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Rare Diseases Drug Development
Published in Wei Zhang, Fangrong Yan, Feng Chen, Shein-Chung Chow, Advanced Statistics in Regulatory Critical Clinical Initiatives, 2022
Shein-Chung Chow, Shutian Zhang, Wei Zhang
FDA recognized that issues that are encountered in rare disease drug development are frequently more difficult to be addressed because there is often limited medical and scientific knowledge, natural history data, and drug development experience. This draft guidance addresses the importance of the following elements in development programs for rare diseases: (i) adequate description and understanding of the disease's natural history, (ii) adequate understanding of the pathophysiology of the disease and the drug's mechanism of action, (iii) nonclinical pharmacotoxicology and human toxicology considerations to support the proposed clinical investigation or investigations, (iv) selection or development of outcome assessments and endpoints, (v) evidence to establish safety and effectiveness, (vi) drug manufacturing considerations during drug development (e.g., pharmaceutical quality system considerations), (vii) participation of patients, caretakers, and advocates in development programs, and most importantly, (viii) interactions with the Agency (FDA, 2015, 2019). As FDA pointed out, early consideration of these issues gives sponsors the opportunity to efficiently and effectively address the issues and to have productive meetings with FDA.
Introduction
Published in Frank A. Barile, Barile’s Clinical Toxicology, 2019
Fast-forward to the latter half of the twentieth century—once again, the field of toxicology derived impetus from analytical chemists, who sought to understand the action of xenobiotics by isolating and identifying the components. Until these developments crystallized, most traditional toxicologists were trained in classical quantitative chemical analysis as well as organic and inorganic chemistry. Eventually, the field would flourish into a variety of specialties, which today are well accepted as part of the biomedical sciences. Currently, clinical toxicology (also known as pharmacotoxicology) enjoys its own particular designation, the subject of which is advanced in the subsequent chapters.
Methods for Labeling Nonphagocytic Cells with MR Contrast Agents
Published in Michel M. J. Modo, Jeff W. M. Bulte, Molecular and Cellular MR Imaging, 2007
Joseph A. Frank, Stasia A. Anderson, Ali S. Arbab
Although most pharmacotoxicology studies of new drugs are usually performed in at least two species (i.e., mouse or rat, canine or swine or nonhuman primate), the safety and toxicity studies for ferumoxides-protamine sulfate complex labeling of autologous human stem cells will not require testing in a large-animal species and will go directly from mouse into humans. Large-animal (i.e., swine, canine, nonhuman primate) models may better present the types of challenges or have a similar disease course as humans; however, preclinical cell labeling studies using ferumoxides-protamine sulfate complexes for labeling human stem cells for inclusion in investigative new drug (IND) submission are performed in immune-compromised mice and rats. Cell escalation (e.g., 105, 106, or 107 cells per animal) experimental studies using human stem cells labeled in a clinical GMP facility are presently required in the animal models, with the results included as part of the IND submission. The investigator-driven IND for using human cells (i.e., stem cells or other mammalian cells) labeled with ferumoxides-protamine sulfate complexes, along with institution review board (IRB) phase I clinical trials, will probably be evaluated by the Office of Cellular, Tissue and Gene Therapies in the Center for Biologics Evaluation and Research (CBER) at the FDA. CBER has indicated that the ferumoxide-labeled human stem cells will be considered a biologic or cellular contrast agent for phase I/II clinical trials using MRI to monitor cell trafficking.
Safety and pharmacokinetics of a biosimilar of denosumab (KN012): Phase 1 and bioequivalence study in healthy Chinese subjects
Published in Expert Opinion on Investigational Drugs, 2021
Hong Zhang, Cuiyun Li, Jingrui Liu, Min Wu, Xiaojiao Li, Xiaoxue Zhu, Qianqian Li, Boguang Wang, Yanhong Mao, Yanhua Ding, Qinglong Jin
Denosumab (Prolia®, Amgen Manufacturing Limited, Thousand Oaks, CA, USA) is a specific antibody for RANKL [5]. It has been approved to increase the bone mass in postmenopausal women with osteoporosis and men with osteoporosis who are at high risk for fractures. Denosumab biosimilars are being actively developed globally. KN012 is an IgG2 monoclonal antibody and has a primary structure similar to that of the denosumab reference product (Prolia®). Furthermore, similarities also have been noticed in the posttranslational modifications, biochemical properties, and biological functions. The high degree of similarity between KN012 and Prolia® observed in preclinical pharmacokinetics (PK), pharmacodynamics (PD), and pharmacotoxicology support the further development of KN012 as a biosimilar to Prolia® by testing their bioequivalence in humans (data not published).
Non-alcoholic fatty liver disease (NAFLD) models in drug discovery
Published in Expert Opinion on Drug Discovery, 2018
Banumathi K. Cole, Ryan E. Feaver, Brian R. Wamhoff, Ajit Dash
To gain the most out of animal and organotypic models used in drug discovery and development in NAFL/NASH, it is imperative to creatively combine them with the advances in tools to measure global cellular responses such as the various – ‘omics (proteomics, transcriptomics, lipidomics, and metabolomics). These approaches, coupled with big data analytics, provide unbiased ways to understand disease pathways and drug pharmacotoxicology. For instance, comparative transcriptomic analysis of pathway perturbations in NASH disease models in the presence and absence of drugs that reverse the NASH-associated lipotoxic changes (e.g. OCA), as well as in normal physiological models that are treated with drugs that induce the steatohepatitic process (e.g. amiodarone), might offer insights into unique or novel targets. These models also provide a relatively quick and easy way to test any newly generated hypotheses or targets in a physiologically meaningful context. The field of NAFLD is also currently invested in the development/validation of circulating biomarkers that would help track the progress of the disease and response to therapies that is currently reliant on liver biopsies. Once available, these biomarkers could add further value to the use and applications of animal and organotypic models.
A controlled, randomized phase II clinical trial for efficacy and safety evaluation of mannuronic acid in secondary progressive form of multiple sclerosis
Published in International Journal of Neuroscience, 2022
Soheil Najafi, Nahid Beladi Moghadam, Payam Saadat, Seyyedeh Masoomeh Noorbakhsh, Anita Vali Mohammadi, Ali Manouchehrinia, Mostafa Hosseini, Hidenori Matsuo, Abbas Mirshafiey
β-D-mannuronic acid (M2000) is a small molecule with low molecular weight (patent number: DE/102016113018.4-PCT/EP2017/067919), anti-inflammatory property, which has not resulted in any toxicity on bone marrow, liver and kidney [18–22]. In a preclinical study, the safety of this drug was assessed based on the evaluation of acute and chronic pharmacotoxicology in an experimental model [19]. Therapeutic effectiveness of M2000 with a proper tolerability and efficacy, have been demonstrated in various experimental models, like experimental autoimmune encephalomyelitis, adjuvant-induced arthritis, acute glomerulonephritis and nephrotic syndrome [20, 23, 24]. In a study by Mirshafiey, the anti-inflammatory and immunosuppressive features of mannuronic acid were evaluated in experimental models of rheumatoid arthritis (AIA) and multiple sclerosis (EAE). The immunosuppressive property of M2000 could notably reduce clinical manifestations and histological destructions in the EAE model. Lymph node cell proliferation assay in EAE approved the immunosuppressive effectiveness of mannuronic acid [25]. In another study, it has been demonstrated that the treatment of EAE with M2000 could notably dampen disease progression both prophylactically and therapeutically; following the administration of M2000, the onset and clinical signs of EAE in Lewis rats could be diminished. Clinical improvement was followed by a significant decline in the mean number of vessels with perivascular cellular infiltration in the rats treated with M2000 compared with non-treated control group [20]. Furthermore, several clinical trials were conducted on some autoimmune diseases such as a phase I/II clinical trial in treatment of ankylosing spondylitis (AS), a phase II clinical trial in breast cancer, a phase I/II clinical trial in rheumatoid arthritis (RA) and a phase III clinical trial in RA and the results of all these studies confirmed the safety and effectiveness of M2000 [21, 22, 26, 27].