What is Rett syndrome (RTT)?
Kate, age 9,
living with
Rett syndrome
RTT is a complex neurodevelopmental disorder with multisystem impact1
Within the US alone, there are approximately 6,000 to 9,000 individuals living with RTT.2
RTT primarily affects females, but in rarer cases it can also affect males.1
A variety of physical and behavioral symptoms can occur and while there is no cure,3 many individuals with RTT live well into middle age and beyond.4
Causes of RTT
In the majority of patients, RTT is caused by mutations in the MECP2 gene located on the X chromosome.5,6 MECP2 is an essential gene for normal brain development and function.7 The MeCP2 protein regulates multiple signaling pathways—and influences neuronal synaptic function and morphology.8,9
Based on RTT preclinical studies, deficiency in MeCP2 may lead to abnormalities in9-11:
Neuronal differentiation
Neuronal maturation
Experience-driven remodeling
Neuronal structure maintenance
Symptoms of RTT
Individuals with RTT develop a heterogeneous constellation of symptoms with evolving presentation over time.1
Key features of RTT12:
Loss of speech
Loss of purposeful hand use
Impaired or absent mobility
Stereotypic hand movements such as hand wringing, clapping, tapping, and/or mouthing
Individuals with RTT can develop a wide range of comorbidities that are often treated with symptom-based management13:
Irregular breathing patterns
Epileptic seizures
Movement disorders
Behavioral disturbances
Gastrointestinal complications
Cardiac issues
Skeletal abnormalities
Diagnosing RTT
RTT includes both typical and atypical presentations.12 And while RTT requires a clinical diagnosis, mutational analysis may provide insights that help predict clinical severity.12,14
The diagnostic criteria for both typical and atypical RTT are listed below:
Timing of RTT Stages and Symptom Onset15
Given the heterogeneity of RTT symptoms, a multidisciplinary team is needed to help manage this disorder.1
Actor portrayals
The impacts of RTT
The key features of RTT impact both individuals and their caregivers.1,16
Every individual with RTT has multiple features or symptoms, which can be associated with physical and behavioral impact.12
The perspectives below are based on qualitative interviews with 40 caregivers of children with RTT regarding the range of potential impacts to themselves and their childa
Potential impacts of core symptoms and behaviors of RTT
Individuals17,a (Caregiver perspectives)
Impaired ability to communicate
Risk of injury
Difficulty interacting with toys
Inability to self-feed
Loss of independence
Impaired focus at school
Caregivers17,a
Physically demanding care
Emotionally draining
Provides emotional support
Constant supervision
Worry
aCommon themes were derived from select interviews and are not inclusive of all 40 caregivers.
“The burden of both Rett syndrome and the therapies required to address symptoms is tremendous, not only for individuals living with Rett syndrome, but for their caregivers and families.”
– Rett Syndrome Voice of the Patient Report 202218
Collaborative management of RTT
RTT is multisystemic, unpredictable, and heterogeneous.1 A multidisciplinary team of physicians, specialists, and specialized therapists is needed to help address the wide range of symptoms.1
The care team
Given the medically complex nature of RTT—with evolving comorbidities throughout life—coordination across multidisciplinary specialties is important.13
To help paint a comprehensive picture for current and future care, members of the care team can collaborate to:
compile symptom history
discuss treatment goals
document observations
Caregivers
Caregivers also hold key detailed information that can be useful in the management of RTT. As such, they can play an essential role within this extended care team because they:
are experts on their children’s unique symptom history and current challenges
help to coordinate efforts across the large care team
can clarify any additional symptoms of RTT that may impact their child’s care
Important Safety Information and Indication
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 of mild or moderate severity in 96% of cases. In the 12-week study, antidiarrheal medication was used in 51% of patients treated with DAYBUE.
Patients should stop taking 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.
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 moderate or severe renal impairment.
DAYBUE is available as an oral solution (200mg/mL).
Indication
DAYBUE is indicated for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older.
Please read the full Prescribing Information.
Important Safety Information and Indication
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 of mild or moderate severity in 96% of cases. In the 12-week study, antidiarrheal medication was used in 51% of patients treated with DAYBUE.
Patients should stop taking 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.
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 moderate or severe renal impairment.
DAYBUE is available as an oral solution (200mg/mL).
Indication
DAYBUE is indicated for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older.
Please read the full Prescribing Information.
References: 1. Fu C, Armstrong D, Marsh E, et al. Consensus guidelines on managing Rett syndrome across the lifespan. BMJ Paediatr Open. 2020;4(1):e000717. 2. Acadia Pharmaceuticals Inc. Data on file. RTT US Prevalence. March 2022. 3. National Institute of Neurological Disorders and Stroke. Rett syndrome fact sheet. July 13, 2023. https://www.ninds.nih.gov/rett-syndrome-fact-sheet 4. Tarquinio DC, Hou W, Neul JL, et al. The changing face of survival in Rett syndrome and MECP2-related disorders. Pediatr Neurol. 2015;53(5):402-411. 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. Percy AK, Neul JL, Glaze DG, et al. Rett syndrome diagnostic criteria: Lessons from the Natural History Study. Ann Neurol. 2010;68(6):951-955. 7. Tillotson R, Bird A. The molecular basis of MeCP2 function in the brain. J Mol Biol. 2019;S0022-2836(19)30595-3059. 8. Ricciardi S, Boggio EM, Grosso S, et al. Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Hum Mol Genet. 2011;20(6):1182-1196. 9. 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. 10. 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. 11. Mellios N, Feldman DA, Sheridan SD, et al. MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling. Mol Psychiatry. 2018;23(4):1051-1065. 12. Neul JL, Kaufmann WE, Glaze DG, et al for the RettSearch Consortium. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010;68(6):944-950. 13. Fu C, Armstrong D, Marsh E, et al. Multisystem comorbidities in classic Rett syndrome: a scoping review. BMJ Paediatr Open. 2020;4(1):e000731. 14. Cuddapah VA, Pillai RB, Shekar KV, et al. Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome. J Med Genet. 2014;51(3):152-158. 15. Kyle SM, Vashi N, Justice MJ. Rett syndrome: a neurological disorder with metabolic components. Open Biol. 2018;8(2):1-17. 16. Palacios-Ceña D, Famoso-Pérez P, Salom-Moreno J, et al. “Living an obstacle course”: a qualitative study examining the experiences of caregivers of children with Rett syndrome. Int J Environ Res Public Health. 2019;16(41):1-13. 17. The Henne Group. Meaningful Improvements in Rett Syndrome Behaviors: A Qualitative Study of Caregivers. September 2022. 18. International Rett Syndrome Foundation and the Rett Syndrome Research Trust. Voice Of The Patient Report: Rett Syndrome Externally-Led Patient-Focused Drug Development Meeting. 2022. July 13, 2023. https://rettpfdd.org/site/assets/files/1/2022-rett-syndrome-voice-of-the-patient-report.pdf. 19. Acadia Pharmaceuticals Inc. DAYBUE [Package Insert]. San Diego, CA, 2023. 20. Acadia Pharmaceuticals announces U.S. FDA approval of DAYBUE™ (trofinetide) for the treatment of Rett syndrome in adult and pediatric patients two years of age and older. [press release]. Acadia Pharmaceuticals Inc. March 10, 2023.
Welcome to the DAYBUE™ (trofinetide) website.
This information is intended for US healthcare professionals only.
Using the RSBQ, caregivers were asked to score 45 symptoms of RTT on a scale from 0 (not true) to 2 (very/often true) .1
The rating scale and items in the RSBQ are shown below.9
Hand movements are uniform and monotonous
Has difficulty in breaking/stopping hand stereotypies
There are times when breathing is deep and fast (hyperventilation)
There are times when breath is held
The amount of time spent looking at objects is longer than the time spent holding or manipulating them
Makes mouth grimaces
There are times when parts of the body are held rigid
Restricted repertoire of hand movements
Has wounds on hands as a result of repetitive hand movements
Makes grimacing expressions with face
Swallows air
Does not use hands for purposeful grasping
Tendency to bring hands together in front of chin or chest
Air or saliva is expelled from mouth with force
Seems frightened when there are sudden changes in own body position
Spells of laughter for no apparent reason during the day
Grinds teeth
Uses eye gaze to convey feelings, needs, and wishes
Shifts gaze with a slow horizontal turn of head
Spells of inconsolable crying for no apparent reason during the day
Spells of laughter for no apparent reason during the night
Spells of apparent panic
Has frequent naps during the day
Spells of screaming for no apparent reason during the day
Makes repetitive hand movements with hands apart
Screams hysterically for long periods of time and cannot be consoled
Spells of screaming for no apparent reason during the night
Vocalizes for no apparent reason
Rocks self when hands are prevented from moving
There are times when she appears miserable for no apparent reason
Abrupt changes in mood
Spells of inconsolable crying for no apparent reason during the night
Makes repetitive movements involving fingers around tongue
Rocks body repeatedly
Appears isolated
Vacant “staring” spells
Abdomen fills with air and sometimes feels hard
There are certain periods where she performs much worse than usual
There are times when she is irritable for no apparent reason
Seems to look through people into the distance
Although can stand independently tends to lean on objects or people
Expressionless face
Spells of apparent anxiety/fear in unfamiliar situations
Makes repetitive tongue movements
Walks with stiff legs
Select inclusion criteria6
Female subjects 5 to 20 years of age
Body weight ≥12 kg at screening
Could swallow the study medication provided as a liquid solution or could take it by gastrostomy tube
Had classic/typical RTT
Had a documented disease-causing mutation in the MECP2 gene
Had a stable pattern of seizures, or had no seizures within 8 weeks of screening