Cystic Fibrosis (CF) CFTR Modulator Therapy Coverage — Alyftrek, Kalydeco, Orkambi, Symdeko, Trikafta
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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.
No material clinical or coverage changes in this revision.
Coverage Criteria for CFTR Modulators
Alyftrek Initial Therapy
Covered when ALL of the following are met for Alyftrek (initial):
Kalydeco, Orkambi, Symdeko Initial Therapy
Covered when ALL of the following are met for Kalydeco, Orkambi, and Symdeko (initial):
Trikafta Initial Therapy
Covered when ALL of the following are met for Trikafta (initial):
Continuation Therapy
Continuation of therapy covered when ALL initial criteria are met AND there is clinically meaningful response demonstrated by ANY of the following:
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
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 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.
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.
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.
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.
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.
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.
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).
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.
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 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.
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.
Definitions and Terminology
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.
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