Investigational New Drug Filing Research Articles

Abstract 4058: In vitro binding, efficacy and safety studies to support engineered T cell therapies

Abstract Engineered T cell therapies such as Chimeric Antigen Receptor (CAR) T cells and T cell receptor (TCR)-engineered T cells have emerged as a promising cancer therapy. To date, four anti-CD19 CAR-T and two anti-BCMA CAR-T products have been approved by the FDA for the treatment of hematological malignancies. Many more T cell therapy products are currently being explored, directed towards both liquid and solid tumors as well as for other clinical indications. High-quality and robust in vitro and in vivo assays are essential for the discovery and characterization of lead T cell therapy products. Furthermore, despite demonstrating therapeutically successful, the further development of T cell immunotherapies has been hindered by safety concerns. Selected target antigens might be expressed in healthy tissues or engineered T cells may non-specifically bind to antigens in healthy tissues, potentially resulting in severe side effects. In addition, the random integration of the CAR- or TCR-encoding DNA cassettes in the host cell genome has the potential risk of causing insertional mutagenesis and may contribute to oncogenic transformation of the T cells. The aim of this study was to develop several in vitro assays for the assessment of target cell binding, efficacy and safety of T cell therapies using CAR-T cells targeting the Human Epidermal growth factor Receptor 2 (HER2) as a model system. The z-Movi cell avidity analyzer was used to study the binding strength between the CAR-T cells and target tumor cells. Cytotoxicity co-culture assays were developed using increasing effector:target cells ratios and an impedance-based readout to quantify the viability of HER2-positive and -negative cancer cell lines in real-time, to confirm the activity and selectivity of the HER2-CAR-T cells. Furthermore, co-culture assays were also developed for a variety of primary or iPSC-derived healthy human cells (representing various tissues) to assess potential off-tumor effects of the HER2-CAR-T cells against healthy cells. In addition, an oncogenicity assay was developed to quantify the survival and proliferation of the HER2-CAR-T cells in the absence and presence of cytokines by flow cytometry, to determine whether the genomic editing of the T cells affected their cytokine-dependency. In conclusion, Charles River Laboratories developed several in vitro assays for the preclinical assessment of T cell therapy binding, efficacy, potency, specificity and safety to aid early-stage lead discovery, optimization and development, and to support Investigational New Drug (IND) applications. Charles River has the capabilities to support a full CAR/TCR program from inception to IND filing. Citation Format: Sophie Vermond, Benita Quist, Monique Hazenoot, Rene McLaughlin, David Cobeta Lopez, Namrata Jayanth, Folkert Verkaar, Omar Aziz, Maria LH Vlaming, Sabrina de Munnik, Gemma Moiset. In vitro binding, efficacy and safety studies to support engineered T cell therapies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4058.

Status and thoughts of Chinese patent medicines seeking approval in the US market.

Veregen™ and Fulyzaq are the first two botanical drug products that were approved by the Food and Drug Administration (FDA) to market in the US in recent years. Additional herbal medicines, including Compound Danshen Dripping Pills, Fuzheng Huayu Tablets, Xuezhikang Capsule, Guizhi Fuling Capsule, Kanglaite Capsule and Kanglaite Injection, have filed the investigational new drug (IND) application to the FDA and are in phase II or phase III clinical development. In order to gain better understanding of the process of botanical drug approval in the US, this article examines the aforementioned drugs by looking at their composition, indication, prior clinical experience and clinical development process, and summarizes key features that enabled IND filing and marketing approval by the FDA.

What ADME tests should be conducted for preclinical studies?

The pharmaceutical industry has been evolving in recent years, which made numerous CROs and biotech companies conducting drug discovery and development programs and services in China. As a very comprehensive and important technology platform bridging efficacy and safety, the DMPK has become a mature discovery function to optimise ADME properties in drug design and screening, and dramatically mitigate attrition rates during the last decades. In this article, the author addresses several frequent questions associated with ADME/DMPK studies, e.g., what ADME tests should be conducted for preclinical studies? What should a typical investigational new drug (IND) enabling package cover? Which ADME/DMPK studies require good laboratory practice (GLP) or non-GLP? What does a good PK profile look like? The author presents a straightforward overview of these basic questions from his many years’ experience in both pharmaceutical research and CRO in supporting drug discovery projects and IND filing.

New drug development by United States pharmaceutical firms with analyses of trends in the acquisition and origin of drug candidates, 1963-1979.

The average number of self-originated new chemical entities (NCEs) first tested in man by 39 United States-owned pharmaceutical firms in the 3-year period from 1977 to 1979 was 26 a year, approximately half the number investigated annually in the previous decade. Investigational New Drug (IND) Exemption filings on self-originated NCEs, but not those on acquired NCEs, were also comparatively low. Consequently, the contribution of self-originated NCEs to total IND filings fell from 81% in 1963 through 1975 to 68% in 1976 through 1979. (There was a similar decline, from 78% to 61%, in the proportion of compounds synthesized in the United States.) The relative increase in IND filings on acquired NCEs was greatest for smaller firms. By the late 1970s acquired NCEs accounted for almost 50% of the INDs filed by smaller firms, but only 10% to 25% of those filed by large and medium-sized firms. The importance of NCEs acquired from abroad has increased since the mid-1970s. The number of INDs filed on Japanese-originated NCEs rose from approximately one a year in 1963 through 1975 to an average of 3.5 a year in 1976 through 1979. Initial clinical testing of self-originated drugs abroad, which increased sharply in the early 1970s to reach a peak of 36% in 1976, declined to approximately 21% in 1977 through 1979. Self-originated drugs approved in 1977-1979 spent an average of 6 years in United States clinical testing and 2 in regulatory review, a total of 8 years from IND filing to NDA approval. The percentage of IND filings on self-originated NCEs that received New Drug Application (NDA) approval after 8 years or more was 9% overall, although ultimate success rates will be higher. There was a higher success rate for anti-infective drugs (17%) than for other pharmacologic categories (7%). For acquired NCEs, the overall approval rate was much larger (28%).