RANK

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

The study, which assessed the pharmacokinetics, safety, and tolerability of AVT03 compared to Prolia® in healthy adult subjects, met its primary endpoints Prolia® and Xgeva® (denosumab) are indicated for the treatment of bone disease REYKJAVIK, Iceland, Jan. 29, 2024 (GLOBE NEWSWIRE) -- Alvotech (NASDAQ: ALVO), a global biotech company specializing in the development and manufacture of biosimilar medicines for patients worldwide, announced today positive top-line results from a pharmacokinetic (PK) study for AVT03, a biosimilar candidate to Prolia® and Xgeva®, which both contain denosumab. The PK study (AVT03-GL-P01), which assessed the pharmacokinetics, safety, and tolerability of AVT03 compared to Prolia® in healthy adult subjects, met its primary endpoints. A confirmatory efficacy study for AVT03 in patients is currently underway, as well as a PK study comparing AVT03 to Xgeva® in healthy adult subjects. “We are very pleased with the progress in our AVT03 program. This milestone, and recent positive top-line results from other clinical studies clearly demonstrate our capabilities and the excellence of Alvotech’s biosimilars development platform,” said Joseph McClellan, Chief Scientific Officer. Prolia (denosumab) is indicated for the treatment of osteoporosis in postmenopausal women and for bone loss in adult men and women at increased risk of fracture. Xgeva, which is also denosumab but in a different presentation, is indicated for prevention of skeletal-related events such as pathological fractures in adults with advanced malignancies involving bone. It is also indicated for the treatment of giant cell tumor in bone. In the last twelve months before September 30, 2023, reported combined net revenues worldwide from sales of Prolia and Xgeva were over US$6 billion, based on the manufacturer’s reported quarterly sales. 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. Biosimiliarity has not been established by regulatory authorities and is not claimed. [1] https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Prolia/prolia_pi.pdf Use of trademarksProlia and Xgeva are registered trademarks of Amgen Inc. About AlvotechAlvotech 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. Alvotech’s current pipeline includes eight 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. 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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.