OBJECTIVESBased on the hypothesis of a role for folate and vitamin B12 in major depressive disorders (MDD), we aimed at validating the association between folate pathway biomarkers and depression or antidepressant response in clinical trial populations.METHODSWe investigated serum levels erythrocyte folate and serum levels of homocysteine, vitamin B12, and folate as disease and response biomarkers for MDD in two independent randomised, placebo-controlled clinical trials, where paroxetine or venlafaxine were used as active controls, for a total of 881 patients.RESULTSSignificant but weak correlations between depression severity and biomarker levels could be detected in the paroxetine study for serum folate and vitamin B12, with no correlations for any biomarker in the venlafaxine study. Besides a weak association for erythrocyte folate in the venlafaxine study, no significant associations were observed between treatment response and pre-treatment levels of any of the biomarkers tested.CONCLUSIONSNotwithstanding the relatively large number of patients tested, we did not find consistent associations between folate biomarkers and MDD severity, or response to paroxetine and venlafaxine. Our results may be related to the particular study design or clinical population; however, our findings do not support the hypothesis of a dysfunction of one-carbon metabolism in MDD.

Translational Psychiatry2区 · 医学

Biomarkers for response in major depression: comparing paroxetine and venlafaxine from two randomised placebo-controlled clinical studies

2区 · 医学

ArticleOA

作者: Learned, Susan M ; Ratti, Emiliangelo ; McCarthy, Dennis J ; Delafont, Bruno ; Carboni, Lucia ; Alexander, Robert ; Filosi, Michele ; Ivanchenko, Elena ; Domenici, Enrico

AbstractThe identification of biomarkers of response might speed drug development and set the premises to assist clinical practice in psychiatry. In this work, we evaluated a panel of peripheral biomarkers (including IL-6, IL-10, TNF-α, TNFRII, BDNF, CRP, MMP9 and PAI1) in depressed patients receiving paroxetine, venlafaxine, or placebo. Samples were obtained from two randomised placebo-controlled studies evaluating the efficacy and tolerability of a novel drug candidate, using either paroxetine or venlafaxine as active comparators. In both studies, the biomarker candidates were analysed in plasma collected at randomization and after 10 weeks of treatment with either placebo or active comparator (for a total of 106 and 108 subjects in the paroxetine and venlafaxine study, respectively). Data were obtained by multiplexing sandwich-ELISA system. Data were subjected to statistical analysis to assess their correlation with baseline severity and with response outcome. Increases in biomarker levels were correlated with reduction in depression severity for TNF-α, IL-6 IL-10 and CRP. Response to paroxetine treatment correlated with baseline IL-10, IL-6 and TNF-α levels, with the strongest signal being observed in males. In the venlafaxine study, a correlation was observed only between CRP level at randomisation and response, suggesting differences between the two active treatments and the two studies. Our investigations suggest that a combination of pro- and anti-inflammatory cytokines may predict response outcome in patients treated with paroxetine. The potential for IL-10, IL-6 and TNF-α as response biomarkers for a wider range of antidepressants warrants further investigations in clinical trials with other monoamine reuptake inhibitors.

项与 Leadiant GmbH 相关的新闻（医药）

2023-08-01

·生物制药小编

裁员预计一千人，渤健却转头斥资73亿买下了Reata

在宣布裁员近1000人的计划的三天后，渤健又有了新动作——以每股172.50美元（约合73亿美元）的价格收购Reata Pharmaceuticals，该交易预计将于2023年第四季度完成。受到该消息影响，截止7月28日收盘，Reata的股价飙涨了54%，考虑到渤健现阶段大幅裁员以及业务转型下的节衣缩食，在这种业务困难的情况下渤健仍然选择了这家企业进行收购，足以说明这家公司的特殊性。Reata Pharmaceuticals值不值73亿美元？Reata Pharmaceuticals是一家主要开发罕见疾病的Biotech公司，该公司主要产品以Nrf2激动剂为主（还有一款尚处于黑盒状态的Hsp90调节剂），不过Nrf2激动剂开发并不是一番风顺，该公司的不少临床都遇到了数据疗效可能不足以向FDA证明其有效性的窘境。其中黑石集团（Blackstone）旗下黑石生命科学曾经为该公司的Alport综合症药物bardoxolone投资3.5亿美元，然而这项药物最终因临床数据不足以说明其有效性而被FDA拒绝，最终致使该公司放弃了bardoxolone的临床开发。不过，该公司的另外一款Nrf2激动剂Omaveloxolone（RTA-408，商品名：Skyclarys®）却有着截然不同的命运，Omaveloxolone开发的适应症是弗里德赖希共济失调，最初FDA方面认为Reata所提交的证据并不足以证明Omaveloxolone可以减缓疾病发展。直到之后Reata提交了弗里德赖希共济失调患者社区的20年自然病史的额外数据，FDA方面才最终通过了该药物的审批，当然这一过程中对于来自患者社区的数据是否可靠也有一些争议。不过可以确定的是，作为第一款被批准的弗里德赖希共济失调药物，尚且没有竞争对手，市场尚且空白，如果按照该公司的定价每年37万美元，加之于该公司统计的全美6000名患者，该药物能够成为“重磅药物”的潜力显然巨大。就像此前的囊性纤维化药物一样，既然Reata已经构建起了一定的与患者社区的销售网络，就算以粗略计算的市场渗透率只有50%也能达到10亿美元销售额的门槛。考虑到还有欧洲等其他市场的参与，这一数据可能有进一步上涨的空间。因此从Biogen的73亿美元的价格来看，似乎是值得的。此外，收购报告提到，Biogen将以现金和后续发放的债券进行收购，虽然尚未清楚Biogen为了此次收购发放债券的规模，如果后续的消息可以看到这一点，可以应证此次收购Biogen的决心。反垄断会介入吗？从安进收购Horizon Therapeutics被联邦贸易委员会（FTC）制止以来，大型生物制药企业的并购一直受到了这家反垄断机构的关注。例如，辉瑞收购Seagen目前就进入了照常的反垄断调查程序，从业务重合度来看，Reata Pharmaceuticals显然具有弗里德赖希共济失调这一适应症的市场独占，这种仅有一款获批的罕见病是否能被FTC视为问题尚且不明。但一些存在的例子则表明了一些公司在进行收购之后提价的行为：一个关于罕见病药物例子是在欧洲，Leadiant公司收购了一款用于治疗罕见遗传代谢疾病脑腱黄瘤病的药物鹅去氧胆酸，但是收购之后，该药物的价格暴涨了很多倍。因此该公司被荷兰和西班牙的监管机构处以一定罚款，但这种行为似乎没有除了处罚以外的实质性行为。另外一些非罕见病的典型案例则例如臭名昭著的图灵制药的前CEO Martin Shkreli的抬价行为，迈兰制药的肾上腺素笔Epipen。不过，这些行为都是基于原本定价较低而突然涨价，弗里德赖希共济失调药物本身定价（每年37万美元）就极高，是否合理或许仍待观察……总结渤健自2021年以来遭遇了来自竞争对手，专利到期，阿尔兹海默症药物有效性疑云等诸多挑战，维稳事实上就已经很困难了，几乎没有什么收购行为，此前甚至以高达23亿美元的价格出售三星Bioepis合资企业的股权。此次收购是否能够作为渤健退出颓势的信号，还是踩下下坡的油门的信号仍待观察。参考来源：https://www.reatapharma.com/our-science/default.aspx#pipelinehttps://www.biogen.com/扩展阅读：上市被拒，慢性肾病新药终被放弃开发46亿美元，黑石宣布完成生命科学领域最大私募基金的募集肾小球滤过屏障（GFB）靶点综述为何不被看好获批的药能让一家企业股价飙升151%？

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