DAFFODIL™ Study Results Highlight Long-Term Safety and Efficacy of DAYBUE® (Trofinetide) in Younger Patients with Rett Syndrome
Acadia Pharmaceuticals Inc. has announced the publication of results from the open-label DAFFODIL™ study in the journal Med. The study evaluated the long-term safety, tolerability, and exploratory efficacy of DAYBUE® (trofinetide) in girls aged two to four with Rett syndrome. The study, which included 15 participants, demonstrated that DAYBUE was well-tolerated in younger patients, showing similar safety profiles to those observed in older patients from prior studies. These findings further support the FDA approval of DAYBUE for use in both adults and pediatric patients aged two years and older.
Safety and Tolerability Across Age Groups
Rett syndrome is a neurodevelopmental disorder that often leads to the loss of previously acquired motor and communication skills, typically between six and 18 months of age. The DAFFODIL™ study results add to the growing body of evidence regarding the safety and tolerability of DAYBUE in younger children. In particular, the study confirmed that the treatment’s safety profile in children aged two to four years was consistent with results from the 12-week LAVENDER™ study and the long-term LILAC-1™ and LILAC-2™ extension studies in older patients.
Dr. Alan Percy, Professor of Pediatrics, Neurology, Neurobiology, Genetics, and Psychology at the University of Alabama and the lead author of the DAFFODIL study, commented on the significance of these results: “Rett syndrome is a debilitating condition, and these outcomes further underscore trofinetide’s safety and tolerability across patient age groups. The findings also provide valuable data that can inform treatment plans and dosing for younger patients who are closer to the onset of symptoms.”
Common Side Effects and Management Strategies
As part of the study, researchers monitored treatment-emergent adverse events (TEAEs). The most commonly reported TEAEs were diarrhea (80%) and vomiting (53.3%), though all cases were classified as mild or moderate in severity. Importantly, the use of a diarrhea management plan, which included discontinuation of laxatives and the initiation of fiber, helped to reduce the incidence of diarrhea-related discontinuations. Only one participant discontinued the study due to diarrhea over the course of the 78-week study. In total, four serious TEAEs were reported, but none were considered related to the treatment.
Ponni Subbiah, M.D., M.P.H., Acadia’s Senior Vice President and Chief Medical Officer, remarked, “The final DAFFODIL results provide critical insights into the safety and tolerability of DAYBUE in younger pediatric Rett syndrome patients, including strategies to manage common side effects. These findings, together with caregiver feedback from exit interviews, help to further our understanding of trofinetide’s potential in managing this complex condition.”
Exploratory Efficacy Results Indicate Symptom Improvement
The DAFFODIL study also included several exploratory efficacy endpoints to assess the impact of DAYBUE on the symptoms of Rett syndrome. These endpoints showed positive trends in symptom improvement over the course of the study. Notable improvements were observed in multiple assessments, including:
- Clinical Global Impression–Improvement (CGI-I): The CGI-I scale scores showed improvement over time, with a mean score of 3.3 ± 0.19 at Week 4 and a further improvement to 2.2 ± 0.22 at Week 78, indicating that participants’ conditions were reported to be “much improved” or “very much improved” by the end of the study.
- Caregiver Global Impression–Improvement (CaGI-I): Caregiver assessments also indicated improvements, with a score of 2.3 ± 0.12 at Week 12 and 2.1 ± 0.31 at Week 78. This reflected positive changes in the participants’ overall condition as reported by caregivers.
- Impact of Childhood Neurologic Disability-Quality of Life (ICND-QoL): This scale, which measures quality of life, also showed improvement from a baseline score of 3.9 ± 0.24 to 4.6 ± 0.31 by Week 78, indicating a better quality of life for the children involved in the study.
Caregiver Insights on Treatment Impact
At the conclusion of the study, caregivers were interviewed to provide feedback on their experiences. The exit interviews revealed that the most impactful symptom of Rett syndrome, as reported by caregivers, was the inability to communicate (42.9%). Notably, caregivers identified improved communication as the most desired effect of treatment (71.4%).
The study found that many caregivers reported improvements in various aspects of communication and motor skills, including:
- Verbal communication: 71.4% of caregivers reported improvements in their child’s ability to say new words.
- Eye contact: 57.1% of caregivers observed better eye contact.
- Hand use: 57.1% of caregivers noted improved hand use.
These caregiver-reported improvements further emphasize the potential of DAYBUE in enhancing key aspects of Rett syndrome, such as communication and motor skills, which are critical for patients and their families.
Conclusion: Promising Data for Younger Rett Syndrome Patients
The DAFFODIL™ study adds to the growing body of evidence supporting the safety and efficacy of DAYBUE (trofinetide) in treating Rett syndrome across different age groups. The results from this open-label study are particularly important in understanding how DAYBUE can benefit younger patients, who are closer to the onset of symptoms. With improvements in key symptoms such as communication, motor skills, and overall quality of life, DAYBUE shows promise as an effective treatment option for those affected by this debilitating condition.
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.
