PKD2

Novartis has identified farabursen as a good fit for its burgeoning kidney disease portfolio.\n Novartis has committed another $1.7 billion to its ambition to become a kidney disease leader. The Swiss drugmaker is making the outlay, around half of which is upfront, to buy Regulus Therapeutics for a rare renal disease drug that is set to enter phase 3 in the third quarter.Regulus published top-line data from a phase 1b trial of its lead candidate, farabursen, in March. The trial enrolled patients with autosomal dominant polycystic kidney disease (ADPKD). People who received the oligonucleotide every other week for three months had statistically significant increases in urinary PC1 and PC2, proteins that inversely correlate with disease severity.Height-adjusted total kidney volume (htTKV), a predictor of renal insufficiency, increased 0.05% over four months in patients on farabursen. HtTKV grew 2.58% in the placebo cohort. Buoyed by the data, Regulus forged ahead with plans to start a phase 3 trial that could support a filing for accelerated approval.Novartis has identified farabursen as a good fit for its burgeoning kidney disease portfolio. The company has agreed to pay $7 a share upfront to acquire Regulus. The upfront payment, which amounts to $800 million, is more than double the closing price of Regulus’ stock Tuesday. Novartis has agreed to pay another $7 a share if Regulus achieves a milestone tied to the regulatory approval of farabursen. The total value, should all these targets be hit, would reach $1.7 billion.  Regulus has designed its phase 3 trial to support a filing for accelerated approval based on htTKV after 12 months. The trial will serve as its own confirmatory study, with the biotech tracking changes in a measure of kidney function, eGFR, out to 24 months to support full approval.If approved, farabursen will enter a market already served by Otsuka’s Jynarque. Otsuka said (PDF) U.S. sales “increased significantly” over the first three months of the year because ADPKD prescriptions rose. Regulus told investors in January that Jynarque is only used in about 7% of the addressable population, a fact the biotech’s CEO Joseph Hagan said is “in large part because of its safety and tolerability profile.”Regulus claimed farabursen is a multibillion-dollar opportunity. Novartis wants to seize the opportunity to advance the kidney care business that it has built out through deals such as the $3.2 billion Chinook Therapeutics acquisition and development of internal programs. The commercial portfolio now includes Fabhalta and Vanrafia. 

Taylor Tieden for BioSpace At the heart of the acquisition is Regulus’ farabursen, an miRNA-targeting oligonucleotide in early-stage development for rare autosomal dominant polycystic kidney disease. Novartis is buying Regulus Therapeutics for $800 million upfront , beefing up its oligonucleotide pipeline with the San Diego biotech’s miRNA-targeting assets, according to a press announcement on Wednesday. Under the terms of the acquisition agreement, Novartis will procure all of Regulus’ shares for $7 a pop—a purchase price that represents a 108% premium to the biotech’s closing price on Tuesday. Novartis is also offering Regulus’ shareholders a $7-per-share contingent value right, payable after hitting certain milestones. All told, the acquisition could be worth $1.7 billion. Boards of directors of both companies have unanimously approved the transaction, which is expected to close in the back half of the year, pending customary closing conditions. The centerpiece of Wednesday’s merger is Regulus’ farabursen—its regulatory approval is the trigger for Novartis’ contingent value right offer—an oligonucleotide being developed for autosomal dominant polycystic kidney disease (ADPKD), a rare, hereditary condition that affects around 160,000 patients in the U.S., according to Regulus. The disease is caused by mutations in the Pkd1 or Pkd2 gene, leading to the accumulation of fluid-filled cysts in and across the kidneys and worsening kidney function over time. When left unchecked, ADPKD can lead to kidney failure and eventually death. According to Regulus, Pkd1 or Pkd2 mutations are tied to the upregulation of miR-17, a microRNA molecule that “ directly leads ” to suppression of certain genes, ultimately dampening the production of the proteins encoded by those genes, polycystin 1 (PC1) and 2 (PC2). Farabursen binds to miR-17 to disrupt this pathway to “correct the underlying pathology of ADPKD,” according to Regulus. Through this mechanism of action, farabursen can restore PC1 and PC2 levels, in turn reducing the growth of cysts. Farabursen is in a Phase Ib study that is expected to complete later this year. Aside from farabursen, Regulus is also advancing another nephrology asset and is working on a program for an undisclosed central nervous system indication. The Regulus move is in line with Novartis’ business development philosophy this year. During the pharma’s year-end report for 2024, CEO Vas Narasimhan told reporters the company would “continue our strategy to look for primarily bolt-on acquisitions that we think will bolster our growth in the 2030 and beyond period.” A few days later, Novartis put $3.1 billion on the line to acquire Anthos Therapeutics and its anticoagulant antibody abelacimab.

衰老，是个不可避免的自然过程，伴随着细胞和分子损伤的逐渐累积，进而导致身体功能衰退和与年龄相关疾病风险上升。准确预测生物年龄（BA）对于深入理解衰老机制以及制定有效的干预策略至关重要。然而，目前的生物年龄预测模型由于衰老过程的复杂性以及现有模型的局限性，难以实现精准预测。来自日本大阪大学的研究团队在《Science Advances》上发表了一项创新性研究，提出了一种基于类固醇生物合成途径的深度神经网络（DNN）模型，用于预测生物年龄。该模型通过分析个体血清中的类固醇水平，不仅能够反映随时间扩大的衰老异质性，还揭示了性别特异性差异。研究方法1、数据采集与处理研究团队收集了148名20-73岁健康个体的血清样本，并通过液相色谱-串联质谱（LC-MS/MS）技术定量分析了22种类固醇。按性别将98份样本用于模型训练，50份样本用于验证。研究者采用了基于累积分布函数（CDF）的比例缩放方法，以保持类固醇浓度的相对比例，同时减少批次效应。2、DNN模型构建DNN模型的设计充分考虑了类固醇生物合成的顺序阶段，从孕烯醇酮（P5）开始，经过中间代谢物，直至生理指标——压力指数（PI）和性指数（SI），并最终预测BA。模型中包含22个输入节点，代表经过缩放的P5和21种中间类固醇数据；24个偏差节点，用于捕捉其他生物过程的影响；以及24个连接节点，代表21种中间类固醇、PI、SI和最终BA输出之间的中间输出。共有37个加权边连接上游输入或连接节点与下游节点，捕捉这些生物组分之间的相互作用。研究者还设计了一个自定义的加权对称反正切损失（WSATL）函数，捕捉衰老异质性随时间扩增的特征，避免传统均方误差的局限。通过五折交叉验证优化学习率（lr）和训练周期数（t）等超参数。最终确定女性模型的学习率为0.005，训练周期数为4000；男性模型的学习率为0.003，训练周期数为8000。研究发现1、模型性能DNN模型成功捕捉了衰老的异质性，并通过可视化连接权重和节点影响，揭示了类固醇对BA预测的贡献层次。皮质类固醇和性激素途径对BA预测贡献显著，且在男女模型中表现出不同的影响。例如，雌激素相关节点在女性模型中更为突出，而雄激素相关节点在男性模型中更为显著。此外，皮质醇（COL）在男女模型中均对BA预测具有显著的正敏感性影响，表明其作为应激生物标志物在衰老中的重要性。2、性别特异性衰老路径主成分分析（PCA）显示，男性和女性样本在PC2上存在明显分离，表明性别特异性因素对类固醇浓度有显著影响。女性模型中，雌激素相关节点影响显著；男性模型中，雄激素节点（如睾酮）作用更突出。3、生活方式因素的影响研究还探讨了吸烟对BA预测的影响。结果显示，男性的吸烟者相较于不吸烟者表现出更显著的BA加速，而女性吸烟者与不吸烟者之间未发现显著差异。这可能与男性吸烟频率更高有关。研究意义与展望该研究开发的基于类固醇代谢途径的DNN模型，为生物年龄预测提供了一种新的方法，能够有效整合类固醇生物合成途径中的复杂生物过程，并捕捉随年龄增长的异质性。这一模型不仅提高了生物年龄预测的准确性，还为揭示衰老的分子机制提供了新的视角。通过识别关键类固醇生物标志物，如皮质醇，该研究为未来的个性化衰老干预策略提供了潜在的靶点。此外，模型对生活方式因素（如吸烟）的敏感性分析，强调了在生物年龄预测中考虑这些因素的重要性，有助于制定更精准的健康管理和疾病预防策略。然而，样本量较小、未考虑昼夜节律波动是主要局限。下一步需扩大队列，整合动态激素监测，并探索干预策略（如降低皮质醇）的临床潜力。类固醇代谢是衰老的“系统级指示器”，压力与性激素的平衡深刻影响生物年龄。这一模型不仅为个性化抗衰老干预提供工具，更为理解衰老异质性开辟新路径。参考文献：Biological age prediction using a DNN model based on pathways of steroidogenesishttps://www.science.org/doi/10.1126/sciadv.adt2624撰文丨马德里的天空推荐阅读疑难杂症“开卷考外挂”！登顶Nature的谷歌AMIE，诊断真的靠谱么？清华大学推出AI辅修学位，未来医生的"科技树"怎么点术后1年无复发生存率提升18%！Nature子刊（58.7）：基于AI的心脏消融术可能改写持续性房颤治疗困局