Amgen's Dual-Target Anti-Obesity Drug AMG133 Enters Clinical Trial Application Phase in China

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On September 6, 2023, Amgen's AMG133 was submitted for clinical trials in China for the treatment of overweight or obesity. On December 3, 2022, AMGEN gave an oral presentation at the 20th World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease (WCIRDC), announcing the Phase I trial results of AMG 133 in treating obesity: In the 420mg group, patients experienced continuous weight loss for 210 days, achieving an 11.2% reduction in body weight; in the 280mg group, the weight loss effect reached approximately 10% by day 85 and remained largely unchanged until the end of the observation period. AMG133 demonstrated good safety, with no significant safety issues identified in the study. Most adverse reactions were mild and transient, primarily related to the gastrointestinal system, with nausea and vomiting being the most common. The majority of events resolved within 48 hours.

Among them, AMG133 is a first-in-class bispecific antibody-peptide conjugate, which is a conjugated molecule of an anti-GIPR antibody and a GLP-1 peptide. For the indication of obesity, it only requires subcutaneous injection once every 4 weeks. This drug not only inhibits the glucose-dependent insulinotropic polypeptide receptor (GIPR, also known as gastric inhibitory polypeptide receptor) but also activates the glucagon-like peptide-1 receptor (GLP-1R).

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On September 5, 2023, Ascendis announced new data from a post-hoc analysis of TransCon PTH. The data showed that adult patients with hypoparathyroidism treated with TransCon PTH experienced a significant improvement in estimated glomerular filtration rate (eGFR), indicating improved renal function.

In the Phase III Pathway trial, the mean baseline eGFR for subjects randomized to receive TransCon PTH and placebo were 67.3 and 72.7 mL/min/1.73m², respectively. At week 26, the eGFR of patients treated with TransCon PTH increased by an average of 7.9 mL/min/1.73m² from baseline (p<0.0001), while the eGFR of patients on placebo decreased by an average of -1.9 mL/min/1.73m² from baseline (p=0.3468). By week 52, patients treated with TransCon PTH (including those who began treatment on placebo) experienced an average increase in eGFR of 8.9 mL/min/1.73m² from baseline (p<0.0001). The improvement at week 52 was even greater for patients with a baseline eGFR <60 (the threshold for renal dysfunction), showing an average increase of 11.5 mL/min/1.73m².

Among them, TransCon PTH is a sustained-release long-acting prodrug of parathyroid hormone (PTH[1-34]) developed by Ascendis Pharma using TransCon technology. It aims to restore PTH to physiological levels 24 hours a day, normalizing blood and urine calcium levels, serum phosphate levels, and bone turnover in order to address both the short-term symptoms and long-term complications of the disease.

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2023-09-05, Elicio Therapeutics, a company focused on developing cancer immunotherapies, announced that additional data from the Phase I study (AMPLIFY-201) of its lead pipeline candidate ELI-002 will be presented in a poster session at the AACR Special Conference on Pancreatic Cancer held in Boston from 2023-09-27 to 2023-09-30. This data will supplement the interim results previously presented by Elicio at the ASCO Annual Meeting in June 2023.

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Palatin, dedicated to developing first-in-class drugs, announced that enrollment for the Phase III study (MELODY-1) of its investigational pipeline drug PL9643 for dry eye disease (DED) has been completed, with a total of 570 patients enrolled. The company is expected to release top-line data by the end of Q4 2023.

PL9643 is a cyclic peptide therapeutic and an MCR agonist targeting MCR1 and MCR5. In preclinical studies, it demonstrated efficacy comparable to Restasis (cyclosporine ophthalmic emulsion) with higher potency. It has been shown to treat ocular conditions, including DED and diabetic retinopathy, with efficacy similar to glucocorticoids but with better safety.

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On September 7, 2023, Elicio Therapeutics, a company focused on developing cancer immunotherapies, announced that it had received a $2.6 million grant from the Chicago GI Research Foundation to fund research on two therapeutic cancer vaccines, ELI-007 and ELI-008. This grant supplements the $2.8 million awarded to Elicio in September 2022. The funding will advance research on ELI-007 (a mutant BRAF peptide vaccine) and ELI-008 (a p53 hotspot mutant peptide vaccine), supporting the development of multivalent cancer vaccines targeting various mutations. Both vaccines are designed using Elicio's proprietary lymph node-targeting amphiphile (AMP) platform.

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Rhythm Pharmaceuticals, focused on developing therapies for rare genetic obesity disorders, announced that the new International Classification of Diseases, Tenth Revision (ICD-10) diagnosis code for Bardet-Biedl Syndrome (BBS) has been approved by the U.S. Centers for Disease Control and Prevention (CDC). The new code Q87.83 for Bardet-Biedl Syndrome (BBS) took effect on October 1, 2023.

Among them, BBS is a rare genetic syndrome, with an estimated 4,000-5,000 patients in the United States. BBS is a multisystem disease characterized by brain damage, particularly affecting the MC4R pathway in the hypothalamus, which is the root cause of hunger and subsequent early-onset obesity in this patient population. Patients with BBS may also experience cognitive impairment, polydactyly, renal dysfunction, hypogonadism, and visual impairment.

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Matthew R. Banghart, a professor at the University of California, San Diego, published an article titled "A Biomimetic C‑Terminal Extension Strategy for Photocaging Amidated Neuropeptides" in JACS.

The article raises issues encountered in the study of neuropeptides: Neuropeptides are a class of abundant but insufficiently studied neurotransmitters that activate G-protein-coupled receptors (GPCRs) to modulate neuronal excitability, synaptic transmission, and neuroplasticity. However, traditional research methods cannot simulate the cleavage and release of neuropeptides within living organisms and instead rely on peptide incubation. This approach has extremely poor spatiotemporal resolution and is incompatible with kinetic studies of receptor activation or peptide diffusion in neural tissue preparations. Additionally, it may lead to widespread desensitization of GPCRs, affecting reproducibility and detection throughput.

Based on the above issues, the author designed a biomimetic caging strategy by extending a photocleavable amino acid at the C-terminus of the neuropeptide to mimic the uncleaved and unreleased pro-neuropeptide. After photolysis, the neuropeptide can rapidly bind to its corresponding GPCR, enabling spatiotemporally resolved studies. Meanwhile, the author explored this method with four major neuropeptides: gastrin-releasing peptide (GRP), oxytocin (OT), substance P (SP), and cholecystokinin (CCK). Subsequently, by using caged CCK, the author revealed the role of extracellular proteases in shaping the temporal dynamics of CCK signaling, as well as the "switch-like" cell-autonomous anti-opioid effects of transient CCK signals in hippocampal interneurons.

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Professor Xinyuan Fan and Professor Peng Chen from Peking University, along with Associate Researcher Jie Wang from Southern University of Science and Technology, jointly published an article in JACS titled “Optical Control of Protein Functions via Genetically Encoded Photocaged Aspartic Acids”.

Site-specific photouncaging of proteins has become an effective method for in situ regulation of protein activity. In this paper, the authors report a genetically encoded photocaged aspartic acid (Asp), which enables optical control of various protein functions using this photocaged Asp, including firefly luciferase, kinases (such as BRAF), GTPases (such as KRAS), and mimicking the in situ phosphorylation process on kinases. The authors suggest that this photocaged Asp may have broad applications in gain-of-function studies of different proteins and biological processes in living cells. Overall, by evolving new PylRS mutants to genetically encode two photocaged Asp UAAs (ONBD and MeONBD), researchers achieved the in situ and on-demand release of functionally essential Asp residues in the POI.