Benefits seen with Daybue in Rett girls, ages 2-4, in DAFFODIL trial
Therapy safely led to better communication, eye contact, hand use: Results
One and a half years of daily Daybue (trofinetide) treatment safely improved communication, eye contact, and hand use among girls ages 2-4 with Rett syndrome, according to the final published results of the DAFFODIL trial, which tested the approved therapy in the youngest of patients.
Although most patients experience diarrhea as a side effect of Daybue, adding a diarrhea management plan — including no laxatives and added dietary fiber — led to one sole treatment discontinuation due to this reason throughout the study period, the final data show.
“This study reaffirms that Daybue is safe and well tolerated even among younger children and that a diarrhea management plan improves tolerability even further,” Alan K. Percy, MD, the study’s lead author and a professor of pediatrics, neurology, neurobiology, genetics, and psychology at University of Alabama, Birmingham, said in an interview with Rett Syndrome News.
Percy noted that the benefits seen “have been virtually uniform” among the children.
“These improvements, while not to the level of a cure, are important reasons to justify the medication,” Percy said.
The trial findings were detailed in a study, “Results from the phase 2/3 DAFFODIL study of trofinetide in girls aged 2-4 years with Rett syndrome,” published in the journal Med.
DAFFODIL trial tested Daybue in youngest Rett patients
A twice-daily liquid treatment, Daybue is approved in the U.S. and Canada for Rett syndrome in adults and children at least 2 years old. It contains an analog of glypromate, a protein fragment found naturally in the brain, that’s thought to reduce inflammation and boost the connections between nerve cells that are disrupted in Rett and contribute to its neurobehavioral symptoms.
Data from the Phase 3 LAVENDER clinical trial (NCT04181723), which supported Daybue’s approval, showed that the therapy significantly lessened the main symptoms of Rett with an acceptable safety profile. However, participants in that study had to be at least 5 years old.
Because Rett is typically diagnosed by age 3 or earlier, and given that symptoms may vary widely between children, Acadia then launched the DAFFODIL study (NCT04988867). The Phase 2/3 trial was open-label, meaning there was no placebo group, and enrolled 15 girls, ages 2-4, with Rett syndrome.
These youngers were given 10-30 mL of Daybue solution twice daily for 78 weeks, or 1.5 years, with doses based on body weight. The trial was conducted at seven locations across the U.S.
An interim analysis of the first 12 weeks of the trial, or at about the three-month mark, showed that Daybue eased Rett’s neurobehavioral symptoms with an acceptable safety profile. Treatment also was associated with caregiver- and clinician-reported improvements in life quality and fewer Rett symptoms.
The newly published data show that the most common side effects of Daybue treatment were diarrhea (80%) and vomiting (53.3%), which were mild or moderate in severity. Still, using a diarrhea management plan, including the discontinuation of laxatives — which are commonly taken for Rett-associated constipation — and the introduction of dietary fiber, led to one discontinuation due to diarrhea over the 78-week study. Another treatment discontinuation was due to vomiting.
To improve tolerability, Percy recommended “a titration schedule starting at 50% of the weight-based final dose with increases of 5 mL twice daily every one to two weeks, as tolerated.”
“Potential variations would be to provide the daily dose over three or four times rather than two,” he added.
Percy noted that, “during the trials, we saw little evidence of vomiting in our subjects as we had always advocated the use of proton pump inhibitors for the least indication of increased [gastroesophageal] reflux.”
All caregivers reported being ‘satisfied’ or ‘very satisfied’ with therapy
Among the participants, a clinician’s overall health assessment — as indicated by Clinical Global Impression Scale-Improvement (CGI-I) scores — continued to improve at each visit to the clinic, dropping from a mean of 3.1 at week 12 to 2.2 by week 78. Also, the proportion of patients with a “much improved” CGI-I score increased from 26.7% at week 12 to 55.6% at week 78.
Likewise, as assessed by the Overall Quality-of-Life Rating on the Impact of Childhood Neurologic Disability Scale (ICND-QoL), gains in quality of life improved from 4.2 points at week 12 to 4.6 at week 78.
The mean score for Caregiver Global Impression-Improvement (CaGI-I), as rated by the caregivers of the Rett patients, also improved over time, decreasing from 2.3 at week 12 to 2.1 by week 78.
In exit interviews, all caregivers said they were “very satisfied” or “satisfied” with Daybue. Most caregivers (71.4%) reported better communication, with an ability to say new words. That was the most frequently observed improvement, followed by improved eye contact and better hand use, each reported by 57.1% of caregivers.
“The improvements noted fit within the top five concerns of parents or other caregivers,” Percy said. They included “the number one concern of problems with communication, but may also include hand and gait function.”
I have always thought that benefits would be greater if the treatment was applied at a younger age and, in general, I do believe that the degree of improvement has been greater in the younger individuals.
Percy noted that “the improvement in attention and interaction with the parent or caregiver should reduce the levels of frustration as well as improving the quality of life for both.”
When asked about any notable differences according to patients’ age, Percy said, “I have always thought that benefits would be greater if the treatment was applied at a younger age and, in general, I do believe that the degree of improvement has been greater in the younger individuals.”
In a company press release, Ponni Subbiah, MD, Acadia’s senior vice president, global head of medical affairs, and chief medical officer, said the “results provide critical insight” into the use of Daybue in these youngest patients.
“These findings, along with the caregiver exit interview feedback from the study, further our understanding of [Daybue’s] role in managing this complex condition and the potential benefits of longer-term treatment,” Subbiah said.
About the Author
