Clinical Data from Open-Label DAFFODIL™ Study Evaluating Long-term Safety of DAYBUE® (trofinetide) in Patients with Rett Syndrome Published in Med

Rhea-AI Summary

Acadia Pharmaceuticals (NASDAQ: ACAD) announced the publication of clinical data from the open-label DAFFODIL™ study in the journal Med, evaluating DAYBUE® (trofinetide) in Rett syndrome patients. The Phase 2/3 study focused on children aged 2-4 years (n=15) and demonstrated safety profiles consistent with previous LAVENDER™ and LILAC™ studies.

The 78-week study showed diarrhea (80.0%) and vomiting (53.3%) as common side effects, all of mild or moderate severity. Exploratory efficacy endpoints indicated symptom improvements, with Clinical Global Impression-Improvement (CGI-I) scores improving from 3.3 at Week 4 to 2.2 at Week 78. Caregiver interviews reported improvements in verbal communication (71.4%), eye contact (57.1%), and hand use (57.1%).

These results supported FDA and Health Canada approvals of DAYBUE for treating Rett syndrome in patients aged two years and older, marking it as the first approved treatment for this rare neurodevelopmental disorder affecting 6,000 to 9,000 patients in the U.S.

Positive

• First FDA-approved treatment for Rett syndrome
• Successful safety profile demonstrated in young patients
• Significant efficacy improvements shown over 78 weeks
• Strong caregiver-reported improvements in communication and motor skills

Negative

• High incidence of side effects (80% diarrhea, 53.3% vomiting)
• Two participants discontinued due to adverse events
• Small study size (only 15 patients)
• Requires careful monitoring for weight loss and dehydration

Insights

Pharmaceutical Market Analyst

The publication of DAFFODIL study results in Med provides important validation for DAYBUE in younger Rett syndrome patients. This peer-reviewed data strengthens the clinical foundation for Acadia's commercial product by confirming a consistent safety profile in children aged 2-4 years, potentially expanding adoption in this critical age group where earlier intervention could be most beneficial.

The safety data from this 78-week open-label study shows manageable side effects, with diarrhea (80%) and vomiting (53.3%) being primarily mild/moderate in severity. More importantly, the implementation of a diarrhea management plan proved effective, resulting in only one discontinuation due to this side effect over the entire study period.

While exploratory efficacy markers showed promising improvements in multiple domains, particularly in the areas caregivers identified as most impactful (verbal communication, eye contact, and hand use), the small sample size (n=15) and open-label design limit definitive efficacy conclusions.

For Acadia, this publication reinforces DAYBUE's position in the Rett syndrome market, which affects approximately 6,000-9,000 US patients. The data may increase physician confidence in prescribing to younger patients closer to symptom onset, potentially maximizing developmental benefits. This addition to DAYBUE's clinical evidence portfolio should support continued commercial momentum in this rare disease space where early intervention is increasingly recognized as crucial.

Neurological Disease Specialist

The DAFFODIL study publication provides critical insights into treating Rett syndrome patients during a developmentally sensitive period. Given that Rett typically manifests between 6-18 months when children begin losing acquired skills, the demonstration of a consistent safety profile in 2-4 year olds represents a significant advancement in treatment options closer to disease onset.

The long-term safety data aligns with previous LAVENDER and LILAC studies, confirming DAYBUE's tolerability across age groups. The successful implementation of side effect management strategies—particularly for diarrhea—provides practical guidance for clinicians treating these young patients.

The exploratory efficacy findings are especially noteworthy when considering the natural history of Rett syndrome. Improvements in CGI-I scores (from 3.3 at Week 4 to 2.2 at Week 78) and consistent CaGI-I improvements suggest potential mitigation of symptom progression. Most compelling are the caregiver reports of improvements in verbal communication (71.4%), eye contact (57.1%), and hand use (57.1%)—all core deficits in Rett syndrome.

While the open-label design and small sample size require cautious interpretation, these results provide valuable guidance for clinicians considering DAYBUE in younger patients. The data suggests that earlier intervention may help address the communication deficits identified by caregivers as most impactful, potentially altering the developmental trajectory of this complex neurodevelopmental disorder. This publication strengthens the clinical rationale for treating Rett syndrome patients closer to symptom onset.

-- Study supported FDA and Health Canada approvals of DAYBUE for treatment of Rett syndrome in patients ages two years and older

-- Results consistent with Phase 3 LAVENDER™ and open-label LILAC™ studies

SAN DIEGO--(BUSINESS WIRE)-- Acadia Pharmaceuticals Inc. (Nasdaq: ACAD) today announced that the journal Med published results from the open-label study, DAFFODIL™, evaluating the safety, tolerability and exploratory efficacy of DAYBUE^® (trofinetide) in girls ages two to four living with Rett syndrome (n = 15). The long-term Phase 2/3 study demonstrated DAYBUE had a similar safety profile in children two to four years of age as that observed in individuals with Rett syndrome five years of age and older in the 12-week LAVENDER™ study, and the 40-week LILAC-1™ and 32-month LILAC-2™ open-label extension studies. Results of all four studies supported the FDA approval of DAYBUE in adults and pediatric patients two years of age or older.

“Rett syndrome is a debilitating condition that often causes patients to lose acquired communication and motor skills starting as early as six to 18 months old which presents significant challenges for these children and their families,” said Alan Percy, M.D., Professor of Pediatrics, Neurology, Neurobiology, Genetics, and Psychology at University of Alabama, Birmingham and lead DAFFODIL author. “Outcomes from DAFFODIL further underscore trofinetide’s safety and tolerability across patient age groups and provide additional data to inform treatment plans and dosing for patients closer to the onset of symptoms.”

“The final DAFFODIL results provide critical insights into the safety and tolerability of DAYBUE in younger pediatric Rett syndrome patients, including effective strategies to mitigate common side effects of treatment,” said Ponni Subbiah, M.D., M.P.H., Acadia’s Senior Vice President, Global Head of Medical Affairs and Chief Medical Officer. “These findings, along with the caregiver exit interview feedback from the study, further our understanding of trofinetide’s role in managing this complex condition and the potential benefits of longer-term treatment.”

Diarrhea (80.0%) and vomiting (53.3%) were the most common treatment emergent adverse events (TEAEs), and all cases were of mild or moderate severity. Two participants discontinued the study early due to adverse events. The use of a diarrhea management plan, including discontinuation of laxatives and initiation of fiber, led to only one discontinuation due to diarrhea over the 78-week study. Serious TEAEs (n = 4) were considered unrelated to treatment.

The following exploratory efficacy endpoints supported symptom improvement:

• Clinical Global Impression–Improvement (CGI-I) scale score (7-point scale where 1 is “very much improved” and 7 is “very much worse”) was 3.3 ± 0.19 (mean ± standard error) at Week 4 and continued to improve to 2.2 ± 0.22 at Week 78.
• Caregiver Global Impression–Improvement (CaGI-I) scale score (5-point scale where 1 is “much improved” and 5 is “much worse”) at Week 12 (2.3 ± 0.12) and Week 78 (2.1 ± 0.31) indicated improvement compared with baseline.
• Impact of Childhood Neurologic Disability-Quality of Life (ICND-QoL) scale (6-point scale where 1 is “poor” and 6 is “excellent”) increased from baseline to Week 78 (3.9 ± 0.24 to 4.6 ± 0.31).

Caregivers (n = 7) who participated in the study exit interviews most frequently identified inability to communicate as the most impactful symptom of Rett syndrome (42.9%) and improved communication as the most desired treatment effect (71.4%). The most frequently reported improvements by caregivers during the exit interviews were in verbal communication (ability to say new words) (71.4%), improved eye contact (57.1%) and improved hand use (57.1%).

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

Important Safety Information for DAYBUE^® (trofinetide)

• 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 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 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. 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 neuro-psychiatric and neuro-rare diseases. For more information, visit us at Acadia.com and follow us on LinkedIn and X.

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 DC, Hou W, JL Neul 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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Investor Contact:

Acadia Pharmaceuticals Inc.

Al Kildani

(858) 261-2872

ir@acadia-pharm.com

Media Contact:

Acadia Pharmaceuticals Inc.

Deb Kazenelson

(818) 395-3043

media@acadia-pharm.com

Source: Acadia Pharmaceuticals Inc.

FAQ

What were the main results of ACAD's DAFFODIL study for DAYBUE in Rett syndrome?

The study showed DAYBUE was safe in children 2-4 years old, with mild to moderate side effects. Key improvements were seen in CGI-I scores (from 3.3 to 2.2) over 78 weeks, with 71.4% of caregivers reporting better verbal communication.

What are the most common side effects of DAYBUE reported in ACAD's clinical trial?

The most common side effects were diarrhea (80.0%) and vomiting (53.3%), all of mild or moderate severity. A diarrhea management plan was implemented successfully during the trial.

How long did ACAD's DAFFODIL study for DAYBUE last and how many patients participated?

The DAFFODIL study lasted 78 weeks and included 15 Rett syndrome patients aged 2-4 years.

What improvements did caregivers report in ACAD's DAFFODIL study of DAYBUE?

Caregivers reported improvements in verbal communication (71.4%), eye contact (57.1%), and hand use (57.1%) during exit interviews.