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Substrate Reduction Therapy Prior Authorization with Quantity Limit Program Summary
Policy Number: PH-1074
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 |
07-01-2024 |
01-01-2018 |
FDA LABELED INDICATIONS AND DOSAGE
Agent(s) |
FDA Indication(s) |
Notes |
Ref# |
Cerdelga® (eliglustat) Capsule |
Long-term treatment of adult patients with Gaucher disease type 1 who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test for determining CYP2D6 genotype Limitations of Use:
|
|
1 |
Opfolda™ (miglustat) Capsule |
Treatment of adult patients with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency) weighing greater than or equal to 40 kg and who are not improving on their current enzyme replacement therapy (ERT); Opfolda (an enzyme stabilizer) is indicated in combination with Pombiliti (a hydrolytic lysosomal glycogen-specific enzyme) |
|
11 |
Zavesca® (miglustat)* Capsule |
Monotherapy for treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g., due to allergy, hypersensitivity, or poor venous access) |
* Generic available
|
2 |
See package insert for FDA prescribing information: https://dailymed.nlm.nih.gov/dailymed/index.cfm
CLINICAL RATIONALE
Gaucher Disease |
Gaucher disease (GD), the most common of the lysosomal storage disorders (LSDs), is a rare autosomal recessive metabolic disorder affecting only 1 in 40,000 in the general United States population.(4,7) Mutations in the GBA (glucocerebrosidase) gene cause reduced activity of the lysosomal enzyme glucocerebrosidase (also known as acid beta-glucosidase), resulting in the accumulation of harmful quantities of the glycolipid glucocerebroside (also known as glucosylceramide, or GLC) and other related sphingolipids. This multisystemic accumulation of GLC in various tissues, especially in lysosomes of macrophages, compromises the bone marrow, spleen, and liver, and less often the lungs, skin, kidneys, and heart.(3,4,7,8,9,10) GD is classified into 3 clinical types, distinguished by their clinical features, management, and prognosis. However, as with most genetic diseases, there is a continuum of clinical findings and overlap within and between types, resulting in identification of additional subtypes.(4,5,7,9) GD Type 1 (GD1) is distinguished from GD Types 2 (GD2) and 3 (GD3) by the lack of characteristic involvement of the central nervous system (CNS).(3,4,5,7,8) As such, it is also known as non-neuronopathic GD.(3,4,7) In the United States, Europe, and Israel, 90% of GD patients have GD1, with a high carrier frequency in the Ashkenazi-Jewish population.(3,4,5,7,8) Age of onset for GD1 is variable, with some patients presenting between 12 and 24 months of age and others having no clinical signs until late adulthood.(3,4,7) Manifestation in the first or second decades of life typically results in more aggressive and severe symptoms than those manifesting at a later stage of life.(7) Presentation of symptoms among patients with GD1 is variable. Splenomegaly is the most common symptom; hepatomegaly is also common, but the liver increases relatively less than the spleen. Other common presenting symptoms are anemia, thrombocytopenia, bone disease, and delayed growth.(3,4,5,7,8,10) GD2 is an acute neuronopathic form of GD characterized by early onset, typically in the first year after birth. Neurologic complications are extensive and severe, with limited psychomotor development. Death occurs within the first 2 years of life, usually due to respiratory failure.(3,5,7) GD3 is the subacute or chronic neuronopathic form, has later onset than GD2, and has slower disease progression with patients typically surviving to second or third decades of life. The distinction between GD2 and GD3 is difficult.(3,4) A diagnosis of GD should be considered in patients with unexplained anemia and easy bruising, particularly if they have enlargement of the spleen and liver.(3) Definitive diagnosis of GD can be confirmed by the finding of reduced glucocerebrosidase activity in leukocytes, fibroblasts, or other nucleated cells.(3,4,5,7,9,10) This enzyme assay test is typically known as BGL (beta-glucosidase leukocyte), and a finding of 15% or less of mean normal glucocerebrosidase enzyme activity is indicative of GD.(4,5) If BGL results are not conclusive and/or further confirmatory testing is desired, genetic testing is an option. Identification of two pathogenic alleles in the GBA gene can also determine diagnosis of GD.(3,4,5,9) The presence of neurologic complications has critical implications for prognosis and treatment and should be determined as soon as possible after diagnosis. Neuronopathic symptoms indicative of GD2 and GD3 include bulbar signs (e.g., stridor, strabismus, swallowing difficulty), pyramidal signs (e.g., opisthotonus, head retroflexion, spasticity, trismus), oculomotor apraxia, tonic-clonic seizures, myoclonic epilepsy, dementia, and ataxia. If not already performed as part of the diagnostic process, baseline measurement of hemoglobin level, platelet count, liver volume, and spleen volume should be documented.(4,5,7,10) When possible, management of a patient with GD should occur with a multidisciplinary team at a Comprehensive Gaucher Treatment Center(5) (list of facilities nationwide available at www.gaucherdisease.org. Goals of treatment are elimination or improvement of symptoms, prevention of irreversible complications, and improvement in overall health and quality of life. An additional goal in children is optimization of growth.(3,6,8) Currently, two different therapeutic approaches for the treatment of GD1 are used: enzyme replacement therapy (ERT) [Cerezyme (imiglucerase), VPRIV (velaglucerase alfa), Elelyso (taliglucerase alfa)] and substrate reduction therapy (SRT) [Cerdelga (eliglustat), Zavesca (miglustat)].(3,5,6,8,9) ERT, intravenously administered, targets macrophages and increases the breakdown of accumulated glycolipids.(8) SRT, orally administered, reduces the amount of synthesized GLC to a level that can be effectively cleared by the mutated enzyme’s residual activity.(5,6,8) The decision to offer ERT or SRT in patients with GD1 is based upon disease severity and/or significant disease progression.(6,7,8,10) To begin treatment with ERT or SRT, clinically significant manifestations must be present. Thrombocytopenia of sufficient magnitude to justify initiation of treatment is defined by platelet counts less than 100,000 microliter, as well as symptomatic presentation of splenomegaly, anemia, bone disease, and/or delayed growth.(3,4,5,7,8,9) |
Pompe Disease |
Pompe disease, also known as acid maltase deficiency (AMD) or glycogen storage disease type II (GSDII), is an autosomal recessive disorder caused by mutations in the GAA gene for enzyme acid alpha-glucosidase (GAA).(12,13) Deficiency of lysosomal enzyme GAA leads to accumulation of glycogen in lysosomes and cytoplasm, resulting in tissue destruction.(13) Infantile-onset Pompe disease (IOPD) is characterized by cardiomyopathy, severe generalized hypotonia, respiratory distress typically requiring ventilator support, and failure to thrive. Most patients with this form die within the first year or two of life without treatment. The juvenile-adult form (late onset Pompe disease [LOPD]) is characterized by skeletal myopathy, delayed gross-motor development, and respiratory insufficiency and/or failure.(12,13) Diagnosis can be confirmed by demonstration of reduced acid alpha-glucosidase glycogen enzyme activity in dried blood spots or leukocytes (skin fibroblasts or skeletal muscle tissue are also options). GAA gene mutational analysis is the preferred test to confirm the diagnosis (with two pathogenic alleles), since it is routinely available, less invasive, and may help predict cross-reactive immunologic material (CRIM) status.(12,13,14) Prenatal diagnosis is possible by DNA analysis of cultured amniocytes or chorionic villus samples, if the mutation in the family is known.(13,14) Guidelines note that a trial of ERT may be considered in patients who receive invasive ventilation support, if there are predefined outcomes which can be evaluated and which, if achieved, would improve the functional status of the patient. After one year, decisions regarding the continuation of ERT in patients receiving invasive ventilation support should be made on a case-by-case basis.(15,16) Opfolda (miglustat) in combination with Pombiliti (an ERT; cipaglucosidase alfa) was approved by the FDA in September 2023 as a new treatment for adults with LOPD. Pombiliti provides an exogenous source of GAA, which exerts enzymatic activity in cleaving accumulating glycogen. Opfolda binds with, stabilizes, and reduces inactivation of Pombiliti in the blood after infusion.(11) |
Efficacy - Gaucher Disease |
Until the FDA approval of the SRT Cerdelga in 2014, ERT was the mainstay of therapy in patients with GD1. A 12-month phase 3, open-label, noninferiority study (ENCORE) in 106 adults (18 years of age and older) with GD1, stable after greater than or equal to 3 years of ERT with Cerezyme or VPRIV, found Cerdelga noninferior to Cerezyme in maintaining stability of four component domains (i.e., hemoglobin level, platelet count, liver volume, spleen volume). A 9-month randomized, double-blind, placebo-controlled study (ENGAGE) in 40 treatment-naïve GD1 patients 16 years of age and older, demonstrated that treatment with Cerdelga led to greater improvements in spleen and liver volume, platelet count, and hemoglobin level compared to placebo. These findings provided Cerdelga its designation as first-line or maintenance therapy in adult patients with GD1.(1,5,6,8) The SRT Zavesca, approved in 2003, is indicated only for GD1 patients for whom ERT is not an option (e.g., due to allergy, hypersensitivity, or poor venous access). Studies of Zavesca have demonstrated significant reductions from baseline in liver and spleen volume, and a non-significant increase from baseline in hemoglobin level and platelet count.(2,5,6) |
Efficacy - Pompe Disease |
PROPEL was a randomized, double-blind, active-controlled, international, multi-center clinical trial (NCT#03729362) in patients greater than or equal to 18 years old diagnosed with late-onset Pompe disease (LOPD). Patients were randomized 2:1 to receive Pombiliti in combination with Opfolda, or a non-U.S.-approved alglucosidase alfa product with placebo every other week for 52 weeks. The efficacy population included a total of 123 patients of whom 95 (77%) had received prior treatment with U.S.-approved alglucosidase alfa or a non-U.S.-approved alglucosidase alfa product (ERT-experienced) and 28 (23%) were ERT-naïve. More than two thirds (n=64, 67%) of ERT-experienced patients had been on ERT treatment for more than 5 years prior to entering the trial (mean of 7.4 years). Demographics, baseline sitting forced vital capacity (FVC) (% predicted), and 6-minute walk distance (6MWD) were generally similar between the 2 treatment groups. Key efficacy endpoints included assessment of sitting FVC (% predicted) and 6MWD. The ERT-experienced patients treated with Pombiliti in combination with Opfolda showed a numerically favorable change in sitting FVC from baseline at Week 52 (p=0.006).(11) Patients treated with combination Pombiliti and Opfolda walked on average 21 meters farther from baseline as compared to those treated with a non-U.S.-approved alglucosidase alfa product with placebo who walked 8 meters farther from baseline; the estimated treatment difference was 14 meters (95% CI: -1, 28). The ERT-experienced patients treated with Opfolda in combination with Pombiliti showed a numerically favorable change in 6MWD from baseline at Week 52 (p=0.047).(11) Opfolda in combination with Pombiliti is not approved for use in ERT-naïve patients with LOPD. The ERT-naïve patient subgroup enrolled too few patients to conclusively interpret the data.(11) A U.S.-approved alglucosidase alfa product was not used in this clinical trial. Conclusions cannot be drawn from this clinical trial regarding comparative effectiveness between a U.S.-approved alglucosidase alfa product and Opfolda in combination with Pombiliti for the treatment of adult patients with LOPD.(11) |
Safety |
Cerdelga (eliglustat) is contraindicated in the following patients based on CYP2D6 metabolizer status due to the risk of cardiac arrhythmias from prolongation of the PR, QTc, and/or QRS cardiac intervals:(1)
Opfolda in combination with Pombiliti is contraindicated in pregnancy.(11) Zavesca (miglustat) has no contraindications.(2) |
REFERENCES
Number |
Reference |
1 |
Cerdelga prescribing information. Genzyme Corporation. December 2022. |
2 |
Zavesca prescribing information. Actelion Pharmaceuticals US, Inc. August 2022. |
3 |
National Organization for Rare Disorders (NORD) – Physicians Guides. Gaucher Disease. Last updated March 2020. Available at: https://rarediseases.org/physician-guide/gaucher-disease/. |
4 |
Hughes D, Sidransky E, et al. Gaucher Disease: Pathogenesis, Clinical Manifestations, and Diagnosis. UpToDate. Last updated June 2022. Literature review current through December 2023. |
5 |
Pastores GM, Hughes DA. Gaucher Disease. July 2000 [Updated December 2023]. In: Adam MP, Ardinger HH, Pago RA, et al. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1269/. |
6 |
Hughes D, Sidransky E, et al. Gaucher Disease: Treatment. UpToDate. Last updated August 2022. Literature review current through December 2023. |
7 |
Martins AM, Valadares ER, Porta G, et al. Recommendations on Diagnosis, Treatment, and Monitoring for Gaucher Disease. J Pediatr. 2009;155(4):S10-S18. |
8 |
Biegstraaten M, Cox TM, Belmatoug N, et al. Management Goals for Type 1 Gaucher Disease: An Expert Consensus Document from the European Working Group on Gaucher Disease. Blood Cells Mol Dis. 2018;68:203-208. |
9 |
Wang RY, Bodamer OA, Watson MS, et al. American College of Medical Genetics (ACMG) Work Group on Lysosomal Storage Diseases: Diagnostic Confirmation and Management of Presymptomatic Individuals. Genet Med. 2011 May;13(5):457-484. |
10 |
Weinreb NJ, Aggio MC, Andersson HC, et al. Gaucher Disease Type 1: Revised Recommendations on Evaluations and Monitoring for Adult Patients. Semin Hematol. 2004;41(suppl 5):15-22. |
11 |
Opfolda prescribing information. Amicus Therapeutics US, LLC. September 2023. |
12 |
Kronn DF, Day-Salvatore D, Hwu WL, et al. The Pompe Disease Newborn Screening Working Group on Management of Confirmed Newborn-Screened Patients with Pompe Disease Across the Disease Spectrum. J Pediatrics. 2017 Jul;140(1):S24-S45. |
13 |
Hahn S, et al. Lysosomal Acid Alpha-Glucosidase Deficiency (Pompe Disease, Glycogen Storage Disease II, Acid Maltase Deficiency). UpToDate. Last updated November 2021. Literature review current through December 2023. |
14 |
Reuser AJJ, et al. Pompe Disease. National Organization for Rare Disorders (NORD). Last updated January 2024. Available at: https://rarediseases.org/rare-diseases/pompe-disease/. |
15 |
Cupler EJ, Berger KI, Leshner RT, et al. American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) Position Statement: Consensus Treatment Recommendations for Late-Onset Pompe Disease. Muscle Nerve. 2012 Mar;45(3):319-333. |
16 |
Tarnopolsky M, Katzberg H, Petrof BJ, et al. Pompe Disease Diagnosis and Management: Evidence-Based Guidelines from a Canadian Expert Panel. Can J Neurol Sci. 2016;43:472-485. |
POLICY AGENT SUMMARY PRIOR AUTHORIZATION
Target Brand Agent(s) |
Target Generic Agent(s) |
Strength |
Targeted MSC |
Available MSC |
Final Age Limit |
Preferred Status |
|
||||||
Cerdelga |
eliglustat tartrate cap |
84 MG |
M ; N ; O ; Y |
N |
|
|
Opfolda |
miglustat (gaa deficiency) cap |
65 MG |
M ; N ; O ; Y |
N |
|
|
Yargesa ; Zavesca |
miglustat cap |
100 MG |
M ; N ; O ; Y |
O ; Y |
|
|
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 |
|
|||||||||
Cerdelga |
Eliglustat Tartrate Cap 84 MG (Base Equivalent) |
84 MG |
60 |
Capsules |
30 |
DAYS |
|
|
|
Opfolda |
miglustat (gaa deficiency) cap |
65 MG |
8 |
Capsules |
28 |
DAYS |
|
|
|
Yargesa ; Zavesca |
Miglustat Cap 100 MG |
100 MG |
90 |
Capsules |
30 |
DAYS |
|
|
|
CLIENT SUMMARY – PRIOR AUTHORIZATION
Target Brand Agent Name(s) |
Target Generic Agent Name(s) |
Strength |
Client Formulary |
Cerdelga |
eliglustat tartrate cap |
84 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
Opfolda |
miglustat (gaa deficiency) cap |
65 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
Yargesa ; Zavesca |
miglustat cap |
100 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 |
Cerdelga |
Eliglustat Tartrate Cap 84 MG (Base Equivalent) |
84 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
Opfolda |
miglustat (gaa deficiency) cap |
65 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
Yargesa ; Zavesca |
Miglustat Cap 100 MG |
100 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
PRIOR AUTHORIZATION CLINICAL CRITERIA FOR APPROVAL
Module |
Clinical Criteria for Approval |
||||||||||
Cerdelga, Zavesca |
Initial 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. *Step therapy requirement may not apply if a prior health plan paid for the medication - documentation of a paid claim may be required.
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. |
||||||||||
Opfolda |
Initial Evaluation Opfolda 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.
Renewal Evaluation Opfolda 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: up to 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.
ALBP _ Commercial _ CSReg _ Substrate_Reduction_Therapy_PAQL _ProgSum_ 07-01-2024 _ © Copyright Prime Therapeutics LLC. May 2024 All Rights Reserved