Delivering on the Promise of New Modalities: An Interview with SJ Lee, CEO, Orum Therapeutics

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As part of WuXi AppTec’s ongoing efforts to collaboratively foster new thinking and actionable approaches in advancing breakthroughs for patients, we have launched a new interview series in 2022 – “Delivering on the Promise of New Modalities” – so leading voices of R&D can share how their approaches are addressing the barriers standing in the way of breakthroughs.

In our latest interview, we’re joined by SJ Lee, CEO of Orum Therapeutics. Orum is a biotech company pioneering the development of targeted protein degraders to treat cancer. In June 2021, the company closed $84 million Series B financing to advance the company’s lead therapeutic candidates into clinical trials. Orum’s proprietary platform merges the power of protein degraders with the precise cell delivery mechanisms of antibodies. Unlike traditional ADCs, the targeted protein degrader (TPD) payloads of Orum’s TPD2 approach can specifically degrade intracellular target proteins within cancer cells via the E3 ubiquitin ligase pathway. ORM-5029, one of its lead candidates, was dosed in its first patient last October. By selectively delivering catalytic GSPT1 protein degraders to the cancer cells, the candidate has the potential to treat HER2-expressing tumors via a novel MoA.

Congratulations on your progress in clinical programs and thank you for joining us. Orum is developing innovative drugs to treat cancer. In your opinion, what are the challenges in current therapeutic intervention, or current modalities?

SJ: An industry-wide challenge is targeting “undruggable” targets. Targeted protein degraders are a powerful modality that have the potential to address undruggable targets. However, like all small molecules, there are safety concerns as they are unable to distinguish between targets in healthy and diseased cells. Moreover, heterobifunctional degraders also hold a lot of promise in terms of broadening the range of proteins to target but can be stifled by issues such as low cell permeability, bioavailability, PK, and the hook effect. Antibody drug conjugates (ADCs) have been successful in oncology by making cytotoxic agents safe and effective, but the biggest challenge in the field is highly toxic payloads wiping out normal cells that expresses express the target cell antigen of interest such as CD33. This restricts the use of ADCs to certain tumor types and disease indications.

How is Orum’s platform helping to address these challenges? How is it different from existing approaches?

SJ: We have developed an approach that we call TPD² – or dual-precision targeted protein degradation – to generate antibody-enabled targeted protein degraders. We’re merging the aspects of these modalities. Orum’s TPD² drug candidates offer novel payloads with a new cell-killing mechanism of action to target proteins that are considered undruggable. Furthermore, by conjugating protein degraders to an antibody, TPD² drug candidates are designed to specifically target diseased cells to increase efficacy and safety to overcome the challenges inherent to small molecule degraders. In addition, the degrader payload itself has lineage dependant activity. For example, GSPT1 degraders can kill leukemia cells while sparing normal hematopoietic stem cells.

Orum’s lead candidate already has been dosed in its first patient this year. To fully realize the potential of your new platform, what are the critical challenges remain to be solved?

SJ: The challenge of realizing the full potential of our TPD² approach is there are almost an unlimited number of combinations possible via cell surface antigen and TPD target protein pairings. We are engaging partners that either have expertise in a disease area, or degrader or antibody assets that can be conjugated to its counterpart. While we are currently focused on oncology, Orum’s TPD2 approach is agnostic to therapeutic areas. We have a unique opportunity to partner with others who have deep expertise in non-oncology indications, such as immunology, to explore TPD2 projects, where we can design degraders to be delivered to specific immune cells.

Orum is still a relatively young biotech. What does global collaboration mean to your company?

SJ: Orum is a global company with wet labs in the US and South Korea. We benefit from that by accessing diverse and skilled talent pools. We also work with high-quality partners, such as WuXi AppTec, in East China that are two hours flight away from Seoul. This shaves days off the lead optimization cycle, speeding up drug discovery efforts significantly.

Thanks for your insights! If we were to gather here again in 10 or 15 years’ time, what do you think we’re going to be talking about in terms of what we have already achieved in the industry?

SJ: We will see more creative fusions of established modalities. ADCs are chemotherapy agents on antibodies, CAR-Ts are antibody fragments on T cells. More innovation will come from the novel fusion of such validated components. A good example is Enhertu, which is a novel fusion of validated approaches – topoisomerase 1 inhibition on an approved antibody. We think TPDs on antibodies will become mainstream 15 years from now, and we believe Orum is a leader in this field.

SJ Lee, Ph.D.

CEO, Orum Therapeutics

SJ Lee is the CEO of Orum Therapeutics, a clinical stage biotech pioneering the development of tumor-directed targeted protein degraders. Before founding Orum to address the undruggable target problem, he was at Sanofi as the head of research for Asia Pacific R&D. He oversaw teams and projects around a virtual biotech model to co-invent drugs with biotech and academia teams for Asia related diseases such as hepatocellular carcinoma. SJ has led international teams to improve the therapeutic landscape for various diseases, including oncology and infectious diseases. He earned a Ph.D. in Biophysics from the University of California, Berkeley, and worked as a postdoctoral scholar at Stanford University.

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