Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study

Rett syndrome is a rare, genetic neurodevelopmental disorder. Trofinetide is a synthetic analog of glycine–proline–glutamate, the N-terminal tripeptide of the insulin-like growth factor 1 protein, and has demonstrated clinical benefit in phase 2 studies in Rett syndrome. In this phase 3 study (https://clinicaltrials.gov identifier NCT04181723), females with Rett syndrome received twice-daily oral trofinetide (n = 93) or placebo (n = 94) for 12 weeks. For the coprimary efficacy endpoints, least squares mean (LSM) change from baseline to week 12 in the Rett Syndrome Behaviour Questionnaire for trofinetide versus placebo was −4.9 versus −1.7 (P = 0.0175; Cohen’s d effect size, 0.37), and LSM Clinical Global Impression–Improvement at week 12 was 3.5 versus 3.8 (P = 0.0030; effect size, 0.47). For the key secondary efficacy endpoint, LSM change from baseline to week 12 in the Communication and Symbolic Behavior Scales Developmental Profile Infant–Toddler Checklist Social Composite score was −0.1 versus −1.1 (P = 0.0064; effect size, 0.43). Common treatment-emergent adverse events included diarrhea (80.6% for trofinetide versus 19.1% for placebo), which was mostly mild to moderate in severity. Significant improvement for trofinetide compared with placebo was observed for the coprimary efficacy endpoints, suggesting that trofinetide provides benefit in treating the core symptoms of Rett syndrome.

provide written or oral assent if deemed able by the Investigator.The process of obtaining informed consent will be conducted in accordance with IRB or EC policy and applicable local law.
o For subjects who are not minors: written informed consent will be obtained from the LAR or the subject if deemed able by the Investigator.If the subject is deemed not able to provide consent, the subject should provide written or oral assent if deemed able by the Investigator.The process of obtaining informed consent will be conducted in accordance with IRB or EC policy and applicable local law.
o The subject's caregiver must also provide written informed consent regarding their participation in the study prior to participating in any study procedures.
• Female subjects 5 to 20 years of age, inclusive, at Screening.
• Can swallow the study medication provided as a liquid solution or can take it by gastrostomy tube (G-tube).
• The subject's caregiver is English-speaking and has sufficient language skills to complete the caregiver assessments.

Diagnosis
• Has classic/typical Rett syndrome.
• Has a documented disease-causing mutation in the MECP2 gene.
• Is post-regression at Screening, defined as: • Has a Clinical Global Impression-Severity (CGI-S) score of ≥4 at Screening and Baseline.

Concomitant Treatment
• If the subject is taking or was taking an anticonvulsant or any other psychoactive medication (including cannabinoids): o The treatment regimen has been stable for at least 4 weeks before Baseline and there is no current plan to change the dose, or o If the medication was discontinued, the discontinuation has occurred no fewer than 2 weeks or 5 half-lives (whichever is greater) before Baseline.
• If the subject is taking or was taking any other medication daily for chronic illness (not including antibiotics, pain relievers, and laxatives): o The treatment regimen of the medication has been stable for at least 4 weeks before Baseline, and there is no current plan to change the dose, or o If the medication was discontinued, the discontinuation has occurred no fewer than 2 weeks or 5 half-lives (whichever is greater) before Baseline.
• If the subject is receiving or was receiving a nonpharmacologic somatic treatment (e.g., a ketogenic diet or vagal nerve stimulation): o The treatment regimen has been stable for at least 4 weeks before Baseline, and there is no current plan to change the treatment, or o If the treatment was discontinued, the discontinuation has occurred no fewer than 2 weeks before Baseline.
• If the subject is receiving or was receiving nonpharmacologic treatments such as an educational, behavioral, physical, occupational, or speech therapy: o The treatment regimen has been stable for at least 4 weeks before Baseline, and there is no current plan to change the treatment (note: changes to a treatment regimen that are due to school schedules or are otherwise seasonally related are not exclusionary), or o If the treatment was discontinued, the discontinuation has occurred no fewer than 2 weeks before Baseline.

Seizures
• Has a stable pattern of seizures, or has had no seizures, within 8 weeks of Screening.

Childbearing Potential
• Subjects of childbearing potential must abstain from sexual activity for the duration of the study and for at least 30 days thereafter.If a subject is sexually active or becomes sexually active during the study, she must use 2 clinically acceptable methods of contraception (e.g., oral, intrauterine device, diaphragm plus spermicide, injectable, transdermal, or implantable contraception) for the duration of the study and for at least 30 days thereafter.Subject must not be pregnant or breastfeeding.

Place of Residence
• Subject and caregiver(s) must reside at a location to which study drug can be delivered and have been at their present residence for at least 3 months prior to Screening.

Concomitant Treatment
• Has been treated with growth hormone within 12 weeks of Baseline.
• Has been treated with insulin-like growth factor 1 within 12 weeks of Baseline.
• Has been treated with insulin within 12 weeks of Baseline.

Medical Conditions Other Than Rett Syndrome
• Has current clinically significant cardiovascular, endocrine (such as hypo-or hyperthyroidism, Type 1 diabetes mellitus, or uncontrolled Type 2 diabetes mellitus), renal, hepatic, respiratory, or gastrointestinal disease (such as celiac disease or inflammatory bowel disease) or has major surgery planned during the study.
• Has a history of, or current, cerebrovascular disease or brain trauma.
• Has significant, uncorrected visual or uncorrected hearing impairment.
• Has a history of, or current, malignancy.

Laboratory Studies, Vital Signs, and Electrocardiogram
• Has a clinically significant abnormal laboratory value at Screening.Laboratory testing may be repeated during the Screening period with agreement of the Medical Monitor.
• Has serum potassium below the normal range for the subject (according to the central laboratory) at Screening.Serum potassium may be repeated during the Screening period with the agreement of the Medical Monitor.
• Has a thyroid-stimulating hormone value outside the normal range for the subject (according to the central laboratory) at Screening.
• Has clinically significant abnormality in vital signs at Screening or Baseline.
• Has any of the following: o QTcF interval of >450 ms at Screening or Baseline (before dosing).
o History of a risk factor for torsades de pointes (e.g., heart failure or family history of long QT syndrome).
o History of clinically significant QT prolongation that is deemed to put the subject at increased risk of clinically significant QT prolongation.
• Has any other clinically significant finding on ECG at Screening or Baseline (before dosing).
• Has a positive pregnancy test at Screening.

Other Criteria
• Has a significant sensitivity or allergic reaction to trofinetide or its excipients.
• Has participated in another interventional clinical study within 30 days prior to Screening.
• Is judged by the Investigator or the Medical Monitor to be inappropriate for the study for any reason.

o
No loss or degradation of ambulation (including gait, coordination, independence of walking/standing) within 6 months of Screening o No loss or degradation of hand function within 6 months of Screening o No loss or degradation of speech (including babbling, words or previously developed communicative vocalizations) within 6 months of Screening o No loss or degradation of nonverbal communicative or social skills (including eye gaze, using body to indicate communicative intent, social attentiveness) within 6 months of Screening • Has a severity rating of 10 to 36, inclusive, on the Rett Syndrome Clinical Severity Scale (RTT-CSS) at Screening.