Antipsychotic meds found to be effective against bacteria that cause meningitis

Medical Xpress | March 26, 2019

A team of researchers affiliated with multiple institutions in France has found that a class of antipsychotic drugs known as phenothiazines was successful in treating a form of meningitis in mice when used with antibacterial agents. In their paper published in the journal Nature Microbiology, the group describes experiments they conducted with meningitis mouse models and what they found. Meningitis is not a disease, but a condition caused by viral, bacterial or fungal infections. The condition occurs when infections result in swelling of the meninges (membranes that cover the brain and spinal column). Different types of infectious agents can result in different degrees of danger to a patient. One agent, a kind of bacteria called Neisseria meningitidis, is well known for the severity of its infections—typically, 10 percent of people die from it. In this new effort, the researchers report on experiments they conducted with a class of antipsychotic medicines that allowed antibacterial agents to perform better against Neisseria meningitidis.

Spotlight

Recruitment, retention, and diversity are critical elements of clinical trials that, if insufficient, can jeopardize successful trial completion. 

Spotlight

Recruitment, retention, and diversity are critical elements of clinical trials that, if insufficient, can jeopardize successful trial completion. 

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AI, INDUSTRIAL IMPACT

Cimeio Therapeutics Presents SCIP Platform Proof-of-Concept Data at ASH

Cimeio | December 12, 2022

The two studies demonstrate proof-of-concept that genetically engineered variants of cell surface receptors harboring single amino acid substitutions are fully functional but evade a paired immunotherapy directed against the wild-type molecule. This technology will enable the development of more efficient and safer targeted conditioning regimens for hematopoietic stem cell transplantation, gene therapies, and opens the path to more efficient cell and immunotherapy-based treatment approaches for hematological malignancies. The first abstract was titled “Function-preserving single amino acid substitutions shield hematopoietic stem and progenitor cells from CD117 targeted immunotherapy in vivo.” The receptor tyrosine kinase c-KIT is expressed on normal hematopoietic stem cells but also on leukemia cells. Consequently, it is an attractive target for an antibody-based conditioning therapy. The study showed that cells expressing a genetically engineered variant of CD117 are fully functional in vitro and contributed to the blood development in vivo, similar to unmodified HSCs expressing the wt receptor. Mice transplanted with a mix of human HSCs expressing either wt CD117 or the Cimeio shielded CD117 variant showed a selective depletion of wt CD117 cells, while those cells expressing the variant receptor were spared following the treatment with a monoclonal antibody directed against wt CD117. The second abstract, titled “Engineered Single Amino Acid Substitutions Protect Hematopoietic Stem and Progenitor Cells From CD123 Targeted Immunotherapy,” focused on targeting the interleukin-3 receptor alpha-chain a cytokine receptor highly expressed on various hematological malignancies as well as normal hematopoietic cells. This abstract demonstrated that shielded CD123 cells were not depleted by a highly efficient CD123 targeted immunotherapy. Collectively, these preclinical studies demonstrate the feasibility and efficacy of Cimeio’s SCIP platform, a novel and promising therapeutic approach to improve the outcomes for patients with benign and malignant hematological diseases in need of an HSC transplant. “Many severe and late side effects following an HSC transplant are caused by untargeted and broadly toxic chemotherapeutics and radiation in conditioning regimens. The presented work is an encouraging and important step towards safer and efficient approaches to overcome these hurdles. Cimeio’s SCIP platform could allow more patients facing debilitating and fatal diseases to receive a life-saving HSC transplant.” Suneet Agarwal, M.D., Ph.D., Co-Program Leader for the Stem Cell Transplant Center at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Associate Professor of Pediatrics at the Harvard Medical School, and member of the Cimeio Scientific Advisory Board Last month, Cimeio announced the issuance of a foundational patent that covers a method for in vivo selective depletion of edited primary hematopoietic cells or non-edited primary hematopoietic cells, the basis of its SCIP platform. About Cimeio Cimeio is an applied gene editing and immunotherapy company developing a portfolio of Shielded-Cell & Immunotherapy Pairs™ which has the potential to transform hematopoietic stem cell transplant. Cimeio’s technology platform is based on the design and expression of modified variants of naturally occurring cell surface proteins in HSCs. These novel variants maintain their function but are resistant to depletion when targeted by a paired immunotherapy which has high affinity for the wild-type version of these proteins. This technology has significant therapeutic potential, which Cimeio is using to develop curative treatments for patients with genetic diseases, hematologic malignancies, and severe autoimmune disorders.

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INDUSTRIAL IMPACT, MEDICAL

Emulate Publishes Landmark Study Validating Organ-on-a-Chip Technology for Predictive Toxicology in Preclinical Development

Emulate, Inc. | December 07, 2022

Emulate, Inc., the leading provider of next-generation in vitro models announced the publication of a landmark study, “Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology,” in Nature Communications Medicine demonstrating that the Emulate human Liver-Chip could improve patient safety and reduce small-molecule clinical trial failures due to liver toxicity by up to 87%. These findings conclude the single largest Organ-Chip study to date, in which researchers compared the performance of human Liver-Chips in predicting drug-induced liver injury (DILI) to those of animal in vivo models—the current industry standard—and primary human 3D hepatic spheroids. In addition to assessing and quantifying model performance, this study effectively qualifies the Emulate human Liver-Chip model against the guidelines defined by IQ MPS, an affiliate of the International Consortium for Innovation and Quality in Pharmaceutical Development. “This first-of-its-kind study demonstrates the Emulate human Liver-Chip can better predict drug safety than other methods for modeling liver toxicity. In light of these findings, the pharmaceutical industry and government agencies have a responsibility to both patients and researchers to bring efficient, accurate, and safe preclinical testing models—like Organ-Chips—into the drug development process.” Jim Corbett, Chief Executive Officer of Emulate Researchers assessed the performance of 870 Emulate human Liver-Chips across a blinded set of 27 known hepatotoxic and non-toxic drugs. In line with the IQ MPS guidelines, the tested drugs included seven matched pairs that demonstrate the chip’s ability to distinguish toxic drugs from their less toxic structural analogs. Furthermore, the study demonstrated that the Emulate human Liver-Chip was able to correctly identify 87% of the tested drugs that caused drug-induced liver injury in patients despite passing animal testing evaluations. At the same time, the Emulate human Liver-Chip did not falsely identify any drugs as toxic leading to a 100% specificity and supporting its use in toxicology screening workflows. Pharmaceutical companies can encounter many challenges in developing human drugs. Often, compounds showing promise in preclinical efforts face high attrition during human trials due to poor predictive validity of preclinical models, especially for biologics. Therefore, the researchers also modeled the potential economic impact that routine use of the Emulate human Liver-Chip could have on drug development productivity. By simply improving the ability to detect hepatotoxicity with 87% sensitivity, they estimated that broad adoption of the Emulate human Liver-Chip could increase research and development productivity by $3 billion dollars on an annual basis for the small molecule drug development industry. Additionally, their computational economic value analysis estimated that routine use of Organ-Chips to assess cardiovascular, neurological, immunological, and gastrointestinal small molecule toxicities could similarly generate approximately $24 billion dollars per year due to increased research and development productivity. With 40% of current drugs in the pipeline being biologics, this value is expected to increase even more as Organ-Chips are further incorporated into the biopharmaceutical drug development pipeline. “The predictive validity of a model is the rate limiting step in drug research and development,” said Jack Scannell, PhD, CEO of Etheros Pharma Corp, Author of Eroom’s Law. “These models are under-evaluated, and the financial value of good models remains opaque; consequently, model innovation is poorly incentivized. Two outcomes from the Emulate study have implications that extend well beyond toxicity. First, it sets the benchmark for model evaluation, and secondly it shows how to map from model validity to decision quality to dollar value. After all, if we want the scientific community to invest in better models, we need to work out how much they are worth.” The authors suggest that researchers could employ the Emulate human Liver-Chip in the lead optimization phase of their drug development pipeline, where projects have identified three to five chemical compounds that have the potential to become a candidate drug. By doing so, a chemical compound that produced a toxic signal in the Emulate human Liver-Chip could be deprioritized from early in vivo studies, thus reducing animal testing, and permitting safer candidates to progress through the development pipeline. “This study is one of the most critical developments in the field of Organ-on-a-Chip technology,” said Zaher Nahle, PhD, MPA, Chief Science Officer at the Center for Contemporary Sciences. “It shows the primacy and utility of the technology in predictive toxicology. It also demonstrates the immediate readiness of such technology to transform critical phases of the drug development process, in particular lead optimization and preclinical assessment, making the entire process safer, cheaper, faster, and more effective.” Full study: Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology, Nature Communications Medicine, December 6, 2022 Co-authors include: Lorna Ewart, Athanasia Apostolou, Skyler A. Briggs, Christopher V. Carman, Jake T. Chaff, Anthony R. Heng, Sushma Jadalannagari, Jeshina Janardhanan, Kyung-Jin Jang, Sannidhi R. Joshipura, Mahika Kadam, Marianne Kanellias, Ville J. Kujala, Gauri Kulkarni, Christopher Y. Le, Carolina Lucchesi, Dimitris V. Manatakis, Kairav K. Maniar, Meaghan E. Quinn, Joseph S. Ravan, Ann Catherine Rizos, John F.K. Sauld, Josiah Sliz, William Tien-Street, Dennis Ramos Trinidad, James Velez, Max Wendell, Prathap Kumar Mahalingaiah, Donald E. Ingber, Jack Scannell, Daniel Levner About Emulate, Inc. Emulate is igniting a new era in human health with industry-leading Organ-on-a-Chip technology. The Human Emulation System provides a window into the inner workings of human biology and disease, offering researchers an innovative technology designed to predict human response with greater precision and detail than conventional cell culture or animal-based experimental testing. Pioneered at the Wyss Institute for Biologically Inspired Engineering at Harvard University and backed by Northpond Ventures, Founders Fund, and Perceptive Advisors, Organ-on-a-Chip technology is assisting researchers across academia, pharma, and government industries through its predictive power and ability to recreate true-to-life human biology.

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CELL AND GENE THERAPY, MEDTECH

Nkarta Announces Updated Clinical Data on Anti-CD19 Allogeneic CAR-NK Cell Therapy NKX019 for Patients

Nkarta, Inc. | December 06, 2022

Nkarta, Inc. a biopharmaceutical company developing engineered natural killer cell therapies to treat cancer, today announced positive updated data from its Phase 1 dose escalation study of NKX019 as monotherapy to treat patients with relapsed or refractory non-Hodgkin lymphoma. Seven of ten patients treated at the higher dose levels in a three-dose regimen showed a complete response including two patients with aggressive large B cell lymphoma one patient with mantle cell lymphoma and one patient with marginal zone lymphoma. No dose limiting toxicity, neurotoxicity / ICANS, graft versus host disease cytokine release syndrome were observed in the study. “NKX019 continues to demonstrate impressive single-agent activity, preliminary durability and an encouraging safety profile as an off-the-shelf, on-demand cell therapy for heavily pre-treated patients with NHL. Based on this initial success, we recently opened dose expansion cohorts to explore combination and single-agent regimens in patients with LBCL, an especially aggressive form of lymphoma, and to address the large unmet need in patients who have received prior autologous CAR T therapy. We remain committed to improved access for patients through the integration of cell therapy into the broader outpatient setting.” Paul J. Hastings, President and CEO of Nkarta Nkarta plans to provide updates from the NKX019 program, including data from the dose expansion cohorts, in 2023. Evaluating NKX019 in r/r B cell malignancies NKX019 is an allogeneic, cryopreserved, off-the-shelf cancer immunotherapy candidate that uses NK cells engineered to target the B-cell antigen CD19, a clinically validated target for B-cell cancer therapies. The NKX019 Phase 1 study is evaluating the safety and anti-tumor activity of NKX019 as a multi-dose, multi-cycle therapy in patients with r/r B cell malignancies. As of November 28, 2022, 19 patients were enrolled and dosed. Fourteen patients entered the study with a diagnosis of non-Hodgkin lymphoma 7 of which were aggressive large B cell lymphoma. Patients had received a median of 4 prior lines of therapy (range of 2 to 10). To date, enrollment has included patients with aggressive disease characteristics and extensive lesions throughout the body. Patients were enrolled at clinical trial sites in Australia and the United States. “Autologous CAR T cell therapy has undeniably changed the NHL treatment landscape, but the possibility of severe toxicity and the limited access of these therapies leave many potentially eligible patients without a cellular therapy option,” said Michael Dickinson, M.D., Lead, Aggressive Lymphoma disease group, Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, and investigator in the NKX019 trial. “In the data so far, NKX019 has shown encouraging anti-tumor activity, including in patients with aggressive histologies, who are the patients who are most in need.” About the NKX019 Clinical Trial NKX019 is an allogeneic, cryopreserved, off-the-shelf cancer immunotherapy candidate that uses natural killer (NK) cells engineered to target the B-cell antigen CD19, a clinically validated target for B-cell cancer therapies. The dose-finding portion of the NKX019 Phase 1 study evaluates the safety and anti-tumor activity of NKX019 as a multi-dose, multi-cycle monotherapy following lymphodepletion in patients with r/r B-cell malignancies. Patients must have received at least two prior therapies. Patients that received prior autologous CAR-T therapy were not eligible. About Nkarta Nkarta is a clinical-stage biotechnology company advancing the development of allogeneic, off-the-shelf natural killer (NK) cell therapies for cancer patients. By combining its cell expansion and cryopreservation platform with proprietary cell engineering technologies and CRISPR-based genome engineering capabilities, Nkarta is building a pipeline of future cell therapies engineered for deep anti-tumor activity and intended for broad access in the outpatient treatment setting.

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