Lonafarnib (Zokinvy) Form

Lonafarnib (Zokinvy™) is farnesyltransferase inhibitor. FDA Approved Indication(s) Zokinvy is indicated in patients 12 months of age and older with a body surface area of 0.39 m2 and above: • To reduce risk of mortality in Hutchinson-Gilford progeria syndrome (HGPS) • For treatment of processing-deficient progeroid laminopathies with either: o Heterozygous LMNA mutation with progerin-like protein accumulation o Homozygous or compound heterozygous ZMPSTE24 mutations Limitation(s) of use: Zokinvy is not indicated for other progeroid syndromes or processing- proficient progeroid laminopathies. Based upon its mechanism of action, Zokinvy would not be expected to be effective in these populations. 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 Zokinvy is medically necessary when the following criteria are met:
I. Initial Approval Criteria A. Progeria and Progeroid Laminopathy (must meet all):

1. Diagnosis of one of the following (a or b): a. HGPS with documentation of genetic mutation in the LMNA gene; b. Processing-deficient progeroid laminopathy with documentation of one of the following (i or ii): i. Heterozygous LMNA mutation with progerin-like protein accumulation; ii. Homozygous or compound heterozygous ZMPSTE24 mutations;
   2. Prescribed by or in consultation with a geneticist, metabolic disorder specialist, or progeria specialist;

2. Age ≥ 1 year;

   4. Body surface area (BSA) ≥ 0.39 m2;
   5. Dose does not exceed any of the following (a or b): a. New starts or treated for less than 4 months: 230 mg/m2 per day, rounded to the nearest 25 mg dose (see table in Section V) for a total of 4 months; Page 1 of 7

   CLINICAL POLICY Lonafarnib b. Maintenance after 4 months: 300 mg/m2 per day, rounded to the nearest 25 mg dose (see table in Section V).
   Approval duration:
   New starts: 4 months Maintenance: 12 months B. Other diagnoses/indications (must meet 1 or 2):

3. 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
4. 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. Progeria and Progeroid Laminopathy (must meet all):
5. 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);
   2. Member is responding positively to therapy;
   3. If request is for a dose increase, new dose does not exceed 300 mg/m2 per day, rounded to the nearest 25 mg dose (see table in Section V). Approval duration: 12 months B. Other diagnoses/indications (must meet 1 or 2):

6. 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 7

   CLINICAL POLICY Lonafarnib 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

7. 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; B. Other progeroid syndromes; C. Processing-proficient progeroid laminopathies. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key BSA: body surface area FDA: Food and Drug Administration HGPS: Hutchinson‐Gilford progeria syndrome Appendix B: Therapeutic Alternatives Not applicable Appendix C: Contraindications/Boxed Warnings
   • Contraindication(s): concomitant use of Zokinvy with: o Strong or moderate CYP3A inhibitors o Strong or moderate CYP3A inducers
   o Midazolam o Lovastatin, simvastatin, or atorvastatin
   • Boxed warning(s): none reported Appendix D: General information
   • The diagnosis of HGPS is established in a proband with characteristic clinical features, along with identification of a heterozygous pathogenic variant in LMNA that results in production of the abnormal lamin A protein, progerin. HGPS is characterized by the following clinical features that typically develop in childhood and resemble some features of accelerated aging: o Growth deficiency: Profound failure to thrive usually occurs during the first year. Poor weight gain and loss of subcutaneous fat results in weight less than the third percentile for age, and weight that is distinctly low for height. Stature also decreases to below the third percentile for age. Page 3 of 7

   CLINICAL POLICY Lonafarnib o Characteristic facial features: a head that appears disproportionately large for face, narrow nasal ridge with a narrow nasal tip, thin vermilion of the upper and lower lips, small mouth, retrognathia, and micrognathia. o Cardiovascular/cerebrovascular: Individuals with HGPS develop severe atherosclerosis, usually without obvious abnormalities in lipid profiles. Systolic dysfunction is usually present in the setting of advanced disease, with or without identified coronary vascular insufficiency. Clinical symptoms of angina, dyspnea on exertion, or overt heart failure appear as late findings in the course of disease. o Endocrine: Affected individuals do not become sexually mature. Females reach Tanner Stage 1 (78%) or 2 (22%) during pubertal years, and approximately 60% of females experience menarche o Musculoskeletal: Individuals with HGPS are particularly susceptible to hip dislocation because of the progressive coxa valga malformation, which can be accompanied by avascular necrosis of the hip (osteonecrosis).
   • Individuals with classic genotype HGPS are heterozygous for pathogenic variant c.1824C>T (~90% of individuals with HGPS). Individuals with non-classic genotype HGPS have the characteristic clinical features of HGPS and are heterozygous for another LMNA pathogenic variant in exon 11 or intron 11 that results in production of progerin (~10% of individuals with HGPS). • Genetic testing can be obtained through The Progeria Research Foundation Diagnostic Testing Program, provided at no cost to families. Current link can be found here: https://www.progeriaresearch.org/the-prf-diagnostic-testing-program/.
   Maximum Dose 300 mg/m2/day V. Dosage and Administration Indication Dosing Regimen Progeria and progeroid laminopathy Initial BSA-based dosage for the starting dosage of 115 mg/m2 twice daily for 4 months: BSA (m2) Total Daily Dosage Rounded to Nearest 25 mg Morning Dosing Number of Capsule(s) Evening Dosing Number of Capsule(s) Zokinvy 50 mg Zokinvy 75 mg Zokinvy 50 mg Zokinvy 75 mg 0.39 - 0.48 100 0.49 - 0.59 125 0.6 - 0.7 150 0.71 - 0.81 175 0.82 - 0.92 200 225 0.93 – 1 1 2 2 1 1 1 1 1 1 2 2 1 1 Page 4 of 7

   CLINICAL POLICY Lonafarnib Indication Dosing Regimen Maximum Dose Maintenance BSA-based dosage of 150 mg/m2 twice daily: BSA (m2) Total Daily Dosage Rounded to Nearest 25 mg Morning Dosing Number of Capsule(s) Evening Dosing Number of Capsule(s) Zokinvy 50 mg Zokinvy 75 mg Zokinvy 50 mg Zokinvy 75 mg 0.39 - 0.45 125 0.46 - 0.54 150 0.55 - 0.62 175 0.63 - 0.7 200 0.71 - 0.79 225 0.8 - 0.87 250 0.88 - 0.95 275 300 0.96 – 1 2 2 1 1 1 1 1 1 2 2 1 2 2 1 1 1 1 1 1 2 VI. Product Availability Capsules: 50 mg, 75 mg VII.