CurrentBlue Cross Blue Shield - IowaPolicy 05.01.39

Cystic Fibrosis (CF) CFTR Modulator Therapy Coverage — Alyftrek, Kalydeco, Orkambi, Symdeko, Trikafta

Defines prior authorization, coverage criteria, and continuation requirements for CFTR modulator agents (Alyftrek, Kalydeco, Orkambi, Symdeko, Trikafta) for Wellmark Blue Cross and Blue Shield members; applies to prescribers and pharmacists managing CF therapy.

Policy Summary

PayerBlue Cross Blue Shield - Iowa

PolicyCystic Fibrosis (CF) CFTR Modulator Therapy Coverage — Alyftrek, Kalydeco, Orkambi, Symdeko, Trikafta

Policy CodePolicy 05.01.39

Change TypeRoutine review — no material changes

Effective DateMay 22, 2025

Next Review DateApr 1, 2026

Key ActionSubmit prior authorization with genetic test report and records demonstrating eligibility and clinical response.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

5Products covered

6 moInitial approval

12 moContinuation approval

≥20Appendix lists

NoneCPT codes listed

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

Coverage Criteria for CFTR Modulators

Alyftrek Initial Therapy

Covered when ALL of the following are met for Alyftrek (initial):

Alyftrek initial criteria: Genetic testing was conducted to detect a mutation in the CFTR gene; The member has one of the mutations in the CFTR gene listed in Appendix A; The member is at least 6 years of age; Alyftrek will not be used in combination with Kalydeco, Orkambi, Symdeko, or Trikafta

Kalydeco, Orkambi, Symdeko Initial Therapy

Covered when ALL of the following are met for Kalydeco, Orkambi, and Symdeko (initial):

Kalydeco initial criteria: Genetic testing was conducted to detect a mutation in the CFTR gene; The member has one of the mutations in the CFTR gene listed in Appendix B; The member is at least 1 month of age; Kalydeco will not be used in combination with Alyftrek, Orkambi, Symdeko, or Trikafta

Orkambi initial criteria: The member is at least 1 year of age; Genetic testing was conducted to detect a mutation in the CFTR gene; The member is positive for the F508del mutation on both alleles of the CFTR gene; Orkambi will not be used in combination with Alyftrek, Kalydeco, Symdeko, or Trikafta

Symdeko initial criteria: Genetic testing was conducted to detect a mutation in the CFTR gene; The member has one of the mutations in the CFTR gene listed in Appendix C or is homozygous for F508del; The member is at least 6 years of age; Symdeko will not be used in combination with Alyftrek, Kalydeco, Orkambi, or Trikafta

Trikafta Initial Therapy

Covered when ALL of the following are met for Trikafta (initial):

Trikafta initial criteria: The member is at least 2 years of age; Genetic testing was conducted to detect a mutation in the CFTR gene; The member has at least one mutation of the CFTR gene listed in Appendix D; Trikafta will not be used in combination with Alyftrek, Kalydeco, Orkambi, or Symdeko

Continuation Therapy

Continuation of therapy covered when ALL initial criteria are met AND there is clinically meaningful response demonstrated by ANY of the following:

Continuation criteria: Member meets all initial authorization criteria; AND member achieves a clinically meaningful response demonstrated by any of the following: improvement in percent predicted FEV1 from baseline, increased BMI, decreased pulmonary exacerbations, or improvement in CFQ-R respiratory domain score

Orkambi (lumacaftor/ivacaftor) is indicated for patients aged ≥1 year who are homozygous for the F508del CFTR mutation; the efficacy and safety of Orkambi have not been established in patients with CF other than those homozygous for F508del. Genetic testing (an FDA‑cleared CF mutation test) is recommended when genotype is unknown to confirm F508del on both alleles before use.

The policy includes multiple appendix sections that enumerate CFTR gene variants reported as responsive to specific modulators (e.g., appendices listing mutations responsive to Alyftrek, Kalydeco, and Symdeko). These appendices function as molecular‑criteria references and do not, within their text, state explicit coverage exclusions beyond serving as lists of responsive mutations.

No specific CPT, HCPCS, revenue, or ICD procedure/billing codes are provided for reporting these services in the policy; the document states No applicable codes under the Procedures and Billing Codes section.

Continuation authorization requires that the member meet all initial criteria and demonstrate a clinically meaningful response (for example, improvement in ppFEV1, increased BMI, decreased pulmonary exacerbations, or improved CFQ‑R respiratory domain score). If these continuation criteria are not met, Kalydeco, Orkambi, Symdeko, and Trikafta are considered not medically necessary.

The mutation appendices list CFTR gene variants reported as responsive to specific modulators but do not themselves include statements declaring any listed or unlisted mutation as not medically necessary; the appendices serve only as responsiveness references for coverage review.

Procedures and Billing Codes

Billing Rule

Provider Action / Billing Notes

No applicable CPT, HCPCS, revenue, or ICD-10 codes are listed for this policy. Providers should include genotype documentation and Appendix-listed CFTR gene mutation(s) when submitting requests. Do not bill for concomitant CFTR modulator therapies concurrently when policy disallows combination use. Required submission documents include clinical/genetic test results showing drug-responsiveness per the Appendix (see Appendix: CFTR mutation listings and drug responsiveness guidance).

No applicable CPT/HCPCS/Revenue/ICD codes provided
Include genotype documentation (genetic test results) with submissions
Reference Appendix for CFTR mutation listings and drug-responsiveness guidance
Do not bill for concomitant CFTR modulators when not permitted
Required submission documents: clinical history, genetic test report, prior therapy documentation as applicable

Provider Actions, Prior Authorization and Documentation

Prior Authorization

Prior authorization required; initial approval typically 6 months

Prior authorization is required for all CFTR modulators; initial approvals are issued for 6 months when the specified genetic and age criteria (and non-concomitant use requirements) are met.

Initial approval duration: 6 months for Alyftrek, Kalydeco, Orkambi, Symdeko, and Trikafta.

Note

Use appendix mutation lists to identify responsive variants

Appendices provide enumerated lists of CFTR gene mutations reported as responsive to specific modulators (e.g., Alyftrek, Kalydeco, Symdeko) to identify variants eligible for therapy.

Use Appendix A for Alyftrek, Appendix B for Kalydeco, and Appendix C for Symdeko responsive-mutation lists.

Prior Authorization

Definitions and Terminology

inv-24: Responsive mutation — definition of a CFTR mutation likely to respond to a specific modulator

DefinitionA CFTR gene mutation for which laboratory or clinical data indicate the encoded CFTR protein will respond to a specified CFTR modulator (as listed in each product's appendix or labeling).

Evidence sourcesResponsiveness is established by product labeling based on clinical and/or in vitro assay data (package inserts for Alyftrek, Kalydeco, Symdeko, Trikafta).

Testing requirementIf genotype is unknown, an FDA‑cleared CF mutation test should be used to confirm the presence of an indicated responsive mutation.

Age/context specificityResponsiveness is interpreted in the context of each product's indication (e.g., Alyftrek: ≥6 years with at least one F508del or other responsive mutation; Kalydeco: ≥1 month with a mutation responsive to ivacaftor; Symdeko: ≥6 years with responsive mutation or homozygous F508del; Trikafta: ≥2 years with at least one F508del or other responsive mutation).

Use for coverage decisionsAppendix lists of mutations reported as responsive to each agent are used as molecular criteria for prior authorization and coverage determinations.

Background

Cystic fibrosis (CF) is a genetic disorder treated with targeted CFTR modulator therapies selected based on the patient’s CFTR genotype. Product labeling and this policy require confirmation of a responsive CFTR mutation (via FDA‑cleared genetic testing) prior to initiating modulator therapy. Continuation decisions rely on documented clinical benefit measures such as percent predicted FEV1 (ppFEV1), BMI, pulmonary exacerbation frequency, and improvement in the CFQ‑R respiratory domain.

Appendices and References

Appendices are referenced in the policy as the source of enumerated lists of CFTR gene mutations reported to be responsive to specific modulators (Alyftrek, Kalydeco, Symdeko, etc.). Prior authorization reviewers and prescribers should consult these appendices to confirm that the member’s genotype matches a responsive variant listed for the requested agent.

The policy maps drug‑specific mutation appendices to the corresponding products: Kalydeco and Symdeko appendices provide extensive lists of CFTR variants reported to produce CFTR protein and be responsive to those agents; similar appendix listings are provided for other modulators and are intended to be used as the molecular basis for coverage determinations.

References supporting the policy include the package inserts for Alyftrek, Kalydeco, Orkambi, Symdeko, and Trikafta, and selected peer‑reviewed literature (for example, Rowe et al. and Taylor‑Cousar et al.). These are cited in the References section and should be consulted for product labeling and evidence details.

Policy Summary

PayerBlue Cross Blue Shield - Iowa

PolicyCystic Fibrosis (CF) CFTR Modulator Therapy Coverage — Alyftrek, Kalydeco, Orkambi, Symdeko, Trikafta

Policy CodePolicy 05.01.39

Change TypeRoutine review — no material changes

Effective DateMay 22, 2025

Next Review DateApr 1, 2026

Key ActionSubmit prior authorization with genetic test report and records demonstrating eligibility and clinical response.

SourceLink

On This Page

Confirm genotype is listed as responsive in appendices

Prior authorization reviewers must confirm the member's CFTR mutation(s) are listed in the appropriate appendix as responsive to the requested agent and may use package-insert responsiveness lists as evidence.

Documentation of genotype matching an appendix-listed responsive mutation is required for coverage review.

Step Therapy

Do not use CFTR modulators concomitantly

Requested CFTR modulators must not be used in combination with other listed CFTR modulators; each agent is specified as not to be used concomitantly with the other modulators.

Alyftrek, Kalydeco, Orkambi, Symdeko, and Trikafta are all specified as not to be used in combination with one another.

Note

See appendices/operations for additional provider actions

See appendices and operational guidance for additional provider actions and submission workflows related to mutation lists and authorization processing.

Step Therapy

No explicit step therapy sequencing provided

This policy does not specify an explicit step-therapy sequence; there is no mandated agent-to-agent sequencing in the document.

Consult other policy sections for agent-specific sequencing if needed.

Documentation Required

Provide genetic test report and clinical records with PA request

Submit a genetic testing report confirming the presence of the appropriate CFTR gene mutation and medical records (e.g., chart notes, labs, pulmonary function tests, CFQ‑R score) documenting clinical benefit to initiate prior authorization review.

Genetic test report showing the CFTR mutation.
Clinical records showing baseline and follow-up measures (ppFEV1, BMI, exacerbation history, CFQ‑R).

Note

Appendices are the molecular criteria reference

Appendices contain enumerated CFTR gene mutation listings that serve as the molecular criteria reference for coverage decisions for specific modulators.

Appendix lists are used to determine which mutations are considered responsive to each agent.

Documentation Required

Document CFTR variant(s) per appendices

Document the patient’s CFTR genotype and include evidence that the identified variant is listed in the policy appendices as responsive to the requested CFTR modulator.

Include genotype test results that map to appendix-listed responsive mutations.

Denial Risk

Denial risk if continuation criteria or response not met

Coverage will be denied (agent considered not medically necessary) for continuation requests if the member does not meet the continuation criteria, including failure to demonstrate a clinically meaningful response.

Continuation criteria include improvement in ppFEV1, increased BMI, decreased pulmonary exacerbations, or improved CFQ‑R respiratory domain score.
Agents are not medically necessary for patients who do not meet these continuation criteria.

Note

Appendices list mutations only; not PA/denial triggers

Appendix mutation lists enumerate responsive CFTR variants only and do not themselves state prior authorization triggers or explicit denial criteria.

Appendices list mutations responsive to specific modulators but do not specify PA or denial triggers.

inv-25: Responsive mutation list — enumerated nucleotide/amino-acid variant mappings from product appendices

Source lists includedAppendices in product labeling enumerate CFTR nucleotide and amino‑acid variant mappings reported as responsive to specific modulators (e.g., Appendix entries for Alyftrek, Kalydeco, Symdeko).

Example entries (Alyftrek)Mutation entries include nucleotide→amino acid mappings such as 1341G→A = D513G, 1507_1515del9 = D565G/G463V/L102R/Q98R/S1159P, 1898+3A→G = D579G/G480C/L1065P/R1048G/S1235R.

Example entries (Kalydeco/Symdeko)Appendix B and C list many responsive protein‑producing variants (examples include D1152H, G576A, S589N, A349V, A455E among others as shown in the package appendices).

PurposeThese enumerated mappings are intended to identify which specific CFTR sequence variants produce CFTR protein and are reported as responsive to the named CFTR modulator.

inv-26: Responsive CFTR gene mutation — definition per product package insert

Package‑insert definitionA responsive CFTR gene mutation is a CFTR variant identified in the product package insert as producing CFTR protein and demonstrating responsiveness to the specified CFTR modulator.

Demonstration of responsivenessResponsiveness is based on clinical evidence and/or in vitro assay data reported in the product labeling (package insert appendices).

Implication for authorizationPrior authorization reviewers should confirm the patient's CFTR genotype matches a mutation listed in the product package‑insert responsiveness list.

Verification recommendationIf the patient's genotype is unknown, use an FDA‑cleared CF mutation test (with bidirectional sequencing when recommended) to verify the presence of the listed responsive mutation.