Peptide education
Trofinetide
NNZ-2566 · DAYBUE · DAYBUE STIX
Trofinetide is a synthetic analog of an IGF-1-derived tripeptide. In the United States, DAYBUE and DAYBUE STIX are prescription formulations for Rett syndrome in adults and children aged 2 years and older.
A controlled Rett syndrome study found improvements on two clinical rating measures compared with placebo. Diarrhea and vomiting were common, and the U.S. label gives product-specific dosing and safety instructions.
Overview
Quick answer
Trofinetide was also studied as NNZ-2566 in fragile X syndrome and traumatic brain injury. Those are separate research programs, not FDA-approved indications. An older intravenous study is not the labeled oral product.
Who is the U.S. medicine approved for?
The label covers Rett syndrome in adults and pediatric patients aged 2 years and older. The phase 3 efficacy trial itself enrolled females aged 5 to 20 years.
What happened in the Rett trial?
LAVENDER randomized 187 participants; 184 had post-baseline efficacy assessments. The estimated change from baseline in the caregiver-rated behavior score was 3.1 points lower with trofinetide than placebo at 12 weeks. The clinician global improvement score was 0.3 points lower. Lower scores indicated improvement on these measures.
Is trofinetide approved for fragile X or brain injury?
Those conditions are not included in the U.S. label. An exploratory fragile X trial and an intravenous brain-injury trial used different populations and study regimens from the Rett program.
What are the main adverse effects?
Diarrhea and vomiting were more frequent with trofinetide in the Rett trial. The label also warns about weight loss and provides instructions for monitoring and managing severe symptoms.
Evidence
Evidence snapshot
The efficacy analysis included 184 participants. At 12 weeks, the estimated change in behavior score from baseline was 3.1 points lower than placebo; the clinician score was 0.3 points lower.
The higher-dose group met prespecified exploratory criteria in a short study.
A later analysis reported no significant group difference in global outcome; the registry listed 261 participants without posted results.
These rates compare trofinetide with placebo during the controlled trial.
Claims
Common claims vs evidence
| Claim | Human evidence | Mechanistic evidence | Verdict |
|---|---|---|---|
| Trofinetide has evidence for a Rett syndrome indication. | In LAVENDER, caregiver and clinician primary outcome ratings favored trofinetide over placebo after 12 weeks in females aged 5 to 20 years. | The label says how the drug produces its therapeutic effects in Rett syndrome is unknown. | U.S. approval covers Rett syndrome in adults and children aged 2 years and older. |
| The Rett approval also proves a treatment for fragile X syndrome. | A separate 28-day study in 72 adolescent and adult males found an exploratory signal at 70 mg per kg twice daily. It was not a confirmatory Rett trial and fragile X is not in the U.S. indication. | Fragile X results are preliminary and indication-specific. | |
| Brain injury studies justify using the Rett product for stroke or trauma. | A traumatic brain injury trial studied intravenous NNZ-2566. A later analysis reported no significant difference in global outcome; a separate stroke experiment treated rats, not people. | Neither source establishes an approved human use for these conditions. |
Bottom line
Main takeaway
DAYBUE and DAYBUE STIX are prescription treatments for Rett syndrome, not a cure or a general cognitive enhancer.
The controlled trial found group-level improvements alongside substantially more diarrhea and vomiting than placebo.
Compare the oral Rett and fragile X trials separately from the intravenous NNZ-2566 brain injury registration and rat experiment.
Identity
What it is
Trofinetide is a modified analog of glycine-proline-glutamate, a tripeptide related to IGF-1. NNZ-2566 is an earlier research code for the same compound.
DAYBUE is an oral solution and DAYBUE STIX is a powder that must be dissolved for oral solution. Their preparation instructions differ.
Use context
Routes, doses, and cycle patterns
The labeled Rett regimen and historical study regimens apply to different formulations and populations.
Human studies and product labels
DAYBUE and DAYBUE STIX U.S. label
- Purpose
- Rett syndrome in patients aged 2 years and older
- Context
- U.S. prescription label
- Route
- Oral or gastrostomy tube
- Amount
- For patients weighing at least 9 kg with no or mild renal impairment, 5,000 to 12,000 mg per dose according to the label's weight bands
- Frequency
- Twice daily
- Duration
- As prescribed and monitored
The label reduces doses for moderate renal impairment. For doses below 5,000 mg, it specifies DAYBUE oral solution and says not to use partial STIX packets. The products are not recommended in severe renal impairment; no dose is specified below 9 kg.
LAVENDER Rett phase 3
- Purpose
- Caregiver and clinician Rett outcome measures
- Context
- Study-reported human regimen
- Route
- Oral or gastrostomy tube
- Amount
- 6, 8, 10, or 12 g per dose according to study weight bands
- Frequency
- Twice daily
- Duration
- 12 weeks
The trial enrolled females aged 5 to 20 years and compared trofinetide with placebo.
Fragile X phase 2
- Purpose
- Safety and exploratory clinical assessments
- Context
- Study-reported human regimen
- Route
- Oral
- Amount
- 35 or 70 mg per kg per dose
- Frequency
- Twice daily
- Duration
- 28 days
The higher-dose group met prespecified exploratory criteria; this is not an approved fragile X regimen.
INTREPID traumatic brain injury trial
- Purpose
- Safety and effectiveness research after traumatic brain injury
- Context
- Registered investigational human regimen
- Route
- Intravenous
- Amount
- 20 mg per kg bolus followed by 1, 3, or 6 mg per kg per hour
- Frequency
- Continuous infusion after the bolus
- Duration
- 72 hours of infusion
This was an intravenous formulation, not the labeled oral products. A later analysis reported no significant group difference in global outcome; the registry did not post results.
Experimental rat stroke model
- Purpose
- Infarct area after induced focal ischemia
- Regimen
- No single reliable dose, schedule, or cycle showed up in the materials reviewed.
- Route
- Intravenous or oral experimental formulations
- Amount
- Intravenous 3 to 10 mg per kg per hour, or oral 30 to 60 mg per kg
- Frequency
- Four-hour infusion in the intravenous experiment
- Duration
- Outcome assessed on day 5 in the intravenous experiment
Investigators reported smaller infarct areas in the model; this does not establish a human stroke treatment.
What varies
- A clinician selects the labeled dose by weight and kidney function. The current label should be consulted for dose modifications and preparation.
- DAYBUE STIX powder must be dissolved according to its instructions. For moderate-renal-impairment doses below 5,000 mg, the label specifies oral solution and says not to use partial STIX packets.
- The label addresses hydration, diarrhea, vomiting, and weight loss during treatment.
Research
Research evidence
Controlled Rett and exploratory fragile X trials studied different populations and doses. A later analysis of the separate intravenous brain-injury trial reported no significant group difference in global outcome.
| Study / evidence area | Population | Design | Product context | Main outcome | Limitations | Weight |
|---|---|---|---|---|---|---|
| LAVENDER, Rett syndrome | 187 females aged 5 to 20 years randomized | Randomized, double-blind, placebo-controlled phase 3 trial | Weight-band oral or gastrostomy administration twice daily for 12 weeks | The estimated change in caregiver behavior score from baseline was 3.1 points lower than placebo; the clinician global improvement score was 0.3 points lower. | Three randomized participants had no post-baseline efficacy assessment; the controlled period was 12 weeks and did not directly enroll children under 5 or males | Controlled evidence for the Rett indication |
| Fragile X phase 2 | 72 adolescent and adult males with fragile X syndrome | Randomized, double-blind, placebo-controlled exploratory study | Oral trofinetide 35 or 70 mg per kg twice daily for 28 days | The 70 mg per kg group met prespecified exploratory criteria across selected measures | Short duration and exploratory analysis; not an approved indication | Preliminary controlled signal |
| INTREPID traumatic brain injury registry | 261 patients with traumatic brain injury | Randomized, double-blind, placebo-controlled phase 2 trial | Intravenous NNZ-2566 bolus followed by infusion | A later analysis reported no significant group difference in adverse events or global outcome; the registry has no posted results. | The published statement appears in a later analysis, not a full primary trial report. | Controlled trial with outcome context from a later analysis |
Cautions
Safety and unknowns
- In LAVENDER, diarrhea occurred in 80.6% of the trofinetide group and 19.1% of the placebo group; vomiting occurred in 26.9% and 9.6%, respectively.
- Adverse events led to withdrawal in 16 of 93 participants receiving trofinetide and 2 of 94 receiving placebo. Diarrhea was the most common reason for withdrawal in the trofinetide group.
- The U.S. label warns about diarrhea, dehydration, weight loss, and vomiting, and describes when treatment may need to be interrupted, reduced, or stopped.
- Aspiration and aspiration pneumonia have been reported after vomiting in patients treated with DAYBUE, according to the U.S. label.
- The label reduces the dosage for moderate renal impairment and does not recommend the products for severe renal impairment.
- The phase 3 controlled trial lasted 12 weeks. Its group results do not establish every person's response or all longer-term outcomes.
Product quality
Product identity and quality
DAYBUE oral solution and DAYBUE STIX powder are labeled prescription formulations with different preparation and handling instructions.
Formulation
Powder packets must be dissolved as directed, while oral solution is measured using an appropriate calibrated device.
Weight and kidney function
The labeled dose depends on weight and is modified for moderate renal impairment.
Investigational products
The historical intravenous formulation was a separate study preparation, not the approved oral product.
Mechanism
How it is proposed to work
Trofinetide is related to a fragment of IGF-1, but the label states that its therapeutic mechanism in Rett syndrome is unknown.
Experimental brain-injury and stroke models explore possible biological effects, but cannot establish how the drug works in people with Rett syndrome.
Details
Technical details
Sources
References
- 1.
DailyMed. DAYBUE and DAYBUE STIX U.S. prescribing information
Current U.S. label: Rett indication, product-specific dosing, renal precautions, and adverse reactions.
- 2.
PubMed. Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study
doi:10.1038/s41591-023-02398-1 PMID:37291210 NCT04181723
LAVENDER trial in females with Rett syndrome, including efficacy and adverse event results.
- 3.
PubMed. A randomized, placebo-controlled clinical study of trofinetide in fragile X syndrome
doi:10.1016/j.pediatrneurol.2020.04.019 PMID:32660869 NCT01894958
Exploratory 28-day study in adolescent and adult males with fragile X syndrome.
- 4.
ClinicalTrials.gov. INTREPID2566 traumatic brain injury trial registration
NCT00805818
Randomized intravenous traumatic brain injury trial; the registry has no posted results.
- 5.
PubMed Central. Continuous electroencephalography after moderate to severe traumatic brain injury
doi:10.1097/CCM.0000000000003639 PMID:30624278 NCT00805818
A later analysis reports no significant INTREPID group differences in adverse events or global outcome; it is not a full primary trial report.
- 6.
PubMed. NNZ-2566 in a rat model of acute focal stroke
doi:10.1016/j.jns.2008.12.003 PMID:19157421
Rat stroke model with intravenous and oral experimental formulations; not evidence of stroke treatment in people.