IL-33R

Tozorakimab performed better in patients who had experienced moderate or severe exacerbations in the past year. AstraZeneca executives say they are “not worried” that the failure of tozorakimab in a phase 2 chronic obstructive pulmonary disease (COPD) trial will throw their plans for the anti-IL-33 monoclonal antibody off track.The U.K.-based Big Pharma unveiled data from the phase 2 FRONTIER-4 study at the European Respiratory Society 2024 Congress in Vienna, Austria on Sunday. The study saw 135 COPD patients with chronic bronchitis receive either 600 mg of tozorakimab or placebo every four weeks for 12 weeks.The trial missed the primary endpoint of demonstrating an improvement in pre-bronchodilator forced expiratory volume (FEV), the amount of air that a person can exhale during a forced breath, according to the abstract.AstraZeneca is already running phase 3 trials of tozorakimab in patients who had experienced two or more moderate exacerbations or one or more severe exacerbations in the previous 12 months. When zooming into this sub-group in today’s phase 2 data, the company had better news—a 59 mL improvement in FEV.Among this subgroup, tozorakimab was also shown to reduce the risk of so-called COPDCompEx—a catch-all term for moderate and severe exacerbations as well as the study dropout rate—by 36%, the pharma noted. AstraZeneca's Caterina Brindicci, M.D., Ph.D., global head of respiratory and immunology late-stage development, BioPharmaceuticals R&D, told Fierce that today’s phase 2 fail would “not at all” impact the pharma’s late-stage strategy for tozorakimab.“In the phase 3 program we are targeting exactly the population where we saw a stronger signal in phase 2,” Brindicci said in an interview.Unlike other anti-IL-33 antibodies, tozorakimab has a dual mechanism of action that not only inhibits interleukin-33 signaling via the RAGE/EGFR pathway but also affects a separate ST2 receptor pathway involved in inflammation, Brindicci explained.“This dual pathway that we can target really gives us confidence that we will very likely have efficacy demonstrated in phase 3,” she added. “So we are not worried currently.”AstraZeneca is running a trio of phase 3 trials for tozorakimab in patients with a history of COPD exacerbations, with data set to read out “after 2025,” Brindicci said. There is also a late-stage trial ongoing in patients hospitalized for viral lung infection who require supplemental oxygen. Today’s readout isn’t the first time that tozorakimab has struggled in the clinic. Back in February, AstraZeneca dropped plans to develop the drug in diabetic kidney disease after it failed a phase 2 trial in that indication. A year earlier, the pharma stopped work on the molecule in atopic dermatitis.The company’s Big Pharma peers have also had some bad luck with IL-33. GSK dropped its candidate in 2019, and the following year Roche axed a candidate aimed at the IL-33 pathway after seeing asthma data.However, Sanofi and Regeneron overcame their own phase 2 setback and are now just weeks away from finding out if Dupixent will become the first biologic approved by the FDA for chronic COPD.

MONDAY, June 24, 2024 -- Automated quantitative tests for NT-proBNP and interleukin 1 receptor-like 1 (IL-1 RL1) can identify high-risk congenital heart disease (CHD) in newborns, according to a study published online June 24 in JAMA Network Open . Henning Clausen, M.D., from Lund University in Sweden, and colleagues examined the performance of two diagnostic tests using minimal amounts of dried blood spots (DBS) to identify high-risk CHD in a Swedish cohort of neonates. Automated quantitative tests for NT-proBNP and IL-1 RL1 (formerly known as soluble ST2) were compared against established CHD screening methods among 313 newborns. The DBS samples analyzed included 217 CHD cases and 96 controls; of the CHD cases, 89.3 percent (188 cases) were high-risk types, of which 38.8 percent (73 cases) were suspected prenatally. The researchers found that 94 (50.0 percent) of the high-risk cases passed pulse oximetry screening and 36 (19.1 percent) were discharged after birth without diagnoses. Compared with existing screening methods, combining NT-proBNP and IL-1 RL1 tests performed well, enabling additional identification of asymptomatic babies, with a receiver operating characteristic area under the curve of 0.95. "Tests were accurate and performed well in differentiating healthy controls from high-risk CHD cases," the authors write. "This warrants prospective evaluation to improve early diagnosis of CHD in this vulnerable population of newborns." Two authors disclosed ties to the pharmaceutical industry; one reported having a patent pending for screening products. Abstract/Full Text Whatever your topic of interest, subscribe to our newsletters to get the best of Drugs.com in your inbox.

Although periodontitis is an extremely prevalent disorder, it is challenging to conduct detailed and comprehensive analyses of its progression at the cellular level. Recently, researchers developed an improved periodontitis mouse model that simplifies the collection and analysis of multiple periodontal tissue types. Using this model, they clarified the role of an important signaling pathway in the inflammatory response of periodontal tissue, paving the way for better diagnostic and therapeutic strategies for periodontitis. Periodontal disease, represented by periodontitis, is the leading cause of tooth loss and affects close to one in five adults worldwide. In most cases, this condition occurs as a result of an inflammatory response to bacterial infection of the tissue around teeth. As the condition worsens, the gums begin to pull away, exposing teeth roots and bone. Notably, the incidence of periodontitis becomes more prevalent with age and with populations worldwide living longer, developing a solid understanding of its underlying causes and progression is important. In a study recently published in Nature Communications on March 28, 2024, researchers from Tokyo Medical and Dental University (TMDU) found a way to achieve this by improving upon a widely used animal model to study periodontitis. Studying periodontitis directly in humans is challenging. As a result, scientists often resort to animal models for preclinical research. For instance, the "mouse ligature-induced periodontitis model," since its inception in 2012, has enabled researchers to study the cellular mechanisms underlying this condition. Simply put, with this model, periodontal disease is artificially induced by ligating silk threads onto the molars of mice models, which induces plaque accumulation. While convenient and effective, this model, however, fails to capture the complete picture of periodontitis. "Even though the periodontal tissue is composed of gingiva, periodontal ligament, alveolar bone, and cementum, analyses are usually performed exclusively on gingival samples due to technical and quantitative limitations," remarks lead author Mr. Anhao Liu. "This sampling strategy limits the conclusions that may be drawn from these studies, so methods that allow for the simultaneous analysis of all tissue components are needed." To address this limitation, the research team developed a modified ligature-induced periodontitis model. Instead of the classic single ligature, they used a triple ligature approach on the upper left molar of male mice. This strategy expanded the range of bone loss without causing severe bone destruction around the second molar, increasing the yield of the different types of periodontal tissue. "We isolated the three main tissue types and evaluated the RNA yield between the two models. The results showed that the triple-ligature model effectively increased the yield, achieving four times the yield of normal peri-root tissue and supporting the high-resolution analysis of different tissue types," explains senior author Dr. Mikihito Hayashi. After confirming the efficacy of their modified model, the researchers proceeded to investigate the effects of periodontitis on gene expression among the different tissue types over time, focusing on genes related to inflammation and osteoclast differentiation. One of their main findings was that the expression of the Il1rl1 gene was markedly higher in peri-root tissue five days after ligation. This gene encodes the protein ST2 in both receptor and decoy isoform, which binds to a cytokine called IL-33 that is involved in inflammatory and immunoregulation processes. To gain further insights into the role of this gene, the team induced periodontitis in genetically modified mice that lacked the Il1rl1 or Il33 genes. These mice exhibited accelerated inflammatory bone destruction, highlighting the protective role of the IL-33/ST2 pathway. Further analysis of cells containing the ST2 protein in its receptor form, mST2, revealed that most of them were of macrophage lineage. "Macrophages are typically classified into two main types, pro-inflammatory and anti-inflammatory, based on their activation process. We found that mST2-expressing cells were unique in that they expressed some markers of both types of macrophages simultaneously," comments senior author Dr. Takanori Iwata. "These cells were present in the peri-root tissue before inflammation was triggered, so we named them 'periodontal tissue-resident macrophages.'" Together, the findings of this study showcase the power of this modified animal model to study the full scope of periodontitis in greater detail, right down to the biomolecular level. "We suggest the possibility that a novel IL-33/ST2 molecular pathway regulating inflammation and bone destruction in periodontal disease, alongside specific macrophages in peri-root tissue, is deeply involved in periodontal disease. This will hopefully lead to the development of new treatment strategies and prevention methods," concludes senior author Dr. Tomoki Nakashima.