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Clinical data demonstrated treatment with AGA2118 resulted in dose-dependent increases in bone mineral densityWOODLAND HILLS, Calif., Sept. 30, 2024 (GLOBE NEWSWIRE) -- Angitia Biopharmaceuticals, a clinical-stage biotechnology company focused on the discovery and development of innovative therapeutics for serious musculoskeletal diseases, today announced data from its ongoing program evaluating AGA2118 for the treatment of osteoporosis, as presented at the American Society for Bone and Mineral Research 2024 Annual Meeting (ASBMR) on September 27-30, 2024, in Toronto, ON, Canada. Treatment with AGA2118, a bispecific antibody targeting both sclerostin and DKK1, led to rapid and durable increases in bone formation, decreases in bone resorption, and improvements in bone mineral density (BMD) and bone strength in humans and in animal models, as highlighted in multiple abstracts presented at the conference. “AGA2118 is the first clinical stage bispecific antibody to target two key regulators of bone metabolism, and our first-in-human data demonstrate clinical proof-of-concept for AGA2118,” said David Ke, M.D., Chairman and Chief Executive Officer of Angitia. “AGA2118 is well-tolerated and possesses a pharmacokinetic profile that has translated well to the clinic. In men and otherwise healthy postmenopausal women, we observed rapid and robust bone mineral density gains. We look forward to engaging regulators and continuing development in a diseased population.” In the first-in-human (FIH) trial, 88 men and otherwise healthy postmenopausal women, received AGA2118 or placebo (randomized 6:2) either subcutaneously or intravenously. Subjects were either dosed with a single dose of AGA2118 up to 15 mg/kg or multiple doses of AGA2118 up to 12mg/kg every 4 weeks for a total of three doses and were followed for 85 days in the single ascending dose (SAD) cohort or 169 days in the multiple ascending dose (MAD) cohort. AGA2118 was safe and well-tolerated at all dose levels tested, with adverse events balanced between treatment and placebo. No treatment-related serious adverse events (SAEs) were reported. In addition to safety, the Company observed clinical activity, including dose-dependent increases in bone formation markers P1NP, BSAP, and osteocalcin, as well as dose-dependent decreases in the bone resorption marker CTX-1. In both SAD and MAD cohorts, BMD increased from baseline in the lumbar spine, total hip, and femoral neck in a dose- and exposure-dependent manner. “The rapidity and robustness of the BMD and biomarker responses with AGA2118 in this first-in-human trial demonstrate the potential of AGA2118 to become an important new treatment option for patients with skeletal disease,” said Matthew Drake, M.D., Ph.D., Associate Professor of Medicine at the Mayo Clinic, Divisions of Endocrinology and Hematology. “In addition, the pharmacokinetics and safety of AGA2118 support further development.” The abstract and oral presentation outlining the FIH trial is entitled, “AGA2118, a Bispecific Antibody Neutralizing both Sclerostin and DKK1, Increased Bone Formation, Decreased Bone Resorption, and Led to Rapid BMD Gains in a First in Human, Single- and Multiple-Dose, Placebo-Controlled Randomized Study." Angitia made three additional presentations at ASBMR, including a second oral presentation and two posters. Those presentations summarize data from AGA2118 in a non-human primate (NHP) model of osteoporosis, AGA2118 pharmacokinetics (PK) in NHPs and humans, and long-term follow-up in NHPs treated with AGA2118. Results translated well from preclinical models to humans, and the PK profile of AGA2118 is supportive of future development. About Osteoporosis Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis has become a global epidemic, especially for older women, due to an aging population and longer life expectancies. Estimates indicate that more than 200 million patients worldwide suffer from osteoporosis. Although there are a number of approved therapies for osteoporosis, limitations remain regarding the efficacy and/or safety of each of these options. Research also indicates that most severely osteoporotic individuals do not receive a bone-active agent. As a result, a large unmet medical need remains for the development of new osteoporosis therapies. About AGA2118 AGA2118 is a bispecific antibody that targets sclerostin and DKK1 and is in clinical development for the treatment of osteoporosis. Sclerostin and DKK1 are two critical, negative regulators of WNT signaling in osteoblasts and of bone metabolism. By targeting both proteins, AGA2118 is thought to prevent compensatory increase of either agent, aiming to improve the magnitude of bone mineral density gains in osteoporotic patients. Angitia wholly owns the bispecific antibody. About Angitia Biopharmaceuticals Angitia Biopharmaceuticals is a clinical-stage biotechnology company focused on the discovery and development of innovative therapeutics for serious musculoskeletal diseases. Angitia is currently studying 3 biologic product candidates in the clinic for the treatment of osteoporosis, osteogenesis imperfecta (OI), and spinal fusion. Leveraging the team's extensive experience and scientific acumen in novel drug development, Angitia is committed to providing groundbreaking therapies to satisfy key unmet medical needs. Learn more at www.angitiabio.com. Investor & Media Contact: William WindhamSolebury Strategic Communicationswwindham@soleburystrat.com646-378-2946 Forward-Looking Statements This press release is prepared by Angitia (the “Company”, “We”) for informational purposes only. Forward-looking statements include all statements that are not historical facts, and in some cases, can be identified by terms such as “anticipate”, “expect”, “intend”, “plan”, “believe”, “continue”, “could”, “potential”, “may”, “will”, “goal” or similar expressions and the negatives of those terms. However, not all forward-looking statements contain these identifying words. These forward-looking statements involve substantial known and unknown risks, uncertainties, and other factors that are beyond the Company’s control and are difficult to predict and may cause our actual results, timing of results, or achievements to be materially different from the information expressed or implied by these forward-looking statements. We anticipate that subsequent events and developments may cause our expectations and assumptions to change, and we undertake no obligation to update or revise any forward-looking statements, whether as a result of new information, future events, or otherwise, except as may be required by law. Except as expressly required by law, the Company and/or its officers, directors, employees, and agents shall not assume responsibility for the accuracy and completeness of the forward-looking statements in the information provided.

On March 14th, British pharmaceutical giant AstraZeneca announced its intention to acquire Amolyt Pharma, a clinical-stage biotech company focused on the development of innovative therapies for rare endocrine diseases. The acquisition is set to further strengthen AstraZeneca's rare disease business unit, Alexion, by bolstering its late-stage product development pipeline and adding a critical component to its bone metabolism portfolio - eneboparatide (AZP-3601), a therapeutic peptide currently in phase III clinical trials. This drug has a novel mechanism of action aimed at addressing key therapeutic goals for patients with hypoparathyroidism. It is reported that patients with hypoparathyroidism, due to insufficient production of parathyroid hormone (PTH), suffer from severe calcium and phosphate metabolism dysregulation, leading to symptoms and complications that can alter quality of life, including chronic kidney disease among others. There are an estimated 115,000 patients in the United States and about 107,000 in the European Union affected by this condition, with approximately 80% being female. Parathyroid hormone is secreted by the four tiny parathyroid glands located near the thyroid gland. When there is an insufficiency or absence of PTH secretion, it leads to a decrease in the concentration of calcium ions in the blood and an increase in phosphate levels, which is the most significant laboratory finding for the diagnosis of hypocalcemia. The most common cause of the loss of PTH is injury or removal of the parathyroid glands during thyroid or neck surgery. This condition disrupts the normal balance of calcium and phosphate metabolism in the body, causing a range of symptoms and complications including, but not limited to, muscle cramps, twitching, tremors, fatigue, emotional instability, and potentially, if left untreated, osteomalacia, increased risk of fractures, and dental issues. Therefore, finding therapies that can substitute the function of PTH is crucial for patients with hypocalcemia, with the goal of restoring calcium-phosphate homeostasis and improving patient quality of life. As a PTH receptor 1 (PTH1R) agonist, eneboparatide employs a novel mechanism of action specifically designed for the therapeutic aim of treating hypoparathyroidism. This peptide is capable of highly affinity binding to the R0 conformation of PTH1R receptors. Despite its short pharmacokinetic half-life, eneboparatide is still able to induce a sustained elevation in serum calcium levels in vivo. Such a design allows eneboparatide to vigorously promote calcium reabsorption in the renal tubules and exert physiologically significant effects on bone turnover, which has been confirmed by animal experiments and human studies. In the year 2016, a research team from Harvard Medical School developed two murine models of acquired hypoparathyroidism and utilized these models to evaluate the efficacy of PTH(1-34) and a long-acting PTH analog (LA-PTH) in regulating blood calcium levels. The results show that a single subcutaneous injection of LA-PTH can more effectively increase serum calcium levels compared to PTH(1-34) administered at a dose tenfold higher, with the effect lasting over 24 hours, and without leading to excessive urinary calcium excretion. In a phase I clinical trial conducted on healthy volunteers, eneboparatide demonstrated the ability to rapidly induce a steady increase in serum calcium levels along with the dosage increment, and this elevation was maintained throughout the entire treatment period. More importantly, there was no observed increase in urinary calcium excretion during the study, nor were there any changes in bone biomarkers. This indicates that eneboparatide can raise serum calcium levels without causing negative effects on urinary calcium excretion or bone metabolism, showing good safety and potential efficacy. Phase II clinical data have shown that enboparatide successfully restores serum calcium levels to normal and holds promise for eliminating the patient's dependency on daily calcium and vitamin D supplements. In adults with chronic hypophosphatemia and hypercalciuria, the results indicate that enboparatide can normalize calcium content in the urine. Moreover, for patients with hypophosphatemia, enboparatide also helps maintain bone mineral density, which is a significant potential benefit for patients at increased risk of osteoporosis or reduced bone density. About PTH1R Currently, the main clinical targets for the treatment of hypoparathyroidism are the PTH1R (developing safer and more effective synthetic PTH analogues or oral small-molecule PTH1R agonists) and the vitamin D receptor (a type of nuclear receptor, with vitamin D receptor agonists able to control calcium and bone metabolism, and regulate growth and differentiation of various cell types). Parathyroid hormone 1 receptor 1 (PTH1R) belongs to the Class B G protein-coupled receptor family. This receptor can be activated by two different endogenous peptide agonists, namely parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), leading to the activation of Gs, Gq, and β-arrestin, thereby modulating various signaling pathways and exerting different biological effects. Research has shown that PTH can regulate the calcium and phosphate balance in bones and kidneys, while PTHrP regulates the cellular proliferation and differentiation in developing bones and other tissues. Natural PTH and modified agonist peptides can induce significant anabolic bone formation and have been used in clinical treatments for osteoporosis. Therefore, PTH1R is also considered a key target for the treatment of hypoparathyroidism and osteoporosis, and can be treated through the injection of PTH or PTHrP analogues. According to statistics from the Synapse database, there are currently a total of 87 therapeutic drug development projects worldwide targeting PTH1R. The types of drugs primarily consist of recombinant peptides, biosimilars, hormones, etc., with only a small portion being small-molecule drugs. The natural ligands for Class B GPCRs are peptide hormones, which activate the receptors by binding to a larger open pocket within the transmembrane domain. Additionally, the extracellular domain is required for high-affinity ligand-receptor interactions. Therefore, drug development targeting Class B GPCRs primarily involves biologics or recombinant peptides, which is significantly different from the current market trend where drugs targeting Class A family GPCR members are mainly small molecules. Class B GPCRs belong to the peptide hormone receptor family and are common drug targets for various metabolic disorders, including osteoporosis, Type 2 diabetes, obesity, cardiovascular diseases, and migraines. Developing oral medications targeting Class B GPCRs, to improve patient quality of life, minimize side effects, and reduce costs still poses certain challenges. Other Drugs for the Treatment of Hypoparathyroidism Currently, other candidate drugs targeting PTH1R for the clinical treatment of hypoparathyroidism include the PTH1R agonist PCO-371, which is developed by Chugai Pharmaceutical and is in Phase 1 clinical studies. In 2016, Chugai Pharmaceutical published an article in the journal Nature Communications, detailing the development of an orally active small molecule PTHR1 agonist, PCO-371, for the treatment of hypoparathyroidism. PCO-371 is a novel orally active small molecule that functions as a full agonist of PTHR1. Oral administration of PCO-371 in osteoporotic rats significantly increased bone turnover rate, although the increase in bone mass was limited. In rats with hypocalcemia, PCO-371 restored serum calcium levels without increasing urinary calcium, and its effect was stronger and more sustainable than that of injected PTH. These results suggest that PCO-371 may offer a new therapeutic option for PTH-related disorders, including hypoparathyroidism. PCO371 was obtained through cellular-level functional screening. It can stimulate COS-7 cells expressing PTH1R to produce cAMP as well as enhance the activity of phospholipase C. The action of PCO371 on PTH1R is primarily through interaction with the transmembrane region and is not affected by the receptor's extracellular domain. DOI: 10.1038/ncomms13384 PCO371 not only can dose-dependently increase the expression of bone-related messenger RNAs such as Fos, osteocalcin, and receptor activator of nuclear factor-κB ligand (RANKL), but it can also dose-dependently reduce the mRNA expression of osteoprotegerin and sclerostin. DOI: 10.1038/ncomms13384 Additionally, PCO371 is capable of inducing bone resorption activity similar to that of PTH in fetal rat long bone organ cultures. Using concentrations of 1 μmol l^-1 or higher, PCO371 stimulated the release of isotopically labeled ^45Ca from pre-labeled bone as effectively as hPTH(1-34). Moreover, the authors investigated the effects of combined treatment with PCO371 and alfacalcidol in a hypocalcemic rat model following parathyroidectomy. Administration of 75 ng kg^-1 of alfacalcidol alone normalized serum calcium to within or above the target therapeutic range but was accompanied by substantial urinary calcium excretion. A daily oral dose of 6 mg/kg^-1 of PCO371 with 38 ng kg^-1 of alfacalcidol raised serum Ca to levels comparable to those achieved with 75 ng kg^-1 of alfacalcidol alone. The combination of PCO371 and alfacalcidol allowed for a reduction in the dose of alfacalcidol, thereby decreasing urinary calcium excretion. This suggests that PCO371 can be used in the treatment of hypoparathyroidism, either as a monotherapy or as an adjunct to conventional therapy. DOI: 10.1038/ncomms13384 In 2020, the Chugai team continued to publish articles in the "Journal of Medicinal Chemistry," where they discussed the small molecule hPTHR1 agonist PCO371 and its lead compound 1 (CH5447240), which could induce hypocalcemic and bile acid synthesis suppression effects similar to PTH in rats with parathyroidectomy. The compound is currently undergoing Phase I clinical trials for the treatment of hypoparathyroidism. On December 11, Ascendis Pharma Inc. announced that the U.S. FDA had accepted the company's resubmitted New Drug Application (NDA) for palopegteriparatide (TransCon PTH) for the treatment of adult patients with hypoparathyroidism. The resubmitted application was a complete response to a Class II resubmission and set a Prescription Drug User Fee Act (PDUFA) target date of May 14, 2024.  TransCon PTH is an investigational PTH hormone prodrug developed by Ascendis Pharma. It is a mPEGylated modification of the parathyroid hormone (PTH 1-34) designed for once-daily injection to provide sustained release of active PTH. The drug is currently being developed for the treatment of adult hypoparathyroidism. Targeted PTH1R Therapy for Osteoporosis On November 21, Apotex Inc. also announced that the U.S. FDA approved the company's Teriparatide injection for the treatment of osteoporosis. The Teriparatide injection is supplied in the form of single-patient use prefilled pens, with each pen containing 250 mcg/mL and a dosage of 20 mcg per administration. On November 17, the U.S. FDA also approved the marketing of a Teriparatide injection by Teva Pharmaceuticals, similarly intended for the treatment of osteoporosis. Teriparatide is a recombinant peptide and a synthetic form of natural human parathyroid hormone. This medication can help the body to form new bone, increase bone mineral density, and strengthen bones. Abaloparatide was originally developed by Ipsen SA as an N-terminal analog of parathyroid hormone-related protein (PTHrP) and is also an agonist for the parathyroid hormone type 1 receptor (PTH1R). It is a synthetic peptide consisting of 34 amino acids and shares 41% homology with human parathyroid hormone 1-34 and human PTHrP 1-34. Following its approval in the United States in 2017, it has also been approved in countries and regions such as Japan and the European Union for the treatment of osteoporosis and postmenopausal osteoporosis.

NextCure, Inc. (Nasdaq: NXTC), a clinical-stage biopharmaceutical company committed to discovering and developing novel, first-in-class immunomedicines to treat cancer and other immune-related diseases, today announced the publication of a manuscript titled “Anti-Siglec-15 Antibody Prevents Marked Bone Loss after Acute Spinal Cord Injury-Induced Immobilization in Rats” in JMBR Plus, a journal of the American Society for Bone and Mineral Research (ASBMR). The data demonstrated that NC605, a novel anti-Siglec-15 (S15) antibody, prevented bone loss, but more importantly preserved bone strength in animal models of severe immobilization resulting from acute spinal cord injury. Following spinal cord injury, patients typically suffer rapid and extensive bone loss. While anti-resorptive therapies have shown some efficacy in inhibiting bone loss, these agents also inhibit bone formation. In preclinical testing, NC605 has been shown to prevent bone loss by inhibiting osteoclast maturation and bone resorption by binding S15, which is expressed on the cell surface of immature osteoclasts and upregulated in differentiated osteoclasts. Unlike anti-resorptive therapies, NC605 enhances osteoblast recruitment, resulting in overall enhanced bone quality. “Bone loss due to severe immobilization is rapid, progressive and severe. Skeletal fragility in patients with immobilization injuries, including many veterans under long term care in VA centers, places them at great risk for fractures. With no practical interventions currently available, there is a substantial unmet clinical need for therapeutics that can prevent bone loss due to severe immobilization,” said Solomon Langermann, Ph.D., NextCure’s chief scientific officer. “The data highlight the unique and favorable features of Siglec-15 antibodies relative to current anti-resorptive agents, and suggest encouraging potential for NC605 to mitigate the striking bone loss and preserve bone strength in patients with spinal cord injury or other immobilization injuries.” In the animal model of spinal cord injury, bone mineral density (BMD) was assessed and compared to control animals. Key findings from the study include: Treatment with anti-S15 antibody completely prevented loss of BMD in the femur and tibia. High-resolution imaging analysis revealed almost complete prevention of trabecular bone volume loss. Blood and bone structure analyses revealed that the anti-S15 antibody was able to greatly inhibit bone resorption while maintaining bone formation and quality. Ex vivo analysis showed increased numbers of osteoblasts as well as increased levels of mRNA encoding osteocalcin and bone sialoprotein (BSP), markers of bone formation and integrity, demonstrating a unique ability of the antibody to reduce osteoclast formation and bone resorption while promoting osteoblast recruitment to maintain bone integrity. The data were generated in collaboration with Dr. Weiping Qin, Icahn School of Medicine at Mount Sinai and collaborators at the Spinal Cord Damage Research Center, James J. Peters Veteran Affairs Medical Center, Bronx, New York. NextCure is a clinical-stage biopharmaceutical company committed to discovering and developing novel, first-in-class immunomedicines to treat cancer and other immune related-diseases. Our focus is to bring hope and new treatments to patients who do not respond to current therapies, patients whose disease progresses despite treatment and patients with diseases not adequately addressed by available therapies. www.nextcure.com The content above comes from the network. if any infringement, please contact us to modify.