Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: Acadia Pharmaceuticals (Netherlands) B.V., Strawinskylaan 3051, 1077 ZX Amsterdam, Netherlands
Pharmacotherapeutic group: Other nervous system drugs
ATC code: N07XX24
Trofinetide is a synthetic analogue of the N-terminal tripeptide of insulin-like growth factor 1. The precise molecular mechanism of trofinetide activity in the treatment of neurobehavioural symptoms of Rett syndrome is not known.
The efficacy of trofinetide for the treatment of neurobehavioural symptoms of Rett syndrome was evaluated in Study ACP-2566-003 (Study 1), a 12-week randomized, double-blind, placebo-controlled study in female patients (N=187) with Rett syndrome 5 to 20 years of age. The overall mean age was 10.9 years (range 5 to 20 years). About half of the subjects (58.2%) were in the age category of 5 to <12 years, with 24.5% in the 12 to <17 years old category and 17.4% in the ≥17 years old category. Mean body weight was 29.7 kg (range 13 to 78 kg).
Patients were randomised to receive trofinetide (N=93) or matching placebo (N=94) for 12 weeks. The trofinetide dosage was based on patient weight to achieve similar exposure in all patients (section 4.2).
The co-primary efficacy measures were change from Baseline after 12 weeks of treatment in the total score of the Rett Syndrome Behaviour Questionnaire (RSBQ) and the Clinical Global Impression-Improvement (CGI-I) score. The RSBQ is a 45-item rating scale completed by the caregiver that assesses a range of symptoms of Rett syndrome (breathing, hand movements or stereotypies, repetitive behaviours, night-time behaviours, vocalizations, facial expressions, eye gaze, and mood). Each item is scored as 0 (not true), 1 (somewhat or sometimes true), or 2 (very true or often true), with a maximum possible score of 90 points. Lower scores reflect lesser severity in signs and symptoms of Rett Syndrome. The items of the RSBQ total score are grouped into 8 subscales for General Mood, Breathing Problems, Hand Behaviours, Repetitive Face Movements, Body Rocking/ Expressionless Face, Night-Time Behaviours, Fear/Anxiety, Walking/Standing, and seven ungrouped items. The CGI-I is rated by clinicians (using Rett syndrome-specific anchors) to assess whether a patient has improved or worsened on a 7-point scale (1=very much improved to 7=very much worse) in which a decrease in score indicates improvement.
The key secondary endpoint was change from Baseline to Week 12 in the Communication and Symbolic Behaviour Scales Development Profile Infant-Toddler Checklist – Social Composite Score (CSBS-DP-IT Social). The CSBS-DP-IT Checklist assesses communication and pre-linguistic skills in young children and in older children with developmental delay. The CSBS-DP-IT Social has 13 items with a possible score between 0 to 26. The Social Composite Score evaluates a range of non-verbal communication modalities commonly used by patients with Rett syndrome and an increase in score indicates improvement.
Treatment with trofinetide showed a statistically significant improvement compared to placebo on the co-primary efficacy endpoints, the change from baseline in RSBQ total score, and the CGI-I score at week 12 (Table 4 and Figure 1). A statistically significant difference compared to placebo was observed on CSBS-DP-IT-Social Composite Score at Week 12.
Table 4. Summary of efficacy results for patients completing Study 1:
| Mean baseline score (SE) | Mean week 12 score (SE) | LS mean change from baseline to week 12 (SE) | Trofinetide-placebo treatment difference, LS mean (95% CI) | ||
| RSBQ | Trofinetide | 43.7 (1.21) | 39.9 (1.38) | -4.9 (0.94) | -3.1 (-5.7, -0.6) |
| Placebo | 44.5 (1.26) | 42.8 (1.42) | -1.7 (0.90) | ||
| CGI-I | Trofinetide | -- | 3.5 (0.08) | -- | -0.3 (-0.5, -0.1) |
| Placebo | -- | 3.8 (0.06) | |||
| CSBS-DP-IT- Social | Trofinetide | 8.7 (0.35) | 8.9 (0.44) | -0.1 (0.26) | 1.0 |
| Placebo | 8.8 (0.34) | 7.5 (0.33) | -1.1 (0.25) | ||
CI=confidence interval; LS mean=least-squares mean; SE=standard error
Out of 187 patients, 82% (n=154) were enrolled in an open-label extension (OLE) study and received trofinetide for up to 40 weeks. 54% of patients (n=84) completed the OLE study.
The European Medicine Agency has waived the obligation to submit the results of studies with trofinetide in patients less than 2 years of age with Rett syndrome (see section 4.2 for information on paediatric use). Limited data are available in patients 2 to 4 years of age.
Trofinetide exhibits linear kinetics with no time- or dose-dependent effect on pharmacokinetic parameters. Systemic exposure to trofinetide was dose-proportional across the clinical dose range (up to 12 g daily). Minimal to no accumulation was observed following multiple-dose administration.
Table 5. Summary of trofinetide steady state pharmacokinetic parameters as estimated from population PK models in overall Rett syndrome population:
| Recommended dosagea | Cmax (μg/mL) | tmax (h) | AUCτ (μg•h/mL) |
| 5 g twice daily (N=3) | 203.1 | 1.71 | 1108.3 |
| 6 g twice daily (N=23) | 161.1 | 1.97 | 966.5 |
| 8 g twice daily (N=41) | 156.8 | 1.98 | 926.5 |
| 10 g twice daily (N=21) | 146.3 | 2.17 | 933.3 |
| 12 g twice daily (N=7) | 143.9 | 2.03 | 853.0 |
a Recommended dosage: twice daily, morning and evening, according to patient weight.
The time to maximum drug concentration (tmax) is about 2 to 3 hours after administration. Based on the mass balance study, at least 84% of the administered dose was absorbed following oral administration of 12 g trofinetide.
Following oral administration, the apparent volume of distribution of trofinetide was approximately 60 L. Trofinetide protein binding in human plasma is less than 6%.
Trofinetide is not significantly metabolised by CYP450 or UGT enzymes. Hepatic metabolism is not a significant route of trofinetide elimination.
Elimination of orally administered trofinetide in human subjects was characterised by an initial rapid elimination phase (half-life of the initial phase of 1.5 hours) followed by a relatively slow elimination phase (half-life of the terminal phase of 30 hours). More than 80% of the administered dose was recovered unchanged in urine, with minor excretion in feces.
Based on population pharmacokinetics analysis of clinical trials data, patients with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m²) showed no significant impact on the exposure of trofinetide compared to patients with normal renal function. Based on a renal impairment study in adult subjects, the effect of moderate renal impairment (eGFR 30 to 59 mL/min /1.73 m²) increases the exposure (AUC0-inf) of trofinetide approximately 80% compared to patients with normal renal function administered the same dose (see section 4.2). The effect of severe renal impairment (eGFR 15 to 29 mL/min/1.73 m²) on trofinetide exposure has not been investigated.
The pharmacokinetics in patients with hepatic impairment have not been studied. However, hepatic impairment is not expected to impact the exposure of trofinetide because hepatic metabolism is not a significant route of trofinetide elimination (see section 4.2).
Age had no clinically relevant effect on the systemic exposure of trofinetide at the recommended dosage of trofinetide. The population pharmacokinetic analyses included subjects with Rett syndrome (age: 2 to 4 years (n=13), >4 to 12 years (n=46), >12 to 17 years (n=98), and ≥18 years (n=41)).
Median exposure (AUC0-12,ss) was within the target range (800 to 1200 μg·h/mL) in all weight groups except in subjects >100 kg, where 71% had exposures below the target range.
No clinically relevant effect of sex on the systemic exposure of trofinetide was observed in population pharmacokinetic analyses, which included 196 male and 259 female subjects.
No clinically relevant differences in systemic exposure of trofinetide were observed between Hispanic/Latino (n=58) and Non-Hispanic/Latino (n=397) subjects in population pharmacokinetic analyses.
Trofinetide inhibits UGT enzymes, UGT1A9, 2B7, and 2B15. No clinically relevant inhibition of UGTs is expected.
No inhibition of the CYP450 enzymes, CYP1A2, 2B6, 2C8, 2C9, 2C19, and 2D6, is expected at therapeutic systemic concentrations.
Trofinetide is a weak inhibitor of OATP1B1 and OATP1B3. No clinically relevant inhibition of OATP1B1 and OATP1B3 transporters is expected.
No inhibition was observed at therapeutic systemic concentrations on P-gp, BCRP, BSEP, OAT1, OAT3, and OCT2.
Non-clinical data are based on conventional studies of safety pharmacology, repeated dose toxicity, carcinogenic potential, or toxicity to reproduction and development. In non-clinical data, the plasma exposure (AUC) at the highest doses tested was less than that of the clinical exposure in humans at the maximum recommended human dose (MRHD) of 12 g twice daily (24 g/day).
A carcinogenicity study in transgenic mice with oral administration of trofinetide for 26 weeks revealed no increase in tumour incidence compared to placebo group.
A 2-year oral rat carcinogenicity study is ongoing. The carcinogenic potential of trofinetide is currently unknown.
No GLP compliant genotoxicity studies were conducted. However, based on the minimal modification of the methylated proline which does not contain a structural alert for genotoxicity, and the lack of carcinogeneticity findings in the transgenic mouse study, it can be concluded that trofinetide has no genotoxic potential.
Oral administration of trofinetide to male and female rats prior to and throughout mating and continuing in females through gestation day 7 resulted in no adverse effects on fertility or reproductive function. Animal fertility studies may be insufficient to adequately assess fertility and reproductive risk.
Oral administration of trofinetide to pregnant rabbits, during the period of organogenesis, and to pregnant rats throughout organogenesis, pregnancy and lactation, resulted in no adverse effects. Animal development studies may be insufficient to adequately assess developmental risk.
Studies in lactating and pregnant rats confirmed maternal trofinetide exposure following oral administration, with exposure increasing in a ≥ dose proportional manner, and the absence of accumulation potential. In pregnant rabbits, systemic exposure following oral administration also increased in a ≥ dose proportional manner, however accumulation (approximately 4- to 9-fold) was observed during the gestational period; rabbit exposures overall were much lower than the exposures obtained in repeat dose toxicity studies in the other species. This accumulation appears specific to pregnant rabbits. Animal studies may be insufficient to adequately assess pregnant and lactating toxicity risk.
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