Palisade Bio, Inc.

对于一家初创公司来说，技术验证失败无疑是对公司的最大打击，股价的暴跌反映的更是投资者不看好这家公司具有美好的未来，可以说是半只脚踏进了棺材板。 近日，以人工智能为卖点的Alto Neuroscience可能就要面临这种情况了，随着验证性临床的失利，截止收盘公司股价暴跌69.99%，而这距离该公司今年2月份IPO还不到一年。 管线失败到底是患者群体不对，还是管线不行？ Alto Neuroscience的技术模式实际上和近年来涌现的一批“捡垃圾”公司有些类似，也就是采用的是选其他人临床失败过的管线进行开发。这类“捡垃圾”经常会为已经失败的临床管线换个适应症开发。但Alto Neuroscience不一样，他们认为“失败管线”的失败不一定在于药品本身，而在于找错了患者。 通过Alto Neuroscience独有的人工智能技术筛选患者特定生物标志物来分类病人就能够提高临床的成功率，让失败管线“起死回生”。 如果真如Alto Neuroscience所言，那么近日发布的核心管线ALTO-100 II期重度抑郁症临床数据应该是证明人工智能平台有效性的证据，就算是没有达到统计学意义，一部分的改善也能证明确实有望实现“变废为宝”。 但这次却成为了“催命绳”，原因在于这次的临床数据，主要终点没有达到，关键二次分析中，次要终点甚至不如安慰剂。虽然在抑郁症这类精神疾病的临床中，临床失败非常常见，但是这次算是Alto Neuroscience一败涂地。 为何说是一败涂地？ 这次出现事故的核心管线ALTO-100最初来自于Palisade Bio的管线NSI-189，2021年时秘密转让给了Alto Neuroscience。（交易总额490万美元，预付款50万美元） 说到Palisade Bio，这家公司本身是Seneca Biopharma（前名：Neuralstem）和Leading BioSciences两家的合并，在还叫做Neuralstem时期，该公司从陶氏手中获得了专利授权开发了如今ALTO-100的前身NSI-189，适应症也是重度抑郁症。（根据协议Alto需要向陶氏支付专利权使用费） 不过值得诟病的是，NSI-189本身的机制实际上并不明确。此前，它在多种临床前模型中已被发现能增强海马体的神经可塑性和神经生成，尤其是能够以剂量依赖来增大啮齿类动物的海马体体积，但NSI-189达成此效果的机制并不明确，猜测是通过脑源性神经营养因子(BDNF)进行调节的。 考虑到重度抑郁症患者中患者海马体体积会缩小，海马体神经元也会死亡，因此就被用于了重度抑郁症。 不过虽然此前在啮齿类动物中海马体的改善很显著，但到了人体临床，似乎也没有检测到有显著影响患者海马体的情况。在这种情况下，Neuralstem的NSI-189 II期临床也在2017年时因未抵达临床终点而失败了。 但关键在于没有对比就没有伤害。 2017年时，NSI-189的临床在多个次要抑郁和认知终点方面均出现了具有统计学意义的改善，2017年末和2018年初的更详细数据分析也显示，在患者报告的抑郁量表评分以及每天服用40毫克剂量对认知方面的改善上，均出现了具有统计学意义的改善。 而反观ALTO-100，虽然2023年发布的IIa期临床时，确实在第六周展现出对生物标志物定义的患者人群的MADRS评分的显著改善(-15.5 vs .-10.5；p=0.0001)，但到了IIb期临床就原形毕露，次要终点不及安慰剂。 最令投资者担心的是在这个过程中Alto Neuroscience的人工智能平台可能就完全没起到作用。猜疑链会这样继续下去：Alto买来的管线都是失败管线，那么和ALTO-100类似，该失败的药物可能还是会失败，人工智能平台并不能改变失败药物的结局，公司将失去未来。 所幸Alto Neuroscience账面的钱还足够支撑到2027年，明年即将发布的ALTO-300和ALTO-203临床数据或许是这家公司翻盘的重要期望。 参考来源： https://investors.altoneuroscience.com/news/news-details/2024/Alto-Neuroscience-Reports-Topline-Results-from-a-Phase-2b-Trial-Evaluating-ALTO-100-as-a-Treatment-for-Major-Depressive-Disorder/default.aspx 本周好文推荐 如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·

Neuropsychiatric drug development is rife with clinical trial failures, but Alto Neuroscience aims to overcome these hurdles with a precision medicine approach that matches a patient to a drug. A clinical trial failure for an Alto depression drug is now casting doubt on this program and the technology that is the foundation for the biotech company’s approach. The Phase 2b failure of the drug, ALTO-100, comes nearly nine months after Mountain View , California-based Alto raised more than $128 million in an IPO priced at $16 per share. Alto shares opened Wednesday at $5.15 each, down 64.5% from Tuesday’s closing stock price. Alto’s platform technology analyzes brain-based biomarkers, looking for the biomarkers that predict response to a drug. Last year, an open-label Phase 2a test of ALTO-100 posted results showing the twice-daily pill led to significant improvement in depressive symptoms in patients characterized by impaired cognition, compared to patients who did not have objectively defined cognitive impairment. sponsored content Upcoming Webinar: Battle of the Budget: Employers vs. Rising Healthcare Costs Gain valuable knowledge and practical insights on how employers are addressing an increasingly complex healthcare budget landscape. By Personify Health The preliminary results announced after Tuesday’s market close are from a placebo-controlled Phase 2b test of ALTO-100, a novel small molecule that Alto acquired from Palisade Bio. The study enrolled 301 patients with major depressive disorder, or MDD, defined by an objective biomarker that was assessed before randomization. This biomarker is low levels of BDNF, a brain protein that promotes neuron survival and health. Participants included those who were already taking depressions drugs, in which case ALTO-100 was evaluated as an adjunct to those therapies. The main goal was measuring the change in score after six weeks according to a rating scale used to assess depression symptoms. Without reporting specific figures, Alto said patients treated with ALTO-100 did not show a statistically significant improvement in depressive symptoms compared to those given a placebo. The drug also failed to beat a placebo in patients who received the study drug as a monotherapy, which was a secondary trial goal. There’s more at stake than MDD. The negative data readout could affect Alto’s plans to test the drug in post-traumatic stress disorder and bipolar depression using the same biomarker as the one used for the MDD trial. William Blair analyst Myles Minter spoke with Alto executives, who told him the trial was well conducted and the placebo response was within historical norms. That’s important because in some depression trials, the test drug shows trending improvement but a high placebo response results in a study failure. If the placebo response in the ALTO-100 trial was normal, then the failure is likely due to the drug not working. Alto management reiterated to Minter that the company will analyze the full data set to determine the next steps for the drug in MDD. “While today’s data points draw increased scrutiny on the biomarker stratification approach, historically placebo-controlled MDD studies have been high-risk, and this one appears no different,” Minter wrote in a note sent to investors. “Still, in our discussions with management, it remained confident in the stratification approach, and we will await a fuller dataset to better understand this optimism despite the negative Phase 2b readout.” presented by Sponsored Post The Promise of Value-Based Care and MedTech Innovation Monica Vajani, Executive Director for mHUB’s MedTech Accelerator, discusses how mHUB is helping innovators transition healthcare towards value-based care. By Monica Vajani - mHUB Alto’s patient-selection strategy may yet prove itself. A Phase 2b test is ongoing for Alto’s ALTO-300 in MDD. This small molecule, which has the non-proprietary name agomelatine, has approvals in Europe and Australia and is sold in those markets by Servier. Novartis held U.S. rights to the molecule, but stopped Phase 3 tests due to liver toxicity. ALTO-300 is the lower of the two doses that Novartis had evaluated in Phase 3. Alto’s trial, which enrolled patients who have a biomarker that could predict response to ALTO-300, is expected to post preliminary data in the first half of 2025. Minter said that compared to ALTO-100, ALTO-300 has already demonstrated antidepressant efficacy in its commercialized markets. Also, this drug’s biomarker is less subjective than the one used for ALTO-100, “which bodes well for stratifying patients, albeit likely tougher to vet and we expect investors to remain cautious after today’s failure,” Minter said. So far, Alto does not have any internally discovered drugs. Besides ALTO-100 and ALT-300, the company’s pipeline includes two other in-licensed assets in development for MDD, both of them going after different targets. The company also has an in-licensed program in development for schizophrenia. As of the end of the second quarter of this year, Alto reported a cash position of $193 million, which it said would be sufficient to fund operations into 2027. Image: Jolygon, Getty Images

– Company has received a No Objection Letter from Health Canada in response to submission of its Phase 1 Clinical Trial Application (CTA) – The study is a Phase 1 Single Ascending Dose (SAD) /Multiple Ascending Dose (MAD) and food effects (FE) and includes multiple dose treatment of UC patients; Global UC market is expected to grow to nearly $10 Billion by 2028 Oct. 10, 2024 -- Palisade Bio, Inc. (Nasdaq: PALI) (“Palisade,” “Palisade Bio” or the “Company”), a biopharmaceutical company focused on developing and advancing novel therapeutics for patients living with autoimmune, inflammatory, and fibrotic diseases, today announced that it has received a No Objection Letter from Health Canada for its Phase 1 human clinical study for PALI-2108 for the treatment of UC. “We are thrilled to receive a No Objection Letter from Health Canada in response to our Clinical Trial Application. This achievement marks the most important milestone to date for our PALI-2108 development program. We continue to believe in the potential of PALI-2108 to be the first approved PDE4 inhibitor for UC and more importantly, provide a much-needed effective and safe solution for UC patients still experiencing significant medical need. Our team remains focused on continuing preparations for the initiation of our Phase 1 clinical trial which is on track to commence before year end,” commented J.D. Finley, Chief Executive Officer. PALI-2108 is an orally administered PDE4 inhibitor prodrug which is locally bioactivated in the colon and is in development for patients affected by UC. The Phase 1 study will evaluate PALI-2108 in a single-center, double-blind, placebo-controlled study focused on safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers, alongside an open-label study involving a patient cohort with UC. As previously announced, the Company has established dose levels and trial design for PALI-2108 and plans to enroll approximately 90 patients across the SAD, FE, MAD and UC cohorts. “Patients are actively seeking new and more effective treatment options for their ulcerative colitis. Currently, existing therapies achieve complete remission in fewer than a quarter of patients, and many of the most effective treatments involve injections or carry black box warnings due to serious side effects. A safe and effective oral medication for UC would be highly desirable for the majority of patients,” said Florian Rieder, MD, a member of the Palisade Bio Clinical Advisory Board and Associate Staff in the Department of Gastroenterology, Hepatology, and Nutrition, as well as an Investigator in the Department of Pathobiology at the Cleveland Clinic. The primary objective of the study will be to assess the safety and tolerability of single (healthy subjects) and repeated (healthy subjects and UC patients) oral doses of PALI-2108. Secondary objectives include determining the plasma, urinary, and fecal (MAD healthy subjects and UC patients only) pharmacokinetics (PK) of PALI-2108 and its metabolites following PALI-2108 single (healthy subjects) and repeated (healthy subjects and UC patients) oral doses, as well as the effect of food on the PK of PALI-2108 and its metabolites following a single oral dose in healthy subjects. Exploratory objectives will include PDE4-related pharmacodynamic (PD) biomarkers, concentrations of the active form of PALI-2108, high sensitivity C-reactive protein (hsCRP), fecal calprotectin (CalPro), colonic tissue Absolute Lymphocyte Count (ALC), Modified Mayo score, as well as colonic histological changes in UC patients following repeated PALI-2108 oral doses. Preparations for the clinical study remain ongoing and the Company is on track commence site initiation and enrollment for the study before year end. Palisade Bio is a biopharmaceutical company focused on developing and advancing novel therapeutics for patients living with autoimmune, inflammatory, and fibrotic diseases. The Company believes that by using a targeted approach with its novel therapeutics it will transform the treatment landscape. For more information, please go to www.palisadebio.com. The content above comes from the network. if any infringement, please contact us to modify.