation of Real-World Effectiveness and Safety of Trofinetide in Patients with Rett Syndrome: A Retrospective Chart Review (AES 2025) - "This study provides valuable insights into the real-world use of trofinetide in patients with RTT, including its effectiveness, safety, and treatment patterns. These findings will help inform clinical decision-making and optimize patient care in routine practice."

Late-breaking abstract • Real-world • Real-world effectiveness • Real-world evidence • Retrospective data • Review • Developmental Disorders • Movement Disorders • Respiratory Diseases

Remarkable Seizure Reduction with Trofinetide in An Adult with Rett Syndrome (AES 2025) - "To our knowledge, this patient is the first reported case of an older individual with RTT with significant seizure reduction after starting trofinetide. This suggests that long-term use of trofinetide may result in sustained symptom improvement in older individuals and in people who were diagnosed later in life with RTT. Our patient had seizure recurrence when an attempt was made to reduce the dose of lacosamide."

Clinical • CNS Disorders • Constipation • Developmental Disorders • Epilepsy • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Movement Disorders • Nephrology • Psychiatry

Real-World Benefits and Tolerability of Trofinetide for the Treatment of Male Patients With Rett Syndrome: Interim Results of the LOTUS Study (AES 2025) - "The results of the 7 males with RTT included in this follow-up suggest that the real-world benefits and tolerability of trofinetide in males follow similar trends with the general population of LOTUS."

Clinical • Late-breaking abstract • Real-world • Real-world evidence • CNS Disorders • Developmental Disorders • Infectious Disease • Movement Disorders • Pneumonia • Psychiatry • Respiratory Diseases

Trofinetide Improves Cognitive Function in APP/PS1 Mice by Suppressing Inflammation and Apoptosis. (PubMed, Mol Neurobiol) - "Mechanistically, trofinetide upregulated PPAR-γ, reduced BACE1, suppressed NF-κB phosphorylation, inhibited caspase-3 activation, and restored Bax/Bcl-2 balance, alleviating neuroinflammation and apoptosis. This study provides the first evidence that trofinetide improves cognitive function and mitigates Aβ pathology, neuroinflammation, and apoptosis in APP/PS1 mice and AβO-treated cells, highlighting its therapeutic potential for AD."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • BCL2 • CASP3 • IGF1 • IL6 • TNFA