Chronic Kidney Disease-Mineral and Bone Disorder

Ad hoc announcement pursuant to art. 53 SIX Swiss Exchange Listing Rules Sandoz reaches agreement with Amgen resolving all patent litigation related to its US denosumab biosimilars Agreement clears path for launch of Jubbonti® and Wyost® on May 31, 2025 or earlier under certain circumstancesJubbonti® and Wyost® are first and only FDA-approved biosimilars to and interchangeable with Prolia*® and Xgeva*®Anticipated launch further strengthens Sandoz biosimilar portfolio and advances growth strategy Basel, April 30, 2024 – Sandoz, the global leader in generic and biosimilar medicines, today announced that it has reached agreement with Amgen to resolve all patent disputes between the two companies relating to the US Food and Drug Administration (FDA)-approved Sandoz denosumab biosimilars. Patent infringement proceedings were initially filed by Amgen in the US Federal District Court for the District of New Jersey in May of 2023 pursuant to the Biologics Price Competition and Innovation Act (BPCIA). Resolution of the BPCIA litigation followed months of vigorous defense by Sandoz against claims by Amgen that the company infringed up to 21 patents expiring as late as 2037, protecting reference medicines Prolia® and Xgeva®. Under the terms of the agreement, Sandoz may enter the US market with a biosimilar version of Prolia® and Xgeva® on May 31, 2025, or earlier under certain circumstances if customary acceleration provisions are triggered. Sandoz received FDA approval for the first and only denosumab biosimilars, Jubbonti® and Wyost®, on March 5, 2024. Jubbonti® and Wyost® are interchangeable with and approved by FDA for all indications of reference medicines Prolia® and Xgeva®. They have the same dosage form, route of administration, dosing regimen and presentation as the respective reference medicines. The settlement clears the path to bring both Jubbonti® and Wyost® to the US market on May 31, 2025, or earlier under certain circumstances. Bringing denosumab to market allows us to further our Purpose of pioneering access for patients, by providing them with affordable high-quality medicines. The terms of the agreement will not impact our previously disclosed 2024 guidance. About Wyost® (denosumab-bbdz)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 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 SELECT IMPORTANT SAFETY INFORMATION CONTRAINDICATIONSHypocalcemia and known clinically significant hypersensitivity to denosumab products. WARNINGS AND PRECAUTIONSSame Active Ingredient: Patients receiving Wyost should not receive other denosumab products concomitantly. Hypersensitivity reactions including anaphylaxis may occur. Discontinue permanently if a clinically significant reaction occurs. Hypocalcemia: Denosumab products can cause severe symptomatic hypocalcemia. Fatal cases have been reported with denosumab products use. Correct hypocalcemia prior to initiating Wyost. Monitor calcium levels during therapy, especially in the first weeks of initiating therapy, and adequately supplement all patients with calcium and vitamin D. Osteonecrosis of the jaw (ONJ) has been reported in patients receiving denosumab products. Perform an oral examination prior to starting Wyost. Monitor for symptoms. Avoid invasive dental procedures during treatment with Wyost. Atypical femoral fracture: Evaluate patients with thigh or groin pain to rule out a femoral fracture. Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone and in Patients with Growing Skeletons: Monitor patients for signs and symptoms of hypercalcemia, and manage as clinically appropriate. Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation: When Wyost treatment is discontinued, evaluate the individual patient’s risk for vertebral fractures. Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to the fetus and to use effective contraception. ADVERSE REACTIONSBone Metastasis from Solid Tumors: Most common adverse reactions (≥ 25%) were fatigue/asthenia, hypophosphatemia, and nausea. Multiple Myeloma: Most common adverse reactions (≥ 10%) were diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash, and headache. Giant Cell Tumor of Bone: Most common adverse reactions (≥ 10%) were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. Hypercalcemia of Malignancy: Most common adverse reactions (> 20%) were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea. USE IN SPECIFIC POPULATIONSPediatric patients: Recommended only for treatment of skeletally mature adolescents with giant cell tumor of bone. Renal impairment: Patients with creatinine clearance less than 30 mL/min or receiving dialysis are at risk for hypocalcemia. Adequately supplement with calcium and vitamin D. This is not the complete list of all the safety information for Wyost. Please click to see full Prescribing Information for Wyost. About Jubbonti® (denosumab-bbdz)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 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 SELECT IMPORTANT SAFETY INFORMATION WARNING: SEVERE HYPOCALCEMIA IN PATIENTS WITH ADVANCED KIDNEY DISEASESee full prescribing information for complete boxed warning. Patients with advanced chronic kidney disease are at risk of severe hypocalcemia following denosumab products administration. Severe hypocalcemia requiring hospitalization, life-threatening events and fatal cases have been reported.The presence of chronic kidney disease-mineral bone disorder (CKD-MBD) markedly increases the risk of hypocalcemia.Prior to initiating Jubbonti in patients with advanced chronic kidney disease, evaluate for the presence of CKD-MBD. Treatment with Jubbonti in these patients should be supervised by a healthcare provider with expertise in the diagnosis and management of CKD-MBD. CONTRAINDICATIONSHypocalcemia; pregnancy; and known hypersensitivity to denosumab products. WARNINGS AND PRECAUTIONSHypocalcemia: Pre-existing hypocalcemia must be corrected before initiating Jubbonti. Adequately supplement all patients with calcium and vitamin D. Concomitant use of calcimimetic drugs may also worsen hypocalcemia risk. Evaluate for presence of chronic kidney disease mineral-bone disorder. Monitor serum calcium. Same Active Ingredient: Patients receiving Jubbonti should not receive other denosumab products concomitantly. Hypersensitivity including anaphylactic reactions may occur. Discontinue permanently if a clinically significant reaction occurs. Osteonecrosis of the jaw (ONJ): Has been reported with denosumab products. Monitor for symptoms. Atypical femoral fractures: Have been reported. Evaluate patients with thigh or groin pain to rule out a femoral fracture. Multiple vertebral fractures have been reported following treatment discontinuation. Patients should be transitioned to another antiresorptive agent if Jubbonti is discontinued. Serious infections including skin infections: May occur, including those leading to hospitalization. Advise patients to seek prompt medical attention if they develop signs or symptoms of infection, including cellulitis. Dermatologic reactions: Dermatitis, rashes, and eczema have been reported. Consider discontinuing Jubbonti if severe symptoms develop. Severe bone, joint, muscle pain may occur. Discontinue use if severe symptoms develop. Suppression of bone turnover: Significant suppression has been demonstrated. Monitor for consequences of bone over-suppression. ADVERSE REACTIONSPostmenopausal osteoporosis: Most common adverse reactions (> 5% and more common than placebo) were: back pain, pain in extremity, hypercholesterolemia, musculoskeletal pain, and cystitis. Pancreatitis has been reported in clinical trials. Male osteoporosis: Most common adverse reactions (> 5% and more common than placebo) were: back pain, arthralgia, and nasopharyngitis. Glucocorticoid-induced osteoporosis: Most common adverse reactions (> 3% and more common than active-control group) were: back pain, hypertension, bronchitis, and headache. Bone loss due to hormone ablation for cancer: Most common adverse reactions (≥ 10% and more common than placebo) were: arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials. USE IN SPECIFIC POPULATIONSPregnant women and females of reproductive potential: Denosumab products may cause fetal harm when administered to pregnant women. Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of Jubbonti. Pediatric patients: Denosumab products are not approved for use in pediatric patients. Renal impairment: No dose adjustment is necessary in patients with renal impairment. Patients with advanced chronic kidney disease (eGFR <30 mL/min/1.73 m2), including dialysis-dependent patients, are at greater risk of severe hypocalcemia. The presence of underlying chronic kidney disease-mineral bone disorder markedly increases the risk of hypocalcemia. This is not the complete list of all the safety information for Jubbonti. Please click to see full Prescribing Information for Jubbonti.References1. Wyost®. Prescribing Information. Available at: Prescribing Information [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/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: Prescribing Information [Last accessed: March 2024]5. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Osteoporosis. 2022. Available at: https://www.niams.nih.gov/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/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] *Xgeva® and Prolia® are registered trademarks of Amgen Inc. DisclaimerThis Media Release contains forward-looking statements, which offer no guarantee with regard to future performance. These statements are made on the basis of management’s views and assumptions regarding future events and business performance at the time the statements are made. They are subject to risks and uncertainties including, but not confined to, future global economic conditions, exchange rates, legal provisions, market conditions, activities by competitors and other factors outside of the control of Sandoz. Should one or more of these risks or uncertainties materialize or should underlying assumptions prove incorrect, actual outcomes may vary materially from those forecasted or expected. Each forward-looking statement speaks only as of the date of the particular statement, and Sandoz undertakes no obligation to publicly update or revise any forward-looking statements, except as required by law. About SandozSandoz (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. More than 20,000 people of 100 nationalities work together to ensure 800 million patient treatments are provided annually by Sandoz, generating substantial global healthcare savings and even larger social impact. Its leading portfolio of approximately 1,500 products addresses diseases from the common cold to cancer. Headquartered in Basel, Switzerland, Sandoz traces its heritage back to 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 2023, Sandoz recoded sales of 9.6 billion. Global Media Relations contacts Investor Relations contacts Global.MediaRelations@sandoz.com Investor.Relations@sandoz.com Joerg E. Allgaeuer+49 171 838 4838 Karen M. King+1 609 722 0982 Chris Lewis+49 174 244 9501 Laurent de Weck+41 79 795 7364 Attachment Media Release Deno Agreement 24-04-30

Pictured: Amgen's office in Tampa, Florida/iStock, JHVEPhoto The FDA on Friday updated the label of Amgen’s osteoporosis medicine Prolia (denosumab) to include a boxed warning for the risk of hypocalcemia, or severely low calcium levels, when used to treat patients with chronic kidney disease. According to the regulator, Prolia’s hypocalcemia risk is much higher in chronic kidney disease (CKD) patients who also have mineral and bone disorder (MBD), which could lead to serious harm including hospitalization, various life-threatening events and death. Severe hypocalcemia may come without symptoms or may manifest as confusion, seizures, fainting and uncontrolled muscle spasms, among other signs. Per the adjusted label, prescribers should first evaluate patients for the presence of CKD-MBD. Patients with this condition who nevertheless require Prolia treatment should be “supervised by a healthcare provider with expertise in the diagnosis and management of CKD-MBD.” The FDA found that the risk of severe hypocalcemia was highest in patients with advanced CKD, including those who were dependent on dialysis and those with concurrent MBD. The adverse event typically developed within two to 10 weeks after Prolia injection, though its risk peaked at weeks two through five. Despite these risks, the FDA has told patients to not stop taking Prolia without consulting their doctors, as doing so might aggravate the risk of bone fractures “including in the spine.” A boxed warning is the FDA’s most serious precautionary signal for drugs. It signals to prescribers that there is “an adverse reaction so serious in proportion to the potential benefit from the drug … that it is essential that it be considered in assessing the risks and benefits of using the drug,” according to an October 2011 guidance document. These risks include fatal or life-threatening events, or adverse reactions that could result in permanent disability. In the case of Prolia, a review by the Centers for Medicare and Medicaid Services flagged a “significant increase” in the risk of severe hypocalcemia in patients treated with Amgen’s drug versus other bisphosphonate-based osteoporosis therapies. The FDA’s Adverse Event Report System also identified 25 cases of severe hypocalcemia from July 2010 through May 2021. An Amgen spokesperson In a statement to Fierce Pharma said that safety is of the “utmost importance” to the company and that it remains “confident” in the benefit/risk pro Prolia. A monoclonal antibody, Prolia binds and blocks the RANK protein which in turn suppresses the action of osteoclasts, bone cells that normally degrade bone to promote repair and remodeling. In many bone diseases, like osteoporosis, osteoclasts often play a pathologic role. Prolia was first approved in 2010 for postmenopausal women with osteoporosis who are at a high risk of fracture. The therapy has since been approved for other indications, such as improving bone mass in men with osteoporosis, including those undergoing androgen deprivation therapy. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

January 19, 2024 Audience: Patient, Health Professional, Endocrinology, Nephrology, Pharmacy January 19, 20204 -- Based on a completed FDA review of available information, FDA has concluded that the osteoporosis medicine Prolia ( denosumab ) increases the risk of severe hypocalcemia, very low blood calcium levels, in patients with advanced chronic kidney disease (CKD), particularly patients on dialysis. Severe hypocalcemia appears to be more common in patients with CKD who also have a condition known as mineral and bone disorder (CKD-MBD). In patients with advanced CKD taking Prolia, severe hypocalcemia resulted in serious harm, including hospitalization, life-threatening events, and death. As a result, the FDA is revising the Prolia prescribing information to include a new Boxed Warning, FDA’s most prominent warning, communicating this increased risk. Severe hypocalcemia can be asymptomatic or may present with symptoms that include confusion; seizures; irregular heart rhythm; fainting; face twitching; uncontrolled muscle spasms; or weakness, tingling, or numbness in parts of the body. FDA is adding a Boxed Warning to the Prolia prescribing information about the significant risk of developing severe hypocalcemia in patients with advanced CKD. This warning and new labeling contains information to help reduce this risk, including appropriate patient selection for Prolia treatment, increased monitoring of blood calcium levels, and other strategies. The FDA is adding this updated information to the patient Medication Guide and the Prolia Risk Evaluation and Mitigation Strategy (REMS) , a drug safety program required by FDA. BACKGROUND: Prolia is a monoclonal antibody initially developed for the treatment of osteoporosis in postmenopausal women at increased risk of fracture or who are refractory to or cannot tolerate other therapies. Prolia was later approved to increase bone mass in men with osteoporosis; to treat men with high risk for fracture receiving androgen deprivation therapy for prostate cancer; to treat women at high risk for fracture receiving aromatase inhibitor therapy for breast cancer; and, to treat men and women with glucocorticoid-induced osteoporosis. Prolia works by blocking a protein called RANK (receptor activator of nuclear factor kappa beta) and helps prevent bone cells called osteoclasts from breaking down bone in the body. Prolia may lower the calcium levels in your blood, and it is administered as a subcutaneous injection under the skin by a health care professional once every 6 months. Common side effects of Prolia include back pain, muscle pain, and pain in the arms or legs. RECOMMENDATIONS: Patients For patients considering Prolia for osteoporosis treatment, talk to your health care professional about your kidney function and the risk of severe hypocalcemia. Whether Prolia treatment is appropriate for patients with advanced CKD should be determined by a health care professional with expertise in the diagnosis and management of CKD-MBD, including renal osteodystrophy. For patients already taking Prolia for osteoporosis, maintain adequate calcium and vitamin D intake while receiving this medicine. Since your health care professional administers Prolia by subcutaneous injection every 6 months, you should discuss with them if you are at increased risk, and if so, whether continuing this treatment is best for you. If discontinuation of Prolia treatment is recommended, your health care professional may advise other measures to monitor for and minimize the risk of rebound fractures. For patients with advanced kidney disease, especially those on dialysis treated with Prolia, frequent monitoring of calcium in the blood, especially for the first 2 to 10 weeks after each Prolia injection, is recommended. Talk to your health care professional about specific instructions for the dose and type of calcium and vitamin D supplements that may be needed. Do not stop taking Prolia without talking with your health care professional as your risk of bone fracture, including in the spine, is increased after stopping, skipping, or delaying Prolia. Tell your health care professional if you develop symptoms suggestive of hypocalcemia such as confusion; seizures; irregular heart rhythm; fainting; face twitching; uncontrolled muscle spasms; or weakness, tingling, or numbness in parts of the body. Health Care Professionals It is important that the appropriateness of Prolia treatment in patients with advanced CKD be determined by a health care professional with expertise in the diagnosis and management of CKD-MBD including renal osteodystrophy, a complication that weakens bone. Treating bone disease in patients with advanced and dialysis-dependent CKD is challenging because of the difficulty in diagnosing and confirming the underlying altered bone metabolism responsible for the low bone mass and increased fracture risk, and the complex benefit-risk considerations of approved osteoporosis treatments in this population. Before prescribing Prolia, health care professionals should assess their patients’ kidney function. For patients with advanced CKD, particularly those on dialysis, health care professionals should consider the risk of severe hypocalcemia with Prolia in the context of other available treatments for osteoporosis. If Prolia is still being considered for these patients, for initial or continued use, check their calcium blood levels and assess them for evidence of CKD-MBD. Treatment with Prolia in patients with advanced CKD, including those on dialysis, and particularly patients with diagnosed CKD-MBD should involve a health care provider with expertise in the diagnosis and management of CKD-MBD. Proper management of CKD-MBD, correction of hypocalcemia, and supplementation with calcium and activated vitamin D prior to Prolia treatment is expected to decrease the risk of developing severe hypocalcemia and any associated complications. Following Prolia administration, close monitoring of blood calcium levels and prompt management of hypocalcemia is essential to prevent complications such as seizures or arrhythmias. Advise patients to promptly report symptoms that could be consistent with hypocalcemia. RELATED INFORMATION: Hypocalcemia Osteoporosis The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective Think It Through: Managing the Benefits and Risks of Medicines Health professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program: Complete and submit the report online . Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on form, or submit by fax to 1-800-FDA-0178. Source: FDA More news resources FDA Medwatch Drug Alerts Daily MedNews News for Health Professionals New Drug Approvals New Drug Applications Drug Shortages Clinical Trial Results Generic Drug Approvals Subscribe to our newsletter Whatever your topic of interest, subscribe to our newsletters to get the best of Drugs.com in your inbox.