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ph-1045

Homozygous Familial Hypercholesterolemia Agents (HoFH) Prior Authorization with Quantity Limit Program Summary

Policy Number: PH-1045

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	07-01-2013

FDA LABELED INDICATIONS AND DOSAGE

Agent(s)	FDA Indication(s)	Notes	Ref#
Juxtapid® (lomitapide) Capsule	Adjunct therapy to a low-fat diet and other lipid lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B), and non-high density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH). Limitations of Use: The safety and effectiveness of Juxtapid have not been established in patients with hypercholesterolemia who do not have HoFH, including those with heterozygous familial hypercholesterolemia (HeFH) The effect of Juxtapid on cardiovascular morbidity and mortality has not been determined		1

Agent(s)

FDA Indication(s)

Notes

Ref#

Juxtapid®

(lomitapide)

Capsule

Adjunct therapy to a low-fat diet and other lipid lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B), and non-high density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).

Limitations of Use:

The safety and effectiveness of Juxtapid have not been established in patients with hypercholesterolemia who do not have HoFH, including those with heterozygous familial hypercholesterolemia (HeFH)
The effect of Juxtapid on cardiovascular morbidity and mortality has not been determined

See package insert for FDA prescribing information: https://dailymed.nlm.nih.gov/dailymed/index.cfm

CLINICAL RATIONALE

HoFH

Homozygous familial hypercholesterolaemia (HoFH) is a rare autosomal semi-dominant disease affecting males and females equally, characterized by markedly elevated levels of low-density lipoprotein cholesterol (LDL-C) from conception and accelerated atherosclerotic cardiovascular disease (ASCVD), often resulting in early death. Estimated global prevalence of HoFH by United Nations world region based on 2020 population data, estimates HoFH prevalence ranging from 1:250,000 to 1:360,000. Inadequate awareness and a disconnect between clinical diagnosis and interpretation of genetic results by health providers and payers contribute to underdiagnosis and undertreatment of HoFH. To address this, the European Atherosclerosis Society (EAS) has recently updated clinical guidance for HoFH care to improve education, early diagnosis, and improve cardiovascular health for patients with HoFH worldwide. Recent estimates indicate that about 30,000 people worldwide have HoFH but less than 5% are identified.(2)

In 2014, the EAS statement on HoFH focused attention on this rare life-threatening disease which at the time had limited therapeutic options. The last decade has shown great progress in understanding the genetic complexity of HoFH, with new highly efficacious LDL-C-lowering therapies leading to improved survival and quality of life. The 2023 EAS consensus statement includes updated criteria for the clinical diagnosis of HoFH and the recommendation to prioritize phenotypic (clinically suspected in the absence of genetic data) features over genotype.(2)

The EAS notes plasma LDL-C is the critical discriminator for clinical diagnosis of HoFH. The updated 2023 clinical criteria recommends an untreated LDL-C of >10 mmol/L (>400 mg/dL) is suggestive of HoFH requiring further investigation to confirm the diagnosis (including a detailed medical and family history and/or genetic testing). Additional criteria includes cutaneous or tendon xanthomas before age of 10 years and/or untreated elevated LDL-C levels consistent with heterozygous FH (HeFH) in both parents (or in digenic form, one parent may have normal LDL-C levels and the other may have LDL-C levels consistent with HoFH). Due to the large variety of lipid-lowering treatments that these patients typically receive, the historic cut-offs for a treated LDL-C are likely now obsolete.(2)

However, LDL-C criteria are not the sole guide to diagnosis, given the genetic complexity of HoFH and variability in LDL-C levels and clinical phenotype. The updated 2023 genetic criteria are genetic confirmation of bi-allelic pathogenic/likely pathogenic variants on different chromosomes at the LDLR, ApoB, PCSK9, or LDLRAP1 genes or greater than or equal to 2 such variants at different loci. The benefits outweigh the limitations of genetic testing in HoFH with increased certainty of diagnosis and access to, use of, and compliance with appropriate treatment. A significant limitation of genetic testing has and continues to be accessibility and cost. Additionally predicting individual phenotype and clinical response from genotype is not straightforward, and pathogenicity for many detected DNA variants cannot be definitively established. Some patients with phenotypic HoFH have only one or even no pathogenic variant detected, and some patients with bi-allelic pathogenic variants express HeFH but not HoFH phenotypically.(2)

The LDL-C level (i.e., the phenotype) and not the presence of a genetic diagnosis drives therapeutic decisions. Combination lipid-lowering therapy, both pharmacologic intervention and lipoprotein apheresis (LA), is foundational, together with lifestyle measures (diet and smoking cessation). Patients should start on a high-intensity statin and ezetimibe rather than statin monotherapy, but most will require additional therapies to attain goal. Within 8 weeks PCSK9-directed therapy should be considered where available. Response to these treatments is dependent on LDL receptor (LDL-R) activity. If patients show >15% additional LDL-C reduction, PCSK9-directed therapy may be continued, but if response is poor, clinicians should consider stopping this therapy. While PCSK9 therapy is likely to reduce the risk of ASCVD events, LDL-C levels will remain substantially above recommended goals for most patients. Other options include LDL receptor–independent therapies (such as evinacumab or lomitapide) and/or LA. Lomitapide is noted to provide better control of LDL-C than LA. Preliminary findings from the Pan-European Project in HoFH including 75 patients with HoFH showed that lomitapide treatment for up to 9 years (median 19 months) resulted in more than half attaining at least 50% reduction from baseline in LDL-C at last visit, with less need for apheresis in a substantial proportion of patients. If LA, evinacumab, or lomitapide are not available, liver transplantation can be considered.(2)

The National Organization for Rare Disorders (NORD) states that patients with HoFH should be initially started on statins with preference given to higher potency statins (atorvastatin or rosuvastatin) used at the maximal dose noting that statins can be relatively ineffective in HoFH. This is because the mechanism of action of statins normally “triggers” the liver to express additional LDL receptors (LDL-R). In the most severe cases of HoFH, the LDL-R are completely inactive which makes this response futile. Statins can be effective in individuals with HoFH if there is some residual LDL-R activity, or if they have causal DNA variants in the APOB or PCSK9 genes. Patients with HoFH often require additional treatment strategies including lomitapide and evinacumab-dgnb. Additional treatment options include LA or liver transplantation.(4)

Safety

Juxtapid has a boxed warning for risk of hepatotoxicity.(1)

Juxtapid can cause elevations in transaminases and increase hepatic fat, with or without concomitant increases in transaminases. Hepatic steatosis associated with Juxtapid treatment may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis. Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiating treatment and then ALT and AST regularly as recommended. During treatment, adjust the dose of Juxtapid if the ALT or AST are greater than or equal to three times the upper limit of normal. Discontinue Juxtapid for clinically significant liver toxicity. Because of the risk of hepatotoxicity, Juxtapid is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Juxtapid should be prescribed only to patients with a clinical or laboratory diagnosis consistent with HoFH. The safety and effectiveness of Juxtapid have not been established in patients with hypercholesterolemia who do not have HoFH.

Juxtapid is contraindicated in the following conditions:(1)

Pregnancy
Concomitant use with moderate or strong CYP3A4 inhibitors as this can increase Juxtapid exposure
Patients with moderate or severe hepatic impairment (based on Child-Pugh category B or C) and patients with active liver disease, including unexplained persistent elevations of serum transaminases

REFERENCES

Number	Reference
1	Juxtapid prescribing information. Aegerion Amryt Pharmaceuticals, Inc. Cambridge, MA. September 2020.
2	Cuchel, M., Raal, F. J., Hegele, R. A., Al-Rasadi, K., Arca, M., Averna, M., Bruckert, E., Freiberger, T., Gaudet, D., Harada-Shiba, M., Hudgins, L. C., Kayikcioglu, M., Masana, L., Parhofer, K. G., Roeters van Lennep, J. E., Santos, R. D., Stroes, E. S., Watts, G. F., Wiegman, A., ... Ray, K. K. (2023). 2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance. European Heart Journal, 44(25), 2277-2291. https://doi.org/10.1093/eurheartj/ehad197
3	Reference no longer used
4	National Organization for Rare Disorders (NORD). (2023, May 25). Familial Hypercholesterolemia. https://rarediseases.org/rare-diseases/familial-hypercholesterolemia/
5	Gidding, S. S., Champagne, M., de Ferranti, S. D., Defesche, J., Ito, M. K., Knowles, J. W., McCrindle, B., Raal, F., Rader, D., Santos, R. D., Lopes-Virella, M., Watts, G. F., & Wierzbicki, A. S. (2015). The Agenda for Familial Hypercholesterolemia. A Scientific Statement from the American Heart Association. Circulation, 132(22), 2167–2192. https://doi.org/10.1161/cir.0000000000000297
6	Reference no longer used

POLICY AGENT SUMMARY PRIOR AUTHORIZATION

Target Brand Agent(s)	Target Generic Agent(s)	Strength	Targeted MSC	Available MSC	Final Age Limit	Preferred Status

Juxtapid	lomitapide mesylate cap	10 MG ; 20 MG ; 30 MG ; 5 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

Juxtapid	Lomitapide Mesylate Cap 10 MG (Base Equiv)	10 MG	30	Capsules	30	DAYS
Juxtapid	Lomitapide Mesylate Cap 20 MG (Base Equiv)	20 MG	60	Capsules	30	DAYS
Juxtapid	Lomitapide Mesylate Cap 30 MG (Base Equiv)	30 MG	60	Capsules	30	DAYS
Juxtapid	Lomitapide Mesylate Cap 5 MG (Base Equiv)	5 MG	30	Capsules	30	DAYS

CLIENT SUMMARY – PRIOR AUTHORIZATION

Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	Client Formulary
Juxtapid	lomitapide mesylate cap	10 MG ; 20 MG ; 30 MG ; 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
Juxtapid	Lomitapide Mesylate Cap 10 MG (Base Equiv)	10 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Juxtapid	Lomitapide Mesylate Cap 20 MG (Base Equiv)	20 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Juxtapid	Lomitapide Mesylate Cap 30 MG (Base Equiv)	30 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx
Juxtapid	Lomitapide Mesylate Cap 5 MG (Base Equiv)	5 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: ONE of the following: The patient has the diagnosis of homozygous familial hypercholesterolemia (HoFH) and ALL of the following: ONE of the following: Genetic confirmation of bi-allelic pathogenic/likely pathogenic variants on different chromosomes at the LDLR, Apo-B, PCSK9, or LDLRAP1 genes, or greater than or equal to 2 such variants at different loci OR History of untreated LDL-C greater than 400 mg/dL (greater than 10 mmol/L) AND ONE of the following: The patient had cutaneous or tendon xanthomas before age of 10 years OR Untreated elevated LDL-C levels consistent with heterozygous FH in both parents, (or in digenic form, one parent may have normal LDL-C levels and the other may have LDL-C levels consistent with HoFH) AND ONE of the following: The patient has tried a combination of a high-intensity statin (e.g., atorvastatin 40-80 mg, rosuvastatin 20-40 mg daily) and ezetimibe for 2 months and had an inadequate response OR The patient has an intolerance or hypersensitivity to ALL combinations of a high-intensity statin and ezetimibe OR The patient has an FDA labeled contraindication to ALL combinations of a high-intensity statin and ezetimibe AND ONE of the following: The patient has tried and had an inadequate response to a PCSK9 inhibitor OR The patient has an intolerance or hypersensitivity to ALL PCSK9 inhibitors OR The patient has an FDA labeled contraindication to ALL PCSK9 inhibitors AND The patient will be using with a low-fat diet and/or other lipid-lowering therapy (e.g., statin, PCSK9 inhibitor, lipoprotein apheresis, evinacumab) AND The prescriber is a specialist in the area of the patient’s diagnosis (e.g., cardiologist, endocrinologist, lipid specialist, geneticist), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND The patient has another FDA labeled indication for the requested agent and route of administration OR The patient has another indication that is supported in compendia for the requested agent and route of administration AND The patient does NOT have any FDA labeled contraindications to the requested agent Compendia Allowed: AHFS, or DrugDex 1 or 2a level of evidence 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 for renewal when ALL of the following are met: The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND The patient has had clinical benefit with the requested agent AND If the patient has a diagnosis of HoFH, BOTH of the following: The patient will continue to use with a low fat diet and/or other lipid-lowering therapy (e.g., statin, PCSK9 inhibitor, lipoprotein apheresis, evinacumab) AND The prescriber is a specialist in the area of the patient’s diagnosis (e.g., cardiologist, endocrinologist, lipid specialist, geneticist), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND The patient does NOT have any FDA labeled contraindications to the requested agent Length of Approval: 12 months NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Module

Clinical Criteria for Approval

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

ONE of the following:
1. The patient has the diagnosis of homozygous familial hypercholesterolemia (HoFH) and ALL of the following:
  1. ONE of the following:
    1. Genetic confirmation of bi-allelic pathogenic/likely pathogenic variants on different chromosomes at the LDLR, Apo-B, PCSK9, or LDLRAP1 genes, or greater than or equal to 2 such variants at different loci OR
    2. History of untreated LDL-C greater than 400 mg/dL (greater than 10 mmol/L) AND ONE of the following:
      1. The patient had cutaneous or tendon xanthomas before age of 10 years OR
      2. Untreated elevated LDL-C levels consistent with heterozygous FH in both parents, (or in digenic form, one parent may have normal LDL-C levels and the other may have LDL-C levels consistent with HoFH) AND
  2. ONE of the following:
    1. The patient has tried a combination of a high-intensity statin (e.g., atorvastatin 40-80 mg, rosuvastatin 20-40 mg daily) and ezetimibe for 2 months and had an inadequate response OR
    2. The patient has an intolerance or hypersensitivity to ALL combinations of a high-intensity statin and ezetimibe OR
    3. The patient has an FDA labeled contraindication to ALL combinations of a high-intensity statin and ezetimibe AND
  3. ONE of the following:
    1. The patient has tried and had an inadequate response to a PCSK9 inhibitor OR
    2. The patient has an intolerance or hypersensitivity to ALL PCSK9 inhibitors OR
    3. The patient has an FDA labeled contraindication to ALL PCSK9 inhibitors AND
  4. The patient will be using with a low-fat diet and/or other lipid-lowering therapy (e.g., statin, PCSK9 inhibitor, lipoprotein apheresis, evinacumab) AND
  5. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., cardiologist, endocrinologist, lipid specialist, geneticist), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
2. The patient has another FDA labeled indication for the requested agent and route of administration OR
3. The patient has another indication that is supported in compendia for the requested agent and route of administration AND
The patient does NOT have any FDA labeled contraindications to the requested agent

Compendia Allowed: AHFS, or DrugDex 1 or 2a level of evidence

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 for renewal when ALL of the following are met:

The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND
The patient has had clinical benefit with the requested agent AND
If the patient has a diagnosis of HoFH, BOTH of the following:
1. The patient will continue to use with a low fat diet and/or other lipid-lowering therapy (e.g., statin, PCSK9 inhibitor, lipoprotein apheresis, evinacumab) AND
2. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., cardiologist, endocrinologist, lipid specialist, geneticist), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
The patient does NOT have any FDA labeled contraindications to the requested agent

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
QL with PA	Quantity limit for the Target Agent(s) will be approved when ONE of the following is met: The requested quantity (dose) does NOT exceed the program quantity limit OR ALL of the following: The requested quantity (dose) exceeds the program quantity limit AND The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit Length of Approval: up to 12 months

Module

Clinical Criteria for Approval

QL with PA

Quantity limit for the Target Agent(s) will be approved when ONE of the following is met:

The requested quantity (dose) does NOT exceed the program quantity limit OR
ALL of the following:
1. The requested quantity (dose) exceeds the program quantity limit AND
2. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
3. The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit

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.