Using the modified Rodnan skin score (mRSS) as a surrogate for disease activity, a phase 2a study in patients with systemic sclerosis (SSc) measured efficacy of the autotaxin inhibitor ziritaxestat. Mathematical modeling of mRSS was used to predict disease progression, examine candidate trial designs, and predict the probability of successfully discriminating treatment effect.

Methods:

Patients with SSc receiving 600 mg of ziritaxestat or placebo for 24 weeks were included, in addition to data up to week 52 of the open‐label extension (OLE). Longitudinal mRSS data were described using a disease progression model; drug effect was a binary variable. Parameters used to predict the OLE mRSS outcome were estimated using data from the 24‐week double‐blind phase and validated with observed data. Three trial designs were simulated to identify which had the highest probability of detecting a treatment effect. Power to detect a treatment effect was quantified using the simulations.

Results:

Maximum decreases from baseline in mRSS were 50.4% (ziritaxestat) and 34.7% (placebo). Study designs based on 300 patients randomized 2:1 or 1:1 to 600 mg of ziritaxestat or placebo had similar probabilities of detecting a significant treatment effect. Power to detect a treatment effect was >80% for all simulations.

Conclusion:

Disease progression and drug effect could be predicted beyond the range of observed data. This modeling and simulation approach may inform future trial design, including study duration, and predict the probability of success.

2024-03-01·Anticancer research

BBT-877, a Novel Autotaxin Inhibitor, Abrogates Drug Resistance in Epithelial Ovarian Cancer Stem Cells

Article

作者: Shin, Min Joo ; Kim, Dae Kyoung ; Lee, Seo Yul ; Kim, Jae Ho ; Choi, Kyung-Un ; Suh, Dong-Soo ; Kim, Jun Se ; Choi, Seong Min

BACKGROUND/AIM:

Cancer stem cells (CSCs) contribute significantly to the poor prognosis of patients with epithelial ovarian cancer (EOC) due to their roles in drug resistance and tumor metastasis. Autotaxin (ATX) plays a pivotal role in the maintenance of the CSC-like properties of EOC tumors. BBT-877 is a novel ATX inhibitor used in clinical treatment of idiopathic pulmonary fibrosis. However, the effects of BBT-877 on drug resistance and metastasis in ovarian CSCs remain unknown. In this study, we aimed to investigate the effects of BBT-877 on drug resistance and intraperitoneal metastasis of EOC.

MATERIALS AND METHODS:

Spheroid-forming CSCs, which were isolated from two EOC cell lines, A2780 and SKOV3, were investigated by cell viability, western blot, PCR, Spheroid-forming assay, and in vivo experiments.

RESULTS:

Spheroid-forming CSCs exhibited increased CSC-like properties and paclitaxel (PTX) resistance. BBT-877 treatment inhibited the viability of spheroid-forming CSCs more potently than that of adherent ovarian cancer cell lines. Combinatorial treatment with BBT-877 and PTX significantly attenuated the viability of spheroid-forming CSCs. In a SKOV3 cells-derived intraperitoneal metastasis model, BBT-877 treatment reduced the number of metastatic tumor nodes, while combinatorial treatment with BBT-877 and PTX more potently attenuated the formation of metastatic nodes and accumulation of ascitic fluid.

CONCLUSION:

These results suggest that BBT-877 can be combined with conventional anticancer drugs for the treatment of patients with recurrent or drug-resistant EOC.

2024-02-01·Expert opinion on investigational drugs

Experimental autotaxin inhibitors for the treatment of idiopathic pulmonary fibrosis

Review

作者: Simonetti, Jacopo ; Sgalla, Giacomo ; Richeldi, Luca ; Ficili, Marco

INTRODUCTION:

Idiopathic Pulmonary Fibrosis (IPF) is a progressive, irreversible, and fatal lung disease with unmet medical needs. Autotaxin (ATX) is an extracellular enzyme involved in the generation of lysophosphatidic acid (LPA). Preclinical and clinical data have suggested the ATX-LPAR signaling axis plays an important role in the pathogenesis and the progression of IPF.

AREAS COVERED:

The aim of this review is to provide an update on the available evidence on autotaxin inhibitors in IPF and further details on the ongoing clinical studies involving these molecules.

EXPERT OPINION:

The development of autotaxin inhibitors as a potential therapy for idiopathic pulmonary fibrosis has gained attention due to evidence of their involvement in the disease. Preclinical and early-phase clinical studies have explored these inhibitors' efficacy and safety, offering a novel approach in treating this disease. Combining autotaxin inhibitors with existing anti-fibrotic agents is considered for enhanced therapeutic effects. Large phase III trials assessed Ziritaxestat but yielded disappointing results, highlighting the importance of long-term observation and clinical outcomes in clinical research. Patient stratification and personalized medicine are crucial, as pulmonary fibrosis is a heterogeneous disease. Ongoing research and collaboration are essential for this advancement.

项与 FP10.47 相关的新闻（医药）

2024-06-20

·PRNewswire

iOnctura announces EUR80 million Series B financing to progress pipeline through Phase II trials

Led by new investor Syncona, with participation from the European Innovation Council Fund as well as existing investors To progress pipeline of innovative, first-in-class, oral cancer treatments targeting neglected and hard-to-treat cancers To accelerate development of lead asset roginolisib for treatment of uveal melanoma and a number of other oncology indications GENEVA and AMSTERDAM, June 20, 2024 /PRNewswire/ -- iOnctura, a clinical-stage biopharmaceutical company combating neglected and hard-to-treat cancers, today announces that it has closed an EUR80 million Series B financing. The funding round was led by new investor Syncona Limited with participation by the EIC Fund, the venture arm of the European Innovation Council (EIC), as well as existing investors M Ventures, Inkef Capital, VI Partners, Schroders Capital and 3B Future Health Fund. iOnctura is developing a portfolio of precision oral small molecules that target cancers in novel ways. The bold new treatments extend lives and improve healthspans, changing the outlook for patients and their families. The Company has progressed two therapeutic candidates into mid-stage clinical development. Lead asset roginolisib is the first allosteric modulator of PI3Kδ, with a unique chemical structure and binding mode. It is being developed for indications burdened by immune mediated resistance and a high expression of PI3Kδ in cancer cells and tumor-infiltrating immune cells. Roginolisib has potential to become the first successful, clinically meaningful therapy to target the critical PI3Kδ cancer pathway. It has demonstrated an unprecedented and first-in-class clinical profile in solid and hematological malignancies, with over 48 patients treated to date. The financing will be used to accelerate development of roginolisib for the treatment of uveal melanoma (UM), a rare cancer of the eye with few available treatments. Eye melanoma is a rapidly growing market which is projected to be worth USD 9.56B by 2032[1] . In a Phase Ib clinical trial, roginolisib demonstrated long-term safety and promising efficacy in UM with sustained clinical activity over many months. Full results will be announced in the coming months. The successful UM data reported so far, combined with a rich preclinical data package, supports the rationale to expand into other indications. iOnctura plans to commence trials in other cancer indications, including non-small cell lung cancer and primary myelofibrosis, later in 2024. iOnctura's second clinical asset, cambritaxestat, is the only autotaxin inhibitor in clinical development to treat cancer. It has excellent potency and specificity, and is being developed for highly fibrotic tumors that overexpress autotaxin. A Phase Ib study of cambritaxestat in combination with chemotherapy in metastatic pancreatic cancer is ongoing. Catherine Pickering, Chief Executive Officer, iOnctura, said: "This financing is validation of iOnctura's approach to developing precision cancer treatments with maximum clinical impact. These therapies have the potential to significantly prolong the healthspan of patients suffering with neglected cancer types, such as uveal melanoma. We are pleased to welcome our new investors Syncona and the EIC Fund alongside our existing strong syndicate. Their experience will be invaluable as we look to advance our pipeline and take iOnctura to its next stage of growth." Roel Bulthuis, Managing Partner and Head of Investments at Syncona and Board member of iOnctura, added: "iOnctura represents a compelling opportunity to invest in line with our strategy and capital allocation focus in a clinical-stage company, and take a promising lead programme through to late-stage development. To date, no company has been able to successfully target this well-known cancer pathway with sufficient precision. By allosterically modulating PI3Kδ, iOnctura has achieved a new level of precision and could be the first company to develop a clinically meaningful medicine targeting this pathway. Its programmes have potential utility across a range of cancers, which we are supporting the company to unlock through a refined clinical strategy." About iOnctura iOnctura is a clinical-stage biopharmaceutical company combating neglected and hard-to-treat cancers with precision oral small molecules that target cancers in novel ways. The bold new treatments extend lives and improve healthspans, changing the outlook for patients and their families. Two therapeutic candidates have progressed into mid-stage clinical development: roginolisib is the first allosteric modulator of PI3Kδ and cambritaxestat is the only autotaxin inhibitor in clinical development to treat cancer. iOnctura BV is headquartered in Amsterdam, The Netherlands with its wholly owned Swiss subsidiary, iOnctura SA, located in Geneva, Switzerland. iOnctura is backed by specialist institutional investors including Syncona, EIC Fund, M Ventures, Inkef Capital, VI Partners and Schroders Capital. About roginolisib Roginolisib is the first allosteric modulator of PI3Kδ with a unique chemical structure and binding mode. The PI3K signalling pathway is one of the most commonly dysregulated pathways in cancer and the precise targeting of the PI3Kδ isoform delivers substantial anti-tumor effects with a low-toxicity profile. Clinical data have demonstrated roginolisib's excellent safety profile and sustained clinical activity in uveal melanoma (UM), a rare eye cancer with few available treatments. Randomized Phase II trials are planned to start in late 2024 in UM and other cancers, including non-small cell lung cancer and primary myelofibrosis. About cambritaxestat Cambritaxestat is a first-in-class autotaxin inhibitor that has shown preclinically to inhibit the growth and proliferation of cancer cells, stimulate immune cell infiltration and inhibit the development of fibrosis. It offers a new therapeutic approach for treating highly fibrotic hard-to-treat tumors such as pancreatic cancer. A Phase Ib study of cambritaxestat in combination with chemotherapy in metastatic pancreatic cancer is ongoing. [1] Emergen Research, Jan 2024 SOURCE iOnctura

临床1期临床2期临床结果

2024-06-06

·Science Daily

The body's own lipids affect mental disorders: Can specific inhibitors help?

A genetic disorder leads to an increase in bioactive lipids in the brain, resulting in an imbalance between excitation and inhibition in neural circuits and promoting mental disorders. However, treatment with an enzyme inhibitor that prevents the activation of lipids can restore balance and alleviate symptoms. A genetic disorder leads to an increase in bioactive lipids in the brain, resulting in an imbalance between excitation and inhibition in neural circuits and promoting mental disorders. However, treatment with an enzyme inhibitor that prevents the activation of lipids can restore balance and alleviate symptoms. Increased levels of bioactive lipids produced naturally in the body, which affect excitatory transmission between brain cells, promote mental disorders. However, this mechanism can be rebalanced by treatment with an inhibitor that prevents the activation of these lipids in the brain. That is the result of a recent study on the correlation between synaptic lipid signals in the brain and mental disorders. The results of the study 'Altered cortical synaptic lipid signaling leads to intermediate phenotypes of mental disorders' have now been published in Molecular Psychiatry and could create new opportunities for the treatment of mental illness. The teams led by Johannes Vogt (MD) at the Department of Molecular and Translational Neurosciences at the University of Cologne, Robert Nitsch (MD, PhD) at the Institute of Translational Neuroscience at the University of Münster and partners at other universities investigated the role of the enzyme autotaxin and its opponent, the protein PRG-1, in regulating the balance between excitation and inhibition in the brains of humans and mice. The research was carried out within the framework of Collaborative Research Centre 1451 'Key Mechanisms of Motor Control in Health and Disease' (speaker: Professor Dr Gereon Fink, University of Cologne). The project under the leadership of Vogt and Nitsch within the CRC deals with the balance between excitation and inhibition in the brain and its effect on motor function. This balance plays an important role in mental disorders. In the case of excitation, neural circuits cause information to be passed on and other neurons to be activated; in the case of inhibition, this information transfer is interrupted. The project groups in Cologne and Münster had already shown in previous studies that the body's own lipids in the brain are activated by the enzyme autotaxin and stimulate nerve cell activity at the central checkpoint of signal transmission, the cortical synapse. As a result, they alter information processing in the brain's networks. In the current study, the researchers analysed the functional consequences of altered signal balance in 25 individuals induced by the antagonist of autotaxin, which reduces the activated lipids at the synapse. Using various methods for measuring brain waves and brain activity as well as psychological tests, they found specific changes that also occur in patients, so-called intermediate phenotypes of mental disorders. This means, for example, that comparable patterns of brain activation can be found in both patients and their clinically healthy relatives. Additional studies in the mouse model revealed that animals with a similar genetic disorder showed comparable symptoms: increased anxiety, a depressive phenotype and lower stress resilience. Synchronization and information transfer between brain areas was similarly altered in humans and mice. "The study indicates that the regulation of excitation and inhibition by synaptic lipid signals plays a crucial role in the development of mental disorders," said Professor Vogt. Autotaxin is the key enzyme of lipid activation in the brains of mice and humans. The increased excitation state of the networks caused by the genetic disorder could be restored by administering specific inhibitors of autotaxin. According to the researchers, these findings open up new perspectives for the diagnosis and treatment of such disorders. "Targeted modulation of synaptic lipid signals using autotaxin inhibitors that can reach the brain could open up possibilities to treat mental disorders," concluded Professor Nitsch. In future studies, the researchers plan to further investigate these approaches and to test their effectiveness and safety in clinical trials.

100 项与 FP10.47 相关的药物交易

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