CEO Conversations XLVIII: Dr. Lih-Ling Lin, Chief Scientific Officer, PharmaEssentia (6446 TT)
In an exclusive interview with Dr. Lih-Ling Lin, the Chief Scientific Officer at the Global Headquarters of PharmaEssentia, we gained insights into her vision for the future of biopharmaceuticals. Dr. Lin, the guiding force behind PharmaEssentia's new drug development direction, greeted us with her sharp, cropped hair, displaying her readiness even before our scheduled meeting began. With over 25 years of experience in drug development at Pfizer and Sanofi, Dr. Lin has held leadership roles and possesses extensive expertise in both small molecule compounds and large molecule protein drug development, particularly in immunology and immuno-oncology.
Below are excerpts from our interview:
Q: How do you envision the future of biopharmaceuticals? Some believe that biologics represent the future of the pharmaceutical market, while others argue that small molecule compounds still dominate the majority of drug products. Given that PharmaEssentia has been focused on biologic drug since BESREMi, what is your perspective on the future of biopharmaceuticals?
Dr. Lin: Biologics, or biologic drugs, often targeted therapies, offer a promising outlook in drug development. Unlike small molecule compounds, which may exhibit off-target effects and unpredictable toxicities, biologics demonstrate high selectivity for designated targets, making them increasingly popular in recent years. Moreover, the development of biologics follows clear guidelines, whether in the realm of antibodies or cytokines. Small molecule compounds provide a wide array of structural diversity, thus rendering the development pathway for such compounds more intricate. Recent advancements in biologics, such as bispecific and trispecific antibodies, exhibit a similar structural framework but possess the capability to bind to multiple targets. These innovations have enabled scientists to design antibodies targeting multiple antigens, showcasing success in clinical applications, as seen with the FDA approval of bispecific T cell engager antibodies Furthermore, emerging therapeutic modalities, including conditional antibody designs, present exciting opportunities for novel antibody development. While PharmaEssentia has yet to venture into T cell engager antibodies, it remains an area of active research, with anticipation for groundbreaking discoveries. Additionally, innovative approaches like antibody-drug conjugates (ADCs) offer distinct advantages, functioning independently of immune cell cooperation to deliver small molecule compounds.
In recent years, there has been a resurgence of interest in chemical drugs, with intriguing advancements in treatment modalities such as degraders. Unlike traditional small molecule compounds that inhibit protein activity, degraders offer a unique mechanism by inducing protein degradation, altering the pharmacokinetic and pharmacodynamics fundamentally. This mechanism operates distinctively, as it does not necessitate binding to the active site but rather orchestrates the degradation and eventual disappearance of the protein. Only upon the subsequent regeneration of the protein does a new cycle commence. Through these therapeutic innovations, previously deemed elusive or challenging drug targets now become amenable to medical intervention. Moreover, small molecule compounds have expanded their scope to target RNA, further broadening their therapeutic potential. While antibodies have their constraints, limited to targeting extracellular proteins on the cell membrane, both membrane and secreted proteins, they struggle to penetrate intracellular targets. However, certain proteins reside intracellularly, like some kinases, yet small molecule compounds can access and target these proteins intracellularly or extracellularly. Notably, peptides derived from the intracellular proteins or tumor antigens can sometimes present on the cell surface in the form of peptide-major histocompatibility complex (MHC), recognized by T-cells, resulting in effectively killing cancer cells expressing the intracellular tumor antigens. This field remains nascent but offers tremendous potential. For instance, PharmaEssentia is venturing into TCRT, enable targeting intracellular proteins, albeit a select few, as not all intracellular proteins can be targeted via through the cell surface.
Q: There are various therapeutic modalities in protein-based drugs, such as monoclonal antibodies, bispecific or even trispecific antibodies, antibody-drug conjugates, and cell therapies, and now there is gene therapy. How do you view these different therapies? Which one do you think holds the most potential for the future, or in your opinion, which area of research may have broader applications, a larger market, or solve more human problems?
Dr. Lin: This is a question of different horizon. The efficacy of mRNA technology and gene therapy is undeniable, particularly in treating rare diseases. However, there are still significant challenges to address. Regardless of the therapeutic approach, there must be a straightforward, well-defined development pathway. The choice of therapy depends largely on the disease area. For instance, in the case of cancer, where patients face dire prospects, there's a higher tolerance for adverse effects, allowing for more aggressive treatment approaches like antibody-drug conjugates (ADCs). However, the toxicity associated with ADCs limits their application in chronic and immune-related diseases, where gentler immunomodulatory molecules are preferred. Therefore, each therapeutic modality has its suitable application areas.
Newer modalities are often trialed in cancer treatment first, owing to the urgency of the disease. For instance, CAR-T cell therapy has demonstrated remarkable efficacy in blood cancers, boasting high overall response rates. While costly and involving the modification of autologous T cells, CAR-T has shown significant promise in cancer treatment and is now gaining traction in the realm of immune-related diseases. Scientists have identified CAR-T's potential in targeting B cells, showing efficacy in conditions like systemic lupus erythematosus (lupus). Major pharmaceutical companies are now exploring its application in other immune-related disorders.
Q: What challenges or opportunities do you think Taiwanese companies, including PharmaEssentia, will encounter in developing these various therapeutic modalities of biologics?
Dr. Lin: Firstly, to achieve, or even surpass, the global standard of technology is a challenge. However, I believe Taiwanese are exceptionally bright, hardworking, and eager to excel, which is truly commendable. Secondly, there's the issue of focus. Companies have a better chance if they concentrate on areas in which they specialize. In the United States, it's common for companies to establish themselves by focusing on a specific technology or disease area. Taiwan, on the other hand, may have various attractive opportunities, making it challenging to focus. However, focusing is essential for the proper development of a technology. By empowering the right people with resources and facilitating the development process, we can foster progress in this regard.
Q: With the tremendous success of immune checkpoint inhibitors, there are now numerous imitators flooding the market. How do you view the field of immune oncology, and how does PharmaEssentia plan to avoid becoming just another one of the many imitators while creating a unique position?
Dr. Lin: Only about 30% of patients respond to PD-1 and CTLA-4 inhibitors. So, the simple fact is that most patients do not respond to PD-1 inhibitors. The unmet medical need in the field of immune-oncology remains very significant. In this regard, our approach is to research other targets. Before entering clinical trials, we need evidence to confirm the importance of these targets in killing tumors. Targets like PD-1, CTLA-4, and even TIGIT are expressed on T-cells, and the mechanism of action for treating diseases is similar. One of the research directions of our company is in the tumor microenvironment, where the most abundant cells are macrophages and myeloid cells, rather than T-cells. Unfortunately, these myeloid cells suppress the immune response, contributing to the tumor's ability to grow undisturbed. The original function of macrophages is to identify, engulf, and clear foreign substances. If they detect cancer cells, they will ingest them. However, it has been discovered that macrophages express certain checkpoint molecules on their surface, allowing cancer cells to deceive them. Our focus now is on these macrophages, making them active and not suppressed by cancer cells. In this regard, our approach differs significantly from traditional research. We utilize multi-omics (integrating genomics, proteomics, etc.) techniques, combined with AI analysis of experimental data, to identify targets related to cancer development. Because selecting the right target is crucial, choosing the wrong direction initially renders even the best product useless. This is one of our areas of intense focus.
Q: Dr. Lin, the global pharmaceutical landscape is undoubtedly crowded with companies and scientists all fervently searching for the right targets, essentially engaging in a race, a cutthroat competition. Could you discuss the competitive environment in this field?
Dr. Lin: Certainly. For instance, at major global medical conferences, there's a plethora of clinical data being presented. Some data may support your ideas, while others may not. This sense of competition motivates me to think even harder about our future strategies, how to pinpoint the right targets effectively. Additionally, identifying the most advantageous technologies for us is crucial. Speed is, of course, key. I believe our advantage lies in our experienced team and our ability to quickly identify interesting new targets and swiftly progress from preclinical to IND to clinical trials. Furthermore, in the field of cancer, combination therapy is crucial, as everyone wants to combine with PD-1 antibody. So, developing a good combination therapy product or designing molecules with multispecificity to enhance affinity or capabilities is essential to creating differentiation.
Q: You currently lead the PharmaEssentia Innovative Research Center (PIRC). Looking ahead over the next decade, aside from flagship product BESREMi and its subsequent indications, what kind of 10-year research and development plan do you envision for PharmaEssentia?
Dr. Lin: PharmaEssentia is dedicated to being a leader in best-in-class or first-in-class therapies within the fields of immunology and immuno-oncology. Our vision, mission, and endpoint for the next ten years are clear: to develop transformative therapies and introduce first-in-class drugs for the benefit of patients. Immunology and immuno-oncology-related drugs, from interferons, cytokines, antibody drugs, checkpoint inhibitors, to the currently hot T cell therapy, all fall within this scope.
BESREMi is our current star product and will remain so for many years to come. Interferon-alfa has proven its utility in many different indications. We are currently exploring combining BESREMi with PD-1 antibody, with ongoing clinical trials. Concurrently, we collaborate with academic institutions in Taiwan to explore combining BESREMi with other checkpoint inhibitors. Therefore, the development of BESREMi will continue. Additionally, pegylation technology holds potential for use in many other cytokine products. However, not every cytokine is suitable, so we are focusing on several with confidence to develop best-in-class therapies. For example, we are developing a next-generation IL-2 with great potential for autoimmune diseases. Preliminary results in cell experiments show better efficacy and selectivity compared to competitors. Poor selectivity can lead to off-target effects like vasculitis and vascular leakage. We are also developing a next-generation GCSF and hope to submit an IND in Taiwan by March, 2024. Animal experiments show a longer and better pharmacokinetics and pharmacodynamic profile compared to existing competitors. For chronic immune diseases like atopic dermatitis and rheumatoid arthritis, although the targets are the same, the regulatory directions differ from oncology area, allowing us to explore different avenues. We are also developing other drugs such as new checkpoint inhibitors.
Q: Could you talk about PIRC? Where did you find the staff for PIRC? What kind of organization is PIRC?
Dr. Lin: In simple terms, our colleagues at PIRC are "drug hunters," extremely eager ones at that. Our ultimate goal is successful innovative drug development. We blend both academic and commercial aspects, engaging in cutting-edge drug discovery with an innovative spirit. I believe investing in cutting-edge technology brings the greatest returns. The success of a drug requires a long process, and without the initial stages, there can be no latter stages. PIRC places a greater emphasis on the early stages of development, such as target identification, antibody generation, and even multi-specific antibodies. The staff at PIRC are incredibly talented. Having been with PharmaEssentia for a year and a half, I've observed that while Taiwan companies excel in late-stage R&D, there's a scarcity of emphasis in early-stage drug discovery. Currently, PIRC consists of four major groups. The first group focuses on immunology and pharmacology. The second group specializes in biological platforms, including protein engineering, antibody engineering and yeast display platforms. The third group, translational medicine, is primarily tasked with extending BESREMi's preclinical and clinical research to enhance and realize its clinical potential, even surpassing current research results in myeloproliferative neoplasms (MPN) and extending into solid tumors and other diseases. Additionally, they work on biomarker development for our future products in the pipeline. The fourth group is data science/bioinformatics, responsible for developing and applying AI and machine learning methods in our drug development process. Our staff is outstanding, and I'm fortunate to have found them. With over 15 years of experience, they're at the peak of their physical abilities, experience, and knowledge. This year, we plan to expand to 25 staff members in Boston, adding to our R&D team in Taiwan, resulting in a total of about 100 researchers dedicated to PharmaEssentia's new drug development.
Q: It sounds like PharmaEssentia is venturing into the drug discovery field, which few Taiwanese companies have explored. I feel PharmaEssentia is truly evolving into an integrated, innovative biotech company. Besides this, do you see any other differences between PharmaEssentia and other Taiwanese companies?
Dr. Lin: One crucial point is PharmaEssentia's commitment to innovation and new drug development. Without the front end, how can there be a back end? Core capabilities are essential. An example of this commitment is the establishment of PIRC. Another difference, which is quite evident, is that PharmaEssentia has traversed the entire journey of new drug development from start to finish. From developing proprietary new technologies to IND, clinical validation and FDA approval. This experience is invaluable. Our team in Taiwan is very familiar with applying for IND, knowing what needs to be done and how much it costs. This capability and capacity are all in place. Moreover, our staff is highly experienced and productive. In Taiwan, there aren't many companies that can showcase the entire process and achieve success, making this valuable experience essential.
Q: What do you think is the most important factor for a new drug development company or a biopharmaceutical company to have strong competitiveness? Does PharmaEssentia already possess these factors?
Dr. Lin: I believe several factors are equally important. Firstly, science is always the key to win. It's essential to have a deep understanding of cutting-edge scientific knowledge and to stay at the forefront of technology. This includes selecting the right targets from the outset, understanding the disease thoroughly, possessing core capabilities, having supportive facilities, and having a blueprint for continued development. If the direction isn't right from the start, it's better not to proceed. Secondly, having strong leadership is crucial. A powerful leader can steer the ship in the right direction, which is also very important. Thirdly, corporate culture plays a significant role. Having an environment where employees enjoy working together is essential. When employees are happy, the company succeeds.
Of course, there are no perfect companies in the world, and PharmaEssentia is striving towards that direction. Whether it's in science, technology, leadership, or corporate culture, we are moving towards that benchmark, striving for perfection.
If you would like to arrange a meeting with Dr. Lih-Ling Lin, Chief Scientific Officer of PharmaEssentia, please contact yvonnehuang@qtumic.com.
The QIC team consists of experienced finance industry professionals that have worked in major sell-side and buy-side companies. We leverage our industry knowledge and relationships with institutional investors to assist companies and investors to achieve effective two-way communication to enhance shareholder value. QIC also has many years of experience in corporate access services. We plan, schedule and execute tailor-made roadshows and targeted investor events for high-quality corporate clients. QIC does not provide execution services and is thus considered MiFID II-exempt by institutional investors, who welcome QIC’s services and access to senior management of quality companies. If you are interested in learning more about QIC and its services, we welcome you to contact us.