Background

Evenity (romosozumab-aqqg) is a sclerostin inhibitor indicated for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy. Evenity (romosozumab-aqqg) is an anabolic agent and the first product with the dual effect of increasing bone formation and reducing bone resorption.

The efficacy of Evenity (romosozumab-aqqg) was demonstrated in three clinical trials. Study 1 was a randomized, double-blind, placebo-controlled study in women ages 55 – 90 years with bone mineral density (BMD) T-scores of -2.5 or less at the total hip or femoral neck. Women were randomized to receive subcutaneous injections of either Evenity (romosozumab-aqqg) (N = 3,589) or placebo (N = 3,591) for 12 months. At baseline, 18% of women had a vertebral fracture. After the 12-month treatment period, women in both arms transitioned to open-label anti-resorptive therapy (denosumab) for 12 months while remaining blinded to their initial treatment. Women received 500 to 1,000 mg calcium and 600 to 800 international units vitamin D supplementation daily. The coprimary efficacy endpoints were new vertebral fracture at month 12 and month 24. Evenity (romosozumab-aqqg) reduced the incidence of clinical fracture (a composite endpoint of symptomatic vertebral fracture and nonvertebral fracture) at 12 months. At 12 months, new vertebral fractures had occurred in 16 of 3,321 patients (0.5%) in the romosozumab group as compared to 59 of 3,322 (1.8%) in the placebo group. This represented a 73% lower risk with romosozumab; P < 0.001). Clinical fractures occurred in 58 of 3,589 patients (1.6%) in the romosozumab group as compared to 90 of the 3,591 (2.5%0 in the placebo group. This represented a 36% lower risk with romosozumab; P = 0.008). At 24 months, the rates of vertebral fractures we lower in the romosozumab group than placebo after each group transitioned to denosumab, 0.6% in the romosozumab group vs. 25% in the placebo group, representing a 75% lower risk with romosozumab, P < 0.001) An increase in BMD by 12.7% at the lumbar spine, 5.8% at the total hip, and 5.2% at the femoral neck was also observed.

Study 2 was a randomized, double-blind, alendronate-controlled study of postmenopausal women ages 55 to 90 years (mean age of 74 years) with BMD T-score less than or equal to -2.5 at the total hip or femoral neck and either one moderate or severe vertebral fracture or two mild vertebral fractures, or BMD T-score less than or equal to -2.0 at the total hip or femoral neck and either two moderate or severe vertebral fractures or a history of a proximal femur fracture. Women were randomized (1:1) to receive either monthly subcutaneous injections of Evenity (N = 2,046) or oral alendronate 70 mg weekly (N = 2,047) for 12 months, with 500 to 1,000 mg calcium and 600 to 800 international units vitamin D supplementation daily. After the 12-month treatment period, women in both arms transitioned to open-label alendronate 70 mg weekly while remaining blinded to their initial treatment. This was an event driven trial. The coprimary efficacy endpoints were the incidence of morphometric vertebral fracture at 24 months and time to the first clinical fracture through the primary analysis period, which ended when at least 330 subjects had a clinical fracture and all subjects had completed the 24-month visit. Clinical fracture was a composite endpoint of nonvertebral fracture and symptomatic vertebral fractures. Over the 24 month period a 48% lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group; P < 0.001) Clinical features occurred in 198 of 2,046 patients (9.7%) in the romosozumab-to-alendronate group versus 266 of the 2,047 patients (13%) in the alendronate-to-alendronate group, representing a 27% lower risk with romosozumab; P < 0.001.

Study 3 was a randomized, open label study of 436 postmenopausal women ages 55 to 90 years with osteoporosis and a history of nonvertebral fracture after age 50 or vertebral fracture at any time. The primary efficacy endpoint evaluated was percentage change from baseline in BMD at the total hip through month 12 (mean of months 6 and 12). 436 patients were randomly assigned to romosozumab (n = 218) or teriparatide (n = 218). 206 patients in the romosozumab group and 209 in the teriparatide group were included in the primary efficacy analysis. Through 12 months, the mean percentage change from baseline in total hip areal BMD was 2.6% (95% CI 2.2 to 3.0) in the romosozumab group and -0.6% (-1.0 to -0.2) in the teriparatide group; difference 3.2% (95% CI 2.7 to 3.8; p < 0·0001). The frequency of adverse events was generally balanced between treatment groups. The most frequently reported adverse events were nasopharyngitis (28 [13%] of 218 in the romosozumab group vs 22 [10%] of 214 in the teriparatide group), hypercalcaemia (two [< 1%] vs 22 [10%]), and arthralgia (22 [10%] vs 13 [6%]). Serious adverse events were reported in 17 (8%) patients on romosozumab and in 23 (11%) on teriparatide; none were judged treatment related. There were six (3%) patients in the romosozumab group compared with 12 (6%) in the teriparatide group with adverse events leading to investigational product withdrawal.

As per the FDA labeled package insert, Evenity (romosozumab-aqqg) has a Black Box Warning for Potential Risk of Myocardial Infarction, Stroke and Cardiovascular Death. Evenity (romosozumab-aqqg) may increase the risk of myocardial infarction, stroke and cardiovascular death. It should not be initiated in patients who have had a myocardial infarction or stroke within the preceding year. Consider whether the benefits outweigh the risks in patients with other cardiovascular risk factors. If a patient experiences a myocardial infarction or stroke during therapy, Evenity (romosozumab-aqqg) should be discontinued.

Policy

The use of Evenity is MEDICALLY NECESSARY for the treatment of osteoporosis when the following criteria has been met:

• Diagnosis of osteoporosis; and

• Both of the following:
  • BMD T-score ≤ -2.5 based on BMD measurements from lumbar spine (at least two vertebral bodies), hip (femoral neck, total hip), or radius (one-third radius site); or
  • History of one of the following resulting from minimal trauma:
  • Vertebral compression fracture
  • Fracture of the hip
  • Fracture of the distal radius
  • Fracture of the pelvis
  • Fracture of the proximal humerus

or

• Both of the following:
  • BMD T-score between -1 and -2.5 (BMD T-score greater than -2.5 and less than or equal to -1) based on BMD measurements from lumbar spine (at least two vertebral bodies), hip (femoral neck, total hip), or radius (one-third radius site)
  •  
  • History of one of the following resulting from minimal trauma:
    • Vertebral compression fracture
    • Fracture of the hip
    • Fracture of the distal radius
    • Fracture of the pelvis
    • Fracture of the proximal humerus

OR

• One of the following:
  • FRAX 10-year fracture probabilities: major osteoporotic fracture at 20% or more
  • FRAX 10-year fracture probabilities: hip fracture at 3% or more

• History of failure, contraindication, or intolerance to other available osteoporosis therapy (e.g., oral bisphosphonates, intravenous bisphosphonates)
• Trial of, contraindication, or intolerance to one of the following:
  • Forteo (teriparatide)
  • Tymlos (abaloparatide)
• Patient is not receiving Evenity in combination with any of the following:
  • Parathyroid hormone analogs (e.g., Forteo, Tymlos)
  • RANK ligand inhibitors (e.g., Prolia, Xgeva)

The clinical benefit of Evenity has not been demonstrated beyond 12 months in phase 3 clinical trials. The continued use of Evenity beyond 12 months is unproven and not medically necessary.

References

1. Evenity [package insert]. Thousand Oaks, Ca: Amgen Inc ; April 2020
2. Evenity. Clinicaltrial.gov. Accessed on 4/26/19. Available at: https://clinicaltrials.gov/ct2/show/NCT01631214https://clinicaltrials.gov/ct2/show/NCT01631214 opens a dialog window‌
3. Eventiy. Clinicaltrial.gov. Accessed on 4/26/19. Available at: https://clinicaltrials.gov/ct2/show/NCT01575834https://clinicaltrials.gov/ct2/show/NCT01575834 opens a dialog window‌
4. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375(16):1532-1543.
5. Saag, KG, Petersen J, Brandi ML, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med. 2017;377(15):1417-1427.
6. Camacho PM, Petak SM, et al. American Association of Clinical Endocrinologists/American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis—2020 Update, Endocrine Practice, Volume 26, Supplement 1, 2020, Pages 1-46, ISSN 1530-891X, https://doi.org/10.4158/GL-2020-0524SUPPLhttps://doi.org/10.4158/GL-2020-0524SUPPL opens a dialog window‌. 
7. Langdahl BL, Libanati C, Crittenden DB, et al. Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial. Lancet. 2017 Sep 30;390(10102):1585-1594. doi: 10.1016/S0140-6736(17)31613-6. Epub 2017 Jul 26.
8. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2014.
9. Eastell R, Rosen CJ, Black DM, et al. Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Clinical Practice Guideline. J Clin Endo Metab, Vol 104, Iss 5, May 2019, pps 1595–1622, https://doi.org/10.1210/jc.2019-00221
10. Shoback D, Rosen CJ, Black DM, et al. Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Guideline Update. J Clin Endocrinol Metab, March 2020, 105(3):1–8. https://academic.oup.com/jcem
11. Rosen, HN, Drezner MK. Overview of the management of osteoporosis in postmenopausal women. In: Rosen CJ, Schmader KE, ed. UpToDate. Waltham, MA.: UpToDate; 2020. www.uptodate.com. Accessed March 5, 2021.

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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