Cystic Fibrosis (CFTR) Modulator Agents (Alyftrek, Kalydeco, Orkambi, Symdeko, Trikafta)
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Defines medical necessity and prior authorization requirements for CFTR modulator agents (Alyftrek, Kalydeco, Orkambi, Symdeko, Trikafta) for Wellmark Blue Cross and Blue Shield members; applies to prescribers and pharmacy benefit reviewers assessing coverage.
No material clinical or coverage changes in this revision.
Coverage Criteria for CFTR Modulator Therapy
inv-01: Alyftrek Initial Therapy
Alyftrek (vanzacaftorltezacaftorldeutivacaftor) initial therapy covered when ALL of the following are met
Initial approval: 6 months
inv-02: Kalydeco Initial Therapy
Kalydeco initial therapy covered when ALL of the following are met
Initial approval: 6 months
inv-03: Orkambi Initial Therapy
Orkambi initial therapy covered when ALL of the following are met
Initial approval: 6 months
inv-04: Symdeko Initial Therapy
Symdeko initial therapy covered when ALL of the following are met
Initial approval: 6 months
inv-05: Trikafta Initial Therapy
Trikafta initial therapy covered when ALL of the following are met
Initial approval: 6 months
inv-06: Continuation Therapy
Continuation of therapy covered when ALL initial authorization criteria are met and the member demonstrates a clinically meaningful response as shown by ANY of the following
Approval for continuation: 12 months
inv-07: Mutation-based eligibility
Coverage guided by presence of mutation listed as responsive to the requested modulator in the appendices
Appendices enumerate responsive mutations; provider must supply genotype demonstrating one of these mutations
The policy notes a specific limitation for Orkambi (lumacaftor/ivacaftor): its efficacy and safety have not been established except in patients who are homozygous for the F508del mutation in the CFTR gene. If a patient’s genotype is unknown, an FDA‑cleared CF mutation test should be used to confirm F508del on both alleles prior to considering Orkambi.
Patients whose CFTR genotype does not include a mutation listed in the relevant appendix are not described in the appendices as responsive to the listed CFTR modulators; coverage determinations depend on documentation that the patient’s genotype matches a mutation enumerated for the requested drug.
This section does not provide any applicable CPT, HCPCS, revenue, or ICD procedure/billing codes; the document explicitly states No applicable codes for reporting provider services.
Kalydeco, Orkambi, Symdeko, and Trikafta are considered not medically necessary for members who do not meet the stated initial or continuation criteria (continuation requires meeting initial authorization criteria and demonstrating a clinically meaningful response); failure to meet these requirements may result in denial of coverage.
Quantity Limits, Dosing, and Codes
| Alyftrek (4mg/20mg/50mg) | 84 tablets/28 days |
| Alyftrek (10mg/50mg/125mg) | 56 tablets/28 days |
| Kalydeco | 56 tablets/28 days |
| Kalydeco Pak | 56 packets/28 days |
| Orkambi (tablets) | 112 tablets/28 days |
| Orkambi (granules) | 56 packets/28 days |
| Symdeko | 56 tablets/28 days |
| Trikafta (tablets) | 84 tablets/28 days |
| Trikafta (granules) | 56 packets/28 days |
Prescriber, Prior Authorization, and Documentation Requirements
Prior Authorization and Prescriber Specialty
Prior authorization is required. Submit a completed prior authorization request with supporting medical records to initiate review. The medication must be prescribed by or in consultation with a pulmonologist.
- Prior authorization required with medical record submission (chart notes, labs, PFTs, CFQ-R)
- Prescriber specialty: must be prescribed by or in consultation with a pulmonologist
Genotype Verification Required
Genotype verification is required as part of the prior authorization. The request must include a genetic testing report showing the patient’s CFTR genotype and confirmation that the identified mutation(s) are listed as responsive in the applicable appendix for the requested modulator.
- Include CFTR genotype test report
- Confirm the patient has a mutation listed in the relevant appendix (Appendix A, B, C, or D) for the requested modulator
Appendix Guidance — Genotype to Modulator Matching
The policy references appendices that list CFTR mutations responsive to specific modulators. Clinicians and reviewers should refer to the appendix corresponding to the requested drug to determine whether the patient’s mutation(s) are included and select the modulator that matches the genotype.
- Appendix A: mutations responsive to Alyftrek
- Appendix B: mutations responsive to Kalydeco
- Appendix C: mutations responsive to Symdeko
- Appendix D: mutations responsive to Trikafta (refer to policy appendices)
Combination Therapy Exclusion
CFTR modulators must not be used in combination with other listed modulators. Requests for combination use of two or more CFTR modulators (for example Alyftrek with Kalydeco, Orkambi, Symdeko, or Trikafta) will not meet criteria.
- Combination therapy exclusion: do not co-administer Alyftrek, Kalydeco, Orkambi, Symdeko, or Trikafta with one another
Not Medically Necessary if Continuation Criteria Not Met
Continuation of therapy requires meeting the initial criteria and demonstrating a clinically meaningful response (examples: improvement in ppFEV1, increased BMI, decreased pulmonary exacerbations, or improved CFQ-R respiratory domain score). Coverage is not medically necessary for continuation if these continuation criteria are not met.
- Continuation approval contingent on meeting initial criteria and demonstrating response
- If continuation criteria are not met, treatment is considered not medically necessary
Billing / PA Codes Not Specified
No specific CPT, HCPCS, revenue, or ICD codes are provided in this policy for reporting provider services or claims. Providers should use appropriate procedure and diagnosis codes per standard billing guidance; absence of listed codes in this policy may affect claim submission or adjudication if not billed correctly.
- Procedures and billing codes: No applicable codes listed in this policy
- Coding absence may affect claim submission — verify and apply appropriate CPT/HCPCS/ICD codes when submitting claims
Background on Cystic Fibrosis and CFTR Modulators
Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR gene. CFTR modulators are targeted therapies that aim to improve CFTR protein function for specific CFTR gene variants; coverage in this policy is guided by whether a patient’s CFTR mutation is listed as responsive to a particular modulator in the document appendices.
Key Definitions
Policy Revision History
Policy originally effective in May 2012.
Policy reviewed in April 2025.
Policy revised in April 2025 (document notes revised April 2025).
Current policy effective date set to May 22, 2025.
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