Entering First-in-Human Clinical Study With a Single-Strain Live Biotherapeutic Product: Input and Feedback Gained From the EMA and the FDA

During the last decade, a plethora of novel therapies containing live microorganisms as active substance(s) has emerged with the aim to treat, prevent, or cure diseases in human beings. Both the Food and Drug Administration (FDA) and the European Directorate for the Quality of Medicines and Health Care (EDQM) codified these biotherapies as Live Biotherapeutic Products (LBPs). While these innovative products offer healthcare opportunities, they also represent a challenge for developers who need to set the most suitable designs for non-clinical and clinical studies in order to demonstrate a positive benefit/risk ratio through relevant quality, safety, and efficacy data that are expected by the drug competent authorities. This article describes how YSOPIA Bioscience, supported by the Pharmabiotic Research Institute (PRI), addressed the regulatory challenges during the early development phase of their single-strain LBP, Xla1, in order to obtain the necessary authorizations to bring this drug to the clinical stage.

Characteristics of MSCs in Synovial Fluid and Mode of Action of Intra-Articular Injections of Synovial MSCs in Knee Osteoarthritis

We have been studying mesenchymal stem cells (MSCs) in synovial fluid and the intra-articular injection of synovial MSCs in osteoarthritis (OA) knees. Here, mainly based on our own findings, we overview the characteristics of endogenous MSCs in the synovial fluid of OA knees and their mode of action when injected exogenously into OA knees. Many MSCs similar to synovial MSCs were detected in the synovial fluid of human OA knees, and their number correlated with the radiological OA grade. Our suspended synovium culture model demonstrated the release of MSCs from the synovium through a medium into a non-contacting culture dish. In OA knees, endogenous MSCs possibly mobilize in a similar manner from the synovium through the synovial fluid and act protectively. However, the number of mobilized MSCs is limited; therefore, OA progresses in its natural course. Synovial MSC injections inhibited the progression of cartilage degeneration in a rat OA model. Injected synovial MSCs migrated into the synovium, maintained their MSC properties, and increased the gene expressions of TSG-6, PRG-4, and BMP-2. Exogenous synovial MSCs can promote anti-inflammation, lubrication, and cartilage matrix synthesis in OA knees. Based on our findings, we have initiated a human clinical study of synovial MSC injections in OA knees.

Characterization of robust immune responses to a bispecific antibody, a novel class of antibody therapeutics

Background: Anti-A/B is a bispecific monoclonal antibody that blocks activities of soluble targets A and B. Robust immune responses were observed in a multiple-dose cynomolgus monkey toxicology study, negatively impacting the toxicokinetics/pharmacodynamics profile of anti-A/B in some animals. This was unexpected as similar findings were not observed in the two previously studied parental molecules. Methodology & Results: This paper discusses our characterization strategy for evaluating the immunogenic domain(s) of anti-A/B and our mitigation plan to monitor immunogenicity in the first-in-human clinical study. The characterization results from the cynomolgus monkey and Phase I studies are discussed. Conclusion: The characterization strategy discussed informed understanding of immunogenicity results and clinical impact, which can be broadly applied to other molecules with multiple-binding domains.

Epimedium brevicornum Maxim and its efficacy in treatment of sexual dysfunction

: Epimedium sp. is famous for its potency as sexual enhancer and five species of Epimedium brevicornum, E. sagittatum, E. pubescens, E. koreanum, and E. wushanense were recorded as Epimedium Herba (Yin Yang Huo) in Chinese Pharmacopeia. The aim of this study was to evaluate the potential efficacy of E. brevicornum as remedy for sexual dysfunction and infertility. For preparing this manuscript, we searched in all accessible resources (PubMed, Science direct, Wiley, Springer, and Google), books, thesis, and pharmacopeia. There are different traditional prescriptions from E. brevicornum, which are used for treatment of impotence and sexual disorders. Although, there is no clinical study on efficacy and safety of E. brevicornum on sexual functions, but animal and experimental analysis exhibited that E. brevicornum is and estrogenic plant and its flavonoid glycosides are inhibitors of phosphodiesterase 5 (PDE 5) and improved the erectile dysfunction, libido, impotence, sperm quality and fertility . Due to the lack of clinical study on efficacy of E. brevicornum, designing the human clinical study on safety and efficacy of standard E. brevicornum can be the subject of future studies.