Be confident in the efficacy and safety of WYOST® when substituting for Xgeva® (denosumab)1,2

As an interchangeable biosimilar, WYOST1,2:

  • Can be expected to produce the same clinical results as Xgeva® in any given patient
  • Does not increase risk in terms of safety or diminished efficacy when switching from Xgeva®

WYOST has attributes identical to Xgeva®, including3,4:

SAME mechanism of action

SAME FDA-approved indications

SAME dosage strength (120 mg/1.7 mL)

SAME amino acid sequence

WYOST has been rigorously tested and meets all FDA requirements for biosimilarity

Analytical Studies5,6

Confirmed matching structural and functional profiles

Nonclinical Research5

Comparable toxicity and safety profiles

Pharmacological Study (Study 101)7

Phase 1 clinical trial that demonstrated equivalence in PK/PD

Confirmatory Study (ROSALIA)8

Phase 3 study that demonstrated the same efficacy, safety, PK/PD, and immunogenicity between biosimilar denosumab-bbdz and reference denosumab

The National Comprehensive Cancer Network® (NCCN®) recommends an FDA-approved biosimilar, such as denosumab-bbdz (WYOST) (NCCN Category 2A), as an appropriate substitute for reference denosumab in patients with multiple myeloma or bone metastases from solid tumors in breast or prostate cancer.9-11ab

aCategory 2A: Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.

bThis is not the complete list of conditions for which biosimilar denosumab-bbdz is listed as Category 2A.

PD=pharmacodynamics; PK=pharmacokinetics.

ROSALIA study: The same efficacy, safety, PK/PD, and immunogenicity between biosimilar denosumab-bbdz and reference denosumab8

Trial design

A 52-week, international, randomized, double-blind, multicenter, integrated Phase 1/3 study in postmenopausal women with osteoporosis compared the efficacy, safety, PK/PD, and immunogenicity of biosimilar denosumab-bbdz with reference denosumab.
WYOST study: Randomized, double-blind, multicenter study re-randomizing Xgeva® group at Week 52 to WYOST or Xgeva® WYOST study: Randomized, double-blind, multicenter study re-randomizing Xgeva® group at Week 52 to WYOST or Xgeva®
Treatment Period 1 (randomization to Week 52):
527 patientsa randomized 1:1 to biosimilar denosumab-bbdz (n=263) or reference denosumab (n=264). Patients received 60 mg of biosimilar denosumab-bbdz or reference denosumab subcutaneously at Day 1 and Week 26.
Treatment Period 2 (Week 52 to Week 78):
Patients received a third dose at Week 52. All patients in the reference denosumab group were re-randomized 1:1 to either continue with reference denosumab or transition to biosimilar denosumab-bbdz. All patients in the biosimilar denosumab-bbdz group continued with the biosimilar denosumab-bbdz.
Postmenopausal osteoporosis is a sensitive indication for evaluating clinically meaningful differences between biosimilar and reference denosumab.12
Key eligibility criteria:
  • Postmenopausal women (aged 55 to 80 years)
  • Osteoporosis (T-score measured by DXA ≤−2.5 and ≥−4.0)
  • Body weight (≥50 and ≤90 kg)
aTwenty-five participants discontinued participation in the study in treatment period 1 (10 from biosimilar denosumab-bbdz, 15 from reference denosumab).
DXA=dual-energy X-ray absorptiometry; PD=pharmacodynamics; PK=pharmacokinetics.

Baseline characteristics and study endpoints

WYOST study: Patient demographics and baseline characteristics were similar in patients randomized to biosimilar denosumab-bbdz and reference denosumab WYOST study: Patient demographics and baseline characteristics were similar in patients randomized to biosimilar denosumab-bbdz and reference denosumab
Primary efficacy endpoint:
  • %CfB in LS-BMD at Week 52
Secondary efficacy endpoints:
  • %CfB in LS-BMD at Weeks 26 and 78
  • %CfB in FN-BMD at Weeks 26, 52, and 78
  • %CfB in TH-BMD at Weeks 26, 52, and 78
Primary PK endpoints:
  • AUCinf and Cmax after dose 1 (evaluated at Week 26)
  • Additional PK parameters (AUClast,
    AUC%extrap, Tmax, Lambda_z, and T1/2) were evaluated and analyzed descriptively after the first dose
Primary PD endpoint:
  • AUEC of the %CfB in serum CTX after dose 1 (evaluated at Week 26)
Other endpoints:
  • Immunogenicity was evaluated based on the development of binding ADAs and NAbs
  • Safety endpoints included:
  • Incidence of TEAEs
  • Incidence of serious TEAEs
  • Incidence of fractures
%CfB=percent change from baseline; ADA=anti-drug antibody; AUCinf=area under the serum concentration–time curve extrapolated to infinity; AUEC=area under the effect–time curve; Cmax=maximum drug serum concentration; CTX=C-telopeptide-cross-linked type I collagen; FN-BMD=femoral neck bone mineral density; LS-BMD=lumbar spine bone mineral density; NAb=neutralizing antibody; PD=pharmacodynamics; PK=pharmacokinetics; TEAE=treatment emergent adverse event; TH-BMD=total hip bone mineral density.

Difference between treatment groups met prespecified equivalence margins
WYOST study efficacy figure: Mean difference between biosimilar denosumab-bbdz and reference denosumab and 95% CI WYOST study efficacy figure: Mean difference between biosimilar denosumab-bbdz and reference denosumab and 95% CI
  • The adjusted mean %CfB in LS-BMD (SE) in the FAS population was 4.963 for biosimilar denosumab-bbdz (n=255) and 5.140 for reference denosumab (n=257); difference,
    –0.177 (95% CI: –0.830, 0.475)
Comparable efficacy in patients who switched at Week 52
WYOST study efficacy figure: Percent change from baseline in lumbar spine bone mineral density over 78 weeks WYOST study efficacy figure: Percent change from baseline in lumbar spine bone mineral density over 78 weeks
  • Authors of the ROSALIA study concluded that there was no clinically meaningful difference in efficacy between patients who switched from reference denosumab to biosimilar denosumab-bbdz compared with the continuation groups at Week 78
%CfB=percent change from baseline; CI=confidence interval; FAS=full analysis set; LS-BMD=lumbar spine bone mineral density; SE=standard error.

  • 90% CIs of the geometric mean ratios for AUCinf and Cmax were fully contained within the prespecified equivalence margins after dose 1 (evaluated at Week 26)
  • Additional PK parameters evaluated after the first dose (at Week 26) were also similar between treatment groups
  • 95% CIs of the geometric mean ratios of AUEC of %CfB in serum CTX were fully contained within the prespecified equivalence margins after the first dose (evaluated at Week 26)
%CfB=percent change from baseline; AUCinf=area under the serum concentration–time curve extrapolated to infinity; AUEC=area under the effect–time curve; CI=confidence interval; Cmax=maximum drug serum concentration; CTX=C-telopeptide-cross-linked type I collagen; PD=pharmacodynamics; PK=pharmacokinetics.

Incidence and severity of adverse events were comparable between biosimilar denosumab-bbdz and reference denosumab
  • Most TEAEs across the full 78 weeks were Grade 1 or 2
    • The majority were not treatment related
    • TEAEs led to study discontinuation in 6 participants in Treatment Period 1 and no study discontinuations in
      Treatment Period 2
  • The most common TEAEs were hypocalcemia, nasopharyngitis, and COVID-19 infection
  • Most TEAEs of hypocalcemia occurred at 1 and 2 weeks after the first injection and all cases were Grade 1 or Grade 2
  • There were no clinically meaningful differences in the rate of new vertebral fractures (biosimilar denosumab-bbdz:
    9.9%; reference denosumab: 13.6%; switch group: 13.7%)
WYOST study safety table showed similar TEAEs between biosimilar denosumab-bbdz and reference denosumab at Week 78 WYOST study safety table showed similar TEAEs between biosimilar denosumab-bbdz and reference denosumab at Week 78
aNo serious TEAEs were treatment related.
bThe participant was elderly with preexisting cardiovascular comorbidities and died of unknown causes considered not to be related to the study drug. Fatal TEAEs (death) were classified as Grade 5.
TEAE=treatment-emergent adverse event.
Immunogenicity was comparable between treatment groups8
  • The 502 participants who received dose 3 at Week 52 had a similar incidence of positive ADAs across treatment groups throughout the study (see below), with consistently few positive and low titers (see below)
  • The vast majority (98% overall) of all participants with positive ADAs had ADAs that were borderline detectable by the highly
    sensitive method, which resulted in non-measurable titers
  • At any time during the study, the incidence of NAbs was very low and similar across treatment groups (0.8% in all 3
    treatment groups)
  • Switching from reference denosumab to biosimilar denosumab-bbdz did not affect immunogenicity compared with the
    non-switched population
WYOST study immunogenicity figure: Similar immunogenicity between biosimilar denosumab-bbdz and reference denosumab at Week 78 WYOST study immunogenicity figure: Similar immunogenicity between biosimilar denosumab-bbdz and reference denosumab at Week 78
cBorderline detectable values resulted in non-measurable titers (<20 ng/mL).
d“Transient” indicates a patient experiencing a positive ADA result but not qualifying as “persistent.”
e“Persistent” indicates a patient experiencing a positive ADA result at the final visit and with at least 2 consecutive positive ADA results.
f“ADA titer positive” indicates a patient with a positive ADA result and a reportable titer value.
ADA=anti-drug antibody; NAb=neutralizing antibody.

Identical dosing

WYOST has the same dosing and administration as Xgeva®.

SEE DOSING
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Important Safety Information and Indications
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INDICATIONS

  • WYOST (denosumab-bbdz) is indicated for:

  • Prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors.
  • Treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.
  • Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.
IMPORTANT SAFETY INFORMATION

  • CONTRAINDICATIONS

  • Hypocalcemia: Pre-existing hypocalcemia must be corrected prior to initiating therapy with WYOST.
  • Hypersensitivity: WYOST is contraindicated in patients with known clinically significant hypersensitivity to denosumab products.

  • WARNINGS AND PRECAUTIONS

  • Drug Products with Same Active Ingredient

  • Patients receiving WYOST should not receive other denosumab products concomitantly.

  • Hypersensitivity

  • Clinically significant hypersensitivity including anaphylaxis has been reported with use of denosumab products. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue WYOST therapy permanently.

  • Hypocalcemia

  • Denosumab products can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to WYOST treatment. Monitor calcium levels, throughout WYOST therapy, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Concomitant use of calcimimetics and other drugs that can lower calcium levels may worsen hypocalcemia risk and serum calcium should be closely monitored. Advise patients to contact a healthcare provider for symptoms of hypocalcemia
  • An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/min and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.

  • Osteonecrosis of the Jaw (ONJ)

  • ONJ has been reported in patients receiving denosumab products, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with cancer, the incidence of ONJ was higher with longer duration of exposure. Risk factors include a history of tooth extraction, poor oral hygiene, or use of a dental appliance. Other risk factors include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections, and a history of invasive dental procedures for denosumab-treated patients with multiple myeloma.
  • Perform an oral examination and appropriate preventive dentistry prior to the initiation of WYOST and periodically during WYOST therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with WYOST. Consider temporary discontinuation of WYOST therapy if an invasive dental procedure must be performed.
  • Patients who are suspected of having or who develop ONJ while on WYOST should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery may exacerbate the condition.

  • Atypical Subtrochanteric and Diaphyseal Femoral Fracture

  • Atypical femoral fracture has been reported with denosumab products. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.
  • Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g., prednisone) at the time of fracture.
  • During WYOST treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of WYOST therapy should be considered, pending a risk/benefit assessment, on an individual basis.

  • Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone (GCTB) and in Patients with Growing Skeletons

  • Clinically significant hypercalcemia requiring hospitalization and complicated by acute renal injury has been reported in denosumab product-treated patients with GCTB and patients with growing skeletons within the first year after treatment discontinuation. After treatment is discontinued, monitor patients for signs and symptoms of hypercalcemia and manage patients as clinically appropriate.

  • Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation

  • MVF have been reported following discontinuation of treatment with denosumab products. Patients at higher risk for MVF include those with risk factors for or a history of osteoporosis or prior fractures. When WYOST treatment is discontinued, evaluate the individual patient’s risk for vertebral fractures

  • Embryo-Fetal Toxicity

  • Based on data from animal studies and its mechanism of action, denosumab products can cause fetal harm when administered to a pregnant woman.
  • Advise females of reproductive potential to use effective contraception during therapy and for at least 5 months after the last dose of WYOST. Advise pregnant women and females of reproductive potential that exposure to WYOST during pregnancy or within 5 months prior to conception can result in fetal harm.

  • ADVERSE REACTIONS

  • The most common adverse reactions (incidence ≥25%) in patients receiving denosumab with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation of denosumab were osteonecrosis and hypocalcemia.
  • The most common adverse reactions in patients receiving denosumab with multiple myeloma (incidence ≥10%) were diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash, and headache. The most common serious adverse reaction (incidence ≥5%) was pneumonia. The most common adverse reaction resulting in discontinuation of denosumab (≥1.0%) was osteonecrosis of the jaw.
  • The most common adverse reactions in patients receiving denosumab with giant cell tumor of bone (incidence ≥10%) were arthralgia, back pain, pain in extremity, fatigue, headache, nausea, nasopharyngitis, musculoskeletal pain, toothache, vomiting, hypophosphatemia, constipation, diarrhea, and cough. The most frequent serious adverse reactions were osteonecrosis of the jaw (3.6%), bone giant cell tumor (1.5%), anemia (1.1%), pneumonia (0.9%), and back pain (0.9%). The most frequent adverse reactions resulting in discontinuation of denosumab was osteonecrosis of the jaw (incidence of 3.6%). The adverse reaction profile appeared similar in skeletally mature adolescents and adults.
  • Adverse reactions occurring in >20% of patients receiving denosumab with hypercalcemia of malignancy were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea. The following adverse reactions of Grade 3 or greater severity related to study therapy were reported on-study: fatigue (3%) and infection (6%). Grade 3 laboratory abnormalities included hypomagnesemia (3%), hypokalemia (3%), and hypophosphatemia (76%) of patients. No deaths on-study were related to denosumab therapy.

Please see full Prescribing Information for WYOST.

References: 1. US Food and Drug Administration. Promotional Labeling and Advertising Considerations for Prescription Biological Reference Products, Biosimilar Products, and Interchangeable Biosimilar Products: Questions and Answers Guidance for Industry. April 2024. Accessed March 6, 2025. https://www.fda.gov/media/134862/download 2. US Food and Drug Administration. FDA Approves First Interchangeable Biosimilars to Prolia and Xgeva to Treat Certain Types of Osteoporosis and Prevent Bone Events in Cancer. 2024. Accessed March 6, 2025. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-interchangeable-biosimilars-prolia-and-xgeva-treat-certain-types-osteoporosis-and 3. WYOST. Prescribing information. Sandoz Inc. 4. Xgeva. Prescribing information. Amgen Inc. 5. US Food and Drug Administration. Biosimilar Regulatory Review and Approval. Updated December 13, 2022. Accessed March 6, 2025. https://www.fda.gov/media/151061/download 6. Vogg B, Poetzl J, Schwebig A, et al. The totality of evidence for SDZ-deno: a biosimilar to reference denosumab. Clin Ther.
2024;46(11):916-926. doi:10.1016/j.clinthera.2024.08.007 7. Vogg B, Poetzl J, Galta RE, Fuhr R, Schwebig A, Sekhar S. Pharmacokinetics and pharmacodynamics of proposed denosumab biosimilar and reference denosumab in healthy male subjects. J Clin Oncol. 2023;41(suppl 16):e14500. doi:10.1200/JCO.2023.41.16_suppl.e14500 8. Jeka S, Dokoupilová E, Kivitz A, et al. Equivalence trial of proposed denosumab biosimilar GP2411 and reference denosumab in postmenopausal osteoporosis: the ROSALIA study. J Bone Miner Res. 2024;39(3):202-210. doi:10.1093/jbmr/zjae016 9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma V.1.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed January 9, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 10. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.1.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed January 9, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 11. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.3.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed March 19, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 12. Data on file. Clinical Study Report of Study CGP24112301. Sandoz Inc. September 2022. 13. Jeka S, Dokoupilová E, Kivitz A, et al. Equivalence trial of proposed denosumab biosimilar GP2411 and reference denosumab in postmenopausal osteoporosis: the ROSALIA study. Supplementary data. J Bone Miner Res. 2024;39(3):202-210. doi:10.1093/jbmr/zjae016 14. Jeka S, Dokoupilová E, Kivitz A, et al. Safety and immunogenicity of proposed denosumab biosimilar GP2411 compared with reference denosumab in postmenopausal women with osteoporosis at 78 weeks: the randomized, double-blind, ROSALIA study. Poster presented at: ASBMR 2023; October 13-16, 2023; Vancouver, Canada.

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