RANKL

October 10, 2024 I Alvotech (NASDAQ: ALVO), a global biotech company specializing in the development and manufacture of biosimilar medicines for patients worldwide, announced today that the European Medicines Agency (EMA) has accepted a Marketing Authorization Application for AVT03, a proposed biosimilar candidate to Prolia® and Xgeva® (denosumab). “EMA acceptance marks an important step towards making AVT03 available to patients and caregivers in Europe,” said Joseph McClellan, Chief Scientific Officer of Alvotech. “Successful progression in the development of multiple biosimilar candidates demonstrates how Alvotech is able to leverage its end-to-end biosimilars platform in support of broader access to affordable biologic medicines.” Alvotech develops and manufactures AVT03. STADA Arzneimittel AG and Dr. Reddy’s Laboratories SA, have entered into agreements with Alvotech for the commercialization of AVT03, each partner with semi-exclusive commercial rights in Europe, including Switzerland and the UK. In July 2024, Alvotech announced positive topline results from a confirmatory patient study for AVT03. The AVT03-GL-C01 study, which met its primary endpoints, demonstrated clinical similarity of AVT03 to Prolia in terms of efficacy, safety, immunogenicity, and pharmacokinetics (PK) in 532 postmenopausal women with osteoporosis. Primary endpoints were also met in both the AVT03-GL-P01 study, which assessed the PK, safety, and tolerability of AVT03 compared to Prolia in 209 healthy adult participants, and the AVT03-GL-P03 study that assessed the PK, safety, and tolerability of AVT03 compared to Xgeva in 208 healthy adult participants. Prolia is indicated to treat osteoporosis in postmenopausal women and in men at increased risk of fracture; bone loss in men receiving treatment for prostate cancer that increases their risk of facture; and bone loss in adults at increased risk of fractures who are treated long term with oral or injected corticosteroids [1]. Xgeva is used to prevent bone complications in adults with advanced cancer that has spread to the bone, as well as to treat giant cell tumor of bone in adults and adolescents whose bones have fully developed [2]. Across all indications, the European denosumab market is currently valued at approximately US$1 billion [3]. Biosimilar competition to Prolia and Xgeva could expand patient access considerably at the same or lower overall costs. In 2019 the total direct cost of osteoporotic fractures in the European Union, Switzerland and UK, was estimated at US$63 billion, excluding the individual disease burden. An estimated 32 million individuals in Europe had osteoporosis, 80% of which were women, but 70% of women eligible for treatment did not receive osteoporosis treatment [4]. About AVT03 (denosumab) AVT03 is a human monoclonal antibody and a biosimilar candidate to Prolia® and Xgeva® (denosumab). Denosumab targets and binds with high affinity and specificity to the RANK ligand membrane protein, preventing the RANK ligand/RANK interaction from occurring, resulting in reduced osteoclast numbers and function, thereby decreasing bone resorption and cancer-induced bone destruction [1]. AVT03 is an investigational product and has not received regulatory approval in any country. Biosimilarity has not been established by regulatory authorities and is not claimed. Use of trademarks Prolia and Xgeva are registered trademarks of Amgen Inc. Sources [1] Prolia product information, EMA [2] Xgeva product information, EMA [3] IQVIA [4] Key Statistics for Europe, International Osteoporosis Foundation About Alvotech Alvotech is a biotech company, founded by Robert Wessman, focused solely on the development and manufacture of biosimilar medicines for patients worldwide. Alvotech seeks to be a global leader in the biosimilar space by delivering high quality, cost-effective products, and services, enabled by a fully integrated approach and broad in-house capabilities. Two biosimilars, to Humira® (adalimumab) and Stelara® (ustekinumab) are already approved and marketed in multiple global markets. The current development pipeline includes nine disclosed biosimilar candidates aimed at treating autoimmune disorders, eye disorders, osteoporosis, respiratory disease, and cancer. Alvotech has formed a network of strategic commercial partnerships to provide global reach and leverage local expertise in markets that include the United States, Europe, Japan, China, and other Asian countries and large parts of South America, Africa and the Middle East. Alvotech’s commercial partners include Teva Pharmaceuticals, a US affiliate of Teva Pharmaceutical Industries Ltd. (US), STADA Arzneimittel AG (EU), Fuji Pharma Co., Ltd (Japan), Advanz Pharma (EEA, UK, Switzerland, Canada, Australia and New Zealand), Dr. Reddy’s (EEA, UK and US), Biogaran (FR), Cipla/Cipla Gulf/Cipla Med Pro (Australia, New Zealand, South Africa/Africa), JAMP Pharma Corporation (Canada), Yangtze River Pharmaceutical (Group) Co., Ltd. (China), DKSH (Taiwan, Hong Kong, Cambodia, Malaysia, Singapore, Indonesia, India, Bangladesh and Pakistan), YAS Holding LLC (Middle East and North Africa), Abdi Ibrahim (Turkey), Kamada Ltd. (Israel), Mega Labs, Stein, Libbs, Tuteur and Saval (Latin America) and Lotus Pharmaceuticals Co., Ltd. (Thailand, Vietnam, Philippines, and South Korea). Each commercial partnership covers a unique set of product(s) and territories. Except as specifically set forth therein, Alvotech disclaims responsibility for the content of periodic filings, disclosures and other reports made available by its partners. For more information, please visit https://www.alvotech.com. None of the information on the Alvotech website shall be deemed part of this press release. SOURCE: Alvotech

Prolia® (denosumab) is indicated to treat certain conditions that lead to high risk for fracture, including osteoporosis in postmenopausal women TVB-009P, Teva’s proposed biosimilar to Prolia, showed Phase 3 clinical results in osteoporosis and is part of Teva’s robust biosimilar portfolio – 7 approved biosimilars and 16 in the pipeline – across critical therapeutic areas such as oncology, immunology and respiratory medicine Anticipated decision by both agencies is expected in 2H 2025 Oct. 08, 2024 -- Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA) today announced that the United States (U.S.) Food and Drug Administration (FDA) has accepted, and the European Medicines Agency (EMA) has validated, applications for TVB-009P, a biosimilar candidate to Prolia® (denosumab).1 Both applications, a Biologics License Application (BLA) in the U.S., seeking interchangeability, and a Marketing Authorization Application (MAA) in the European Union (EU), include all indications approved for the reference product, Prolia, including conditions with a high risk for fracture, such as osteoporosis in postmenopausal women. The FDA’s anticipated decision and EMA’s expected opinion are anticipated in the second half of 2025. TVB-009P, Teva’s proposed biosimilar to Prolia, is the first of Teva’s internally developed biosimilars to be submitted to the U.S. FDA. The submissions are supported by a comprehensive analytical and clinical data package including results from the randomized, double-blind TVB009-IMB-30085 Phase 3 trial investigating the safety and efficacy of TVB-009P versus Prolia in women with postmenopausal osteoporosis.2 The submissions also include data from the TVB009-BE-10157 pharmacokinetics and pharmacodynamics study in healthy volunteers, which demonstrated pharmacokinetic similarity to the reference product.3 With over 120 years of experience in providing accessible and affordable medicines, Teva is one of the leaders in the biosimilar market with over 20 biosimilars in our portfolio and pipeline. “The filing acceptance and validation of TVB-009P, our proposed biosimilar to Prolia, underscores Teva’s commitment to broadening global access to biosimilars in both regions,” said Steffen Nock, PhD, Head of Biosimilars and Chief Scientific Officer at Teva. “We are leveraging our strong background in generics and our successful track record with biologics, such as AJOVY®, to drive growth in the biosimilars market. Our goal is to expand our strategic partnerships and enhance our portfolio, ultimately offering more affordable treatment options for patients.” Throughout the U.S. and Europe, over 165 million women are either in menopause or postmenopause.4-6 Hormonal changes during menopause place women at a higher risk for osteoporosis, which affects about 25% of older women in the U.S. and the EU.5-10 Osteoporosis increases the risk of bone fractures, and an estimated one in three women over the age of 50 will suffer a fracture due to this condition.11 Osteoporosis is a disease associated with low bone density as the bones lose the ability to reform and regrow themselves as we age.12 As of 2023, about 15 million women over the age of 50 had osteoporosis in the United States.5,9 In Europe, about 32 million people have osteoporosis, with 25.5 million estimated to be women.13 Of these European women, 14 million went untreated in 2019 despite being eligible.14 TVB-009P is a monoclonal antibody and a biosimilar candidate to Prolia® (denosumab). Denosumab targets RANKL (receptor activator of nuclear factor kappa-B ligand), a key protein involved in the regulation of bone metabolism and osteoclast formation. TVB-009P is an investigational product and has not received regulatory approval in any country. Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA) is a global pharmaceutical leader with a category-defying portfolio, harnessing our generics expertise and stepping up innovation to continue the momentum behind the discovery, delivery, and expanded development of modern medicine. For over 120 years, Teva's commitment to bettering health has never wavered. Today, the company’s global network of capabilities enables its ~37,000 employees across 58 markets to push the boundaries of scientific innovation and deliver quality medicines to help improve health outcomes of millions of patients every day. To learn more about how Teva is all in for better health, visit www.tevapharm.com. Teva Pharmaceuticals, Inc. (2024). A Study to Test if TVB-009P is Effective in Relieving Postmenopausal Osteoporosis. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT04729621. Accessed October 3, 2024. Data on File. Clinical Study report: Phase I Study TVB009-BE-10157. A Randomized, Double-Blind, Single-Dose, Parallel-Group Study to Investigate the Pharmacokinetic and Pharmacodynamic Similarity of TVB-009 Versus Denosumab (Prolia®) in Healthy Subjects Phase 1Study TVB009-BE-10157. Teva Pharmaceuticals. Palacios, S., et al. (2010). Age of menopause and impact of climacteric symptoms by geographical region. Climacteric, 13(5), 419–428. https://doi-org.libproxy1.nus.edu.sg/10.3109/13697137.2010.507886. Accessed October 3, 2024. U.S. Census Bureau. (2022). Age and Sex. American Community Survey, ACS 1 -Year Estimates Subject Tables, Table S0101, 2022. https://data.census.gov/table/ACSST1Y2022.S0101?t=Age and Sex. Accessed October 3, 2024. Eurostat. (2024). Population on 1 January by Age and Sex. https://ec.europa.eu/eurostat/databrowser/view/demo_pjan__custom_12638069/default/bar?lang=en. Accessed on October 3, 2024. Riggs, B.L. (2000). The mechanisms of estrogen regulation of bone resorption. J Clin Invest, 106(10):1203-4. https://www-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/pmc/articles/PMC381441/. Accessed October 3, 2024. Salari, N., et al. (2021). Global prevalence of osteoporosis among the world older adults: a comprehensive systematic review and meta-analysis. J Orthop Surg Res, 16(1), 669. https://doi-org.libproxy1.nus.edu.sg/10.1186/s13018-021-02821-8. Accessed October 3, 2024. Walker, M.D., et al. (2023). Postmenopausal osteoporosis. NEJM, 389(21), 1979–1991. https://doi-org.libproxy1.nus.edu.sg/10.1056/nejmcp2307353. Accessed October 3, 2024. Kanis, J.A., et al. (2021). SCOPE 2021: A New Scorecard for Osteoporosis in Europe. Arch Osteoporos, 16(1):82. Lorentzon M., et al. (2022). Osteoporosis and fractures in women: the burden of disease. Climacteric, (1):4-10. https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/34319208/. Accessed October 3, 2024. What are osteoporosis warning signs? (2024). Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/4443-osteoporosis. Accessed October 3, 2024. Key Statistic for Europe: International Osteoporosis Foundation. (n.d.). https://www.osteoporosis.foundation/facts-statistics/key-statistic-for-europe. Accessed October 3, 2024. Willers C., et al. (2022). SCOPE review panel of the IOF. Osteoporosis in Europe: a compendium of country-specific reports. Arch Osteoporos, 17(1):23. https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/35079919/. Accessed October 3, 2024. The content above comes from the network. if any infringement, please contact us to modify.

2024年9月25日-29日，第27届全国临床肿瘤学大会暨2024年CSCO学术年会在厦门国际会议中心举办。 津立泰®—纳鲁索拜单抗注射液（JMT103）用于骨巨细胞瘤患者的Ib/II 期研究《Efficacy and safety of Narlumosbart (JMT103) in patients with giant cell tumor of bone: a multicenter, single-arm,open-label, phase Ib/II study》，荣获大会优秀论文奖，并由四川华西大学的何宣虹老师在大会做精彩口头汇报。 研究设计 本研究为一项多中心、单臂、开放标签、Ib/II期临床研究，旨在评价纳鲁索拜单抗在骨巨细胞瘤患者中的药效学和安全性。研究纳入不可切除或手术困难的骨巨细胞瘤成人患者，每例受试者每4周（首个4周第8天、第15天负荷用药）接受2mg/kg 纳鲁索拜单抗治疗，直至疾病进展、肿瘤经手术完全切除、不能耐受毒性、受试者要求退出或研究者认为受试者不能再从治疗中获益（以先发生者为准）。主要研究终点为肿瘤反应率（定义：对比基线肿瘤中破骨细胞样巨细胞减少至少90％或12周内影像学肿瘤反应（CR+PR））。 图1：研究流程图 研究结果 本研究入组139例受试者，均接受了至少一次纳鲁索拜单抗治疗，研究结果证明纳鲁索拜单抗用于骨巨细胞瘤患者，临床疗效优、起效快，可以助力手术降级。 ●12周肿瘤反应率93.3%，25周肿瘤反应率94.1% ●102例受试者在研究中接受了骨巨细胞瘤手术治疗，高于基线时计划接受手术的受试者数（81例）。接受手术治疗的102例受试者中，101 例为手术困难的受试者，首次给药至手术切除中位时间为2.94个月（95% CI：2.56, 3.12），其中 96 例受试者的肿瘤被完全切除。 ●  安全性方面，治疗相关不良反应（TRAE）以低磷酸血症和低钙血症为主（主要为1-2级，均可逆），2.2%患者发生≥3级TRAE，未发生导致JMT103治疗终止的TEAE，无受试者发生颌骨坏死 图2：用药期间，患者肿瘤反应率 关于纳鲁索拜单抗注射液 津立泰®—纳鲁索拜单抗注射液为新一代IgG4抗体亚型的RANKL抑制剂，于2023年9月在中国获准上市，获批用于治疗不可手术切除或手术切除可能导致严重功能障碍的骨巨细胞瘤成人患者，为中国骨巨细胞瘤患者提供更优的临床用药选择。 同时，纳鲁索拜单抗用于实体肿瘤骨转移患者的Ib期研究已完成，证明其用于实体瘤骨转移患者的有效性及安全性，进一步的III期临床研究（NCT06221072）处于受试者入组阶段，未来纳鲁索拜单抗将造福于更多中国患者。