[Interview] 'Orum Therapeutics pursues first-in-class therapies focused on patients'

"The essence of drug development is to deliver good medicine to patients. We are a globally competitive company because we have a structure that is organically linked from preclinical to clinical toward this goal."

Biotech companies start with technology at the center of their business. Still, in the end, they have to develop new drugs that save patients, not consumer products. Nevertheless, there are not many companies that talk about new drugs that are needed by “patients” and “clinical fields.”

However, “patients” was an essential topic for Dr. Lee Sang-hyun, who recently joined Orum Therapeutics as its vice president and research site head to strengthen its targeted protein degradation (TPD) research.

Orum Therapeutics has taken on the challenge of developing first-in-class drugs based on degrader-antibody conjugate (DAC) technology. At the center of this is Dr. Lee Sang-hyun, who has experience in TPD research at global biotech companies, such as Arvinas and Prelude Therapeutics. Korea Biomedical Review spoke with Lee to gain a deeper understanding of the company's strategy for developing new DAC drugs utilizing its novel TPD technology.

Question: Can you describe your drug development experience before joining Orum Therapeutics?

A: Before gaining industry experience, I studied cancer biology at Harvard's Dana-Farber Cancer Institute as a postdoctoral fellow. My first job was at Incyte, where I built on my academic research experience. At Incyte, I gained experience in developing small-molecule-based anticancer drugs that utilize epigenetics.

There were several limitations in developing small-molecule-based anticancer drugs. To overcome these limitations, TPD technology emerged, and I joined Arvinas to experience TPD drug discovery at the early stages of development.

I led drug target discovery and preclinical development using TPD. I developed multiple first-in-class candidates, including a prostate cancer-targeted program (ARB-76). I then moved to Prelude to continue my early work in TPD.

Q: Why did you focus on TPD to overcome the limitations of small molecules?

A: Traditional small-molecule inhibitors have many limitations. For example, inhibitors are ineffective against proteins that have no catalytic activity and whose scaffold function is crucial for supporting oncogenes.

TPD, on the other hand, can remove the protein itself, allowing for a more radical approach. It is powerful in inherited neurological diseases and aggregation-based diseases (such as proteins). It may have a more precise mechanism of action than ADCs.

Q: Why did you join Orum Therapeutics based on experience in overseas companies?

A: Orum Therapeutics is the first company worldwide to enter the clinic with a new modality called DAC. Even global biotech firms are still in the preclinical stage for DAC, but Orum Therapeutics is leading the way by entering the clinic.

In addition to the technology, the horizontal and collaborative organizational culture, global bi-directional R&D infrastructure (Boston, USA, and Daejeon, Korea), and a first-in-class orientation were a good fit for the career I wanted to pursue. Orum is a Korean company with a global mindset and execution.

Q: What is the structure and role of the research organization at Orum Therapeutics?

A: Orum Therapeutics has a dual research organization in Korea (antibody development) and the U.S. (chemistry). The U.S leads clinical development. With my experience in preclinical research, target discovery, and TPD, I am comprehensively involved from new idea generation to experimental design and preclinical strategy. It's a horizontal, organic, collaborative structure where we work toward a common goal.

Q: TPD currently has no licensed products. Since TPD has not been commercialized, it won't be easy to develop a DAC that utilizes TPD as a payload.

A: It is natural for a new drug to take more than 10 years to reach the market. Even Avinas, which was founded in 2005, has only recently filed a New Drug Application (NDA). DAC has just started its phase 1 clinical trial so that it will take more time.

However, TPD is showing promise, with Avinas entering phase 3 and expanding indications. Time and data will tell if our DACs have the potential to become new drugs.

Q: How does Orum Therapeutics' DAC platform differentiate itself?

A: The antibody-drug conjugate (ADC) market is already crowded with thousands of candidates, with the majority of payloads based on topoisomerase inhibitors. There is also a significant resistance problem with existing ADCs, as well as a lack of me-too strategies.

By combining TPD as a payload, we are developing a new concept of ADC that utilizes TPD to remove proteins, rather than cytotoxins. We aim to unlock new possibilities in potency, precision, and safety that extend beyond simple inhibition.

Q: Tell us about the clinical discontinuation of ORM-5029, and how it may affect your strategy?

A: ORM-5029 was technically a DAC based on an existing antibody targeting HER2 and a first-generation linker. Patient recruitment, marketability limitations, and limited side effect issues were the reasons for discontinuing development. It was a strategic decision to focus limited resources on programs with more promise.

The successor pipeline, ORM-1153, is based on the same payload (GSPT1), but with a proven linker and antibody combination and preclinical data showing no hepatotoxicity. We are on track for global clinical entry late next year.

Q: You are focusing on oncology. Is it possible to expand to other disease areas?

A: TPD and DAC platforms can be expanded to address inflammatory diseases, immune diseases, rare diseases, and other conditions. Global companies are also expanding into non-oncology areas. The key is to obtain proof-of-concept data in cancer, and then we plan to strategically expand indications based on unmet patient needs.

Q: What is your vision for drug discovery at Orum Therapeutics?

A: We are focusing on developing first-in-class drugs. The essence of drug development and research (R&D) is to provide effective drugs to patients. We have a genuinely global competitive advantage, as our organizational structure is organically linked from preclinical to clinical, all working toward a common goal.