ModifiedCentenePolicy CP.PHAR.600

Clinical Policy: Trofinetide (Daybue, Daybue Stix)

Defines medical necessity criteria, dosing limits, and authorization requirements for trofinetide (Daybue and Daybue Stix) for treatment of Rett syndrome for Centene-affiliated health plans and applicable lines of business.

Policy Summary

PayerCentene

PolicyClinical Policy: Trofinetide (Daybue, Daybue Stix)

Policy CodePolicy CP.PHAR.600

Change TypeCriteria and operational updates (new formulation, CGI-S baseline, 12‑month approvals)

Effective DateMar 10, 2023

Next Review DateN/A

Key ActionSubmit prior authorization with documentation of baseline CGI-S (≥4) and objective response measures (RSBQ or CGI-I improvements) to support initial and continued coverage.

SourceLink

POLICY UPDATE CHANGES

Added Daybue Stix formulation and revised approval durations to 12 months.

Initial criteria updated to require CGI-S ≥ 4 (moderate severity) instead of CGI-I.

For continued therapy, added specific response documentation requirements using RSBQ or CGI-I score improvements.

Added ICHRA line of business.

Added new Daybue Stix formulation and revised approval durations to 12 months.

Updated Initial Approval Criteria requirement from CGI-I to CGI-S with minimum score of 4 to determine moderate disease severity.

For Continued Therapy, added requirement for documentation of response to therapy via specific score improvements on the RSBQ or CGI-I.

Policy updated per FDA labeling and clinical trial inclusion/exclusion criteria after FDA approval.

≥ 2 yrsMinimum covered patient age

≥ 9 kg

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Coverage Criteria

inv-01: Initial Therapy — Rett Syndrome

Covered when ALL of the following are met:

Initial RTT criteria: 1) Diagnosis of classic/typical Rett syndrome AND MECP2 gene mutation confirmed by genetic testing; 2) Prescribed by or in consultation with a pediatric neurologist, geneticist, or developmental pediatrician; 3) Age ≥ 2 years; 4) Weight ≥ 9 kg; 5) No seizures or a stable seizure pattern (no changes in seizure frequency, antiepileptic drugs, or behavioral treatments); 6) Baseline assessment documented by either a Rett Syndrome Behaviour Questionnaire (RSBQ) or a Clinical Global Impression–Severity (CGI-S) with CGI-S ≥ 4; 7) At time of request member does not have Long QT syndrome or baseline QTcF > 450 msec AND is not currently treated with insulin; 8) Requested dose does not exceed the applicable weight‑based maximum for Daybue oral solution or Daybue Stix packets as specified in dosing tables (maximum 24,000 mg/day).

Dose limits: Daybue oral solution and Daybue Stix packet‑equivalents listed by weight ranges up to maximum 24,000 mg/day.

inv-02: Continued Therapy — Rett Syndrome

Covered when ALL of the following are met:

Continued therapy criteria: 1) Member currently receiving medication via Centene benefit or member has previously met initial approval criteria OR member is receiving medication and is in continuity of care per applicable state/product; 2) Member is responding positively to therapy as evidenced by EITHER (a) ≥ 3‑point reduction in overall RSBQ total score from baseline, OR (b) if on therapy ≤ 6 months a CGI‑I score between 1–4, OR (c) if on therapy > 6 months a CGI‑I score between 1–3; 3) If request is for a dose increase, the new dose does not exceed the same weight‑based maximums as for initial approval (Daybue oral solution or Daybue Stix packet equivalents).

Response metrics tied to RSBQ and CGI‑I depending on treatment duration; dosing limits mirror initial approval tables.

inv-03: Initial and Continued Therapy (updated elements)

Key criteria updates referenced in this section

Initial Approval Criteria (summary of updated items): Initial approval criteria updated to align with FDA labeling and clinical trial inclusion/exclusion criteria; baseline severity requirement changed to CGI‑S with a minimum score of 4 to denote moderate disease severity.CGI-S >= 4

Full initial criteria set is documented elsewhere in the policy.

Continued Therapy Criteria (summary of updated items): Continued therapy now requires documented response to therapy using specific score improvements on the RSBQ or CGI‑I as the objective measures of benefit.RSBQ or CGI‑I specified improvements

Exact numeric thresholds for response (e.g., ≥3‑point RSBQ reduction; CGI‑I ranges by treatment duration) are specified in the continued therapy section.

Requests for use of trofinetide for non‑FDA‑approved indications that are not specifically addressed in this policy are not authorized unless the provider submits sufficient documentation of efficacy and safety in accordance with the referenced off‑label use policies (CP.CPA.09 for Commercial, HIM.PA.154 for Health Insurance Marketplace/ICHRA, and CP.PMN.53 for Medicaid) or applicable evidence of coverage documents.

There are no additional explicit exclusion conditions listed in this portion of the policy beyond those described elsewhere; operational and clinical updates are recorded in the policy history and reference section.

Use of trofinetide for indications that are not FDA‑approved and are not specifically addressed in this policy will be considered not authorized unless the request includes the required supporting documentation per the referenced off‑label use policies or evidence of coverage documents.

This section does not present explicit statements labeling services as 'not medically necessary.' Determinations about medical necessity are governed by the full policy, applicable statutes, and benefit‑specific coverage rules; policy updates and rationale are summarized in the references and change history.

Initial Therapy Criteria

inv-24: Initial therapy — Initial coverage requirements for RTT.

Initial coverage requirements for RTT

Initial therapy nodes: See Initial Therapy — must meet all: diagnosis of classic/typical RTT with MECP2 mutation; prescribed by or in consultation with pediatric neurologist, geneticist, or developmental pediatrician; age ≥ 2 years; weight ≥ 9 kg; no seizures or stable seizure pattern; baseline assessment with RSBQ or CGI‑S ≥ 4; absence of Long QT syndrome/ QTcF > 450 msec and not on insulin; dosing within specified weight‑based limits up to 24,000 mg/day.

Dose details and weight bands for Daybue oral solution and Daybue Stix packets are enumerated in the dosing tables.

inv-25: Initial Therapy — Initial approval aligned to FDA labeling and trial criteria.

Initial approval aligned to FDA labeling and trial criteria

Initial therapy requirement: Requires documentation per FDA labeling and clinical trial inclusion/exclusion criteria; baseline CGI‑S score of at least 4 is required to document moderate disease severity for initiation.

Continuation / Continued Therapy Criteria

inv-26: Continued therapy — Continued therapy criteria for Rett syndrome.

Continued therapy criteria for Rett syndrome

Continued therapy nodes: See Continued Therapy — must meet all: member meets continuity/previous approval conditions; member is responding to therapy per RSBQ or CGI‑I thresholds; dose remains within weight‑based maximums if increased.

Response measures: ≥3‑point RSBQ reduction or CGI‑I ranges depending on duration; dosing limits same as initial approval.

inv-27: Continued Therapy — Continuation requires documented clinical benefit.

Continuation requires documented clinical benefit

Continued therapy documentation: Documentation of response to therapy is required for continuation and must include either a ≥ 3‑point reduction in RSBQ total score from baseline or a CGI‑I score within the specified range (1–4 if ≤ 6 months on therapy; 1–3 if > 6 months on therapy).RSBQ >= 3‑point reduction OR CGI‑I 1–4 (≤6 months) OR CGI‑I 1–3 (>6 months)

Coding and Outcome Measures

inv-08: RSBQ improvement — Response threshold

RSBQ response threshold≥ 3-point reduction in overall RSBQ total score from baseline

Context of useUsed as one of the acceptable objective measures to document positive response for continued therapy

Source sectionContinued Therapy response criteria

inv-09: CGI-I for ≤6 months therapy

CGI-I threshold (≤ 6 months)CGI-I score between 1-4 for members receiving Daybue or Daybue Stix for 6 months or less

PurposeAccepted clinician-rated improvement metric for early treatment duration to document continued benefit

Provider Documentation & Authorization Actions

Prior Authorization

Prior Authorization Required — Initial Criteria

Prior authorization — Initial criteria: Prior authorization requires documentation that all initial approval criteria for Rett syndrome are met. Provider must submit clinical documentation (office chart notes, genetic testing results, baseline assessments, seizure history, medications, weight, and relevant labs) supporting that the member meets all applicable criteria before approval.

Diagnosis of classic/typical Rett syndrome with MECP2 mutation confirmed by genetic testing
Prescribed by or in consultation with a pediatric neurologist, geneticist, or developmental pediatrician
Age ≥ 2 years and weight ≥ 9 kg
No seizures or stable seizure pattern (no recent changes in seizure frequency, antiepileptic drugs, or behavioral treatments)
Baseline assessment score documented (RSBQ or CGI-S ≥ 4)
No long QT syndrome or QTcF > 450 msec; not currently treated with insulin
Dosing does not exceed weight-based limits per Daybue formulation labeling

Step Therapy / Routing

When request falls outside listed indications or recent label changes	Action / Refer to policy (by line of business)
If the drug has undergone a label change within the last 6 months (new indication, age expansion, or new dosing regimen) that is not yet reflected in this policy
If drug IS on formulary/PDL: follow the no coverage criteria policy for the applicable line of business — CP.CPA.190 (Commercial), HIM.PA.33 (Health Insurance Marketplace/ICHRA), CP.PMN.255 (Medicaid). If drug NOT on formulary/PDL: follow the non‑formulary policy for the applicable line of business — CP.CPA.190 (Commercial), HIM.PA.103 (Health Insurance Marketplace/ICHRA), CP.PMN.16 (Medicaid).

When request falls outside listed indications or recent label changes

Action / Refer to policy (by line of business)

If the drug has undergone a label change within the last 6 months (new indication, age expansion, or new dosing regimen) that is not yet reflected in this policy

If drug IS on formulary/PDL: follow the no coverage criteria policy for the applicable line of business — CP.CPA.190 (Commercial), HIM.PA.33 (Health Insurance Marketplace/ICHRA), CP.PMN.255 (Medicaid). If drug NOT on formulary/PDL: follow the non‑formulary policy for the applicable line of business — CP.CPA.190 (Commercial), HIM.PA.103 (Health Insurance Marketplace/ICHRA), CP.PMN.16 (Medicaid).

Quantity Limits and Dosing

inv-29: Trofinetide (Daybue / Daybue Stix) — Maximum

Maximum daily dose24,000 mg per day (maximum dose for Trofinetide — Daybue oral solution or Daybue Stix packet-equivalents)

Dose by weight examplesWeight ≥50 kg: 24,000 mg/day (12,000 mg twice daily) — Daybue oral solution or four 6,000 mg Daybue Stix packets

Maximum stated inDosage and Administration; Initial Approval dosing tables

Definitions and Clinical Scales

inv-21: Rett syndrome (RTT) — definition and core features

DefinitionRett syndrome (RTT) is a rare neurodevelopmental disorder, most commonly affecting females and frequently associated with MECP2 gene mutations

Core diagnostic featuresRegression of purposeful hand skills and spoken language, gait abnormalities, and stereotyped hand movements (e.g., hand wringing)

Additional features/supportive signsBreathing disturbances, bruxism, abnormal muscle tone, scoliosis, growth retardation, seizures, and possible need for gastrostomy

inv-22: CGI-S / CGI-I — explanation of Clinical Global Impression scales

CGI-S (Severity)Clinical Global Impression–Severity (CGI-S) is a clinician-rated scale assessing illness severity; policy requires CGI-S ≥ 4 at baseline for initiation

CGI-I (Improvement)

Background

Rett syndrome (RTT) is a rare neurodevelopmental disorder that primarily affects females and is commonly associated with pathogenic variants in the MECP2 gene. Trofinetide (Daybue and the Daybue Stix formulation) is an IGF‑1 analog approved by the FDA for treatment of RTT in patients aged 2 years and older, and may be administered orally or via gastrostomy/gastrojejunal tube. The policy aligns initial approval criteria with FDA labeling and clinical trial inclusion/exclusion standards, which include confirmation of RTT diagnosis and MECP2 mutation status.

Policy Summary

PayerCentene

PolicyClinical Policy: Trofinetide (Daybue, Daybue Stix)

Policy CodePolicy CP.PHAR.600

Change TypeCriteria and operational updates (new formulation, CGI-S baseline, 12‑month approvals)

Effective DateMar 10, 2023

Next Review DateN/A

Key ActionSubmit prior authorization with documentation of baseline CGI-S (≥4) and objective response measures (RSBQ or CGI-I improvements) to support initial and continued coverage.

SourceLink

On This Page

Denial Risk

Non‑FDA Indications — Off‑Label Requests

Non-FDA indications: Requests for indications not FDA-approved and not specifically addressed in this policy will not be authorized unless sufficient documentation of efficacy and safety is provided per applicable off‑label use policies.

Refer to off-label use policies: CP.CPA.09 (Commercial), HIM.PA.154 (ICHRA/Marketplace), CP.PMN.53 (Medicaid) for required supporting evidence
If indication is not listed under section III and recent label change does not apply, follow off-label routing

Documentation Required

Required Documentation to Support Prior Authorization

Documentation required: Provider must submit office chart notes, genetic testing results, baseline assessment scores (RSBQ or CGI‑S), seizure history, current medication list, weight, and any relevant laboratory results (including ECG for QTcF) to support that the member meets all approval criteria.

Office chart notes and consultation documentation
MECP2 genetic testing results
Baseline RSBQ or CGI‑S score (see required clinical scales)
ECG showing QTcF if applicable; medication list including insulin status
Weight documentation to confirm dosing tier

Documentation Required

Required Clinical Scales and Response Measures

Required clinical scales and scores: Document baseline Clinical Global Impression–Severity (CGI‑S) score with minimum ≥ 4 to meet moderate disease threshold for initial approval, or provide baseline Rett Syndrome Behavior Questionnaire (RSBQ) score. For continuation of therapy, document response to treatment using prespecified improvements on the RSBQ or Clinical Global Impression–Improvement (CGI‑I) as outlined in policy.

Baseline CGI‑S score ≥ 4 (required for initial approval if CGI‑S used)
Alternatively, baseline RSBQ documented
For continuation: documented response by specified RSBQ improvement or CGI‑I indicating clinical improvement

Note

Policy Routing for Atypical or Newly Labeled Uses

Policy routing for atypical requests: If the requested use is outside this policy due to a recent FDA label change or is not listed, follow Centene routing for no-coverage, non‑formulary, or off‑label use per the member's line of business.

If label changed within last 6 months and policy not updated, refer to no-coverage criteria or non-formulary policies as applicable (see policy codes below)
If use not listed and criterion for label change does not apply, refer to off‑label use policy for the appropriate line of business