Cell and Gene Therapy Answers: Top considerations for biomarkers in gene therapies
Gene therapies show great potential for addressing previously hard-to-treat diseases. However, optimizing their safety and efficacy requires careful analytical testing. Biomarkers can provide key insights into a gene therapy's effects and mechanisms. To learn more about the crucial role of biomarkers and analytical testing in gene therapy development, we spoke with Akanksha Gupta, PhD, executive director for cell and gene therapy at Labcorp. Here, she discusses the critical role of biomarkers and analytical testing within gene therapy, as well as important considerations for the adoption of a biomarker strategy to support development efforts.
What can you tell us about the role of biomarkers and analytical testing within the gene therapy landscape?
The biomarker and analytical testing for gene therapy clinical trials is complex, involving varied assessments that can range from patient selection, evaluation of the pharmacodynamic response and from a safety perspective.
Biomarkers can play a critical role in patient enrollment strategies, for instance, in the development of adeno-associated virus (AAV)-based viral gene therapies where pre-existing anti-AAV antibodies are analyzed. The analysis of pre-existing anti-AAV antibodies is critical as it can limit patient eligibility, the gene transfer efficiency and sustained transgene expression. Approximately 30% to 60% of individuals have pre-existing anti-AAV antibodies, and seroprevalence is impacted by multiple factors including geography, age, the capsid serotype and the assay type.1 This is assessed by measuring the neutralizing antibody response to AAV (AAV NAb assay) or total antibody response to AAV (AAV TAb assay). Since these assays can be used for patient eligibility, they can also be developed as a potential companion diagnostic (CDx). To that end, the industry saw the first gene therapy CDx approved by the FDA this year, which detects the presence of antibodies that bind to AAV5 (AAV-5 TAb assay). This enables determination of eligibility for patients with severe hemophilia A who are considering treatment with BioMarin’s recently approved gene therapy, RoctavianTM. The FDA has also granted breakthrough designation of a CDx for Sarepta’s approved gene therapy (ELEVIDYS) indicated for Duchenne muscular dystrophy. This assay is a TAb AAV-based assay for the semi-quantitative detection of antibodies to AAVrh74 capsid in human serum.
Another key aspect of patient selection is centered around identifying the right patient population for a specific gene therapy based on mutational analysis. From a safety perspective, vector shedding analysis by PCR-based approach in matrices—such as blood, urine, saliva and feces—is included in clinical trials. Immune monitoring is also very critical and involves the evaluation of the T-cell response to either the capsid or the target protein as well as the evaluation of the innate and adaptive immune response.
The pharmacodynamic response analysis includes assessment of the disease-relevant biomarkers. It’s important to note there is a possibility of insertional mutagenesis where some vectors can integrate randomly into the DNA sequence, and so, needs to be monitored. Due to the long-lasting or permanent effects of the treatment, extended long-term follow-up is required and should be included as part of the clinical development and laboratory testing strategy for the trial.
What are some general considerations for adoption of biomarkers for gene therapy development?
To start, it is important to think holistically and keep the end in mind, from a drug development perspective. The data generated from preclinical and clinical studies is critical to driving toward this goal. For instance, what data insights will be needed to make a model-informed decision in the preclinical stage? What type of information is required to enable more efficient clinical decisions and position the asset as it moves forward? Are there translational opportunities using preclinical models that will help point toward specific biomarkers of interest or be directly translatable in a clinical setting?
In the same way, it is crucial to think about your biomarker strategy holistically. That may require different platforms and flexibility. As the data emerges, the context of use of that data may change. For instance, an exploratory biomarker may generate data demonstrating that you are targeting the right patient with the right therapy. This may require a lift and shift of the assay from an exploratory setting into a regulated environment to further develop the assay in combination with your therapy. Because each patient has a unique set of genes and needs, the key lies in understanding what those are so that you can truly match patient to therapy and deliver a personalized approach.
One challenge commonly seen with biomarker-driven gene therapy trials is acquiring appropriate samples for biomarker assay development and validation. Gene therapies often target rare diseases, so if you’re seeking a validated pathway that needs regulatory assay development, planning holistically for this end goal will help ensure that you have the appropriate samples and matrices to conduct that assay development. Another common but critical hurdle is logistics, which is dependent on your patient population. For instance, in pediatrics, there may be a limitation on the sample volume that can be collected. In this situation, the strategy may require the biomarkers be prioritized to ensure analysis of biomarkers critical to the program are conducted versus the ones that are nice to have.
What is the role of precision medicine in the development of gene therapies?
There can be nothing more personalized or precise than cell and gene therapy. The concept of precision medicine is well mapped out in oncology, with more than 60% of oncology clinical trials incorporating biomarkers. We’re now seeing an extension of biomarker-driven approaches beyond oncology into other therapeutic areas—such as in neurodegeneration, NASH and cardiovascular, including cell and gene therapy clinical trials.
As mentioned above, the growth in relevant biomarkers and the development of CDx within gene therapies has really contributed to more rapid adoption of this approach. The landscape is evolving, and we’ll see more CDx approvals come for gene therapy. Historically, from the assay platform aspect, CDx typically has been NGS or IHC based; however, we’re beginning to see other platforms considered for CDx such as flow cytometry or an immuno-based approach in other therapeutic areas. It’s just the tip of the iceberg, and as we see the advancements in gene editing, that will usher in even more sophisticated and personalized gene therapies. Learn how
Labcorp can support your biomarker needs to advance your cell and gene therapies.
References
1. Schulz M, Levy DI, Petropoulos, et al. Binding and neutralizing anti-AAV antibodies: Detection and implications for rAAV-mediated gene therapy. Mol Ther. 2023;31(3):616-630. doi:10.1016/j.ymthe.2023.01.010