AHFS Class:

• Central Nervous System Agents, Miscellaneous 28:92

Generic Name(s):

• Trofinetide

Trofinetide is a synthetic analog of glycine-proline-glutamate, the N-terminal tripeptide of insulin-like growth factor-1 (IGF-1).3

Rett Syndrome

Trofinetide is used for the treatment of Rett syndrome in adults and pediatric patients ≥2 years of age.1 Trofinetide has been designated an orphan drug by FDA for treatment of Rett syndrome.2 Current consensus recommendations for the treatment of Rett syndrome focus on supportive care measures for progressive multisystem symptoms; the specific role for trofinetide has not yet been established.5

Clinical Experience

The current indication for trofinetide is based principally on the results of a 12-week, randomized, double-blind, phase 3, placebo-controlled study (LAVENDER).1,3,4 Female patients 5-20 years of age with classic or typical Rett syndrome (based on the Rett Syndrome Diagnostic Criteria with documented MECP2 gene mutation), a Rett Syndrome Clinical Severity scale rating of 10-36, and a Clinical Global Impression-Severity (CGI-S) score of ≥4 were eligible for enrollment.1,3 Patients were randomized to treatment with either oral trofinetide at a weight-based dosage or placebo twice daily for 12 weeks.1,3,4 The primary outcomes assessed were change from baseline in Rett Syndrome Behaviour Questionnaire (RSBQ) score at week 12 and Clinical Global Impression-Improvement (CGI-I) score at week 12.1

For the 187 patients enrolled, mean age was 10.9 years, 92% were white, and 74.3% had a baseline RSBQ score ≥35; 35.8, 11.2, and 49.2% had mild, moderate, and severe MECP2 gene mutations.4 The mean baseline CGI-S score was 4.9.4 At 12 weeks, least squares mean change from baseline in RSBQ score was -4.9 and -1.7 in the trofinetide and placebo groups, respectively, for a treatment difference of -3.2.1 At 12 weeks, mean CGI-I score was 3.5 and 3.8 in the trofinetide and placebo groups, respectively, with a treatment difference of -0.3.1 Based on CGI-I scores, 13 and 24.7% of patients receiving trofinetide were much or minimally improved, respectively; 61% of trofinetide-treated patients reported no change.1 In the placebo group, 4.7 and 10.5% of patients were much or minimally improved, respectively, and 81.4% of patients had no change.1

Clinical Perspective

Rett syndrome is a rare, progressive, neurodevelopmental genetic disorder that presents in early childhood; it is characterized by multisystem symptoms that evolve over time.5 Because of this multisystem involvement, treatment is varied and focuses on the specific symptoms present, which may include seizures, ataxia, abnormal movements, urine retention, GI dysmotility, and feeding difficulties.5 Trofinetide is the first treatment approved by FDA for Rett Syndrome; the specific place in therapy for this agent remains to be established.5,6

General

Patient Monitoring

• Monitor for significant weight loss.1
• Monitor for severe diarrhea and/or dehydration.1

Other General Considerations

• Because trofinetide can cause diarrhea, advise patients to discontinue laxatives before starting trofinetide.1

Administration

Trofinetide is administered orally.1 It is available as a 200 mg/mL oral solution.1 Administer trofinetide with or without food.1

Trofinetide may be administered through a gastrostomy (G) tube.1 Doses of trofinetide that are administered through a gastrojejunal (GJ) tube must be given through the G-port.1

The manufacturer recommends obtaining a calibrated measuring device (e.g., oral syringe, oral dosing cup) from the pharmacy for accurate dosing and administration of the prescribed dose.1

If a dose of trofinetide is missed, skip the missed dose and take the next regularly scheduled dose.1 If a dose of trofinetide is vomited, do not take an additional dose.1

Store at 2—8°C; do not freeze.1 Discard any remaining trofinetide solution 14 days after opening the bottle.1

Dosage

Adults

Rett Syndrome

For the treatment of Rett syndrome in adults, the recommended dosage of trofinetide is weight-based, as shown in Table 1; trofinetide is given orally twice daily, in the morning and evening.1

Pediatric Patients

Rett Syndrome

For the treatment of Rett syndrome in pediatric patients 2 years of age and older, the recommended dosage of trofinetide is weight-based, as shown in Table 1; trofinetide is given orally twice daily, in the morning and evening.1

Dosage Modification for Toxicity

Dosage interruption, reduction, or discontinuation of trofinetide is recommended if severe diarrhea or significant weight loss occurs, or if dehydration is suspected.1

Special Populations

Hepatic Impairment

The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1

Renal Impairment

The manufacturer makes no specific dosage recommendations for patients with renal impairment but states that use of trofinetide is not recommended in patients with moderate or severe renal impairment.1

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.1

Contraindications

• None.1

Warnings/Precautions

Diarrhea

In clinical studies of trofinetide, 85% of patients who received trofinetide developed diarrhea.1 Persistent or recurrent diarrhea occurred in 49% of patients despite initiation of antidiarrheals or trofinetide dosage interruptions or reductions.1 In 96% of cases, diarrhea was mild to moderate in severity.1 In the primary efficacy study, 51% of patients who received trofinetide were treated with antidiarrheal medication.1

Advise patients to discontinue laxatives before initiation of trofinetide.1 Patients should notify their healthcare provider if diarrhea develops during treatment and should consider starting antidiarrheals; hydration status should be monitored and oral fluid intake increased if needed.1 If severe diarrhea or suspected dehydration occurs, dosage interruption, reduction, or discontinuation of trofinetide is recommended.1

Weight Loss

In the primary efficacy study for trofinetide, weight loss of more than 7% from baseline occurred in 12% of patients who received trofinetide compared to 4% of patients receiving placebo.1 Weight loss was the reason for treatment discontination in 2.2% of patients in long-term studies of trofinetide.1

Monitor patient weight during treatment.1 If significant weight loss occurs, dosage interruption, reduction, or discontinuation of trofinetide is recommended.1

Specific Populations

Pregnancy

There are no data in pregnant women to adequately assess the developmental risks associated with trofinetide use during pregnancy.1 In animal studies, no adverse developmental outcomes were observed following oral administration of trofinetide at doses resulting in plasma exposures lower than those used clinically in humans.1

Lactation

It is not known whether trofinetide or its metabolites are present in human milk.1 The effects of trofinetide on the breastfed infant and the effects on milk production are not known.1 Consider the developmental and health benefits of breastfeeding in addition to the mother's clinical need for the drug, the potential for adverse effects on the breastfed infant from the drug, and the potential for adverse effects on the infant from the untreated maternal condition.1

Pediatric Use

Safety and efficacy of trofinetide for the treatment of Rett syndrome have been established in pediatric patients ≥2 years of age.1 A 12-week, randomized, double-blind, placebo-controlled study enrolling 108 pediatric patients 5 to <12 years of age and 47 pediatric patients 12 to <17 years of age established the safety and efficacy of trofinetide for the treatment of Rett syndrome in pediatric patients ≥5 years of age.1 Safety and efficacy of trofinetide for the treatment of Rett syndrome in patients 2-4 years of age is supported by evidence from the aforementioned study and a 12-week pharmacokinetic and safety study in 13 patients 2-4 years of age .1

Safety and efficacy of trofinetide in pediatric patients <2 years of age have not been established.1

Geriatric Use

No patients ≥65 years of age were included in clinical studies of trofinetide to assess whether there are differences in response compared to younger adult patients.1 Because trofinetide primarily undergoes renal elimination and there is an increased likelihood of renal impairment in geriatric patients, renal function monitoring may be useful.1

Hepatic Impairment

The pharmacokinetics of trofinetide in hepatic impairment have not been evaluated; however, since hepatic metabolism is not a significant route of trofinetide elimination, hepatic impairment is not expected to impact trofinetide exposure.1

Renal Impairment

The pharmacokinetics of trofinetide have not been evaluated in patients with renal impairment.1 Because trofinetide primarily undergoes renal elimination, it is not recommended in patients with moderate or severe renal impairment.1

Common Adverse Effects

Adverse reactions occurring in ≥10% of patients receiving trofinetide (with a ≥2% higher incidence than placebo) included diarrhea and vomiting.1

Trofinetide weakly inhibits cytochrome P450 (CYP) isoenzyme 3A4 in vitro.1 Trofinetide is not expected to inhibit CYP1A2, 2C8, 2C9, 2C19, or 2D6 at therapeutic concentrations.1 Whether trofinetide inhibits CYP2B6 is inconclusive based on in vitro data.1 In vitro, trofinetide is an inhibitor of uridine diphosphate-glucuronosyltransferase (UGT) enzymes UGT1A9, 2B7, and 2B15.1 Trofinetide is not an inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, multidrug and toxin extrusion (MATE) 1, or MATE2-K, but it is an inhibitor of organic anion transporter polypeptide (OATP) 1B1 and OATP1B3 in vitro.1

In vitro, trofinetide is not a substrate of CYP isoenzymes.1 Trofinetide is not a substrate of the major drug transporters or UGT.1 Because trofinetide is not a substrate of CYP isoenzymes, major drug transporters, or UGT, the concomitant use of inducers or inhibitors of these systems does not have a significant impact on trofinetide exposure.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Concomitant use of trofinetide with a CYP3A4 substrate may increase plasma exposures of the CYP3A4 substrate.1 Monitor patients closely when trofinetide is used concomitantly with orally administered sensitive CYP3A4 substrates that can cause serious toxicities when there are minor changes in substrate plasma concentrations.1

Concomitant use of trofinetide with the orally administered sensitive CYP3A4 substrate midazolam is expected to increase the area under the serum concentration-time curve (AUC) of midazolam by approximately 1.33-fold.1

Drugs Affected by Transport Proteins

Concomitant use of trofinetide with a substrate of OATP1B1 or OATP1B3 may increase plasma concentrations of the substrate.1 Avoid concomitant use of trofinetide with substrates of OATP1B1 or OATP1B3 for which small changes in the plasma concentrations of the substrate could result in serious toxicities.1

Description

Trofinetide is a synthetic analog of glycine-proline-glutamate, the N-terminal tripeptide of insulin-like growth factor-1 (IGF-1).3 It is not known how trofinetide exerts its therapeutic effects in patients with Rett syndrome.1

Trofinetide exposure is dose-proportional, with little to no accumulation observed following repeated dosing.1 Following oral administration of trofinetide, peak plasma concentrations of trofinetide are achieved within 2—3 hours.1 A mass balance study indicates that at least 84% of the dose is absorbed following oral administration of 12,000 mg of trofinetide.1 Administration of trofinetide with a high-fat meal had no impact on the total exposure of trofinetide but peak plasma concentrations of trofinetide were reduced by approximately 20%.1 Trofinetide is less than 6% bound to human plasma proteins.1 Trofinetide does not undergo significant metabolism by cytochrome P450 (CYP) isoenzymes and is not significantly eliminated via hepatic metabolism.1 Trofinetide is primarily excreted as unchanged drug in the urine (approximately 80%) and is excreted minimally in the feces.1 The elimination half-life of trofinetide is approximately 1.5 hours.1 At the recommended dosage, the systemic exposure of trofinetide observed in pediatric patients 2—4 years of age is similar to that observed in children ≥4 years of age and adults.1

Advice to Patients

• Advise caregivers and patients that trofinetide may be taken with or without food.1
• Advise caregivers and patients that a calibrated measuring device, such as an oral syringe or oral dosing cup, should be obtained from the pharmacy to measure and administer doses accurately.1
• Instruct caregivers and patients to refrigerate trofinetide oral solution and to discard any remaining trofinetide 14 days after first opening the bottle.1
• Advise caregivers and patients that because trofinetide can cause diarrhea, laxatives should be stopped before starting trofinetide.1 Instruct caregivers and patients to inform their healthcare provider if diarrhea occurs and to consider starting antidiarrheals.1 Hydration status should be monitored and oral fluid intake increased if necessary.1
• Inform the caregiver or patient that trofinetide may cause weight loss; patients should notify their healthcare provider if weight loss occurs.1
• Advise patients and caregivers that trofinetide may cause vomiting; if vomiting occurs after administration, an additional dose should not be taken and the next dose should be administered at the normal scheduled time.1
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1
• Advise women to inform their clinician if they are or plan to become pregnant or plan to breastfeed.1
• Inform patients of other important precautionary information.1 .

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

1. Acadia Pharmaceuticals Inc. Daybue^® (trofinetide) ORAL solution prescribing information. 2023 Mar.

2. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2023 Dec 2. [Web]

3. Neul JL, Percy AK, Benke TA et al. Design and outcome measures of LAVENDER, a phase 3 study of trofinetide for Rett syndrome. Contemp Clin Trials . 2022 Mar;114:106704.

4. Neul J, Percy A, Benke T, et al. Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study. Nat Med . 2023;29:1468-1475.

5. Fu C, Armstrong D, Marsh E, et al. Consensus guidelines on managing Rett syndrome across the lifespan. BMJ Paediatrics Open . 2020;4:e000717.

6. US Food and Drug Administration. FDA approves first treatment for Rett syndrome. From FDA website. Accessed 2023 Dec 14. [Web]

7. Acadia Pharmaceuticals Inc. Acadia Connect for Daybue^® from healthcare providers website. Accessed 2023 Dec 11. [Web]