Acadia Pharmaceuticals Presents DAYBUE™ (trofinetide) Real-World Evidence and Additional Data in Rett Syndrome at the 2024 International Rett Syndrome Foundation (IRSF) Annual Scientific Meeting

Acadia Pharmaceuticals, Inc. (NASDAQ:ACAD) today announced that interim data from the open-label real-world LOTUS™ study will be presented at the 2024 International Rett Syndrome Foundation (IRSF) Annual Scientific Meeting, being held this week in Westminster, Colorado. LOTUS is an ongoing, caregiver-reported study evaluating the efficacy and tolerability outcomes in patients with Rett syndrome treated with DAYBUE™ (trofinetide).

"These interim data from the LOTUS study reinforce that the clinical effectiveness of DAYBUE in the real-world setting is consistent with results observed in the DAYBUE Phase 3 clinical trial program and further characterize what Rett syndrome symptom improvements may look like to caregivers," said Ponni Subbiah, M.D., M.P.H., Senior Vice President, Global Head of Medical Affairs and Chief Medical Officer. "These initial findings also illustrate caregivers' strategies to manage gastrointestinal tolerability in the real world and underscore the value of education and effective implementation of diarrhea management strategies to help families improve the patient experience."

Six-month interim findings evaluating DAYBUE in 101 Rett syndrome patients with an age range of two to 60 years old from the Phase 4, observational, prospective study showed caregivers of more than two-thirds of enrolled participants reported improvements at Month 1 in at least one Rett syndrome symptoms category. This was measured using the Behavioral Improvement Questionnaire (BIQ) developed by Acadia in consultation with Rett experts and caregivers. The most consistently reported improvements over six months were nonverbal communication (58.5%), alertness (51.2%) and social interaction/connectedness (40.2%). Additionally, diarrhea and formed/normal stool were both common, as measured by the Gastrointestinal (GI) Health Questionnaire also developed by Acadia for this study. Some participants reported initiating therapy on doses less than half of the FDA approved dose and increasing over several weeks; the majority of patients were on >90% of labeled dose by week 10. The results of this six-month follow-up are limited by lack of placebo arm, missing data 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.

This interim analysis of LOTUS data will be presented at the IRSF Scientific Meeting, as well as new findings from health economics and outcomes research in Rett syndrome care and encore data from DAYBUE open-label extension and clinical trial program studies.

IRSF Poster Presentations, Tuesday, June 18, 5pm MDT-7pm MDT:

• Assessing experiences with trofinetide for Rett syndrome: interviews with caregivers of patients in LAVENDER™, LILAC-1™, and LILAC-2™ studies
• Real-world benefits and tolerability of trofinetide for the treatment of Rett Syndrome: the LOTUS study
• Prevalence of respiratory clinical outcomes among patients with Rett syndrome: analysis of real-world data in the United States
• Trofinetide for the treatment of Rett syndrome: long-term safety and efficacy results from the open-label LILAC-2 study
• Prevalence of epilepsy in individuals with Rett syndrome–a real-world evidence analysis
• Prevalence of respiratory comorbidities among patients with Rett syndrome
• Prevalence of nutritional deficiency, underweight status and gastrostomy among patients with Rett syndrome: an analysis of electric health record (EHR) data

About Rett Syndrome

Rett syndrome is a rare, complex, neurodevelopmental disorder that may occur over four stages and affects approximately 6,000 to 9,000 patients in the U.S., with approximately 5,000 patients currently diagnosed according to an analysis of healthcare claims data.^1-4 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.³ Rett syndrome is typically caused by a genetic mutation on the MECP2 gene.⁵ In preclinical studies, deficiency in MeCP2 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.^2,9

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

Important Safety Information for DAYBUE™ (trofinetide)

• Warnings and Precautions
  • Diarrhea: In a 12-week study and in long-term studies, an aggregate of 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 of mild or moderate severity in 96% of cases. In the 12-week study, antidiarrheal medication was used in 51% of patients treated with DAYBUE. Patients should stop taking 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.
  • 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 is a weak CYP3A4 inhibitor; therefore, plasma concentrations of CYP3A4 substrates may be increased if given concomitantly with DAYBUE. Closely monitor when DAYBUE is used in combination with orally administered CYP3A4 sensitive substrates for which a small change in substrate plasma concentration may lead to serious toxicities.
  • Plasma concentrations of OATP1B1 and OATP1B3 substrates may be increased if given concomitantly with DAYBUE. Avoid the concomitant use of DAYBUE with OATP1B1 and OATP1B3 substrates for which a small change in substrate plasma concentration may lead to serious toxicities.

• Use in Specific Population: Renal Impairment
  • DAYBUE is not recommended for patients with moderate or severe renal impairment.

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

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

About Acadia Pharmaceuticals

Acadia is advancing breakthroughs in neuroscience to elevate life. For 30 years 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 FDA-approved drug 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 neuropsychiatric symptoms in central nervous system disorders. For more information, visit us at Acadia.com and follow us on LinkedIn and Twitter.

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 March 31, 2024 filed with the Securities and Exchange Commission on May 9, 2024, 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 Acadia Pharmaceuticals Inc., Data on file. RTT US Prevalence. March 2022.

² Fu C, Armstrong D, Marsh E, et al. Consensus guidelines on managing Rett syndrome across the lifespan. BMJ Paediatrics Open. 2020; 4: 1-14.

³ Kyle SM, Vashi N, Justice MJ. Rett syndrome: a neurological disorder with metabolic components. Open Biol. 2018; 8: 170216.

⁴ Acadia Pharmaceuticals Inc., Data on file.

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 Daniel C, Tarquinio DO, Hou W, 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.

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