Real World Data from LOTUS Study Evaluating Long-term Efficacy and Tolerability Outcomes of DAYBUE® (trofinetide) in Patients with Rett Syndrome Published in Developmental Medicine and Child Neurology

-- Findings reinforce efficacy and tolerability profile in patients prescribed DAYBUE in the U.S. for as long as 12 months, consistent with the Phase 3 LAVENDER™ trial that supported FDA approval and open-label LILAC, LILAC-2 and DAFFODIL studies

Acadia Pharmaceuticals Inc. (NASDAQ:ACAD) today announced that the journal Developmental Medicine and Child Neurology published interim results from the caregiver-reported observational online, open-label, ongoing LOTUS study evaluating effectiveness and tolerability outcomes in patients with Rett syndrome who are prescribed DAYBUE^® (trofinetide) under routine clinical care in the U.S. Findings included reported improvements in symptoms of Rett syndrome, with early insights into managing gastrointestinal (GI) symptoms in the real world among patients receiving up to 12 months of treatment with DAYBUE.

"These findings from LOTUS help deepen our understanding of the potential outcomes associated with long-term treatment of DAYBUE in the real-world setting," said Ponni Subbiah, M.D., M.P.H., Senior Vice President, Global Head of Medical Affairs and Chief Medical Officer. "The data are supportive of what we've seen in DAYBUE clinical trials and offer new scientific insights to clinicians that improvements in Rett syndrome signs and symptoms are possible among a broadly inclusive sample of Rett patients. It's particularly gratifying to document improvements in adult patients, knowing that they may have waited decades without knowing if a treatment would become available within their lifetime."

This interim analysis, which included 227 people living with Rett syndrome with an age range of one to 60 years old, showed:

• 71–90% of those who filled out the Behavioral Improvement questionnaire (BIQ) reported at least one behavioral symptom improvement that were new or maintained when compared with before DAYBUE treatment. The BIQ was developed by Acadia specifically for this study to document caregiver observations.
• Consistent with the previously reported six-month interim analysis, the most frequent caregiver-reported improvements were nonverbal communication (48–71%), alertness (44–70%), and social interaction/connectedness (33–58%), as measured by the BIQ.
• Additionally, the median change from baseline in Quality-of-Life Inventory-Disability Questionnaire (QI-Disability) total score was 4.6 [IQR, -0.2 to 10.2] for those patients (n=33) who had both baseline and 12-month assessments.
• The incidence of diarrhea reported by caregivers varied from weeks 1 to 12 (23–50%) and months 4 to 12 (26–38%). Most reports of diarrhea were contained inside the patient's diaper, as measured by the Gastrointestinal (GI) Health Questionnaire, also developed by Acadia specifically for this study in consultation with Rett experts and caregivers. The most commonly reported diarrhea management strategies included avoiding constipation medications, increasing fluid intake, consuming supplementary fiber, and using antidiarrheal medication.
• Caregivers reported normal stools over the last 3 days immediately prior to completing the GI assessment from weeks 1 to 12 (43−54%) and months 4 to 12 (55−63%).
• The median dose reported at Week 1 was 36% of the target weight-banded FDA approved dose; by Week 10 onwards, the median dose was at least 80% of labeled dose.

The results of this 12-month follow-up are limited by the number of patients who had reached later time points, which resulted in the data being restricted to 12 months, lack of a placebo arm, missing data, lack of validation of BIQ and GI questionnaires, reliance solely on caregiver reports, the use of descriptive statistics and the online nature of this study. Participants are being enrolled in the LOTUS study for at least 12 months from initiation of DAYBUE treatment, with the option to extend participation for an additional 12 months.

About Rett Syndrome

Rett syndrome is a rare, complex, neurodevelopmental disorder that may occur over four stages and occurs in approximately one of every 10,000 to 15,000 female births worldwide.^1-3 In the U.S., 6,000 to 9,000 patients are affected.⁴ A child with Rett syndrome exhibits an early period of apparently normal development until six to 18 months, when their skills seem to slow down or stagnate. This is typically followed by a duration of regression when the child loses acquired communication skills and purposeful hand use. The child may then experience a plateau period in which they show mild recovery in cognitive interests, but body movements remain severely diminished. As they age, those living with Rett may continue to experience a stage of motor deterioration which can last the rest of the patient's life.² Rett syndrome is typically caused by a genetic mutation on the MECP2 gene.⁵ In preclinical studies, deficiency in MeCP2 function is thought to lead to impairment in synaptic communication, and the deficits in synaptic function may be associated with Rett manifestations.^5-7

Symptoms of Rett syndrome may also include development of hand stereotypies, such as hand wringing and clapping, and gait abnormalities.⁸ Most Rett patients typically live into adulthood and require round-the-clock care. ^1,9

About DAYBUE^® (trofinetide)

Trofinetide is a synthetic analog of the N-terminal tripeptide of insulin-like growth factor 1. The mechanism by which trofinetide exerts therapeutic effects in patients with Rett syndrome is unknown. In animal studies, trofinetide has been shown to increase branching of dendrites and synaptic plasticity signals.¹⁰

Indication and Important Safety Information for DAYBUE^® (trofinetide)

Indication

DAYBUE is indicated for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older.

Important Safety Information

• Warnings and Precautions
  • Diarrhea: In a 12-week study and in long-term studies, 85% of patients treated with DAYBUE experienced diarrhea. In those treated with DAYBUE, 49% either had persistent diarrhea or recurrence after resolution despite dose interruptions, reductions, or concomitant antidiarrheal therapy. Diarrhea severity was mild or moderate in 96% of cases. In the 12-week study, antidiarrheal medication was used in 51% of patients treated with DAYBUE.
    
    Advise patients to stop laxatives before starting DAYBUE. If diarrhea occurs, patients should notify their healthcare provider, consider starting antidiarrheal treatment, and monitor hydration status and increase oral fluids, if needed. Interrupt, reduce dose, or discontinue DAYBUE if severe diarrhea occurs or if dehydration is suspected.
  • Vomiting: In a 12-week study, vomiting occurred in 29% of patients treated with DAYBUE and in 12% of patients who received placebo.
    
    Patients with Rett syndrome are at risk for aspiration and aspiration pneumonia. Aspiration and aspiration pneumonia have been reported following vomiting in patients being treated with DAYBUE. Interrupt, reduce dose, or discontinue DAYBUE if vomiting is severe or occurs despite medical management.
  • Weight Loss: In the 12-week study, 12% of patients treated with DAYBUE experienced weight loss of greater than 7% from baseline, compared to 4% of patients who received placebo. In long-term studies, 2.2% of patients discontinued treatment with DAYBUE due to weight loss. Monitor weight and interrupt, reduce dose, or discontinue DAYBUE if significant weight loss occurs.
• Adverse Reactions: The common adverse reactions (≥5% for DAYBUE-treated patients and at least 2% greater than in placebo) reported in the 12-week study were diarrhea (82% vs 20%), vomiting (29% vs 12%), fever (9% vs 4%), seizure (9% vs 6%), anxiety (8% vs 1%), decreased appetite (8% vs 2%), fatigue (8% vs 2%), and nasopharyngitis (5% vs 1%).
• Drug Interactions: Effect of DAYBUE on other Drugs
  • DAYBUE, a weak inhibitor of CYP3A and an inhibitor of P-gp, can increase the plasma concentrations of CYP3A and/or P-gp substrates (e.g., loperamide), which may increase the risk of adverse reactions associated with these substrates.
    
    Closely monitor patients when DAYBUE is administered concomitantly with sensitive CYP3A and/or P-gp substrates for which a minimal increase in substrate plasma concentration (i.e., drugs with a narrow therapeutic index) may lead to serious adverse reactions.
• Use in Specific Population: Renal Impairment
  • DAYBUE is not recommended for patients with severe renal impairment.

DAYBUE is available as an oral solution (200 mg/mL).

Please read the full Prescribing Information, also available at DAYBUEhcp.com

About Acadia Pharmaceuticals

Acadia is advancing breakthroughs in neurological and rare diseases to elevate life. Since our founding we have been working at the forefront of healthcare to bring vital solutions to people who need them most. We developed and commercialized the first and only FDA-approved drug to treat hallucinations and delusions associated with Parkinson's disease psychosis and the first and only approved drug in the United States and Canada for the treatment of Rett syndrome. Our clinical-stage development efforts are focused on Prader-Willi syndrome, Alzheimer's disease psychosis and multiple other programs targeting neuroscience and neuro-rare diseases. For more information, visit us at acadia.com and follow us on LinkedIn and X.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include all statements other than statements of historical fact and can be identified by terms such as "intends," "may," "will," "should," "could," "would," "expects," "plans," "anticipates," "believes," "estimates," "projects," "predicts," "potential" and similar expressions (including the negative thereof) intended to identify forward-looking statements. Forward-looking statements contained in this press release, include, but are not limited to, statements about: (i) the clinical benefits of DAYBUE and continued statistically significant efficacy observed in the DAYBUE Phase 3 clinical trial program, (ii) the safety and tolerability profile of DAYBUE and anticipated Rett syndrome symptom improvements, and (iii) the timing and outcome of future results from, and continued enrollment and possible participation extensions in, the real world, observational LOTUS study. Forward-looking statements are subject to known and unknown risks, uncertainties, assumptions and other factors that may cause our actual results, performance or achievements to differ materially and adversely from those anticipated or implied by our forward-looking statements. Such risks, uncertainties, assumptions and other factors include, but are not limited to: our ability to continue to successfully commercialize DAYBUE, the timing, enrollment and results of ongoing and future clinical trials and our ability to continue to stay in compliance with applicable laws and regulations. Given the risks and uncertainties, you should not place undue reliance on these forward-looking statements. For a discussion of these and other risks, uncertainties, assumptions and other factors that may cause our actual results, performance or achievements to differ, please refer to our quarterly report on Form 10-Q for the period ended June 30, 2025 filed with the Securities and Exchange Commission on August 7, 2025, as well as our subsequent filings with the Securities and Exchange Commission from time to time. The forward-looking statements contained herein are made as of the date hereof, and we undertake no obligation to update them after this date, except as required by law.

References

¹ Fu C, Armstrong D, Marsh E, et al. Consensus guidelines on managing Rett syndrome across the lifespan. BMJ Paediatrics Open. 2020; 4:1-14.

² Kyle SM, Vashi N, Justice MJ. Rett syndrome: a neurological disorder with metabolic components. Open Biol. 2018; 8:170216.

³ May DM, Neul JL, Satija A, et al. Real-world clinical management of individuals with Rett syndrome: a physician survey. J of Med Econ. 26(1), 1570–1580.

⁴ Acadia Pharmaceuticals Inc, Data on file. RTT US Prevalence. March 2022.

⁵ Amir RE, Van den Veyver IB, Wan M, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999; 23(2):185-188.

⁶ Fukuda T, Itoh M, Ichikawa T, et al. Delayed maturation of neuronal architecture and synaptogenesis in cerebral cortex of Mecp2-deficient mice. J Neuropathol Exp Neurol. 2005; 64(6):537-544.

⁷ Asaka Y, Jugloff DG, Zhang L, et al. Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome. Neurobiol Dis. 2006; 21(1):217-227.

⁸ Neul JL, Kaufmann WE, Glaze DG, et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010; 68(6):944-950.

⁹ Tarquinio DO, Hou W, Neul JL, et al. The changing face of survival in Rett syndrome and MECP2-related disorders. Pediatr Neurol. 2015; 53(5):402-411.

¹⁰ Acadia Pharmaceuticals Inc., Data on file. Study Report 2566-026. 2010.

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