Real-World Demographics, Clinical Characteristics, and Predictors of Persistence Among Males with Rett Syndrome Treated with Trofinetide

Abstract

Introduction

Rett syndrome (RTT) is a rare neurodevelopmental disease that primarily affects females but also occurs in males. Trofinetide (TROF) is approved in the USA and Canada for individuals with RTT regardless of sex aged ≥ 2 years; efficacy and safety of TROF was primarily studied among females, thus real-world data for males remain limited. This study evaluated real-world characteristics, treatment persistence, and predictors of non-persistence among males with RTT.

Methods

This retrospective cohort study using IQVIA database linked to TROF specialty pharmacy claims from 01/01/2021 to 09/30/2024 identified males with ≥ 1 medical claim for RTT (ICD-10 F84.2). Two groups were created based on treatment status and their respective index dates: treated and untreated. Continuous enrollment of ≥ 6 months pre-index and post-index was required. Pre-index demographics and clinical characteristics were compared descriptively. Among treated males, Kaplan–Meier analysis assessed time to non-persistence, and logistic regression evaluated predictors of non-persistence.

Results

Of 8047 individuals with RTT identified in the database, 1219 (15.1%) were males; of these, 75 (6.2%) were treated with TROF and 1144 (93.8%) were untreated; after final study criteria, 51 (10.9%) were treated and 415 (89.1%) were untreated. The mean (SD) age for treated vs untreated males was 18.8 (18.3) vs 17.7 (13.2) years. Neurologists managed most patients treated with TROF (64.7% vs 12.7%). Treated males had higher pre-index rates of epilepsy (52.9% vs 25.5%), gastrostomy (31.4% vs 16.1%), and respiratory failure (25.5% vs 13.3%) than untreated (all p < 0.05). Among treated males, 52.9% were persistent and 47.1% were non-persistent. Approximately 70% remained on TROF for ≥ 6 months and > 50% for ≥ 17 months. Pre-index neurologic disorders were significantly associated with non-persistence.

Conclusions

Most males with RTT remained untreated during this study period, while TROF initiation appeared concentrated among those with greater pre-index concomitant comorbidities and neurology involvement. Persistence beyond 6 months was common, supporting continued long-term use of TROF in males with RTT in real-world practice.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s12325-026-03686-1.

Key Summary Points

Why carry out this study?

Rett syndrome mostly affects females, and most trofinetide (TROF) research has also been conducted in females. Consequently, there is still limited information about how it is used in males.

To address this gap, this study examined males treated with trofinetide using real-world data.

The study compared 51 males who were treated with trofinetide versus 415 males who were not, focusing on their demographics and clinical characteristics in routine clinical care.

Simultaneously, among those who initiated TROF, the study evaluated their time on treatment, the percentage of patients who stopped treatment, and the predictors of stopping treatment.

What was learned from the study?

The study found that males who received the drug generally had more severe health issues, such as epilepsy, breathing problems, and feeding tubes, before initiating the medication.

About 70% of the males who started the medication stayed on it for at least 6 months, and more than half continued the treatment for over 17 months.

The data also showed that males who had other neurological disorders before starting the drug were more likely to stop the treatment.

Introduction

Rett syndrome (RTT), a rare and severe neurodevelopmental X-linked condition predominantly presenting in females, is caused by pathogenic variants in the methyl-CpG-binding protein 2 (MECP2) gene in the majority of cases; however, the diagnosis of RTT remains clinical, and not all individuals with RTT will have an identifiable MECP2 mutation [1–3]. Historically, RTT in males was considered exceptionally rare or lethal, largely due to the absence of a second X chromosome to compensate for deleterious MECP2 variants [1, 4]. However, increasing genetic testing, improved diagnostic recognition, and survival into adolescence and adulthood have revealed a clinically meaningful population of males with RTT, including individuals with somatic mosaicism, Klinefelter syndrome, or hypomorphic MECP2 variants [4–6]. Increased availability of next-generation sequencing and broader use of genetic testing in individuals with developmental encephalopathies have further contributed to the identification of males with RTT [6]. Overall, these observations have challenged the long-standing perception of RTT as an exclusively female disorder and suggest that male RTT may have been historically underdiagnosed rather than absent.

Trofinetide (TROF) is the first and only US Food and Drug Administration (FDA) approved pharmacologic therapy for RTT in individuals aged ≥ 2 years regardless of sex and was approved in 2023 on the basis of improvements in core RTT symptoms observed in TROF pivotal clinical trials [7–9]. The TROF phase 3 clinical trials evaluated efficacy and safety in female individuals with RTT, including females aged 5–20 years in the phase 3 LAVENDER trial and its open-label extension trials (LILAC-1 and LILAC-2) [7, 10, 11]. Additionally, female children aged 2–4 years were studied for TROF in the DAFFODIL trial [12]. The TROF clinical trial studies enrolled females only, to primarily reduce population variability and to ensure consistency of RTT diagnosis entry criteria; however, it is recognized that females with RTT can present with considerable variability in clinical features, even among those with the same MECP2 mutation [7]. Other clinical studies of TROF in healthy volunteers, participants with renal impairment, or other patient populations included dosing experience in male patients [13, 14]. These studies have indicated no notable differences in treatment-emergent adverse events, vital signs, laboratory parameters, or other safety assessments based on gender. Although the pivotal trials enrolled females only to reduce population variability, published trial authors indicate that the findings should be applicable to males with RTT as well [7, 13, 14]. Recognizing that there is no pharmacokinetic or mechanistic basis to restrict the use of TROF to females, the US FDA approved it as a treatment for all patients with RTT who are ≥ 2 years of age, regardless of their sex.

Given that TROF is indicated as a treatment for all individuals with RTT and considering both the increased identification of males with RTT and the absence of male-specific clinical trial evidence, real-world data are essential to explore the drivers of treatment uptake in usual practice. It is therefore vital to characterize and compare the demographic and clinical characteristics of males who initiated TROF versus those who did not, and to better understand the profiles of male patients currently being treated with TROF. This study provides insights among males with RTT who initiated TROF vs those who did not initiate TROF, focusing on demographics and clinical characteristics in routine clinical care. Simultaneously, among those who initiated TROF, we also evaluated time on treatment, proportion of patients who were non-persistent, and the predictors of non-persistence.

Methods

Study Design and Data Source

A retrospective observational cohort study was conducted using linked medical and pharmacy claims from IQVIA Anonymized Patient Level Database (APLD) and TROF specialty pharmacy database from 01/01/2021 to 09/30/2024 (study period). The APLD database contains de-identified, anonymized, pre-adjudicated healthcare claims capturing longitudinal information on patient demographics, diagnoses, procedures, and outpatient pharmacy dispensing for over 130 million beneficiaries in the USA. As this study involves deidentified, anonymized, patient level secondary data from other claims data sources without containing any identifiable protected health information (PHI) in accordance with HIPAA Security Act of 1996, patient consent was not required, and the need for ethics committee approval was not applicable.

Study Population and Cohort Selection

Individuals with at least one or more medical claims containing the ICD-10-CM code F84.2 for RTT were initially identified. From the eligible population, males were identified for this analysis and categorized into two groups based on TROF use (treated vs untreated) between 04/01/2023 and 03/31/2024 (identification period; Fig. 1). The treated male group was defined as those individuals who have at least one pharmacy claim for TROF during this identification period. The index date was defined as the date of their first TROF prescription (RX) fill for this group. The untreated male group was defined as those who did not initiate TROF during the identification period. To create an index date for the untreated males that mitigates immortal time bias and ensures comparable person-time between groups given the absence of treatment exposure in the untreated group, a risk set sampling approach was employed to establish comparable index dates between groups [15, 16]. For every individual in the treated group, the duration (in days) from their RTT diagnosis to their first TROF initiation was calculated. A corresponding “risk set” of untreated individuals, defined as those with an RTT diagnosis who had not yet initiated TROF, was then identified. From this eligible pool, five untreated individuals were sampled for every one treated individual (1:5 ratio) and assigned a proxy index date equal to their own RTT diagnosis date plus the treated individual’s specific diagnosis-to-treatment interval.

Fig. 1.

Study schematic

Exclusion Criteria

Females with RTT diagnosis were excluded. Individuals with < 6 months of continuous enrollment before and after their respective index dates were excluded to ensure adequate data were used for the analysis. Individuals with RTT with a history of cerebrovascular disease or brain trauma during any time prior to their RTT diagnosis were also excluded.

Study Variables

Demographics and Clinical Characteristics of Male Individuals with RTT

Individual patient and clinical characteristics were evaluated for both treated and untreated groups, beginning with the assessment of pre-index demographics, specifically age at the index date. Physician specialty (e.g., child neurology, clinical neurophysiology, etc.) was identified based on the provider who was seen closest to the index date among the two groups. To characterize the clinical journey of these patients, differential diagnoses (e.g., non-specific developmental delay [NSDD] and autism spectrum disorder [ASD]) were examined at any time prior to the index date. Additionally, the prevalence of clinical characteristics and comorbidities such as epilepsy, gastrostomy and RTT-related features such as loss of acquired communication skills, behavioral disorders were assessed during pre-index period and compared between the two groups.

Post-Index Treatment Outcomes

Time to Non-Persistence

Among the treated group, time to non-persistence was calculated based on the actual time on treatment. Persistence was defined as a treatment gap that is less than or equal to 90 days between TROF RXs while non-persistence was defined as a treatment gap of > 90 days between TROF RXs. Time to non-persistence was defined as the time from index date to the last TROF RX claim date. Among individuals who remained persistent through the end of follow-up, patients were censored at the last available follow-up date or the study end date, whichever occurred first. Among individuals who became non-persistent, the treatment end date was defined as the last claim date plus days of supply for the final TROF RX fill occurring before a treatment gap of > 90 days. Time to non-persistence, expressed in months, was calculated as: [(end of days’ supply after the last prescription fill − first prescription fill date + 1)/30].

Predictors of Non-Persistence

Pre-index (i.e., baseline) variables including comorbidities that may predict the likelihood of non-persistency among males treated with TROF (n = 51) during the 6 months follow-up were assessed using a two-step process. To alleviate the small sample of patients within each individual concomitant comorbidity and to generate a robust model, we grouped the list of individual pre-index clinical comorbidities into clinically relevant categories and operationalized these as binary indicators based on the presence of ≥ 1 diagnostic claim. The list of individual comorbidities within the respective major categories is presented in Supplementary Table 1. To examine the individual effect of the potential predictors of non-persistence, unadjusted univariate logistic regression models were first used to evaluate the association between each predictor and non-persistence. As a second step, a multivariable logistic regression, adjusted for clinical meaningful predictors (chosen a priori), assessed the combined effect of the individual predictors of treatment non-persistence.

Statistical Methods

Descriptive statistics were used to summarize pre-index characteristics and treatment outcomes. Categorical variables (e.g., physician specialty, comorbidities etc.) were reported as frequencies and percentages. Continuous variables (e.g., age) were summarized using means and standard deviations (SD), as well as medians and interquartile range (IQR). For the cohort of males in the TROF-treated group, the duration of therapy was assessed using Kaplan–Meier analysis, with time to non-persistence expressed in months. As mentioned above, univariate and multivariable logistic regression models were conducted to assess the magnitude of association between pre-index predictors and non-persistence during 6 months of follow-up. As a result of small sample size, a simple model with limited covariates was prioritized in the adjusted model, which included adjusting for age and the four broad clinically meaningful comorbidity categories (i.e. gastrointestinal, infectious, respiratory, and neurological disorders) which were included as covariates in the multivariable logistic regression analyses. Model stability was evaluated by sequentially adding covariates to assess the consistency of estimates.

Results of the multivariable logistic regression models were reported as odds ratios (ORs) and 95% confidence intervals (CIs), with a statistical significance at a p value of < 0.05. All statistical analysis was conducted using Anlitiks proprietary RapidAnalyzer™ analytic platform that is powered by SQL and RStudio.

Results

A total of 8047 individuals with RTT were initially identified; 15.1% (n = 1219) were males. Of the 1219 males, 6.2% (n = 75) were treated with TROF and 93.8% (n = 1144) were untreated. After applying the inclusion and exclusion criteria, there were 466 males treated or untreated with TROF, of which 10.9% (n = 51) formed the treated group and 89.1% (n = 415) formed the untreated group (Fig. 2).

Fig. 2.

Study population selection

Demographics and Clinical Characteristics of Male Individuals with RTT

Overall, the male individuals with RTT in this study had a mean (SD) age at RTT diagnosis of 16.5 (13.5) years and a median (IQR) age of 14 (14) years. Among treated males, the mean (SD) age at RTT diagnosis was 16.6 (16.2) years, with a median (IQR) of 14 (14.5) years, while untreated males had a mean (SD) age of 16.5 (13.2) years and a median (IQR) of 13 (14.5) years at RTT diagnosis. At TROF index, the overall male RTT population had a mean (SD) age of 17.8 (13.8); furthermore, males who initiated TROF had a mean (SD) age of 18.8 (18.3) years, while the untreated group had a mean (SD) age of 17.7 (13.2) years (Table 1).

Table 1.

Pre-index demographics among males treated vs untreated with trofinetide

Patient characteristics	Overall (N = 466)	Treated (N = 51)	Untreated (N = 415)	p valuec
Age at RTT diagnosis (years)
Mean, SD	16.5, 13.5	16.6, 16.2	16.5, 13.2	0.544
Median, IQR	14, 14	14, 14.5	13, 14.5
Age at TROF index (years)
Mean, SD	17.8, 13.8	18.8, 18.3	17.7, 13.2	0.388
Median, IQR	14, 15	14, 17.5	14, 15
Age categories at TROF, n (%)
2–4	48 (10.3%)	12 (23.5%)	36 (8.7%)	0.001
5–10	122 (26.2%)	11 (21.6%)	111 (26.8%)	0.427
11–17	109 (23.4%)	7 (13.7%)	102 (24.6%)	0.084
18–29	111 (23.8%)	12 (23.5%)	99 (23.9%)	0.959
30–39	37 (7.9%)	2 (3.9%)	35 (8.4%)	0.408
40–49	17 (3.6%)	2 (3.9%)	15 (3.6%)	0.912
≥ 50	22 (4.7%)	5 (9.8%)	17 (4.1%)	0.070
Differential diagnosis, n (%)
Non-specific developmental delay	65 (13.9%)	26 (68.4%)	39 (9.4%)	< 0.001
Cerebral palsy	53 (11.4%)	14 (36.8%)	39 (9.4%)	< 0.001
Autism spectrum disorder	121 (26.0%)	9 (23.7%)	112 (27.0%)	0.151
Physician specialty, n (%)
Unknown	123 (26.4%)	0 (0.0%)	123 (29.6%)	< 0.001
Knowna	343 (73.6%)	51 (100.0%)	292 (70.4%)	< 0.001
Child neurologists	70 (20.4%)	33 (64.7%)	37 (12.7%)	< 0.001
Nurse practitioners	20 (5.8%)	5 (9.8%)	15 (5.1%)	0.040
Pediatricians	72 (21.0%)	3 (5.9%)	69 (23.6%)	0.061
Neurologists	13 (3.8%)	3 (5.9%)	10 (3.4%)	0.161
Clinical neurophysiologists	8 (2.3%)	3 (5.9%)	5 (1.7%)	0.046
Other specialtiesb	160 (46.6%)	4 (7.8%)	156 (53.5%)	< 0.001
Insurance type
Third party	257 (55.2%)	36 (70.6%)	221 (53.3%)	0.019
Medicaid	105 (22.5%)	9 (17.7%)	96 (23.1%)	0.376
Cash	21 (4.5%)	3 (5.9%)	18 (4.3%)	0.492
Medicare Part D	38 (8.2%)	2 (3.9%)	36 (8.7%)	0.412
Unknown	45 (9.7%)	1 (2.0%)	44 (10.6%)	0.045

IQR interquartile range, RTT Rett syndrome, SD standard deviation

^aThe percentages were calculated based on the available information regarding physician specialties among treated (n = 51) and untreated (n = 292) groups

^bOther specialties among treated included child and adolescent psychiatry, medical genetics, neurodevelopmental disabilities (psychiatry and neurology), neuromuscular medicine with 1 each; among untreated, other common specialties were behavioral health and social services (n = 30), internal medicine (n = 13), audiology (n = 13), family medicine (n = 10)

^cDifferences in proportions were assessed using chi-square tests (or Fisher’s exact test for small cell sizes n < 5)

The majority of male individuals with RTT were in the 5–10 years age range, but when evaluating the age distribution among the two groups, we found the 2–4 years age group represented the largest proportion of treated males compared to untreated (23.5% vs 8.7%; p = 0.001), respectively. In contrast, the highest proportion of untreated vs treated males (75.3% vs 58.8%) was observed in the 5–29 years age group; similar proportions of untreated vs treated males (16.1% vs 17.6%) were observed among those ≥ 30 years of age, respectively (Table 1). Compared with untreated males, treated males were more often managed by child neurologists (64.7% vs 12.7%; p < 0.001), followed by nurse practitioners (9.8% vs 5.1%; p = 0.040), whereas pediatrician management was more common in the untreated group (23.6% vs 5.9%; p = 0.061) compared to treated group. Treated vs untreated individuals had a higher prevalence of NSDD (68.4% vs 9.4%; p < 0.001) and cerebral palsy (36.8% vs 9.4%; p < 0.001), while ASD was more frequent among untreated individuals (27.0% vs 23.7%; p = 0.151) compared to treated (Table 1).

The highest rates of pre-index concomitant clinical comorbidities for male individuals with RTT were for epilepsy (28.5%), gastrostomy (17.8%), upper respiratory infection (16.5%), dysphagia (15.5%), and respiratory failure (14.6%) (Table 2). Concomitant clinical comorbidities during pre-index were more prevalent in treated vs untreated individuals; epilepsy (52.9% vs 25.5%; p < 0.001), gastrostomy (31.4% vs 16.1%; p = 0.007), and respiratory failure (25.5% vs 13.3%; p = 0.019) (Table 2). Higher rates of dysphagia (23.5% vs 14.5%; p = 0.091), constipation (23.5% vs 13.3%; p = 0.048), and seizures (23.5% vs 14.9%; p = 0.113) were also observed in the treated cohort among others, although differences were not statistically significant. The highest rates of RTT-related features for the male individuals with RTT included nutritional deficiency (10.1%) and behavioral disorders/symptoms (21.5%). Among the treated vs untreated groups, the treated group had higher rates of RTT-related features: nutritional deficiency (13.7% vs 9.6%; p = 0.360), loss of acquired communication skills (11.8% vs 14.7%; p = 0.573), behavioral disorders or symptoms (11.8% vs 22.7%; p = 0.074), and microcephaly (9.8% vs 3.9%; p = 0.053) (Table 3).

Table 2.

Pre-index clinical characteristics among males treated vs untreated with trofinetide

	Overall (N = 466)	Treated (N = 51)	Untreated (N = 415)	p valuea
Gastrointestinal disorders, n (%)
Gastrostomy	83 (17.8%)	16 (31.4%)	67 (16.1%)	0.007
Dysphagia	72 (15.5%)	12 (23.5%)	60 (14.5%)	0.091
Constipation	67 (14.4%)	12 (23.5%)	55 (13.3%)	0.048
Gastroesophageal reflux disorder	48 (10.3%)	9 (17.6%)	39 (9.4%)	0.067
Vomiting	27 (5.8%)	6 (11.8%)	21 (5.1%)	0.053
Infectious/viruses, n (%)
Lower respiratory tract infection	50 (10.7%)	8 (15.7%)	42 (10.1%)	0.225
COVID-19	21 (4.5%)	7 (13.7%)	14 (3.4%)	< 0.001
Upper respiratory infection	77 (16.5%)	5 (9.8%)	72 (17.4%)	0.171
Fever	40 (8.6%)	4 (7.8%)	36 (8.7%)	0.999
Musculoskeletal and nutritional, n (%)
Scoliosis	32 (6.9%)	4 (7.8%)	28 (6.8%)	0.770
Neurological disorders, n (%)
Epilepsy	133 (28.5%)	27 (52.9%)	106 (25.5%)	< 0.001
Seizures	74 (15.9%)	12 (23.5%)	62 (14.9%)	0.113
Respiratory disorders, n (%)
Respiratory failure	68 (14.6%)	13 (25.5%)	55 (13.3%)	0.019
Asthma	45 (9.7%)	10 (19.6%)	35 (8.4%)	0.011
Aspiration	27 (5.8%)	4 (7.8%)	23 (5.5%)	0.521
COPD	11 (2.4%)	4 (7.8%)	7 (1.7%)	0.024
Cough	49 (10.5%)	2 (3.9%)	47 (11.3%)	0.144

The comorbidities were assessed 6 months pre-index

COPD chronic obstructive pulmonary disease

^aDifferences in proportions were assessed using chi-square tests (or Fisher’s exact test for small cell sizes n < 5)

Table 3.

Rett syndrome related features among males treated versus untreated with trofinetide

	Overall (N = 466)	Treated (N = 51)	Untreated (N = 415)	p valuec
Growth abnormalities/nutritional disorders, n (%)
Nutritional deficiency	47 (10.1%)	7 (13.7%)	40 (9.6%)	0.360
Growth abnormalitiesa	15 (3.2%)	3 (5.9%)	12 (2.9%)	0.219
Neurodevelopmental disorders, n (%)
Loss of acquired communication skills	67 (14.4%)	6 (11.8%)	61 (14.7%)	0.573
Behavioral disorders/symptomsb	100 (21.5%)	6 (11.8%)	94 (22.7%)	0.074
Microcephaly	21 (4.5%)	5 (9.8%)	16 (3.9%)	0.053
Development progress delayed	24 (5.2%)	4 (7.8%)	20 (4.8%)	0.319
Weakness/paralysis	41 (8.8%)	3 (5.9%)	38 (9.2%)	0.603
Sleep dysfunction	37 (7.9%)	3 (5.9%)	34 (8.2%)	0.785
Prominent hand apraxia/dyspraxia	23 (4.9%)	3 (5.9%)	20 (4.8%)	0.730
Loss of acquired motor skills	29 (6.2%)	2 (3.9%)	27 (6.5%)	0.758
Respiratory disorders, n (%)
Breathing irregularities	44 (9.4%)	11 (21.6%)	33 (8.0%)	0.002

^aUnderweight/short stature

^bIrritability, aggressive behavior, crying tantrums, self-mutilation, scratching, biting

^cDifferences in proportions were assessed using chi-square tests (or Fisher’s exact test for small cell sizes n < 5)

Post-Index Outcomes

Time to Non-Persistence

Kaplan–Meier analysis showed that approximately 80% of individuals remained on TROF for more than 3 months, and nearly 70% remained on therapy for ≥ 6 months. Additionally, over 50% of the treated population continued TROF treatment for a minimum of 17 months through the end of study follow-up (Fig. 3).

Fig. 3.

Time to non-persistence of trofinetide

Predictors of Non-Persistence

A series of univariate logistic regression models were first used to examine the magnitude of predictive effect of each baseline predictor on TROF non-persistence during follow-up. The unadjusted odds ratios show that pre-index history of neurological (OR 6.46, 95% CI 1.84–22.71; p = 0.004) and infectious disorders (OR 5.71, 95% CI 1.34–24.33; p = 0.018), respectively, were significant predictors of non-persistence. On the other hand, the unadjusted univariate logistic regression models show that mean age, gastrointestinal disorders, and respiratory disorders were not significant predictors of non-persistence. Mean age was not associated with non-persistence (OR 0.99; 95% CI 0.96–1.02; p = 0.520). Although gastrointestinal disorders (OR 1.75; 95% CI 0.58–5.32; p = 0.320) and respiratory disorders (OR 2.86; 95% CI 0.88–9.25; p = 0.080) demonstrated odds ratios above 1.0, the wide confidence intervals indicate substantial uncertainty in these estimates. In the final adjusted multivariate logistic regression model that examined the collective effect of potential predictors of non-persistence, only history of neurological disorders remained a significant predictor of non-persistence (OR 5.17, 95% CI 1.34–19.97; p = 0.017) (Fig. 4).

Fig. 4.

Predictors of trofinetide non-persistence among males with RTT (multivariate logistic regression)

Discussion

This retrospective real-world analysis provides early insights about the demographic and clinical characteristics of males who initiated TROF and those who remained untreated for RTT during the study period. Among all individuals with RTT identified in this database, 15% were male. This proportion was similar to that reported by May and colleagues using the same IQVIA database over an earlier period (2017–2019), in which males accounted for 12–14% of identified patients treated with RTT across the study years [17]. While that prior work helped establish the presence of males within the RTT population captured in claims data, the current analysis extends those findings by characterizing treatment uptake and comparing males who initiated TROF with those who remained untreated in routine clinical practice.

In the current study, approximately 6% of males with RTT identified in the database initiated TROF during the study period whereas 94% remained untreated. This treatment initiation rate appears to be lower than the 20% of treatment uptake among all individuals with RTT reported in real-world research [18]. Although direct comparisons across studies should be interpreted cautiously given differences in study design and eligibility criteria, the findings may suggest slower TROF uptake among males in routine clinical practice. Potential contributors may include the historical under-recognition of RTT in males and the limited male-specific TROF evidence available from clinical trials and other published studies. Our data study period was from 01/01/2021 to 09/30/2024, and the RTT diagnosis could have been given to the male individual prior to the former date. In the current study, the median age at RTT diagnosis among males was 14 years, which was similar to that reported by Davis and colleagues in a smaller commercial claims-based analysis [19]; however, we need to keep in mind that males with RTT could have received the RTT diagnosis prior to our data time period. Our study also adds to the existing literature by examining treated and untreated males separately and by showing that TROF-treated males had a higher rate of concomitant clinical burden (i.e., higher rates of pre-index history of epilepsy, gastrostomy, respiratory failure, and breathing irregularities) than untreated males. Overall, the pre-index comorbidity patterns among TROF-treated males suggests that, in routine practice, clinicians may be preferentially initiating treatment among those with higher touchpoints and clinical complexity. The comparatively lower pre-index comorbidity burden among untreated males suggests that TROF may be an appropriate treatment consideration for a broader range of males with RTT and not only among those with the highest clinical complexity. While TROF-treated males in this analysis appear to be largely managed by child neurologists, untreated males were more often managed by pediatricians who may lack neurology training. Collectively, our findings suggest that TROF uptake among males is occurring preferentially in those with higher clinical complexity and stronger linkage to specialty neurology care. This may indicate “clinical-need prioritization” in early post-approval adoption, given the expanding recognition that males with MECP2-related RTT represent a clinically meaningful population rather than an exceptional rarity.

Despite the greater comorbidity burden among treated males, approximately 70% remained on TROF for ≥ 6 months and more than half continued for ≥ 17 months of follow-up. Results of this analysis also show that early post-initiation period (i.e., the first 3 months after treatment initiation) is particularly relevant because tolerability management and dose optimization are often most active soon after treatment initiation and may influence longer-term continuation. Emerging real-world evidence similarly underscores the importance of proactive tolerability management of gastrointestinal adverse effects and highlights practical mitigation strategies to support TROF continuation in routine care [20, 21]. Given the controlled TROF evidence is predominantly in females, these real-world male continuation patterns in males adds practical context for clinicians and payers considering TROF use in untreated males.

Our findings also suggest that history of neurological disorders was the only significant predictor of non-persistence, with approximately five times greater likelihood of non-persistence. While infectious disorders were significant in unadjusted analyses, this association did not persist in the multivariable model, and gastrointestinal and respiratory disorders only showed only numerical greater likelihood of non-persistence. Together, these results indicate that several factors are likely contributors of non-persistence and that patients with history of greater comorbidities may require closer monitoring and more individualized treatment strategies to support continuation in routine care. Given the small sample size of the treated group (n = 51), logistic regression estimates for non-significant predictors should be interpreted with caution as confidence intervals are wide.

Future male-focused studies should also capture caregiver burden and supportive care intensity, and evaluate whether earlier initiation (e.g., in younger males) changes persistence. Additionally, longitudinal studies incorporating detailed clinical assessments and post-treatment follow-up are needed to evaluate changes in symptom burden, clinical outcomes, and potential treatment-related effects associated with TROF use among males in routine clinical practice. TROF is currently approved in the USA and Canada; however, at the time of this analysis, it has not received regulatory approval in the European Union or the UK. Accordingly, the real-world treatment patterns described in this study reflect a USA-based clinical practice context and may not be generalizable to regions where TROF is not currently approved or accessible. Finally, continuous medical education about the benefits of TROF as a treatment option for all patients, including males, to the broader RTT clinical community may be needed to improve clinical care with TROF among the male RTT population.

As with any retrospective real-world analysis, several limitations should be considered. First, this study relied on administrative and specialty pharmacy claims, which may be subject to diagnosis misclassification and incomplete capture of clinical information due to coding variability, under-coding, or miscoding. Consistent with prior published real-world studies, RTT diagnosis was ascertained using ≥ 1 ICD-10-CM F84.2 claim in any diagnostic position [17]; the claims-based approach does not contain sufficient diagnostic detail for differentiation between clinically or genetically confirmed RTT diagnoses, and this should be considered when interpreting findings. Second, claims databases lack important clinical factors such as genotype, 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. Therefore, tolerability/adverse events/side effects associated with treatment non-persistence is likely to be unknown. Safety of TROF was not assessed in this study, as administrative claims data do not provide sufficient granularity to systematically capture and characterize treatment-emergent adverse events. Finally, persistence measures based on dispensing/refill patterns may not perfectly reflect true medication use or clinician-directed discontinuation. Given the imbalance in cohort sizes between treated and untreated males, statistical comparisons should be interpreted cautiously, and the findings should therefore be interpreted as descriptive rather than inferential. Nevertheless, this study provides valuable early evidence on TROF use and treatment patterns among males with RTT.

Conclusions

In this retrospective real-world analysis, TROF use was observed among males with RTT; however, majority of males remained untreated during the study period, highlighting an important opportunity to improve awareness and optimize access to treatment in this under-recognized subpopulation. Treated males were more frequently managed by child neurologists and exhibited higher pre-index clinical complexity and differential diagnoses compared with untreated males, suggesting that clinicians may be preferentially initiating TROF in patients with greater clinical burden. At the same time, untreated males demonstrated comparatively lower pre-index comorbidity rates, which may provide reassurance that TROF could be considered beyond the most clinically complex patients in routine practice. Among males who initiated TROF, approximately 70% remained on therapy beyond 6 months, with more than half remaining on treatment for at least 17 months through the end of available follow-up. Together, these findings provide early real-world evidence on treatment uptake and persistence among males with RTT and support the need for continued clinician education and further male-focused real-world studies to better define long-term outcomes.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Krithika Rajagopalan, Vinod Yakkala and Nazia Rashid were responsible for study conception and design; Krithika Rajagopalan, Vinod Yakkala were responsible for acquisition and analysis of data; Krithika Rajagopalan, Vinod Yakkala and Nazia Rashid were responsible for interpretation of data for the work. The first draft of the manuscript was written and reviewed by Krithika Rajagopalan, Vinod Yakkala and Nazia Rashid. All authors commented on previous versions of the manuscript and have read and approved of the final version of the manuscript.

Funding

This study was funded by ACADIA Pharmaceuticals Inc, San Diego, CA, USA. The journal’s Open Access and Rapid Service Fee were also funded by Acadia Pharmaceuticals Inc, San Diego, CA, USA.

Data Availability

The data sources used in this analysis are not publicly available, and the databases are syndicated and available upon use with a data license fee.

Declarations

Conflict of Interest

Krithika Rajagopalan and Vinod Yakkala are current employees of Anlitiks Inc., a company that received funding from Acadia Pharmaceuticals to conduct this study. Nazia Rashid is a current employees of Acadia Pharmaceuticals based in San Diego, CA, USA.

Ethical Approval

As this study involves deidentified, anonymized, patient level secondary data from other claims data sources without containing any identifiable protected health information (PHI) in accordance with HIPAA Security Act of 1996, patient consent was not required, and the need for ethics committee approval was not applicable.