Giant Cell Tumor of Bone

Wyost® (denosumab-bddz) and Jubbonti® (denosumab-bddz) interchangeable with and approved by FDA for all indications of reference medicines Xgeva ®* (denosumab) and Prolia®* (denosumab) FDA approval based on robust clinical studies and totality of evidence, which show no clinically meaningful differences from reference medicines March 5, 2024 – Sandoz, the global leader in generic and biosimilar medicines, today announced that the US Food and Drug Administration (FDA) approved Wyost® (denosumab-bbdz) and Jubbonti® (denosumab-bbdz), the first and only FDA-approved denosumab biosimilars, to treat all indications of the reference medicines. Keren Haruvi, President Sandoz North America, said: "Sandoz has achieved the first FDA approval for biosimilars to denosumab, a medicine that can address primary and secondary bone loss, such as osteoporosis, as well as cancer-related skeletal events, which are disease states that can profoundly reduce quality of life for patients. I am proud that Sandoz continues to pioneer access to these life-changing medicines for the patients who need them most." Wyost® is approved to prevent skeletal-related events (SREs) in patients with multiple myeloma and in patients with bone metastases from solid tumors, to treat 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, and to treat hypercalcemia of malignancy refractory to bisphosphonate therapy.1 Bone is the third most frequent site for metastatic tumors.2 Nearly all types of cancer can spread to the bone and cause pain and fractures, though cancers that often metastasize in bones include breast and prostate.3 Jubbonti® is approved to treat postmenopausal women with osteoporosis at high risk for fracture, to increase bone mass in men with osteoporosis at high risk for fracture, to treat glucocorticoid-induced osteoporosis in men and women at high risk for fracture, to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, and to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer.4 Osteoporosis is a bone disease that develops when bone mineral density and bone mass decrease or when bone strength and structure change. People living with osteoporosis typically do not have symptoms and might not know they have the disease until they experience a fracture. More than 10 million US adults aged 50 and over live with osteoporosis, a major cause of fractures in postmenopausal women and in older men.5,6 Half of all women over the age of 50 will experience an osteoporotic fracture during their lifetime.7 The FDA approval is based on robust clinical studies and accompanied by labeling with safety warnings. The Jubbonti® approval is also accompanied by approval of Sandoz’s Jubbonti® Risk Evaluation and Mitigation Strategy (REMS) program, which is designed to inform prescribers and patients about the risk of severe hypocalcemia associated with Jubbonti® in patients with advanced chronic kidney disease, including dialysis-dependent patients. Wyost® and Jubbonti® have the same dosage form, route of administration, dosing regimen and presentation as the respective reference medicines. Wyost® and Jubbonti® are approved as interchangeable with the reference medicines for all indications. Given ongoing patent litigation around these products, Sandoz will not comment on anticipated launch timing or other launch details at this time. Wyost® 120 mg/1.7 mL (70 mg/mL) injection has been approved by the FDA as interchangeable with the reference medicine, a human monoclonal antibody designed to bind to the RANKL protein, an activator of osteoclasts (cells involved in breaking down bone tissue).8,9 Wyost® is indicated in the US to prevent SREs in patients with multiple myeloma and in patients with bone metastases from solid tumors, to treat 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, and to treat hypercalcemia of malignancy refractory to bisphosphonate therapy.1 Jubbonti® 60 mg/1 mL injection has been approved by the FDA as interchangeable with the reference medicine, a human monoclonal antibody designed to bind to the RANKL protein, an activator of osteoclasts (cells involved in breaking down bone tissue).8,9 Jubbonti® is indicated in the US to treat postmenopausal women with osteoporosis at high risk for fracture, to increase bone mass in men with osteoporosis at high risk for fracture, to treat glucocorticoid-induced osteoporosis in men and women at high risk for fracture, to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, and to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer.4 References 1. Wyost®. Prescribing Information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761362s000lbl.pdf [Last accessed: March 2024] 2. Bone Metastasis. Apoorva Jayarangaiah; Alysia K. Kemp; Pramod Theetha Kariyann, Oct 25 2022. Available at https://www-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/books/NBK507911/#:~:text=The%20skeleton%20is%20the%20third,metastasize%20to%20bone%20as%20well. [Last accessed: March 2024] 3. American Cancer Society. Bone Metastases. Available at: https://www.cancer.org/treatment/understanding-your-diagnosis/advanced-cancer/bone-metastases.html [Last accessed: March 2024] 4. Jubbonti®. Prescribing Information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761362s000lbl.pdf [Last accessed: March 2024] 5. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Osteoporosis. 2022. Available at: https://www-niams-nih-gov.libproxy1.nus.edu.sg/health-topics/osteoporosis [Last accessed: March 2024] 6. National Center for Health Statistics. Osteoporosis or Low Bone Mass in Older Adults: United States, 2017–2018. 2021. Available at: https://www-cdc-gov.libproxy1.nus.edu.sg/nchs/products/databriefs/db405.htm [Last accessed: March 2024] 7. Bone Health and Osteoporosis Foundation. Osteoporosis Fast Facts. Available at: https://www.bonehealthandosteoporosis.org/wp-content/uploads/Osteoporosis-Fast-Facts-2.pdf [Last accessed: March 2024] 8. Amgen Inc. Prolia® (Denosumab): Prescribing Information. Available at: https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Prolia/prolia_pi.pdf [Last accessed: March 2024] 9. Amgen Inc. Xgeva® (Denosumab): Prescribing Information. Available at: https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/xgeva/xgeva_pi.pdf [Last accessed: March 2024] Sandoz (SIX: SDZ; OTCQX: SDZNY) is the global leader in generic and biosimilar medicines, with a growth strategy driven by its Purpose: pioneering access for patients. 22,000 people of more than 100 nationalities work together to bring Sandoz medicines to some 500 million patients worldwide, generating substantial global healthcare savings and an even larger total social impact. Its leading portfolio of more than 1500 products addresses diseases from the common cold to cancer. Headquartered in Basel, Switzerland, Sandoz traces its heritage back to the year 1886. Its history of breakthroughs includes Calcium Sandoz in 1929, the world’s first oral penicillin in 1951, and the first biosimilar in 2006. In 2022, Sandoz achieved sales of USD 9.1 billion and core EBITDA of USD 1.9 billion. 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The FDA on Tuesday approved denosumab-bbdz from Sandoz as Wyost to prevent skeletal-related events in certain cancer patients, and as Jubbonti for some patients with osteoporosis. The biosimilars scored interchangeable status with Xgeva and Prolia, respectively, from Amgen. Sandoz, which was spun off from Novartis last year, said it would not comment on a launch for either product due to ongoing patent litigation. Amgen filed suit last year to prevent Sandoz's biosimilars from entering the market until expiration of key US denosumab patents, which could come as early as next year. Wyost and Jubbonti are approved for the same indications and with the same dosing regimens as their respective reference medicines. Last year, Xgeva brought in $2.1 billion in sales, while Prolia raked in $4 billion.Like Xgeva, Wyost is cleared to prevent skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumours; to treat adults and skeletally mature adolescents with giant cell tumour of bone that is unresectable; and to treat hypercalcemia of malignancy refractory to bisphosphonate therapy. Jubbonti has the same label as Prolia – which means it also carries the boxed warning FDA recently bestowed upon the latter for an increased risk of severe hypocalcaemia in patients with advanced chronic kidney disease (CKD), particularly those on dialysis.The biosimilar is approved for individuals at high risk for fracture, including postmenopausal women with osteoporosis, men with osteoporosis, men and women with glucocorticoid-induced osteoporosis, men receiving androgen deprivation therapy for nonmetastatic prostate cancer, and women receiving adjuvant aromatase inhibitor therapy for breast cancer.

SHANGHAI, China I Febuary 1, 2024 I Shanghai Henlius Biotech, Inc. (2696.HK) announced that a phase 1 clinical trial of the company’s denosumab biosimilar HLX14, a recombinant anti-RANKL human monoclonal antibody injection, met its primary endpoint. The results of this study suggest that HLX14 had highly similar PK and PD, as well as comparable safety, tolerability, and immunogenicity to the reference drugs from different sources. This study met all the pre-specified endpoints. The company is also actively conducting an international multicentre phase 3 comparative clinical study (NCT05352516) of HLX14 in postmenopausal women with osteoporosis at high risk of fracture. Henlius independently developed denosumab biosimilar HLX14 in accordance with the NMPA, EMA, FDA, and other international biosimilar guidelines. This is a two-part phase 1 clinical study in Chinese healthy adult male subjects. Part 1 is an open-label, randomised, parallel-controlled, single-dose, two-arm pilot study with the primary objective to compare the PK parameters of HLX14 and EU-sourced denosumab to provide further basis for the study design of part 2. The secondary objective of part 1 is to compare the PD, safety, tolerability, and immunogenicity of HLX14 and EU-sourced denosumab. Part 2 is a double-blind, randomised, parallel-controlled, single-dose, four-arm study with the primary objective to compare the PK similarity of HLX14 with US-, EU-, and CN-sourced denosumab ("reference drug"). The secondary objective of Part 2 is to compare PD, safety, tolerability, and immunogenicity between HLX14 and the reference drugs. The results of this study suggest that HLX14 had highly similar PK and PD to the reference drugs from different sources, with geometric mean ratios (GMRs) of primary PK endpoints near 1 and their 90% confidence intervals (CIs) falling entirely in pre-specified equivalence margins of 0.8 to 1.25. Safety, tolerability, and immunogenicity were also comparable. This study met all of the pre-specified endpoints. HLX14 can specifically bind to RANKL (receptor activator of nuclear factor kappa B ligand) and block the interaction between RANKL and RANK, which is expressed on the surface of osteoclasts, thus inhibiting RANKL/RANK-mediated differentiation, maturation and activation of osteoclasts, thereby reducing bone resorption and the incidence of skeletal-related events [1] . Denosumab has been approved in various countries and regions for a range of indications such as for the treatment of osteoporosis in postmenopausal women at high risk for fracture, osteoporosis in men at high risk for fracture, bone loss in specific populations at high risk for fracture, prevention of skeletal-related events in patients with bone metastases from solid tumours and in patients with multiple myeloma, and the treatment of giant cell tumour of bone and hypercalcemia of malignancy, etc. In 2022, Henlius entered into a license and supply agreement with Organon LLC for the exclusive commercialization of two biosimilar candidates, including HLX14, in ex-China countries, covering mature markets such as the United States, the European Union and Japan, as well as a number of emerging markets. Henlius will always place a high value on patients’ needs and clinical data and will continue to diversify innovation by strengthening internal innovation capabilities and external collaboration, extending new drug forms, and processing more clinical trials, to benefit patients around the world. [1]. Romas E. Clinical applications of RANK-ligand inhibition. Intern Med J 2009;39:110–6. SOURCE: Henlius Biotech