At this year’s National Biotechnology Conference (NBC) in Philadelphia (hosted by AAPS from April 23rd through 26th), advances in—and both challenges and opportunities related to—cell and gene therapies will take center stage. As the number of AAV (Adeno-associated virus)-dosed gene therapy therapeutics entering clinical trials grows, so does the interest from industry leaders in discussing the bioanalytical tools and strategies needed to characterize the performance of these drugs in clinical studies. In fact, in a 2019 statement, then-FDA commissioner Scott Gottlieb released a statement confirming that the agency is receiving an increasing number of cell and gene therapy (CGT) IND submissions, and predicting that by 2025, the FDA would be approving 10 to 20 applications for CGT products each year (FDA, 2019).
The nature of a virally-dosed gene therapy means that bioanalytical scientists must consider multiple elements in the design of relevant assays: the nucleic acid delivered, the protein that is expressed in the body from the instructions in that nucleic acid, and the capsid of the virus used to deliver that nucleic acid. In order to support these submissions in the gene therapy space, bioanalytical scientists must collect data from a range of assay types and modalities, including ligand binding and enzymatic assays to characterize expressed transgene proteins from nucleic acid that has been delivered to the body, nucleic acid amplification assays to measure the distribution and shedding of this nucleic acid, flow cytometry and ELISPOT assays to characterize cellular immune responses, and cell-based assays to monitor antibody levels against the viral drug delivery vector, among many others. Many aspects of gene therapy products and trials add complexity to the bioanalytical component, such as the length of trials, testing of small batches of samples from geographically dispersed sites, instability and heterogeneity of reference materials, need for testing of small volume or tissue samples, and more.
On Monday morning at NBC 2023, a group of bioanalytical experts in the gene therapy space will come together to present a symposium on some of the new advances specific to AAV-dosed gene therapies and the associated bioanalytical strategies and approaches, moderated by Catherine Vrentas, Ph.D. (Principal Scientist, PPD, A ThermoFisher Company). The symposium will kick off with a prologue by Yanmei Lu, Ph.D. (VP, Sangamo Therapeutics), who will provide an overview of different classes of biomarkers and explain how each of these types of biomarkers can be integrated into the design of clinical trials to assess both safety and efficacy, with a focus on AAV-dosed gene therapies. Of particular interest will be discussion of the use of surrogate biomarkers to support evidence of drug efficacy, especially important in the case of diseases with long-term progression. Next, Tong-Yang Yuan, Ph.D. (Senior Scientific Director, Janssen Research and Development) will continue this AAV-focused discussion with a deep dive into the immune responses that are associated with the AAV capsid as well as dosed transgenes and will present potential mitigation strategies. Many individuals in the population carry antibodies against AAVs, due to natural exposure to similar viruses; this pre-existing immunity can compromise efficacy, as can treatment-induced or treatment-enhanced responses to the AAV capsid proteins. Similarly, humoral as well as cellular immune responses to expressed transgene proteins need to be considered and assessed
Third, Prathap Nagaraja Shastri, Ph.D. (Scientific Director, Johnson and Johnson) will focus in on a specific application of AAV-dosed gene therapies: ocular-based therapies. In fact, the first FDA-approved gene therapy to treat a genetic disease, LuxturnaTM (Spark Therapeutics), is dosed via a subretinal injection. However, locally-dosed ocular therapies present challenges related to pharmacokinetic modeling and selection of a first-in-human dose. Dr. Shastri’s talk will consider options for calculation of clinical doses, sharing data from a number of both preclinical and clinical studies to consider dose-response and dose-exposure relationships for these types of therapies.
Finally, the focus on case studies will continue with a presentation from Yan Ni, Ph.D. (Executive Director, Passage Bio), who will present new interim data from her company’s Imagine-1 trial, a Phase 1/2 trial to examine both safety and efficacy of a new gene therapy for treatment of GM1 Gangliosidosis in pediatric patients. This disorder, which is associated with inherited genetic mutations in the gene for a lysosomal enzyme (beta-galactosidase-1), leads to neurogeneration, for which there is no current cure. Dr. Ni’s talk will consider the role of biomarker and bioanalytical data and strategy in the design of this trial.
We hope you can join us for this informative and cutting-edge bioanalytical symposium at NBC 2023.
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