Global Biotech Elites Gather to Explore Trends and Prospects of Cell and Gene Therapies

BIO Asia-Taiwan 2023 Conference was successfully held from July 26 to 28 at Taipei Nangang Exhibition Center, with a total of 15 sessions over three days, bringing together more than 1,500 biotech professionals from over 30 countries. The conference covered a wide range of hot topics in the biomedical industry such as international investment trends, market supply chain, digital medicine, innovative medical devices, mRNA drugs, as well as cell and gene therapies. 

Related article: BIO Asia-Taiwan 2023: Global Biotech Development

Exploring the Frontier in Gene and Cell Therapies

Co-organized by Academia Sinica, the morning session on July 28 was under the theme of “Cell and Gene Therapies with Novel Enabling Platform”, featuring local and international experts and scholars who shared their views on the recent development and future prospects of cell and gene therapies (CGTs). The panelists included John Tsai, M.D., Executive Partner of Syncona; Prof. Luk Vandenberghe, founder of AKOUOS, a US-based precision genetic medicine company; Dr. Wen-Chyi Shyu, CEO of BRIM Biotechnology; Dr. Yu-Ju Chen, Distinguished Research Fellow of Institute of Chemistry, Academia Sinica; and Dr. Wei Wang, Corporate and Business Development Director, Cell and Gene Therapy at Syneos Health.

Dr. Tsai mentioned in his keynote speech on “Frontier in Cell and Gene Therapies” that CGTs have been developing at an unprecedented fast pace over the past few years. By the end of 2022, the number of pipelines of cell therapy and gene therapy drugs under development worldwide exceeded 2,000, with cancer and rare diseases being the most common indications. Taking gene therapy as an example, as of Q2 2023, pipelines that have entered clinical trials accounted for about 25% of all pipelines, covering a wide range of indications such as hematology, dermatology, ophthalmology, otology, neurology, and metabolic disorders. Besides, at least six products have entered the pre-registration stage. 

According to Dr. Tsai, although the development of CGT is still in its infancy, with the emergence of new technologies in the areas of drug delivery systems and manufacturing processes, the landscape of related areas will continue to mature, leading to a substantial improvement in the quantity and quality of new pharmaceutical products. He also expected that the development trend of CGT will continue to shift towards non-tumor indications, and that the scope of application of new drugs in the future is likely to go beyond rare diseases to diseases with higher incidence rates. Nevertheless, in the midst of such promising signs, issues regarding drug prices and health insurance coverage will inevitably come to the forefront as more new drugs are introduced and the population of potential beneficiaries increases dramatically.

Gene Therapy at a Crossroads

Prof. Luk Vandenberghe described the development of gene therapy as “at a crossroads”. With an estimated size reaching US$10 billion, he said that the gene therapy market is indeed growing rapidly, and there have been a number of multinational pharmaceutical companies investing billions of dollars in mergers and acquisitions to strengthen their respective pipelines in recent years. Yet, there are also hidden concerns behind those achievements. First of all, the safety of these new drugs is an issue that requires due attention.

Since there are no precedents for gene therapies, researchers have limited knowledge of the pharmacological control and dosage of the drugs. Unfortunately, in the past few years, there have been unfortunate cases of patients suffering from serious adverse reactions or even death during clinical trials, which subsequently led to clinical holds on these trials. In addition, the manufacturing of gene therapy products may pose a major challenge in terms of cost, talent shortage and scalability. Coupled with the fact that there will be more complex regulatory requirements for gene therapies than for traditional drugs, and that the required quality management mechanisms have yet to be well developed, these factors could potentially hinder the growth of gene therapies. 

Despite these obstacles, Prof. Vandenberghe was optimistic that with the emergence of new technologies such as gene editing, virus-like particles (VLP), lipid nanoparticles (LNP), and adeno-associated viruses (AAV), along with the gradual accumulation of professional talents, regulatory knowledge, and clinical experiences, new gene therapies will continue to bring their transformative benefits into full play and the number of FDA-approved drugs will increase in the near future.

Factors Affecting First-in-Human Dose Selection for Cell and Gene Therapies

Dr. Wen-Chyi Shyu’s presentation focused on the various factors that need to be considered when planning the initial dose of cellular therapies during first-in-human study (FIH) trials. Examples of these factors include ways to improve the therapeutic persistence of CAR-T cells, understanding the relationship between dose and response, and how to effectively translate data from preclinical studies into meaningful information for selecting doses in clinical trials. She also emphasized the differences in the design of FIH trials between conventional oncology drugs and cell therapies, as the efficacy and toxicity of the former are often dose-dependent, and therefore only drug toxicity (safety) is usually considered in dose selection. However, the efficacy of CAR-T cell therapy does not necessarily increase as the dose increases, and therefore both efficacy and toxicity should be taken into account when determining cell dosage.

In fact, in FIH trials for cell and gene therapies, dose selection has been more often based on the empirical methods that allow for manageable toxicity and optimal therapeutic benefit to the patient. Moreover, lawmakers are encouraging developers to use predictive methods, such as enzyme kinetics and allometric scaling, to determine the appropriate dose for FIH trials. For gene therapies using AAV as carriers, Dr. Shyu also proposed to utilize the empirical formula for dose scaling, where the dose data obtained from animal experiments would be multiplied by an activity factor and a scaling factor in order to generate an estimate of the optimal dosage.

Opportunity of Proteomics-guided Precision Oncology – Non-smoking Lung Cancer as an Example

Dr. Yu-Ju Chen, an international pioneer in proteomics research and a Distinguished Research Fellow at the Institute of Chemistry, Academia Sinica, shared her team’s major discovery in exploring the factors contributing to the development of non-smoking lung cancer, as featured in the cover story of July 2020 issue of Cell, a world-class scientific journal. The team employed proteogenomic techniques to create a multi-omics database of early-stage lung cancer patients in Taiwan, identifying important genetic mutations associated with potential pathogenic mechanisms in lung adenocarcinoma (LUAD), the most common lung cancer diagnosed in non-smokers.

The researchers also classified lung adenocarcinomas into five subtypes by proteomic characterization, including a novel “late-like” subtype (Stage 1B ‘late-like’). These new findings suggest an early point of divergence in tumor phenotype where clinicians could identify high-risk (or early-stage) patients to receive more intensive surveillance and possible adjuvant therapy to prevent disease progression. In addition, early stage ‘late-like’ tumors also showed significant increases in MMP11, an enzyme that cuts away at the surrounding tissue, that may also serve as a strong early stage biomarker candidate.

Dr. Chen emphasized that these findings have the potential to bring about a “paradigm shift” in lung cancer treatment, facilitating early detection and treatment, thereby improving cure and survival rates. In addition to non-smoking lung cancer, the team’s research on the development of innovative tumor detection tools using multi-omics data has been extended to breast cancer, and their results will be submitted for review and publication in the near future.

CGT Market Facing a “Perfect Storm” and Challenges in Commercializing Products

Dr. Wei Wang at Syneos Health, gave a presentation on difficulties and challenges encountered in the commercialization of cell and gene therapies from the perspective of an international contract research organization (CRO). He described the current predicament being faced by the CGT market as a “perfect storm”. He first mentioned that although the CGT market is still growing in terms of size, number of products available on the market and product sales, it is becoming increasingly difficult for CGTs to move from the pre-clinical stage to clinical trials and ultimately to commercialization. For instance, the total amount of capital raised by CGT developers has plummeted from approximately $22.7 billion in 2021 to $12.6 billion last year, and the year-over-year investment growth rate recorded in January 2023 was -59% compared to last year. 

In a survey of key decision-makers in biotech companies conducted by Syneos Health, while respondents generally agreed that CGT would be their “sweet spot” where they could push for new breakthroughs, and they expressed overall optimism about the future of CGT, they also recognized an abundance of challenges ahead. One of the biggest obstacles for CGT companies is that there is no comparable drug development experience to follow. The pathway of CGT development is therefore riddled with multiple “trial and error” experiences, ultimately limiting available resources and driving up costs. Furthermore, finding sufficient patients for clinical trials and keeping them motivated to ensure their continued participation also pose significant difficulties to the R&D journey of CGTs.

In addition to these challenges, Director Wei Wang said that the development of CGTs has been hampered by six major issues: evidence generation, infrastructure and logistics supply chain, clinical trial implementation, long-term follow-up studies (which could take up to 15 years), engagement with patients and medical stakeholders, as well as the high drug costs. He pointed out that many biotech companies with CGT businesses have already established strong foundations in core science and technology, leadership teams, and business strategies. Their next step should be developing CGTs into platforms and mature business models for asset development, thereby achieving the goal of product differentiation and creating unique value.

International Experts Exploring Possible Future Direction of CGT Development in Taiwan

Moderated by Dr. Chia-Ning Shen from the Genomics Research Center, Academia Sinica, the panel discussion featured a lively dialogue among five expert speakers, who also offered advice on Taiwan’s pursuit of CGT research and development. Dr. John Tsai firstly emphasized the importance of having a precise understanding of individual patient populations and reverse planning by deriving appropriate steps from the results, while Dr. Wei Wang added that CGT developers need to engage with healthcare providers to understand the needs of their patients and should be aware of those paying for these products once they are launched.

Dr. Shyu once again stressed the key role of predictive methods in determining the initial dose for FIH studies. Moreover, she hoped that Taiwan’s biotech companies could keep an open mind and follow the example of Europe and the United States in promoting pre-competitive collaboration to overcome R&D bottlenecks through experience sharing and knowledge exchange. Both Prof. Vandenberghe and Dr. Tsai agreed, citing the successful cases of AAV vector gene therapy for Duchenne muscular dystrophy and COVID-19 vaccine respectively, to illustrate that more exchanges and collaborations among pharmaceutical companies would be beneficial to the R&D efforts of their respective products. 

Dr. Chen mentioned in the discussion that Taiwan’s regulations for laboratory-developed tests  are currently more focused on genetic testing, but precise protein testing has not yet received enough attention. Prof. Vandenberghe shared that he had discussed and exchanged ideas with Taiwanese experts during his visit and found that Taiwan has unique advantages in microchip production and analytical methods, which could serve as a gatekeeper for the safety of CGTs.

Author

Richard Chau