Guest Column | April 24, 2020

Gene Therapy Innovation And Product Development

By Rasappa Arumugham, PhD, Chief Scientific Officer and Arun Upadhyay, PhD, Director, Research & Development, Ocugen

Rasappa Arumugham, PhD, Chief Scientific Officer and Arun Upadhyay, PhD, Director, Research & Development, Ocugen

Disrupting the current norms of the drug development process has always been the cornerstone of biopharmaceutical innovation. Historically, it has been the case for small molecule therapies, biopharmaceutical proteins, monoclonal antibodies, and complex vaccine biologics. Now we are witnessing breakthrough innovations in the rapidly maturing areas of discovery, development, manufacturing, and commercialization of cell and gene therapy. Although there are similarities in the processes, methodologies, safety, and efficacy evaluations of cell and gene therapies compared to other products, scientists are exploring out of the box concepts and ideas and eventually disrupting the conventional technology with innovation in this exciting field. 

At Ocugen, we are primarily focusing on gene therapy programs for the treatment of several unmet retinal diseases. We believe that new gene therapy treatments will drive innovation in addressing a multitude of challenges, covering both rare diseases as well as diseases that impact larger patient populations. These challenges include, but are not limited to the following discovery, development and manufacturing areas:

  1. Design of vector construct
  2. Multiple Diseases Caused by Different Gene Defects
  3. Scale-up manufacturing, supply demand and cost of goods
  4. Quality control and life cycle management
  5. Patient population
  6. Long-term clinical safety and efficacy
  7. Commercial supply chain
  1. Design of vector construct:

The recombinant adeno-associated virus (AAV) has become the vector of choice for gene delivery, attributed to its many unique characteristics such as non-pathogenicity, relatively less immunogenicity, non-integrating nature, residing in episomal form inside nucleus, efficient and sustained transduction, and ability to transduce non-dividing cells.  AAV-based gene therapy has been shown to be clinically safe and is specifically being used for ocular gene delivery. AAV serotypes differ in their cell and tissue tropism, which influences transduction efficiency and specificity. For example, AAV2, AAV5 and AAV8 are typically chosen to target photoreceptor cells, retinal pigment epithelium and the central nervous system. Still, there is a need to develop engineered serotypes with improved transduction efficiency for local and targeted delivery of gene therapeutics. Improving the transduction efficiency and specificity of AAV vectors is becoming increasingly recognized for broad clinical adaptation depending on the site of administration (local versus systemic). Vector engineering with rational design and/or directed evolution of the capsid protein are being evaluated in several preclinical and clinical studies and may become substitutes for naturally occurring serotypes in the future.

  1. Multiple diseases caused by different gene defects

Most gene therapy development and all approved gene therapeutics have focused on monogenic rare diseases. However, the cost of gene therapy products is significant for patients (especially in countries without mandated health insurance coverage). Even in developed countries, high costs of gene therapy products are a major challenge not only to patients but also to the companies developing them. Glybera, uniQure’s first gene therapy treatment for an ultra-rare disease was approved by the European Medicines Agency in 2012 and priced at $1 million in 2015.  Today it is no longer listed on their pipeline. Developing treatments for inherited retinal diseases presents a similar challenge. For example, Retinitis Pigmentosa (RP) affects approximately 2 million people worldwide; and over 150 unique gene mutations are known to be associated with RP. These mutations are identifiable only in 60% of the affected patients, leaving no therapeutic option for the remaining 40% of patients, even with the gene specific therapeutic approach.

Ocugen is developing a modifier gene therapy that has the potential to not only to eliminate the need to develop more than 150 gene specific products, but also provides a therapeutic option for the RP patients for whom molecular defects are not identified. With this exciting platform technology, Ocugen is completing preclinical studies for OCU400, an AAV vector consisting of the hNR2E3 gene, and anticipates commencing a Phase 1/2a clinical trial in 2021. The development of a single drug product, which targets multiple pathways in similar or related diseases, could be a new option catering to large patient populations sharing clinical phenotypes.

  1. Scale-up manufacturing, supply/demand, and cost of goods

Successful commercialization of gene therapy products relies on a scalable manufacturing process.  Recently, significant progress has been made in optimizing manufacturing for AAV-based gene therapy products for early and late phase programs. With this progress comes significant investment to build the infrastructure to meet the growing demand as products progress toward commercialization. Manufacturing processes must be developed, optimized, and scaled-up during clinical stages to minimize the production risk once it is commercialized, which is driven by three factors: (a) patient population, (b) dosage and number of doses required per patient, and (c) production yield. Previous and ongoing gene therapy drug development programs target rare diseases and were started in academic institutions or small companies during early stages. The preferred method of production in early phases uses HEK293 adherent cell culture and triple plasmids (transgene, helper and rep/cap) transfection. Adherent cell culture requires growing cells in hyperstacks which is costly and labor intensive. The iCELL is a platform, developed by Pall Corporation, that can be utilized for automation of adherent cell-based production. Even after these improvements, adherent cell production is limited by yield and cost and requires many batches to meet the commercial need, even for ultrarare disease populations. Companies are developing HEK293 suspension culture to produce AAV-based gene therapy products. Although the scale-up of HEK293 suspension culture growth could be achieved up to 200-2000L scale, the major bottle neck is optimizing the transfection process beyond 200L scale. Significant efforts are being made toward optimizing the transfection process at a large scale. Current manufacturing processes yield approximately 10^14 vg/L in a crude sample with an overall yield of ~30-40% for the final product. At 200L scale, the product yield is around 6-8*10^15 vg. Significant amounts of product are used in release and stability testing and characterization.  While this yield may be sufficient for early clinical phases for ultra-rare diseases like retinal degenerative diseases or neurological disorders where the drug may be administered at ~10^12 vg per dose locally, the dosing of 1000 patients/year would require around 10^15 vg batch, (i.e. ~200L batch size). In the case of systemic administration where doses may range from of 10^14 to 10^15 vg per dose, ~10^17 to10^18 vg of product would be required to treat 1000 patients. One would have to run 100 or more batches at 200 L scale to achieve this yield. For diseases where patient populations are in the thousands and hundreds of thousands, current production capabilities and scale cannot meet the growing demand. Because of rapid growth in gene therapy clinical development, securing the supply of required critical raw materials, such as plasmids, transfection reagents, and downstream purification resins and other supplies, are challenging and need to be strategized as well ahead of clinical development.  

  1. Quality control and life cycle management

Ensuring the quality of gene therapy products throughout their life cycle with a robust and reproducible manufacturing process is essential to safety and efficacy. Often, AAV-based gene therapy products, owing to their complex structure and large size, pose various quality and stability related challenges during manufacturing and formulation development. Development of comprehensive analytical assays at early stages are needed for in-process controls, product characterization, release, and stability monitoring. Significant gaps exist in methods used to fully characterize the AAV-based product, specifically the vector genome titer quantification, determining the ratio of full and empty capsids, and potency assay. Current methods used to quantify vector genome titers are based on qPCR which may result in batch-to-batch and lab-to-lab variability. Similarly, there is no standardized method to reproducibly quantify the full and empty capsids. Difficulties exist in demonstrating potency because gene therapy products are associated with specific gene defects and developing the potency assay based on mechanism of action requires significant effort and resources. Developing, optimizing, and validating assays for critical quality attributes during early phases of development are crucial for successful clinical trials and commercialization. During CMC development, focus should be on product characterization such as identity, dosage determination, process, and product-related residuals and impurities as well as sterility testing to ensure product safety and potency.  

  1. Patient population

Genetic defects lead to chronic, irreversible, and sometimes life-threatening rare diseases which are large in number, heterogenous and diverse in nature. Until the last decade, most of the drug development companies focused on developing therapeutics for high prevalent diseases, where business successes and rewards were high. Following the advancement in molecular genetics and a better understanding of genetic diseases, academic institutions and small companies began exploring gene therapy as a potential cure, with a focus on rare diseases. At the same time, development of safe and effective delivery agents, such as AAV, led to the initiation of many clinical trials.  The major challenge in development is identifying the right patient pool based on genetic testing. The low patient prevalence, limited knowledge, and scarcity of expertise has also impeded the advancement of gene therapy products. Additionally, there is a lack of natural history of these diseases leading to limited information on disease progression. Natural history studies targeting gene mutation-related patients have long recruitment and monitoring time. These factors contribute to huge financial burdens on drug developers.

Recently, the successful approval of products with premium pricing has boosted the confidence of gene therapy developers leading to logarithmic growth in the number of clinical trials. The patient population for these diseases range between a few hundred to a few thousand. Though patient population is not high, the route of delivery, such as systemic versus local, can significantly affect dosing and thus commercial need.  Doses required for systemic delivery are often 2 to 3 logs higher than local, targeted administration. Understanding patient prevalence in the early phases of development are critical to manufacturing capability, infrastructure, and development time.

  1. Long-term clinical safety and efficacy

Despite the approval of the first AAV-based gene therapy product, (Luxturna™, Spark Therapeutics) in 2017, the use of AAV as a gene delivery agent started during the early 2000s. Over the last two decades, safety and delivery of gene therapy products using an AAV vector in animals and humans has been collected. AAV-mediated transgene delivery to non-dividing cells can help sustained expression at therapeutic levels for longer durations. while transgene copies in dividing cells may decrease as they divide, and therapeutic effect may subside with time. Although safety must remain the priority for gene delivery using viral vectors, achieving therapeutic efficacy in a consistent manner in all patients is critical for clinical and commercial success. In addition, challenges related to AAV vectors such as immunogenicity, efficacy, and potential genotoxicity should be addressed by engineering novel vector.

  1. Commercial supply chain

Building infrastructure and training teams to work with AAV vectors will dictate the successful manufacturing of safe and efficacious products. Consistent supply of plasmids and raw materials, availability of cGMP manufacturing facilities, estimates on batch size and numbers, demand forecast, shipping and storage, and delivery to the patients are all critical elements for commercial success. Currently, industry lacks manufacturing infrastructure and expertise to meet the needs of the growing demand of product for early and late phase trials. Investments are being made in building manufacturing facilities and major pharma companies are also buying gene therapy companies with manufacturing expertise, but the question remains of how the demand for large patient populations will be met in the future.

Recent advances in cell and gene therapy have given new hope to patients whose lives are significantly impacted by rare genetic disorders. Though there are significant challenges in developing and manufacturing gene therapies, addressing the needs of these patients could be a reality as we work to overcome these challenges. Significant progress has been made in the production and delivery of cell and gene therapy products which led to the demonstration of therapeutic benefits in patients and subsequent regulatory approvals. Recent approvals gave hope and boosted confidence for the companies developing cell and gene therapy products which led to rapid growth of clinical pipelines. The potential of gene therapy could revolutionize healthcare across many different disease areas.