TRIKAFTA, Elexacaftor-Tezacaftor-Ivacaftor Form

Elexacaftor/ivacaftor/tezacaftor (Trikafta®) is a triple combination drug for cystic fibrosis (CF). • Elexacaftor and tezacaftor bind to different sites on the cystic fibrosis transmembrane conductance regulator (CFTR) protein and have an additive effect in facilitating the cellular processing and trafficking of F508del-CFTR to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. Ivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface. • • The combined effect of elexacaftor, tezacaftor, and ivacaftor is increased quantity and function of F508del-CFTR at the cell surface, resulting in increased CFTR activity as measured by CFTR mediated chloride transport. FDA Approved Indication(s) Trikafta is indicated for the treatment of cystic fibrosis (CF) in patients aged 2 years and older who have at least one F508del mutation in the CFTR gene or a mutation in the CFTR gene that is responsive based on in vitro data. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to confirm the presence of at least one F508del mutation or a mutation that is responsive based on in vitro data. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that Trikafta is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Cystic Fibrosis (must meet all):

1. Diagnosis of CF confirmed by all of the following (a, b, and c): a. Clinical symptoms consistent with CF in at least one organ system, or positive newborn screen or genetic testing for siblings of patients with CF; b. Evidence of CFTR dysfunction confirmed by one of the following (i or ii) (see Appendix D): i. Elevated sweat chloride ≥ 60 mmol/L; Page 1 of 11

   CLINICAL POLICY Elexacaftor/Ivacaftor/Tezacaftor; Ivacaftor ii. Genetic testing confirming the presence of two disease-causing mutations in CFTR gene, one from each parental allele; c. Confirmation of one of the following (i or ii): i. Member has at least one F508del mutation in the CFTR gene; ii. Member has a mutation in the CFTR gene that is responsive to Trikafta based on in vitro data (see Appendix E);

2. Age ≥ 2 years;
   3. Prescribed by or in consultation with a pulmonologist;
   4. Documentation of one of the following pulmonary function tests performed within the last 90 days (a or b, see Appendix D): a. Member’s baseline percent predicted forced expiratory volume in 1 second (ppFEV1);
      b. For age < 6 years: Lung clearance index (LCI) that is ≥ 7.4;
3. Trikafta is not prescribed concurrently with other CFTR modulators (e.g., Orkambi®, Kalydeco®, Symdeko®);
4. Dose does not exceed one of the following (a, b, c, d, or e): a. Age 2 to < 6 years and weight < 14 kg (both i and ii): i. Elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 119.5 mg per day; ii. One packet (elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) of oral granules and one packet (ivacaftor 59.5 mg) of oral granules per day; b. Age 2 to < 6 years and weight ≥ 14 kg (both i and ii): i. Elexacaftor 100 mg/tezacaftor 50 mg/ ivacaftor 150 mg per day; ii. One packet (elexacaftor 100 mg/tezcaftor 50 mg/ivacaftor 75 mg) oral granules and one packet (ivacaftor 75 mg) oral granules per day; c. Age 6 to < 12 years and weight < 30 kg (both i and ii):
   i. Elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 150 mg per day; ii. 2 tablets (elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg) and 1 tablet (ivacaftor 75 mg) per day; d. Age 6 to < 12 years and weight ≥ 30 kg (both i and ii): i. Elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 300 mg per day; ii. 2 tablets (elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) and 1 tablet (ivacaftor 150 mg) per day; e. Age ≥ 12 years (both i and ii): i. Elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 300 mg per day; ii. 2 tablets (elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) and 1 tablet (ivacaftor 150 mg) per day. Approval duration: 4 months
   B. Other diagnoses/indications (must meet 1 or 2):

5. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or Page 2 of 11

   CLINICAL POLICY Elexacaftor/Ivacaftor/Tezacaftor; Ivacaftor b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

6. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
   II. Continued Therapy A. Cystic Fibrosis (must meet all):
7. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
8. Member is responding positively to therapy as evidenced by one of the following (a or b, see Appendix D): a. Stabilization or improvement in ppFEV1; b. For age < 6 years: Stabilization or decrease in LCI from baseline;
9. Trikafta is not prescribed concurrently with other CFTR modulators (e.g., Orkambi, Kalydeco, Symdeko);

10. If request is for a dose increase, new dose does not exceed (a, b, c, d, or e): a. Age 2 to < 6 years and weight < 14 kg (both i and ii): i. Elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 119.5 mg per day; ii. One packet (elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) of oral granules and one packet (ivacaftor 59.5 mg) of oral granules per day; b. Age 2 to < 6 years and weight ≥ 14 kg (both i and ii): i. Elexacaftor 100 mg/tezacaftor 50 mg/ ivacaftor 150 mg per day; ii. One packet (elexacaftor 100 mg/tezcaftor 50 mg/ivacaftor 75 mg) of oral granules and one packet (ivacaftor 75 mg) of oral granules per day; c. Age 6 to < 12 years and weight < 30 kg (both i and ii):
    i. Elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 150 mg per day; ii. 2 tablets (elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg) and 1 tablet (ivacaftor 75 mg) per day; d. Age 6 to < 12 years and weight ≥ 30 kg (both i and ii): i. Elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 300 mg per day; ii. 2 tablets (elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) and 1 tablet (ivacaftor 150 mg) per day; e. Age ≥ 12 years (both i and ii): i. Elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 300 mg per day; ii. 2 tablets (elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) and 1 tablet (ivacaftor 150 mg) per day. Approval duration: 12 months
    Page 3 of 11

    CLINICAL POLICY Elexacaftor/Ivacaftor/Tezacaftor; Ivacaftor B. Other diagnoses/indications (must meet 1 or 2):

11. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

12. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    III. Diagnoses/Indications for which coverage is NOT authorized:
    A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents.
    IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ACFLD: advanced cystic fibrosis lung disease
    CF: cystic fibrosis CFF: Cystic Fibrosis Foundation CFTR: cystic fibrosis transmembrane conductance regulator Appendix B: Therapeutic Alternatives
    Not applicable FDA: Food and Drug Administration LCI: lung clearance index ppFEV1: percent predicted forced expiratory volume in 1 second Appendix C: Contraindications/Boxed Warnings None reported Appendix D: General Information • The Cystic Fibrosis Foundation (CFF) Mutation Analysis Program (MAP) available here: https://www.cff.org/medical-professionals/mutation-analysis-program. The MAP is a free and confidential genetic testing program for people with a strongly suspected or confirmed diagnosis of CF. Page 4 of 11

    CLINICAL POLICY Elexacaftor/Ivacaftor/Tezacaftor; Ivacaftor • Regarding the diagnostic criteria for CF: o The Cystic Fibrosis Foundation (CFF) guidelines state that CFTR dysfunction needs to be confirmed with an elevated sweat chloride ≥ 60 mmol/L. o “Genetic testing confirming the presence of two disease-causing mutations in CFTR gene” is used to ensure that whether heterozygous or homozygous, there are two disease-causing mutations in the CFTR gene, one from each parental allele. One of those two mutations must be an F508del mutation but does not necessarily require both. • Most children can do spirometry by age 6, though some preschoolers are able to perform the test at a younger age. Some young children aren’t able to take a deep enough breath and blow out hard and long enough for spirometry. Forced oscillometry is another way to test lung function in young children. This test measures how easily air flows in the lungs (resistance and compliance) with the use of a machine. • The two most commonly reported parameters from multiple-breath washout (MBW) tests are the lung clearance index (LCI) and moment ratios (MRs). Measurements of LCI and MR are taken during the washout period. During the washout phase, subjects inhale gases that do not contain the test gas of interest. The principles of the washout are the same regardless of the test gas measured. The washout is stopped once the test gas reaches 1/40 of the initial gas concentration • NHS Clinical Guidelines: Care of Children with Cystic Fibrosis: Normal ranges for LCI are device specific and still being established, but in general a value > 8.0 is above the normal range and > 10.0 is significantly abnormal. Appendix E: CFTR Gene Mutations that are Responsive to Trikafta
    List of CFTR Gene Mutations that are Responsive to Trikafta 3141del9 546insCTA A46D A120T A234D A349V G1069R G1244E G1249R G1349D H139R H199Y L967S L997F L1077P L1324P L1335P L1480P E822K F191V F311del F311L F508C F508C; † S1251N F508del F575Y F1016S F1052V F1074L F1099L G27R G85E G126D G178E G178R G194R A455E A554E A1006E A1067T D110E D110H D192G D443Y D443Y;G576A; † R668C D579G D614G D836Y H939R H1054D H1085P H1085R H1375P I148T I175V I336K I502T I601F I618T I807M M152V M265R M952I M952T M1101K P5L P67L P205S P574H Q98R Q237E Q237H Page 5 of 11 R117L R117P R170H R258G R334L R334Q R347H R347L R347P R352Q R352W R553Q R668C R751L R792G S912L S945L S977F S1159F S1159P S1251N S1255P T338I T1036N T1053I V201M V232D V456A V456F V562I R933G R1066H R1070Q V754M V1153E V1240G

    CLINICAL POLICY Elexacaftor/Ivacaftor/Tezacaftor; Ivacaftor G194V G314E G463V G480C G551D G551S G576A G576A; † R668C G622D G628R G970D G1061R Q359R Q1291R R31L R74Q R74W R74W;D1270N † R74W;V201M R74W;V201M; † D1270N R75Q R117C R117G R117H List of CFTR Gene Mutations that are Responsive to Trikafta D924N D979V D1152H D1270N E56K E60K E92K E116K I980K I1027T I1139V I1269N I1366N K1060T L15P L165S † R1070W R1162L R1283M R1283S S13F S341P S364P S492F V1293G W361R W1098C W1282R Y109N Y161D Y161S Y563N E193K E403D E474K E588V Complex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele. L206W L320V L346P L453S S549N S549R S589N S737F Y1014C Y1032C † V. Dosage and Administration
    Indication Dosing Regimen CF Pediatric patients age 2 to less than 6 years weighing less than 14 kg: • Morning dose: One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg oral granules) • Evening dose: One packet (containing ivacaftor 59.5 mg oral granules)
    Pediatric patients age 2 to less than 6 years weighing 14 kg or more: • Morning dose: One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ ivacaftor 75 mg oral granules) • Evening dose: One packet (containing ivacaftor 75 mg oral granules) Pediatric patients age 6 years to less than 12 years weighing less than 30 kg: • Morning dose: 2 tablets (each containing elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg) • Evening dose: 1 tablet of ivacaftor 75 mg Maximum Dose Age 2 to 6 years weighing less than 14 kg: elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 119.5 mg per day Age 2 to 6 years weighing 14 kg or more and pediatric patients, or age 6 years to less than 12 years weighing less than 30 kg:
    elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 150 mg per day Adults, pediatric patients age 12 years and older, or pediatric patients age 6 years to less than 12 years weighing 30 kg or more: Adults, pediatric patients age 12 years and older, or pediatric patients age 6 Page 6 of 11

    CLINICAL POLICY Elexacaftor/Ivacaftor/Tezacaftor; Ivacaftor Indication Dosing Regimen • Morning dose: 2 tablets (each containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) • Evening dose: 1 tablet of ivacaftor 150 mg Morning and evening dose should be taken PO approximately 12 hours apart with fat- containing food Maximum Dose years to less than 12 years weighing 30 kg or more: elexacaftor 200 mg/ tezacaftor 100 mg/
    ivacaftor 300 mg per day VI. Product Availability
    • Tablets: co-packaged fixed dose combination containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg and ivacaftor 150 mg; co-packaged fixed dose combination containing elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg and ivacaftor 75 mg • Unit-dose packets containing oral granules: fixed dose combination containing elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg co-packaged with ivacaftor 75 mg; fixed dose combination containing elexacaftor 80 mg, tezacaftor 40 mg, ivacaftor 60 mg co-packaged with ivacaftor 59.5 mg
    VII.