University of Debrecen

Novo Nordisk continues to list monlunabant in its midstage diabetes and obesity pipeline.\n Novo Nordisk’s cannabinoid CB1 receptor blocker has run into another problem. Months after sharing obesity data that left investors underwhelmed, the Danish drugmaker has reported the failure of a midphase diabetic kidney disease trial of the molecule.CB1 receptor blockade is an old idea—Sanofi won approval for a drug with the mechanism in 2006—but Novo identified Inversago Pharma as a company capable of realizing the potential of the approach. Novo acquired the Canadian biotech in a deal worth up to $1.1 billion in 2023. Since then, a mix of lackluster efficacy and concerning safety signals for monlunabant in obesity have taken the shine off the deal.The program took another hit Wednesday when Novo reported a phase 2 flop. Investigators randomized 254 diabetic kidney disease patients to receive one of two doses of monlunabant or placebo. After 16 weeks of once-daily dosing, people on the study drug did no better than their counterparts on placebo on a measure of kidney function. The result caused the trial to miss its primary endpoint.Reporting of mild to moderate neuropsychiatric side effects was more frequent with monlunabant than placebo. The safety data add to concerns that the molecule suffers from some of the same problems that held back CB1 blockers in the past. European authorities withdrew the approval of Sanofi’s CB1 obesity drug in 2009 after studies found it doubled the risk of psychiatric disorders. Novo is yet to share safety and efficacy data from the kidney disease trial, with the only other snippet in the disclosure being the detail that the most common adverse events were gastrointestinal and the vast majority of cases were of mild to moderate severity.Martin Holst Lange, M.D., Ph.D., the company’s executive vice president of development, told analysts on its financial call Wednesday morning that Novo wasn’t discouraged by the fail, pointing out that “we never did the acquisition of monlunabant to develop it purely for diabetic kidney disease—our focus was on the weight loss potential.”“Second, I just remind you that that that these are small studies, so obviously, we try to see them in the context of the full picture,” he said. “When we look at the safety and tolerability profile, it was comparable, albeit at a slightly lower rate than in the dedicated obesity study, basically indicating that we can still have an aspiration of exploring this further in phase 2b with lower doses, looking at weight loss potential, but obviously also—and this has been the intent from the get-go—ruling out a potential safety concern.”

Pictured: Illustration of red blood cells iStock, ismagilov Novo Nordisk and Ionis Pharmaceuticals unveiled promising respective data at the American College of Cardiology’s Annual Scientific Session, while Boehringer Ingelheim and Eli Lilly’s Jardiance missed the endpoint in a myocardial infarction study. The American College of Cardiology’s 73rd Annual Scientific Session & Expo (ACC24) took place over the weekend in Atlanta, spotlighting the latest and most impactful innovations in the field of cardiovascular care. BioSpace has highlighted below some of the most notable presentations from ACC’s Annual Scientific Session. Novo Builds Wegovy’s Cardio Case, Eyes Heart Failure Still riding high from winning its recent cardiovascular approval for Wegovy (semaglutide), Novo Nordisk is continuing its expansion into heart health with new promising data from its Phase III STEP-HFpEF study . At 52 weeks, patients treated with the blockbuster obesity drug saw a significantly greater reduction in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) versus placebo. Wegovy also outperformed the placebo group in terms of body weight reduction, six-minute walk distance and C-reactive protein levels. Taken together, these findings suggest that Wegovy could significantly ease symptomatic burden and physical limitations in patients with obesity, heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes mellitus. The GLP-1 treatment also boosted patients’ exercise function and weight loss. Results from the large Phase III trial, which randomized more than 600 patients, were also published on Friday in The New England Journal of Medicine . Novo previously posted heart failure findings for Wegovy, announcing in August 2023 that the weight-loss medication could significantly improve KCCQ-CSS scores in the Phase III STEP trial, which enrolled patients with obesity and HFpEF, but not diabetes. Novo has submitted data from these two studies to the FDA, seeking to expand Wegovy’s label to include HFpEF, STAT News reported. Ionis Moves Toward Rare Metabolic Disorder Approval Ionis Pharmaceuticals unveiled promising results from its Phase III BALANCE study at ACC24, showing that its investigational RNA-targeted antisense therapy olezarsen can reduce triglyceride levels in patients with familial chylomicronemia syndrome (FCS). At six months, patients treated with the 80-mg dose of olezarsen saw a 44% placebo-adjusted reduction in triglyceride levels, an effect that was statistically significant, with a p-value less than 0.001, according to Ionis. This effect continued and improved through 12 months, reaching a 59% placebo-adjusted reduction. Patients in the olezarsen arm also developed “markedly fewer” acute pancreatitis events over 12 months of follow-up. CEO Brett Monia in a statement said that these results from BALANCE support “the potential for olezarsen to be the standard of care for patients with FCS, if approved,” adding that the company is “working closely with the FDA” for olezarsen’s regulatory application, which Ionis expects to this year. Ionis in September 2023 revealed early data from BALANCE. At the time, olezarsen elicited a 100% reduction in acute pancreatitis events versus placebo. Olezarsen is an RNA-targeted ligand-conjugated antisense treatment that works by lowering the body’s production of the apoC-III protein, which is produced in the liver and is involved in the regulation of triglycerides in the blood. Aside from FCS, Ionis is also studying the candidate in severe hypertriglyceridemia. Boehringer, Lilly’s Jardiance Misses in Myocardial Infarction Data from Boehringer Ingelheim and Eli Lilly ’s Phase III EMPACT-MI trial showed that their SGLT2 inhibitor Jardiance (empagliflozin) does not significantly reduce the risk of heart failure hospitalization or death from any cause in patients who had suffered an acute myocardial infarction (MI) episode. At a median follow-up of 17.9 months, 267 patients in the Jardiance arm developed the composite primary endpoint of being hospitalized for heart failure or dying from any cause. This figure corresponds to a rate of 8.2%, whereas the primary outcome arose in 9.1% of those patients in the placebo arm. The between-group difference did not reach statistical significance, with a p-value of 0.21, according to the ACC’s news release on the results. However, disaggregating the primary endpoint into its components showed that Jardiance could significantly lower the risk of a first hospitalization for heart failure by around 23% versus placebo. EMPACT-MI lead author Javed Butler in a statement said that Jardiance “did not reduce mortality after a heart attack, but did reduce the risk of heart failure after heart attack,” adding that this “25% to 30% reduction” in heart failure hospitalizations is “pretty clinically meaningful.” Jardiance also failed to elicit significant improvements in EMPACT-MI’s key secondary endpoints. An exploratory analysis also found no benefit on cardiovascular death, time to death from cardiovascular causes, as well as time to first heart failure hospitalization or cardiovascular death. Arrowhead Shoots for Pivotal SHTG Study for Candidate Arrowhead Pharmaceuticals unveiled Phase IIb data for its investigational RNAi therapy plozasiran at ACC24, demonstrating steep triglyceride reductions at 24 weeks in patients with severely elevated triglyceride levels who are at risk of developing acute pancreatitis. In the mid-stage SHASTA-2 trial, Arrowhead’s asset reduced triglyceride levels by 74% while placebo only elicited a 17% decrease. Plozasiran also met the study’s key secondary endpoint, with its highest doses triggering a 58% average drop in triglyceride at 48 weeks versus 7% in the placebo group. ApoC3, a liver protein that disrupts the clearance of fats from the body, was lowered by 48% among plozasiran-treated patient at 48 weeks. Placebo comparators, meanwhile, saw a 4% increase in ApoC3 at this time point. SHASTA-2 lead author Daniel Gaudet said in a statement that these findings “support the initiation of pivotal studies of plozasiran for the treatment of severe hypertriglyceridemia.” Plozasiran is an investigational RNAi therapeutic that works by interrupting the expression of the ApoC3 gene, resulting in overall lower levels of the protein. This mechanism of action could block the pathologic function of ApoC3 and help normalize lipid levels in patients, according to Arrowhead’s website . Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com .

骨骼肌是损伤后少数能够完全再生的器官之一。尽管骨骼肌干细胞卫星细胞(SC)在再生过程中至关重要，但其激活和分化需要与损伤部位存在或出现的各种细胞类型持续相互作用。 骨骼肌是损伤后少数能够完全再生的器官之一。尽管骨骼肌干细胞卫星细胞(SC)在再生过程中至关重要，但其激活和分化需要与损伤部位存在或出现的各种细胞类型持续相互作用。再生过程始于肌纤维的退化，释放各种危险相关分子(DAMPs)，这些分子可被骨骼肌组织内的细胞识别。 浸润性炎性ly6high MΦs是细胞清除的主要参与者，并释放进一步的促炎细胞因子，促进SC增殖所需的炎症环境。炎症在骨骼肌再生中起着决定性的作用，抑制炎症会完全破坏肌肉修复。 图片来源： https://doi-org.libproxy1.nus.edu.sg/10.1038/s41419-023-06228-7 近日，来自德布勒森大学的研究者们在Cell Death Dis.杂志上发表了题为“Loss of adenosine A3 receptors accelerates skeletal muscle regeneration in mice following cardiotoxin-induced injury”的文章，该研究表明抑制A3Rs可能对损伤后骨骼肌再生具有治疗价值。 骨骼肌再生是一个复杂的过程，由多个相互作用的步骤编排。越来越多的报道表明，炎症反应在将初始肌肉损伤反应与损伤后的及时肌肉再生联系起来方面起着核心作用。核苷腺苷长期以来一直被认为是一种内源性抗炎分子，在组织损伤期间大量产生。它通过四种腺苷受体介导其生理作用。由此可见，腺苷A3受体(A3Rs)不通过骨骼肌表达，但存在于各种炎症细胞的表面。 本文研究了A3Rs缺失对心脏毒素损伤小鼠胫骨前肌(TA)再生的影响。在这里，研究者报道了A3R - / -小鼠骨骼肌再生的特点是更强的初始炎症反应，导致更多的炎症细胞迁移到损伤部位，更快地清除细胞碎片，增强卫星细胞(肌肉干细胞)的增殖和更快的分化，并增加了生成的成肌细胞的融合。这导致加速骨骼肌组织修复和形成更大的肌纤维。 虽然浸润性免疫细胞表达A3Rs，并在损伤的A3R - / -肌肉中表现出增加的炎症特征，但骨髓移植实验表明，组织常驻细胞对组织损伤的反应增加是观察到的现象的原因。总之，该数据表明，A3Rs是损伤相关再生炎症的负调节因子，因此也是TA肌肉纤维生长的负调节因子。 ctx诱导损伤后A3R+/+和A3R - / -小鼠TA肌肉的时间依赖性组织学形态 图片来源：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41419-023-06228-7 综上所述，A3Rs是损伤相关再生炎症的负调节因子，因此也是TA肌肉纤维生长的负调节因子。因此，抑制A3Rs可能对损伤后骨骼肌再生具有治疗价值。(生物谷 Bioon.com） 参考文献 Nastaran Tarban et al. Cell Death Dis. Loss of adenosine A3 receptors accelerates skeletal muscle regeneration in mice following cardiotoxin-induced injury. 2023 Oct 28;14(10):706. doi: 10.1038/s41419-023-06228-7.