Drug development in traumatic brain injury (TBI) has been impeded by the complexity and heterogeneity of the disease pathology, as well as limited understanding of the secondary injury cascade that follows the initial trauma. As a result, patients with TBI have an unmet need for effective pharmacological therapies. One promising drug candidate is cyclosporine, a polypeptide traditionally used to achieve immunosuppression in transplant recipients. Cyclosporine inhibits mitochondrial permeability transition, thereby reducing secondary brain injury, and has shown neuroprotective effects in multiple preclinical models of TBI. Moreover, the cyclosporine formulation NeuroSTAT^® displayed positive effects on injury biomarker levels in patients with severe TBI enrolled in the Phase Ib/IIa Copenhagen Head Injury Ciclosporin trial (NCT01825044). Future research on neuroprotective compounds such as cyclosporine should take advantage of recent advances in fluid-based biomarkers and neuroimaging to select patients with similar disease pathologies for clinical trials. This would increase statistical power and allow for more accurate assessment of long-term outcomes.

2021-07-01·Journal of Neurotrauma2区 · 医学

Evaluation of Diffusion Tensor Imaging and Fluid Based Biomarkers in a Large Animal Trial of Cyclosporine in Focal Traumatic Brain Injury

2区 · 医学

Article

作者: Delso, Nile ; Hansson, Magnus J. ; Chawla, Sanjeev ; Ehinger, Johannes ; Karlsson, Michael ; Wang, Kevin K.W. ; Elmér, Eskil ; Pukenas, Bryan ; Kilbaugh, Todd J. ; Yang, Zhihui ; Hugerth, Matilda ; Margulies, Susan S.

All phase III trials evaluating medical treatments for traumatic brain injury (TBI), performed to date, have failed. To facilitate future success there is a need for novel outcome metrics that can bridge pre-clinical studies to clinical proof of concept trials. Our objective was to assess diffusion tensor imaging (DTI) and biofluid-based biomarkers as efficacy outcome metrics in a large animal study evaluating the efficacy of cyclosporine in TBI. This work builds on our previously published study that demonstrated a reduced volume of injury by 35% with cyclosporine treatment based on magnetic resonance imaging (MRI) results. A focal contusion injury was induced in piglets using a controlled cortical impact (CCI) device. Cyclosporine in a novel Cremophor/Kolliphor EL-free lipid emulsion, NeuroSTAT, was administered by continuous intravenous infusion for 5 days. The animals underwent DTI on day 5. Glial fibrillary acidic protein (GFAP), as a measure of astroglia injury, and neurofilament light (NF-L), as a measure of axonal injury, were measured in blood on days 1, 2, and 5, and in cerebrospinal fluid (CSF) on day 5 post-injury. Normalized fractional anisotropy (FA) was significantly (p = 0.027) higher in in the treatment group, indicating preserved tissue integrity with treatment. For the biomarkers, we observed a statistical trend of a decreased level of NF-L in CSF (p = 0.051), in the treatment group relative to placebo, indicating less axonal injury. Our findings suggest that DTI, and possibly CSF NF-L, may be feasible as translational end-points assessing neuroprotective drugs in TBI.

2016-03-01·Journal of Controlled Release1区 · 医学

Reformulating cyclosporine A (CsA): More than just a life cycle management strategy

1区 · 医学

Review

作者: Préat, Véronique ; Guada, Melissa ; Dios-Viéitez, Maria Del Carmen ; Kumar, M N V Ravi ; Beloqui, Ana ; Blanco-Prieto, Maria J

Cyclosporine A (CsA) is a well-known immunosuppressive agent that gained considerable importance in transplant medicine in the late 1970s due to its selective and reversible inhibition of T-lymphocytes. While CsA has been widely used to prevent graft rejection in patients undergoing organ transplant it was also used to treat several systemic and local autoimmune disorders. Currently, the neuro- and cardio-protective effects of CsA (CiCloMulsion®; NeuroSTAT®) are being tested in phase II and III trials respectively and NeuroSTAT® received orphan drug status from US FDA and Europe in 2010. The reformulation strategies focused on developing Cremophor® EL free formulations and address variable bioavailability and toxicity issues of CsA. This review is an attempt to highlight the progress made so far and the room available for further improvements to realize the maximum benefits of CsA.

项与 NeuroSTAT 相关的新闻（医药）

2023-11-17

·PRNewswire

Owl Therapeutics Enters a Strategic Clinical Collaboration With Abliva to Advance NeuroSTAT® (OWL-1410) for Traumatic Brain Injury

SAN ANTONIO, Nov. 17, 2023 /PRNewswire/ -- Owl Therapeutics, a wholly-owned subsidiary of Gryphon Bio, today announced a global licensing and collaboration agreement with Abliva AB of Lund, Sweden, to advance Abliva's NeuroSTAT® (OWL-1410) for the prevention and treatment of moderate to severe traumatic brain injury (TBI). TBI is an urgent and prominent public health challenge, impacting millions each year as a result of head trauma from accidents, falls, sports-related incidents, and military combat. TBI disrupts the normal functioning of the brain, leading to a range of cognitive, physical, and emotional symptoms. The collaboration agreement provides Owl Therapeutics with a global license to develop, manufacture, and commercialize NeuroSTAT®. "Abliva stands out as an exceptional partner for Owl Therapeutics, and we are excited to join forces in our collective commitment to advance NeuroSTAT® (OWL-1410)," said William E. Haskins, PhD, Co-Founder of Owl Therapeutics and Chief Executive Officer of Gryphon Bio. "We are thrilled to focus our team's scientific, clinical, and business experience on this potentially game-changing treatment for military and civilian TBI patients." Under the terms of the agreement, Abliva will contribute to both the operational and strategic elements of the program through the established steering committee. Owl Therapeutics will lead the clinical development and commercialization of NeuroSTAT®. Upon commercialization, Abliva is eligible for royalties. "Through this important collaboration with Abliva, Owl Therapeutics gains access to an innovative asset for TBI with orphan drug designation (ODD) in Europe and the U.S., as well as an investigational new drug (IND) approval granted Fast Track designation for clinical development and review in the U.S.," said Franklin Okumu, PhD, and Chief Technology Officer of Owl Therapeutics. "We are also excited by the potential to collaborate with clinical investigators to rapidly advance this treatment to patients in need." "NeuroSTAT® has demonstrated promising attributes in advanced experimental TBI models that replicate human disease," said Todd Kilbaugh, a prominent TBI researcher, advisor to Owl Therapeutics. "The scientific community is enthusiastic about collaborating closely with companies like Owl to fully unleash the potential of TBI treatments and accelerate their translation into clinical practice, ultimately enhancing the well-being of patients." "NeuroSTAT® has shown a promising reduction in levels of blood biomarkers of neuronal injury in advanced experimental TBI models and clinical studies," said Kevin KW Wang, PhD, an internationally renowned TBI biomarker pioneer, Co-Founder of Gryphon Bio, and Co-Founder and Chair of the Scientific Advisory Board of Owl Therapeutics. "We see this agreement as a strong endorsement of the TBI expertise that the Owl team brings to this collaboration, and we look forward to demonstrating the clinical profile of this drug with the underserved TBI patient population." TBI places considerable strain on health care systems and society at large, incurring substantial expenses for emergency care, hospitalization, rehabilitation, and long-term care. Notably, TBI continues to be a contributing factor in one-third of injury-related fatalities in the U.S., imposing emotional and financial hardships on both patients and their families. To address this complex and pervasive health issue, it is imperative to prioritize ongoing research aimed at prevention, diagnosis, and treatment. Owl Therapeutics – Unlocking Wisdom for Brain Health Owl Therapeutics, a wholly-owned subsidiary of Gryphon Bio, is a clinical-stage biopharmaceutical company created to develop diagnostic-powered therapeutics for traumatic brain injury (TBI) and brain health. The company has rapidly built a promising, diversified pipeline of small and large molecule medicines poised to address the highly unmet medical needs of patients with neurodegenerative disease. Owl is led by a proven, cohesive, interdisciplinary, and internationally recognized team with deep scientific, clinical, and business experience in drug development and commercialization. Abliva – Delivering Mitochondrial Health Abliva discovers and develops therapies for the treatment of mitochondrial disease. This rare and often very severe disease occurs when the cell's energy provider, the mitochondria, does not function properly. The company has prioritized two projects. KL1333, a powerful regulator of the essential co-enzymes NAD⁺ and NADH, has entered late-stage development. NV354, an energy replacement therapy, has completed preclinical development. Abliva, based in Lund, Sweden, is listed on Nasdaq Stockholm, Sweden (ticker: ABLI). Media Enquiries: [email protected] SOURCE Owl Therapeutics

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