Trofinetide (Acadia’s Daybue) FDA-Approved for Rett syndrome

Generic Name: Trofinetide

Brand Name: Daybue

Manufacturer: Acadia Pharmaceuticals

FDA Approval Date: 10th March 2023

Indications: Rett Syndrome

Trofinetide was approved by the U.S. Food and Drug Administration (FDA) on 10th March 2023, making it the first-ever treatment for Rett syndrome, a rare genetic neurodevelopmental condition that shares some traits with autism [Ref]

What is Rett syndrome?

Rett syndrome is a rare genetic disorder that affects the development of the brain, resulting in severe mental and physical disabilities.

The clinical features of Rett syndrome can vary from person to person, but some of the most common features include:

• Developmental regression:

Children with Rett syndrome typically develop normally for the first few months of life, but then begin to lose previously acquired skills such as the ability to crawl, walk, or use their hands.

• Communication difficulties:

Many children with Rett syndrome have severe communication difficulties, including the inability to speak or communicate effectively with others.

• Repetitive hand movements:

People with Rett syndrome often exhibit repetitive hand movements such as wringing, clapping, or tapping.

• Breathing problems:

Rett syndrome can cause breathing difficulties, including hyperventilation, breath-holding, and irregular breathing patterns.

• Seizures:

Many people with Rett syndrome experience seizures, which can be difficult to control with medication.

• Cognitive impairment:

People with Rett syndrome typically have intellectual disabilities and may have difficulty learning new information or performing tasks that require problem-solving or reasoning skills.

• Social withdrawal:

Many people with Rett syndrome exhibit social withdrawal and avoid interacting with others, although they may be affectionate with family members.

• Scoliosis:

Rett syndrome can cause scoliosis, a curvature of the spine, which can lead to breathing difficulties and other complications.

It’s important to note that the severity and range of symptoms can vary widely among individuals with Rett syndrome, and some people may have milder or more severe symptoms than others.

How is Rett syndrome treated?

There is currently no cure for Rett syndrome, and treatment focuses on managing the symptoms and improving the quality of life for individuals with the condition.

Some of the medications and therapies that may be used to treat Rett syndrome include:

• Anticonvulsants:

These medications are used to control seizures, which is a common symptom of Rett syndrome.

• Gastrointestinal medications:

Rett syndrome can cause gastrointestinal problems such as constipation, reflux, and swallowing difficulties.

Medications such as laxatives, antacids, and prokinetics may be used to manage these symptoms.

• Behavioral therapies:

Behavioral therapies such as speech therapy, occupational therapy, and physical therapy can help improve communication skills, motor function, and daily living skills.

• Communication aids:

Individuals with Rett syndrome may benefit from using communication aids such as sign language, communication boards, or electronic devices that allow them to communicate with others.

• Nutritional support:

Some individuals with Rett syndrome may require nutritional support, such as a feeding tube, to ensure that they are receiving adequate nutrition.

• Psychotropic medications:

In some cases, medications such as antidepressants, antipsychotics, or mood stabilizers may be used to treat behavioral or emotional symptoms such as anxiety, depression, or aggression.

Trofinetide for Rett Syndrome: Indications:

Trofinetide (DAYBUE) has been approved for the treatment of Rett syndrome in both adults and children who are at least 2 years old.

It is not a cure for Rett syndrome but may help alleviate the symptoms of Rett syndrome. It may improve motor function, communication skills, and other aspects of daily life for people with Rett syndrome.

Dose of Trofinetide (DAYBUE) for the treatment of Rett Syndrome:

Note: DAYBUE should not be used with other medications. It can be taken with or without food. It is important to use a calibrated measuring device, such as an oral syringe or dosing cup, to ensure accurate measurement and delivery of the prescribed dose. Unused DAYBUE oral solution should be discarded after 14 days of first opening the bottle.

• If a dose is missed . . .

If a dose of DAYBUE is missed, it should not be doubled to make up for it. Patients should take the next scheduled dose at the appropriate time to avoid unintended side effects.

If vomiting occurs after taking DAYBUE, patients should continue with the regular dosing schedule and not take an extra dose to avoid the risk of an overdose.

Patients should follow up with their healthcare provider if vomiting persists or if they have concerns about their response to the medication.

• Dosage modification for weight loss or diarrhea:

Patients should discontinue the use of any laxatives before starting treatment with DAYBUE. A combination of laxatives and DAYBUE can cause diarrhea, leading to dehydration and weight loss.

Severe diarrhea, dehydration, or significant weight loss may require interruption or reduction of DAYBUE dosage or discontinuation of treatment.

Patients should inform their healthcare provider if they experience any changes in bowel habits while taking DAYBUE to adjust the treatment plan.

Contraindications to Trofinetide (DAYBUE):

There is no contraindication given in the FDA prescribing information

Warning & Precaution:

• Diarrhea:

85% of patients in Study 1 and long-term studies experienced diarrhea as a side effect of DAYBUE.

If diarrhea occurs, patients should discontinue laxatives and consider using antidiarrheal medication.

Severe diarrhea or suspected dehydration may require interruption, dosage reduction, or discontinuation of DAYBUE treatment.

• Weight Loss:

12% of patients in Study 1 experienced weight loss of greater than 7% from baseline compared to 4% of patients who received a placebo.

It is recommended to monitor weight and interrupt, reduce dosage, or discontinue DAYBUE if significant weight loss occurs.

Side effects caused by Trofinetide (Daybue):

Side effects reported in Clinical Trials:

• Adverse reaction rates cannot be directly compared between drugs or reflect rates observed in practice
• 260 patients with Rett syndrome, ages 2 to 40, were treated with DAYBUE in controlled and uncontrolled trials
• 109 patients were treated for more than 6 months
• 69 patients were treated for more than 1 year
• 4 patients were treated for more than 2 years
• However, it is important to note that adverse reaction rates cannot be compared between different drugs or reflect rates observed in actual practice.

Summary of side effects of Trofinetide:

The safety of DAYBUE was evaluated in two studies in patients with Rett syndrome.

Study 1 included adult and pediatric patients aged 5 years and older and showed that 19% of DAYBUE patients experienced adverse reactions leading to discontinuation, with diarrhea being the most common.

The open-label study included pediatric patients aged 2 to 4 years and reported similar adverse reactions to those in Study 1.

Trofinetide Drug Interaction:

Using Trofinetide in specific populations:

Mechanism of action of Trofinetide (Daybue):

The way Trofinetide works to help patients with Rett syndrome is not yet understood.

However, at the highest recommended dose for healthy adults, DAYBUE does not have any significant effect on the QT interval, which measures the electrical activity of the heart.

Trofinetide Pharmacokinetics

Overall, Trofinetide exhibits linear pharmacokinetics with no dose-dependent effect. It is well-absorbed following oral administration with a Tmax of 2-3 hours.

Co-administration with a high-fat meal does not affect total exposure but reduces peak plasma concentration.

Trofinetide has an apparent volume of distribution of approximately 80 L, and protein binding in human plasma is less than 6%.

It has an elimination half-life of about 1.5 hours and is primarily excreted unchanged in the urine, with minor excretion in feces.

Trofinetide is not significantly metabolized by CYP450 enzymes, and hepatic metabolism is not a significant route of elimination.

How to store and handle Trofinetide?

The medication DAYBUE (Trofinetide) comes in a 500 mL bottle with a child-resistant cap and contains 450 mL of oral solution.

It is a pink-to-red, strawberry-flavored solution. It should be stored upright in the refrigerator at 2°C to 8°C (36°F to 46°F) and should not be frozen. After opening the bottle, the unused solution should be discarded after 14 days.

Patient Counseling:

The patient or caregiver should read the Patient Information Leaflet provided by the FDA. DAYBUE can be taken orally or through a gastrostomy tube, but a proper measuring device, like an oral syringe, should be used to ensure the correct dose is administered.

Unused DAYBUE should be discarded within 14 days of opening the bottle. DAYBUE can cause diarrhea, vomiting, and weight loss.

If these symptoms occur, the healthcare provider should be notified. The oral solution of DAYBUE should be stored upright in the refrigerator, but not frozen.