Evenity (romosozumab-aqqg) Clinical Policy Form

Page 1 of 9 AHP- Evenity (romosozumab-aqqg) PART B DRUG MEDICAL/PHARMACY Effective Date May 15, 2025 Policy # EVENITY (romosozumab-aqqg) Evenity (romosozumab-aqqg) Review Date Applicable to: 02/25/2025 Medicare Advantage Commercial Elevance Health HMO Blue Shield Trio Approver’s Name & Title QI & UM Drug Subcommittee Aspire Health Plan applies medical drug clinical criteria as a reference for medical policy information only. Federal and state laws or requirements, contract language, and Plan benefit may take precedence over the application of these clinical criteria. Please consult the applicable certificate or contract for benefit details. This policy is subject to revision at the discretion of the Plan and is therefore subject to change. Refer to the ‘Disclaimer’ section below for more information. POLICY This policy outlines the coverage of Evenity (romosozumab-aqqg) for the treatment of osteoporosis. APPLICABLE HCPCS J3111: Injection, romosozumab-aqqg, 1 mg (1 billable unit = 1 mg) Available as: 105 mg / 1.17 mL solution in a single-use prefilled syringe. CLINICAL CRITERIA A. INITIAL CRITERIA Evenity (romosozumab-aqqg) may be authorized when ALL of the following criteria are met, with supporting documentation: 1. Diagnosis of osteoporosis in postmenopausal women at high risk of fracture High risk for fractures is defined by one or more of the following: a. Alcohol intake of 3 or more drinks per day b. BMI less than 20 c. Current cigarette use d. Glucocorticoid use for 3 months or longer e. Parental history of fragility or osteoporotic hip fracture f. Personal history of fragility or osteoporotic fracture g. Rheumatoid arthritis (confirmed diagnosis)

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AND

2. Bone Mineral Density (BMD) or Fracture History Documentation Documentation of ONE or more of the following: a. Hip/femur DXA (femoral neck or total hip) or lumbar spine T-score ≤ -2.5 and/or forearm DXA at the 33% (one-third) radius site (wrist); OR b. T-score ≤ -1.0 with a history of fragility fracture to the hip or spine; OR

   AND c. T-score between -1.0 and -2.5 with a FRAX 10-year probability for major osteoporotic fracture ≥ 20% or hip fracture ≥ 3%.

3. Prior Treatment Failure or Contraindication to Bisphosphonates Documentation of ONE of the following: a. Treatment failure with a *bisphosphonate (oral or IV) after at least 12 months of compliant therapy, defined as: i. Progression of bone loss as documented by BMD; OR

   ii. Occurrence of an osteoporotic fracture. *Oral bisphosphonate (e.g., alendronate, risedronate, ibandronate); Intravenous bisphosphonate (e.g., ibandronate, zoledronic acid)

   OR b. No contraindication(s), hypersensitivity, or intolerance to bisphosphonates, including but not limited to: i. Hypersensitivity to bisphosphonates or any component of the formulation ii. Hypocalcemia (alendronate, ibandronate, risedronate, zoledronic acid [Reclast]); iii. Abnormalities of the esophagus that delay esophageal emptying, such as stricture or achalasia (alendronate, etidronate, oral ibandronate, risedronate); iv. Increased risk of aspiration (alendronate [effervescent tablet and oral solution]); v. Inability to stand or sit upright for at least 30 minutes (alendronate, risedronate); inability to stand or sit upright for at least 60 minutes (oral ibandronate) vi. Clinically overt osteomalacia (etidronate); vii. Renal impairment (e.g, CrCl < 35 mL/minute for zoledronic acid [Reclast]) (FDA labeling, 2023)

   NOTE: If a member has intolerance to oral administration, an intravenous bisphosphonate (e.g., ibandronate, zoledronic acid) will be required.

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AND

4. Prescriber Attestation and Documentation Prescriber attests or provides documentation of the following:

   a. Evenity will not be administered concurrently with other osteoporosis medications [e.g., a bisphosphonate, denosumab (e.g., Prolia or Xgeva) parathyroid hormone analog [e.g., abloparatide (Tymlos), teriparatide (Forteo)]; and b. Hypocalcemia has been reviewed and corrected prior to initiation of treatment, if applicable; and c. Member is taking calcium and vitamin D supplements in conjunction ( if dietary intake is inadequate); and d. Member has not had a myocardial infarction or stroke within previous 12 months. Note: For patients with other cardiovascular risk factors, Prescriber confirm whether benefits of therapy outweigh the risks.

   B. REAUTHORIZATION / CONTINUATION OF THERAPY CRITERIA

   Evenity (romosozumab-aqqg) is limited to a *single course of therapy for 12 months. Reauthorization for continuation of treatment beyond 12 months will not be approved. NOTE: The anabolic effect of Evenity wanes after 12 monthly doses of therapy. Therefore, the duration of Evenity use should be limited to 12 monthly doses. If osteoporosis therapy remains warranted, continuing therapy with an antiresorptive agent (e.g., with a bisphosphonate or denosumab) to maintain bone density gains should be considered.

   STEP THERAPY

   Step Therapy Does NOT Apply if: • The member is currently being treated with the requested medication, Evenity. • The member has received the requested drug within the last 365 days.

   Step Therapy Applies if: • The member is new to therapy (i.e., has not received the requested drug in the last 365 days). A. PREFERRED PRODUCT(S): Bisphosphonates (IV) [Zoledronic acid (first preferred) and ibandronate (second preferred)] -- NO STEP THERAPY REQUIRED

   B. SECOND-LINE PREFERRED PRODUCT(S): PROLIA (denosumab)

   C. NON-PREFERRED PRODUCT, Evenity (romosozumab-aqqg), may be authorized when ALL the clinical criteria above are met AND the member meets the following with documentation:

5. History of use of bisphosphonates (IV) for osteoporosis (Zoledronic acid [Reclast];

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Ibandronate [Boniva]) AND Prolia (denosumab) resulting in minimal clinical response to therapy (defined as a decrease in BMD or a fracture while on therapy); OR

2. Contraindication, intolerance, or adverse event(s) to one bisphosphonate (IV) (Zoledronic acid [Reclast]; Ibandronate [Boniva]) AND Prolia (denosumab); Contraindications to zoledronic acid: Hypersensitivity to zoledronic acid or any component of the formulation; hypocalcemia (Reclast only); CrCl < 35 mL/minute and in those with evidence of acute renal impairment (Reclast only). Contraindications to Ibandronate: Hypocalcemia; known hypersensitivity to ibandronate or any component of the formulation. Contraindications to Prolia therapy include: hypersensitivity (systemic) to denosumab or any component of the formulation; preexisting hypocalcemia; pregnancy. OR

3. Member has previously received Evenity (romosozumab-aqqg) within the past 365 days and therefore not subject to step therapy requirements.

   DOSAGE AND AUTHORIZATION TIMEFRAMES

4. Recommended Dose: Administer 210 mg subcutaneously once every month. Each monthly dose consists of two consecutive subcutaneous injections.

5. Maximum Quantity: a. 210 mg once every month for 12 months

   b. Monthly dose: Two single-use prefilled syringes (a full dose requires TWO single-use prefilled syringes of 105 mg/1.17 mL per single-use prefilled syringes)

6. Authorization Period: Initial authorization: 12 months: Reauthorization: N/A

   DRUG INFORMATION

   PHARMACOLOGIC CATEGORY: Monoclonal Antibody: Sclerostin inhibitor ROUTE OF ADMINISTRATION: Subcutaneous (SC) injection FDA-APPROVED INDICATION: Treatment of postmenopausal osteoporosis in patients at high risk for fracture, defined as: • Patients with a history of osteoporotic fracture; OR • Patients with multiple risk factors for fracture; OR • Patients who have failed or are intolerant to other available osteoporosis therapies. Limitations of use: • The anabolic effect of romosozumab wanes after 12 monthly doses. Therefore, the duration of therapy should be limited to 12 monthly doses. • If ongoing osteoporosis therapy is warranted after completing a 12-month course of Evenity, transition to an antiresorptive agent (e.g., bisphosphonate or denosumab) is

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recommended to maintain bone density gains. COMPENDIAL APPROVED (OFF-LABEL) USES: None BOXED WARNING: Potential Risk of Myocardial Infarction (MI), Stroke, and Cardiovascular Death • Evenity should not be initiated in patients who have had an MI or stroke within the preceding 12 months. • Consider whether the benefits of Evenity outweigh the risks in patients with other cardiovascular risk factors. CONTRAINDICATIONS: • Hypersensitivity to romosozumab or any component of the formulation (e.g., angioedema, erythema multiforme, urticaria). • Uncorrected hypocalcemia: Hypocalcemia must be corrected prior to initiating therapy.

OTHER CONSIDERATIONS:

Monitoring Parameters
Baseline and Ongoing Monitoring: • Serum calcium levels: Monitor and correct hypocalcemia before and during treatment. • Signs and symptoms of hypersensitivity reactions (e.g., angioedema, rash). • Signs and symptoms of adverse cardiovascular events (e.g., chest pain, shortness of breath, neurological deficits). Bone Mineral Density (BMD): • Assess BMD at baseline and periodically during treatment (e.g., at 6 or 12 months) to evaluate treatment response. Biochemical Markers of Bone Turnover (optional): • Consider monitoring markers such as fasting serum C-telopeptide (CTX) and serum procollagen type I N-terminal propeptide (P1NP) at baseline, 3 months, and 6 months to assess treatment response.

Page 6 of 9 AHP- Evenity (romosozumab-aqqg) CLINICAL SUMMARY / APPENDIX Osteoporosis is diagnosed by: • A T-score of -2.5 or less on dual-energy X-ray absorptiometry (DEXA) at the lumbar spine, femoral neck, or one-third radius (if hip and spine are uninterpretable) (NOF [Cosman 2014]; WHO criteria). • A fragility fracture (e.g., hip or vertebral fracture) in the absence of major trauma (NOF [Cosman 2014]). Fracture Risk Assessment: • The Fracture Risk Assessment Tool (FRAX®) should be used to evaluate the 10-year probability of hip fracture and major osteoporotic fracture (forearm, shoulder, or clinical vertebral fracture) (WHO; NOF [Cosman 2014]). • Treatment is recommended for: Osteopenic patients with a FRAX® score indicating ≥3% risk of hip fracture or ≥20% risk of major osteoporotic fracture (NOF [Cosman 2014]). Monitoring Parameters • Bone Mineral Density (BMD): Serial DXA scans should be performed at baseline and every 1 to 3 years, depending on patient-specific factors and treatment response. The first follow-up scan is typically recommended ~2 years after initiating therapy (AACE/ACE [Camacho et al., 2020]; Endocrine Society [Eastell et al., 2019]; NOF [Cosman et al., 2014]). • Biochemical Markers of Bone Turnover: Monitoring markers such as fasting serum C- terminal telopeptide (CTX) or urinary N-terminal telopeptide (NTX) can be considered at baseline, 3 months, and 6 months to assess treatment response (Eastell et al., 2019). According to UpToDate, there are no head-to-head trials comparing the anti-fracture efficacy of denosumab with other osteoporosis therapies (e.g., bisphosphonates, teriparatide). However, denosumab has shown similar reductions in vertebral fractures compared to subcutaneous teriparatide and intravenous zoledronic acid.Denosumab has demonstrated greater efficacy in reducing vertebral fractures compared to oral alendronate, though these findings are based on indirect comparisons across different trials (Rosen, 2023). Treatment Recommendations Initial Therapy Options: • Bisphosphonates (alendronate, risedronate, zoledronic acid) or denosumab for high- risk patients (AACE/ACE [Camacho 2020]; Endocrine Society [Eastell 2019]). • For very high-risk patients, consider denosumab, teriparatide, abaloparatide, or romosozumab (AACE/ACE [Camacho 2020]). Denosumab: • Denosumab is recommended for patients unable to use oral therapies or as initial therapy for very high-risk patients (AACE/ACE [Camacho 2020]). • Anti-fracture efficacy for vertebral fractures is comparable to teriparatide and zoledronic acid, though head-to-head trials are lacking (UpToDate [Rosen 2023]).

Page 7 of 9 AHP- Evenity (romosozumab-aqqg) American College of Endocrinology (AACE/ACE) Guidelines (2020) The AACE/ACE guidelines stratify treatment based on fracture risk: • High-Risk Patients: Initial therapy options include: ― Bisphosphonates (alendronate, risedronate, or zoledronic acid) ― Denosumab • Very High-Risk Patients: AACE introduced a "very high-risk" category for postmenopausal women with osteoporosis. This includes: ― Patients with a recent fracture (within the past 12 months), fractures while on osteoporosis therapy, multiple fractures, or fractures while on drugs causing skeletal harm (e.g., long-term glucocorticoids). ― Patients with a very low T-score (≤ -3.0). ― Patients with a high risk of falls or a history of injurious falls. ― Patients with a high fracture probability as determined by FRAX (e.g., major osteoporotic fracture risk >30%, hip fracture risk >4.5%) or other validated algorithms. • For very high-risk patients, the following therapies are recommended: ― Anabolic Agents: Abaloparatide, romosozumab, or teriparatide. ― Antiresorptive Agents: Denosumab or zoledronic acid. For high-risk patients who do not meet the very high-risk criteria, initial therapy with bisphosphonates or denosumab remains appropriate (Camacho et al., 2020). Endocrine Society Guidelines (2020) The Endocrine Society recommends: • Initial Therapy: Bisphosphonates (alendronate, risedronate, zoledronic acid, or ibandronate) or denosumab for high-risk patients. • Anabolic Agents: Teriparatide, abaloparatide, or romosozumab are recommended for patients at very high risk of fracture or those who fail initial therapy (Eastell et al., 2019). REFERENCES Government Agency Centers for Medicare and Medicaid Services (CMS). Medicare coverage database (no National Coverage Determination identified; no applicable LCD for MAC identified; search terms: Evenity; romosozumab). Available from CMS. Prescribing Information 1. Boniva Injection (ibandronate) [prescribing information]. South San Francisco, CA: Genentech USA Inc; January 2022. 2. Evenity (romosozumab-aqqg) [prescribing information]. Thousand Oaks, CA: Amgen Inc; April 2020. 3. Prolia (denosumab) [prescribing information]. Thousand Oaks, CA: Amgen Inc; January 2023. 4. Reclast (zoledronic acid) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; April 2020. Peer-reviewed Literature, Guidelines, Consensus 1. Anam AK, Insogna K. Update on osteoporosis screening and management. Medical Clinics of North America 2021;105(6):1117-1134. DOI: 10.1016/j.mcna.2021.05.016. 2. Adler RA. Update on Osteoporosis in Men. Best Practice & Research. Clinical Endocrinology & Metabolism 2018;32(5):759-772. DOI: 10.1016/j.beem.2018.05.007. 3. Camacho, P. M., Petak, S. M., Binkley, N., et al. (2020). American Association of Clinical Endocrinologists/American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis—2020 Update. Endocrine Practice, 26(Suppl 1),

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1–46. https://doi.org/10.4158/GL-2020-0524SUPPL

4. Compston JE, McClung MR, Leslie WD. Osteoporosis. Lancet 2019;393(10169):364-376. DOI: 10.1016/S0140-6736(18)32112-3.
5. Cosman, F., de Beur, S. J., LeBoff, M. S., et al. (2014). Clinician’s Guide to Prevention and Treatment of Osteoporosis. Osteoporosis International, 25(10), 2359–2381. https://doi.org/10.1007/s00198-014-2794-2.
6. Eastell, R., Rosen, C. J., Black, D. M., et al. (2019). Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism, 104(5), 1595–1622. https://doi.org/10.1210/jc.2019-00221
7. World Health Organization (WHO). WHO Fracture Risk Assessment Tool (FRAX®). Available at: https://www.shef.ac.uk/FRAX
8. National Osteoporosis Foundation (NOF). (2023). Clinician’s Guide to Prevention and Treatment of Osteoporosis. Retrieved from https://www.nof.org.
9. Licata AA. Bone density, bone quality, and FRAX: changing concepts in osteoporosis management. American Journal of Obstetrics and Gynecology 2013;208(2):92-96. DOI: 10.1016/j.ajog.2012.10.874.
10. Rosen, HN. Overview of the management of osteoporosis in postmenopausal women. In: UpToDate, Rosen, CJ. (Ed), UpToDate, Waltham, MA, 2023.
11. Rosen, HN. Denosumab for osteoporosis. In: UpToDate, Rosen, CJ. (Ed), UpToDate, Waltham, MA, 2023. Last updated: May 15, 2023. Accessed September 8, 2023.
12. Tsourdi E, Zillikens MC, Meier C, et al. Fracture risk and management of discontinuation of denosumab therapy: a systematic review and position statement by ECTS. J Clin Endocrinol Metab. Published online October 26, 2020. doi:10.1210/clinem/dgaa756[PubMed 33103722]

13. Viswanathan M, et al. Screening to prevent osteoporotic fractures: updated evidence report and systematic review for the US Preventive Services Task Force. Journal of the American Medical Association 2018;319(24):2532-2551. DOI: 10.1001/jama.2018.6537.

    IMPORTANT REMINDER

    This Medicare Part B Step Therapy Medical Necessity Guideline is for informational purposes only and does not constitute or replace professional medical advice. Physicians, hospitals, and other providers are responsible for administering and using drugs/biologicals in the most effective and clinically appropriate manner and are solely responsible for all medical care decisions. This guideline is not a substitute for clinical judgment or individualized patient care.

    Coverage determinations are based on the member's Evidence of Coverage (EOC), which contains specific coverage provisions, limitations, and exclusions. In the event of a conflict between this guideline and the member's EOC, the EOC will govern.

    Aspire Health Plan (AHP) adheres to applicable Medicare guidelines, including National Coverage Determinations (NCDs), Local Coverage Determinations (LCDs), Local Coverage Articles (LCAs), and other relevant Medicare manuals published by the Centers for Medicare & Medicaid Services (CMS). Compliance with these guidelines is required where applicable. For the most current Medicare policies and coverage information, please refer to the CMS website at cms.gov and search the Medicare Coverage Database.

    All LCDs are the same for each state within a Jurisdiction. The Medicare Administrative Contractor (MAC) for California (Jurisdiction E) is Noridian. Active LCDs for JE Part B can be found on the Noridian Medicare website (noridianmedicare.com). In the event of a discrepancy between this guideline and a Medicare NCD or LCD, the NCD/LCD will govern.

    This guideline is used by AHP to determine coverage in the absence of applicable CMS Medicare guidelines. The Medicare source materials used to develop this guideline are referenced below. This document does not replace the official Medicare source materials, which provide detailed information on

Page 9 of 9 AHP- Evenity (romosozumab-aqqg) Medicare coverage requirements. In the event of a conflict between this document and Medicare source materials, the Medicare source materials will prevail. The inclusion of a code in this guideline does not guarantee coverage or reimbursement. Benefit coverage is determined by the member's specific plan document, applicable state and federal laws, and CMS guidelines. Other policies and standards may also apply. Providers are expected to maintain documentation to support coverage decisions and make it available upon request. POLICY HISTORY Version Date Summary of Changes 1 9/27/2023 New Policy 2 02/25/2025 Annual Review. The policy has been revised and reformatted to enhance clarity with no alteration to the intent or clinical criteria. References reviewed and policy updated where applicable. Effective: 05/15/2025