CSL Behring

Yan Zhi

Translational Research Voice

It has been a wild ride for in vivo viral vector-based gene therapy during the last 3 decades or so, starting with a tragic patient death and miraculously evolving to lifesavers for rare or ultra-rare monogenic genetic disorder patients. The basic research of adeno-associated viral vectors (AAVs), together with disease gene mapping and optimized gene expression, has paved the way for FDA and/or EMA approval of eight commercial AAV-based in vivo gene therapy products, including Glybera, Luxturna, Zolgensma, Upstaza, Roctavian, Hemgenix, Elevidys, and Beqvez.

The excitement of curing genetic disorders with these approved gene therapy products has unfortunately subsided, as sponsors are discouraged by the fragmented health care system, complicated payer contracts negotiation, and slower uptake. Glybera was withdrawn in 2017 due to low demand and high cost; Roctavian has been limited to the U.S, Germany, and Italy to reach profitability due to slow uptake; while Beqvez was discontinued. Nevertheless, patients with rare or ultrarare diseases have a positive experience with gene therapy products. Still, they would like to have such a treatment option to save their lives in some cases while significantly improving their life quality in other cases.

Sponsors are exploring innovative payment models for gene therapy products with payers. Meanwhile, COGs for gene therapy products must be controlled to fulfill their full potential of curing genetic disorders. Due to the intrinsic complexity of AAV vectors’ production and purification, and the limited analytical power and resolution to accurately measure their biological activities and fully characterize their payloads, CMC challenges contribute to their high COGs. With the accumulated cGMP manufacturing knowledge, ever-evolving technology platforms, and the collaboration between sponsors and regulators worldwide, it would be highly beneficial to factor COGs into the CMC strategy of gene therapy product development and commercialization.

Develop a manufacturing process and analytical method with the end game in mind.

With significant knowledge existing to support cGMP manufacturing and quality control (QC) testing of gene therapy products, well controlled and fully characterized starting materials in combination with an adequately understood platform technology for manufacturing and/or a platform method for QC testing could be a solid foundation to embark on a gene therapy product development. There is a delicate balance between the race for product approval and the long game of sustainable commercial supply, since it is much easier to improve process or analytics during preclinical or early clinical stages than after product approval. A cumbersome process or testing method will not only require a steeper learning curve for staff during technical transfer or after turnover, but also cause higher variability and be more prone to human error, which will contribute to more deviations, increased investigation burden, and ultimately higher batch rejection rates during routine commercial manufacturing. Therefore, acknowledging that customerization might be inevitable, it would still be a good investment to understand and standardize the process and analytical method as early as possible, which can help control COGs of gene therapy products in the long run.

“Applying the enhanced approach with the QbD concept to developing the manufacturing process and analytical procedure would facilitate science-based and risk-based LCM activities post-approval”

In 2023, FDA issued a draft guidance of potency assurance for cellular and gene therapy products to recommend the development of a potency assurance strategy, which should be based on quality target product profile (QTPP), risk assessment, prior knowledge and experience; and includes controls on material quality, control or monitoring of manufacturing process parameters, and in-process testing together with lot release testing to confirm that potency-related quality attributes meet appropriate acceptance criteria. In principle, such a potency assurance strategy could enable the real-time evaluation of the manufacturing process, which can either abort the failed batch sooner or quickly make necessary adjustments to ensure batch success long before the completion of lot release testing. As a result, COGs could be controlled by reducing the sunk cost of a failed batch or increasing the batch success rate.

Apply the quality-by-design (QbD) concept during process and analytical development to reduce lifecycle management (LCM) burden.

A full-blown QbD approach with a defined design space could be challenging for gene therapy product process development, especially within a compressed CMC timeline. Even so, it is highly desirable to apply the QbD concept early and throughout process development to clearly define the quality target product profile (QTPP), determine critical quality attributes (CQAs), and select essential process parameters (CPPs) to outline the manufacturing process and the corresponding process control strategy.

ICH Q14 “Analytical Procedure Development” has recently been adopted, introducing the QbD concept to analytical method development as an enhanced approach. Such an approach starts with an analytical target profile (ATP) and critical performance attributes, followed by risk assessment to identify analytical procedure parameters that could impact the assay performance. With the accumulated knowledge and data (including robustness data), an analytical control strategy could be developed ideally before assay validation.

Changes after gene product approval are almost inevitable. They could be driven by higher market demand to add manufacturing facilities or increase manufacturing scale, or forced by changes in critical material, essential equipment, assay kits, etc. Applying the enhanced approach with the QbD concept to developing the manufacturing process and analytical procedure would facilitate science-based and risk-based LCM activities post-approval. Hence, COGs could be controlled by reducing the burden of LCM and increasing the chance of regulatory approval by appropriately using change management tools.

Harness the potential of research development activities to design and manufacture the next generation of gene therapy products.

AAV vector capsid engineering and optimizing transgene expression cassettes are active and promising research and development areas. In essence, a novel AAV capsid with increased tissue tropism and minimal pre-existing neutralizing antibodies (Nabs) could reduce the therapeutic dose, which not only aids in controlling COGs but also minimizes toxicity directly caused by the AAV vector. Furthermore, tissue-specific promoter and transgene optimization could produce more effective therapeutic proteins without increasing AAV vector dose, which helps control COGs by limiting the total vector yield requirement.

Innovations such as producer cell lines and specialized resin or matrix that facilitate the separation of full particles from empty ones and increase product recovery could transform the manufacturing of AAV vectors, which also assists in controlling COGs by increasing productivity per batch.

AAV-based in vivo gene therapy products have demonstrated their therapeutic efficacies. However, the harsh reality of slower market uptake and reimbursement challenges has significantly dampened industry enthusiasm. We are at the crossroads of gene therapy. A well-thought-out CMC strategy built with technical, quality, and regulatory considerations in conjunction with the goal of successful routine commercial manufacturing in mind could better manage COGs of a licensed gene therapy product, which might rejuvenate this game-changer therapeutic modality. Commercial viability is critical for a gene therapy product to significantly improve the lives of patients with genetic disorders or even cure those patients.