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Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Prior Authorization with Quantity Limit Program Summary
Policy Number: PH-1032
This program applies to Blue Partner, Commercial, GenPlus, NetResults A series, SourceRx and Health Insurance Marketplace formularies.
POLICY REVIEW CYCLE
Effective Date |
Date of Origin |
04-01-2024 |
|
FDA APPROVED INDICATIONS AND DOSAGE
Agent(s) |
FDA Indication(s) |
Notes |
Ref# |
Kalydeco® (ivacaftor) Oral granules Tablets |
Treatment of cystic fibrosis (CF) in patients age 1 month and older who have at least one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use. |
|
1 |
Orkambi® (lumacaftor/ivacaftor) Oral granules Tablet |
Treatment of cystic fibrosis (CF) in patients aged 1 year and older who are homozygous for the F508del mutation in the CFTR gene. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene. Limitations of Use: |
|
2 |
Symdeko® (tezacaftor/ivacaftor and ivacaftor co-packaged) Tablet |
Treatment of patients with cystic fibrosis (CF) age 6 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ ivacaftor based on in vitro data and/or clinical evidence. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use. |
|
3 |
Trikafta®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor co-packaged) Oral granules Tablet |
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. |
|
8 |
See package insert for FDA prescribing information: https://dailymed.nlm.nih.gov/dailymed/index.cfm
CLINICAL RATIONALE
Cystic Fibrosis |
Cystic fibrosis (CF) is the most common life-threatening autosomal recessive disease among Caucasian populations. CF is a multisystem disorder caused by mutations in the gene for the CF transmembrane conductance regulator (CFTR), which encodes an ion channel protein. Defects in the ion channel protein cause deranged transport of chloride and other CFTR-affected ions (e.g., sodium and bicarbonate), which leads to thick, viscous secretions in the lungs, pancreas, liver, intestine, and reproductive tract, and to increased salt content in sweat gland secretions.(5) Pulmonary disease remains the leading cause of morbidity and mortality in patients with CF.(6) Diagnosis of CF is based upon compatible clinical findings with biochemical or genetic confirmation. Both of the following criteria must be met to diagnose CF:(4,5)
Treatment of CF requires a multidisciplinary approach to care that is best provided at one of more than 120 CF Care Centers (accredited by the CF Foundation), most of which have dedicated programs for both children and adults. Patients treated at these centers are seen by physicians, nurses, dietitians, respiratory therapists, physical therapists, and social workers with special competence in CF care.(4) Sinus infection, nutritional status, glucose control, and psychosocial issues should be assessed at regular intervals. Antibiotics, bronchodilators, anti-inflammatory agents, agents that promote airway secretion clearance, nutritional support, and CFTR modulators are possible therapies for CF patients.(6) CFTR modulators are a new class of drugs that act by improving production, intracellular processing, and/or function of the defective CFTR protein. These drugs represent an important advance in management of CF because they target the defective CFTR protein rather than its downstream consequences. Indications and efficacy of CFTR drugs depend upon the CFTR mutations in the individual patient. Therefore, all CF patients should undergo CFTR genotyping to determine if they carry a mutation that makes them eligible for CFTR modulator therapy.(7,9,10) The following approach is recommended for CFTR modulators, guided by both genotype and age:(7)
|
Efficacy |
Ivacaftor was the first approved CFTR modulator therapy. It was originally approved for patients 12 years or older with a G551D mutation in at least one of their CFTR genes. A phase 3 multicenter randomized trial studied the effect of 48 weeks of ivacaftor, 150 mg twice daily, compared with placebo in 161 subjects aged 12 years or older with at least one G551D mutation. The FEV1 increased 10.4% from baseline in the treated patients compared with −0.2% for those receiving placebo at 24 weeks (p less than 0.001). Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than those receiving placebo (p less than 0.001). There were significant improvements in QOL, as measured by Cystic Fibrosis Questionnaire Revised (CFQ-R), as well as nutritional status. The authors observed a 48.1 mmol/L decrease in sweat chloride concentration in treated patients compared with placebo (p less than 0.001), reflecting the impact of the drug on the basic defect in CF.(1,7,9) Other trials have evaluated the efficacy of ivacaftor in patients with CF and mutations in additional CFTR genes (e.g., G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, S549R, R117H) and have showed beneficial results similar to those reported for patients with the G551D mutation.(1,7,10) Further clinical trials and in vitro studies with ivacaftor have expanded the approved label to 6 years of age and additional CFTR mutations. However, even with the expanded indication only about 10% of patients with CF in the United States carry mutations responsive to ivacaftor.(7,10) The most common CFTR mutation that causes CF is F508del; 50% of CF patients with CF are homozygous, and another 40% are heterozygous.(5,10) Ivacaftor alone is ineffective in treating F508del mutation since these mutations result in decreased CFTR expression (due to incorrect CFTR protein folding) at the respiratory epithelial cell surface, whereas ivacaftor’s mechanism of action is augmentation of ion conductance via gating channel.(1,9,10) Combination lumacaftor and ivacaftor has shown improvements in pulmonary function and reduced the risk of pulmonary exacerbations in CF patients who are homozygous for the F580del mutation.(2,7,10) Lumacaftor partially corrects the CFTR misfolding while ivacaftor improves the gating abnormality. Neither drug is effective as monotherapy for F508del homozygotes.(7,10) The efficacy of lumacaftor-ivacaftor in patients with CF who are homozygous for the F508del mutation in the CFTR gene was evaluated in two randomized, double-blind, placebo-controlled, 24-week clinical trials. The primary efficacy endpoint in both trials was change in lung function as determined by absolute change from baseline in percent predicted FEV1 (ppFEV1) at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24. In both trials, treatment with lumacaftor-ivacaftor resulted in a statistically significant improvement in ppFEV1.(2,7,10) Key secondary efficacy variables included relative change from baseline in ppFEV1 at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24; absolute change from baseline in BMI at Week 24; absolute change from baseline in CFQ-R score at Week 24, a measure of respiratory symptoms relevant to patients with CF such as cough, sputum production, and difficulty breathing; proportion of patients achieving greater than or equal to 5% relative change from baseline in ppFEV1 using the average of Week 16 and Week 24; and number of pulmonary exacerbations through Week 24. For the purposes of these trials, a pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms.(2,10) In patients who are heterozygous for the F508del mutation, lumacaftor-ivacaftor does not appear to have clinically meaning benefit.(2,7) Tezacaftor-ivacaftor combination has shown modest improvements in pulmonary function and reduced the risk of pulmonary exacerbations for individuals who are homozygous for the F508del mutation or a heterozygous F508del mutation in combination with a residual function mutation. Tezacaftor partially corrects the CFTR misfolding, while ivacaftor is a potentiator that improves the gating abnormality.(7) A trial involving F508del homozygotes resulted in modest improvement in FEV1 (absolute change, 4 percentage points versus placebo) and modest improvement in CFQ-R score (5.1 points versus placebo). The rate of pulmonary exacerbations was 35 percent lower in the treatment group compared with placebo (hazard ratio [HR] 0.64, 95% CI 0.46-0.88).(2,7) The October 2019 Priority Review FDA approval of Trikafta (elexacaftor-tezacaftor-ivacaftor combination) brought another CFTR agent to the market with additional benefit for the 50% of CF patients with homozygous F508del mutation, but particularly the 40% of CF patients with heterozygous F508del mutation who were previously unable to be treated unless their other CFTR mutation was an approved mutation for Kalydeco or Symdeko. The efficacy of Trikafta was demonstrated in two trials. The first trial was a 24-week, randomized, double-blind, placebo-controlled trial in 403 patients who had an F508del mutation and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor or tezacaftor/ivacaftor alone. The second trial was a four-week, randomized, double-blind, active-controlled trial in 107 patients who had two identical F508del mutations. Trikafta increased the ppFEV1 in both trials (Trial 1 increased mean ppFEV1 13.8% from baseline compared to placebo; Trial 2 increased mean ppFEV1 10% from baseline compared to tezacaftor/ivacaftor). In the first trial, treatment with Trikafta also resulted in improvements in sweat chloride, number of pulmonary exacerbations (worsening respiratory symptoms and lung function), and body mass index (weight-to-height ratio) compared to placebo.(8) The safety of elexacaftor-tezacaftor-ivacaftor in younger children was evaluated in a 24-week open-label study in 66 children 6 to 11 years old who were homozygous for F508del or heterozygous for F508del with a second minimal function mutation. The safety profile and pharmacokinetics were similar to those in older individuals, and patients experience improvement in percent predicted FEV1 (10.2 percentage points; 95% CI 7.9-12.6), respiratory symptoms, sweat chloride, and body weight.(7,11) On the basis of this study, the drug combination was approved for this age group in June 2021.(8) |
Safety |
Kalydeco, Orkambi, Symdeko, and Trikafta do not have any boxed warnings nor contraindications.(1,2,3,8) |
REFERENCES
Number |
Reference |
1 |
Kalydeco prescribing information. Vertex Pharmaceuticals Incorporated. August 2023. |
2 |
Orkambi prescribing information. Vertex Pharmaceuticals Incorporated. August 2023. |
3 |
Symdeko prescribing information. Vertex Pharmaceuticals Incorporated. August 2023. |
4 |
Farrell PM, White TB, Ren CL, et al. Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation. J Pediatr. 2017 Feb;181S:S4-S15.e1. |
5 |
Katkin JP, et al. Cystic Fibrosis: Clinical Manifestations and Diagnosis. UpToDate. Last updated March 2023. Literature review current through August 2023. |
6 |
Simon RH, et al. Cystic Fibrosis: Overview of the Treatment of Lung Disease. UpToDate. Last updated June 2023. Literature review current through August 2023. |
7 |
Simon RH, et al. Cystic Fibrosis: Treatment with CFTR Modulators. UpToDate. Last updated May 2023. Literature review current through August 2023. |
8 |
Trikafta prescribing information. Vertex Pharmaceuticals Incorporated. August 2023. |
9 |
Mogayzel PJ Jr, Naureckas ET, Robinson KA, et al, of the Pulmonary Clinical Practice Guidelines Committee. Cystic Fibrosis Pulmonary Guidelines: Chronic Medications for Maintenance of Lung Health. Am J Respir Crit Care Med. 2013 Apr;187(7):680-689. |
10 |
Ren CL, Morgan RL, Oermann C, et al. Cystic Fibrosis Pulmonary Guidelines: Use of CFTR Modulator Therapy in Patients with Cystic Fibrosis. Ann Am Thorac Soc. 2018 Mar;15(3):271-280. |
11 |
Zemanick ET, Taylor-Cousar JL, Davies J, et al. A Phase 3 Open-Label Study of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 through 11 Years of Age with Cystic Fibrosis and at Least One F508del Allele. Am J Respir Crit Care Med. 2021;203(12):1522. |
POLICY AGENT SUMMARY PRIOR AUTHORIZATION
Target Brand Agent(s) |
Target Generic Agent(s) |
Strength |
Targeted MSC |
Available MSC |
Final Age Limit |
Preferred Status |
|
||||||
Trikafta |
elexacaf-tezacaf-ivacaf |
100-50-75 & 150 MG ; 100-50-75 & 75 MG ; 50-25-37.5 & 75 MG ; 80-40-60 & 59.5 MG |
M ; N ; O ; Y |
N |
|
|
Kalydeco |
ivacaftor packet |
13.4 MG ; 25 MG ; 5.8 MG ; 50 MG ; 75 MG |
M ; N ; O ; Y |
N |
|
|
Kalydeco |
ivacaftor tab |
150 MG |
M ; N ; O ; Y |
N |
|
|
Orkambi |
lumacaftor-ivacaftor granules packet |
100-125 MG ; 150-188 MG ; 75-94 MG |
M ; N ; O ; Y |
N |
|
|
Orkambi |
lumacaftor-ivacaftor tab |
100-125 MG ; 200-125 MG |
M ; N ; O ; Y |
N |
|
|
Symdeko |
tezacaftor-ivacaftor |
100-150 & 150 MG ; 50-75 & 75 MG |
M ; N ; O ; Y |
N |
|
|
POLICY AGENT SUMMARY QUANTITY LIMIT
Target Brand Agent Name(s) |
Target Generic Agent Name(s) |
Strength |
QL Amount |
Dose Form |
Day Supply |
Duration |
Addtl QL Info |
Allowed Exceptions |
Targeted NDCs When Exclusions Exist |
|
|||||||||
Kalydeco |
ivacaftor packet |
13.4 MG ; 25 MG ; 5.8 MG ; 50 MG ; 75 MG |
60 |
Packets |
30 |
DAYS |
|
|
|
Kalydeco |
ivacaftor tab |
150 MG |
60 |
Tablets |
30 |
DAYS |
|
|
|
Orkambi |
lumacaftor-ivacaftor granules packet |
100-125 MG ; 150-188 MG ; 75-94 MG |
60 |
Packets |
30 |
DAYS |
|
|
|
Orkambi |
lumacaftor-ivacaftor tab |
100-125 MG ; 200-125 MG |
120 |
Tablets |
30 |
DAYS |
|
|
|
Symdeko |
tezacaftor-ivacaftor |
100-150 & 150 MG ; 50-75 & 75 MG |
60 |
Tablets |
30 |
DAYS |
|
|
|
Trikafta |
elexacaf-tezacaf-ivacaf |
100-50-75 & 75 MG ; 80-40-60 & 59.5 MG |
56 |
Packets |
28 |
DAYS |
|
|
|
Trikafta |
elexacaf-tezacaf-ivacaf |
100-50-75 & 150 MG ; 50-25-37.5 & 75 MG |
90 |
Tablets |
30 |
DAYS |
|
|
|
CLIENT SUMMARY – PRIOR AUTHORIZATION
Target Brand Agent Name(s) |
Target Generic Agent Name(s) |
Strength |
Client Formulary |
Kalydeco |
ivacaftor packet |
13.4 MG ; 25 MG ; 5.8 MG ; 50 MG ; 75 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
Kalydeco |
ivacaftor tab |
150 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
Orkambi |
lumacaftor-ivacaftor granules packet |
100-125 MG ; 150-188 MG ; 75-94 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
Orkambi |
lumacaftor-ivacaftor tab |
100-125 MG ; 200-125 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
Symdeko |
tezacaftor-ivacaftor |
100-150 & 150 MG ; 50-75 & 75 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
Trikafta |
elexacaf-tezacaf-ivacaf |
100-50-75 & 150 MG ; 100-50-75 & 75 MG ; 50-25-37.5 & 75 MG ; 80-40-60 & 59.5 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
CLIENT SUMMARY – QUANTITY LIMITS
Target Brand Agent Name(s) |
Target Generic Agent Name(s) |
Strength |
Client Formulary |
Kalydeco |
ivacaftor packet |
13.4 MG ; 25 MG ; 5.8 MG ; 50 MG ; 75 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
Kalydeco |
ivacaftor tab |
150 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
Orkambi |
lumacaftor-ivacaftor granules packet |
100-125 MG ; 150-188 MG ; 75-94 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
Orkambi |
lumacaftor-ivacaftor tab |
100-125 MG ; 200-125 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
Symdeko |
tezacaftor-ivacaftor |
100-150 & 150 MG ; 50-75 & 75 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
Trikafta |
elexacaf-tezacaf-ivacaf |
100-50-75 & 75 MG ; 80-40-60 & 59.5 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
Trikafta |
elexacaf-tezacaf-ivacaf |
100-50-75 & 150 MG ; 50-25-37.5 & 75 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
PRIOR AUTHORIZATION CLINICAL CRITERIA FOR APPROVAL
Module |
Clinical Criteria for Approval |
|
Initial Evaluation Target Agent(s) will be approved when ALL of the following are met:
Length of Approval: 6 months NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.
Renewal Evaluation Target Agent(s) will be approved when ALL of the following are met:
Length of Approval: 12 months NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria |
QUANTITY LIMIT CLINICAL CRITERIA FOR APPROVAL
Module |
Clinical Criteria for Approval |
|
Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met:
Length of Approval: Initial: 6 months, Renewal: 12 months |
This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
The purpose of Blue Cross and Blue Shield of Alabama’s pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients.
Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment.
Commercial _ PS _ CFTR_PAQL _ProgSum_ 04-01-2024