Few boys with Rett received approved treatment, real-world study shows
Young males had more severe health issues before starting Daybue
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Only a small percentage of boys with Rett syndrome received treatment with Daybue (trofinetide) in the more than one year after the therapy was approved in the U.S., according to a real-world study of healthcare claims data.
Before treatment, boys treated with Daybue had a greater burden of coexisting conditions, including epilepsy, feeding-tube use, and respiratory failure, and were more often managed by neurologists than those not treated with the Acadia Pharmaceuticals‘ therapy.
Most boys who did start treatment remained on Daybue for at least 17 months. Overall, the findings highlight “an important opportunity to improve awareness and optimize access to treatment in this under-recognized subpopulation,” researchers wrote.
The study, “Real-World Demographics, Clinical Characteristics, and Predictors of Persistence Among Males with Rett Syndrome Treated with Trofinetide,” was published in the journal Advances in Therapy. One of the authors is an employee of Acadia.
Rett increasingly found to be less rare in males
Rett syndrome is a rare neurodevelopmental disorder that is chiefly caused by mutations in the MECP2 gene, which provides instructions for making a protein important for brain development and function.
As the MECP2 gene is located on the X chromosome, one of the two sex-determining chromosomes, the disorder primarily affects girls. Girls have two X chromosomes, while boys have one X and one Y. This means that girls can have a mutant copy of the MECP2 gene on one X chromosome, but carry a healthy copy that can compensate for the mutated gene in the other X chromosome.
Conversely, since boys have only one X chromosome, disease-causing MECP2 mutations are not compensated by a healthy gene copy. As a result, Rett has been historically viewed as exceptionally rare or lethal in boys.
However, “increasing genetic testing, improved diagnostic recognition, and survival into adolescence and adulthood have revealed a clinically meaningful population of males with [Rett],” the investigators wrote.
Daybue is approved in the U.S. and Canada for people with Rett syndrome ages 2 and older, regardless of sex. However, clinical trials mainly studied girls, so real-world information on Daybue use in boys is limited.
This study, which was funded by Acadia, addressed that knowledge gap by linking U.S. medical and pharmacy claims from January 2021 through September 2024. Of a total of 8,047 people with Rett initially identified, 1,219 of them (15.1%) were boys. Among those, only 75 (6.2%) had received Daybue, while 1,144 (93.8%) had not.
Coexisting disorders more frequent in the treated group
After applying the study’s eligibility criteria, the analysis included 466 males with Rett, 51 who were treated with Daybue and 415 who were untreated. The mean age of the groups was 18.8 in those receiving the therapy and 17.7 in those not taking it. Boys ages 2 to 4 represented 23.5% of the treated group compared with only 8.7% in the untreated, a statistically significant difference.
Boys treated with Daybue were more likely to be managed by child neurologists than untreated boys, 64.7% vs. 12.7%. In contrast, pediatrician management was more common among untreated boys.
Coexisting disorders were more frequent in the treated group. These included epilepsy (52.9% vs. 25.5%), gastrostomy, or the use of a feeding tube placed through the abdomen into the stomach (31.4% vs. 16.1%), and respiratory failure (25.5% vs. 13.3%). The rate of nutritional deficiency was also higher in the treated group, but the difference did not reach statistical significance.
These findings suggest that, “in routine practice, clinicians may be preferentially initiating treatment among those with higher touchpoints and clinical complexity,” the researchers wrote.
Among the 51 males who started Daybue, 52.9% were considered persistent on treatment, while 47.1% were nonpersistent, meaning they had a gap of more than 90 days after the days of supply from the last claim.
These findings provide early real-world evidence on treatment uptake and persistence among males with RTT [Rett] and support continued clinician education and further male-focused real-world studies to better define long-term outcomes.
Further analysis showed that about 80% of treated boys remained on Daybue for more than three months. Nearly 70% stayed on therapy for at least six months, and more than half continued treatment for at least 17 months.
Statistical analysis after adjusting for several variables revealed that neurological disorders were the only significant predictor of nonpersistence, with a more than fivefold higher likelihood of stopping treatment.
Overall, “these findings provide early real-world evidence on treatment uptake and persistence among males with RTT [Rett] and support continued clinician education and further male-focused real-world studies to better define long-term outcomes,” the researchers concluded.
Regarding study limitations, the team noted that “claims databases lack important clinical factors such as genotype [genetic profile], disease severity, caregiver burden, functional status, and socioeconomic variables which may influence treatment initiation and persistence and could contribute to residual confounding. Typical with any administrative claims databases, our study also does not capture the reasons for non-persistence.”
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