[Edaily Reporter NA EUN-KYUNG ] Bristol-Myers Squibb (BMS) has halted development of “ORM-6151” (BMS project name BMS-986497), a treatment for acute myeloid leukemia (AML), which it acquired from #Orum Therapeutics, Inc. for an upfront payment of $100 million. While the review of clinical data was the immediate catalyst, this decision is also seen as a result of BMS’s realignment of its blood cancer strategy to focus its R&D capabilities on multiple myeloma and lymphoma.

According to Orum Therapeutics, Inc. on the 17th, BMS decided to halt development after reviewing the clinical data for ORM-6151 and terminated the asset transfer agreement signed in 2023. While Orum Therapeutics, Inc. will not return the $100 million advance payment (approximately 130 billion won at the exchange rate at the time), it has lost the right to receive an additional $80 million in milestone payments (approximately 111 billion won at the current exchange rate).

In October 2023, Orum Therapeutics, Inc. sold ORM-6151 for a total of $180 million (approximately 234 billion won at the time). At the time, the market focused on the upfront payment, which accounted for 55.6% of the total deal value. BMS renamed ORM-6151 as BMS-986497 and conducted a Phase 1 clinical trial in the U.S., Europe, and Canada for patients with relapsed or refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

BMS Focuses on Multiple Myeloma and Lymphoma… ORM-6151’s Role Diminishes

As recently as late July, BMS had included ORM-6151 in its list of pipeline candidates in Phase 1 clinical development. The company had expanded the clinical trial from 35 to 105 patients and added a combination group receiving azacitidine and azacitidine plus venetoclax. However, approximately seven weeks later, BMS decided to halt development.

While this may appear to be a sudden decision, signs of this move can be found in BMS’s announcement earlier this year regarding a shift in its R&D strategy. At the J.P. Morgan Healthcare Conference last January, BMS announced that it would transition from a strategy focused on individual candidates to a disease-centric strategy featuring core and supporting assets, and that it would prioritize allocating resources to programs with a high probability of success.

A disease-centric strategy involves developing multiple candidates for a specific disease simultaneously while sharing patient cohorts, biomarkers, clinical sites, and experience in regulatory approval and commercialization. This approach offers the advantage of being able to continue research with follow-up assets even if a lead candidate fails, and to build a portfolio of products for combination therapies or different stages of treatment.

In line with this strategy, BMS’s blood cancer pipeline is focused on multiple myeloma and lymphoma. For multiple myeloma, the company is developing iverdomide, mesigdomide, ArloCel, and a BCMA/GPRC5D dual-targeted chimeric antigen receptor T-cell (CAR-T) therapy. In lymphoma, it also holds both commercialized products—such as Breyanzi and golcadoamide—and follow-on candidates.

In contrast, for AML, there were virtually no new clinical assets—other than ORM-6151—to form a disease strategy. With the discontinuation of ORM-6151, the new AML development pillar also disappeared from BMS’s publicly disclosed clinical pipeline. Although there is significant unmet medical need in AML, the patient population is fragmented based on genetic mutations and disease status, and the market size is smaller than that of multiple myeloma or non-Hodgkin lymphoma. Given this landscape, ORM-6151—which lacked follow-on clinical assets and development synergies—appears to have been in a relatively disadvantageous position as BMS reallocated resources to focus on specific diseases.

Of course, this decision cannot be explained solely by a change in strategy. Although BMS halted development after reviewing clinical data, it did not disclose whether the decision was due to safety concerns or because efficacy or pharmacokinetic properties fell short of expectations. It appears that the data were not strong enough to overturn BMS’s strategy, and there was little incentive to invest additional resources in the sole remaining candidate for AML.

Even the $100 million already paid does not appear to have been sufficient reason to continue development. Last year, BMS reported revenue of $48.194 billion (approximately 66.7 trillion won), while cash spent on corporate acquisitions, technology licensing, and partnerships totaled $3.944 billion (approximately 5.5 trillion won). In 2024, a year marked by a concentration of major acquisitions, the company spent $21.821 billion (approximately 30.2 trillion won) on the same items. While the $100 million served as survival capital for Orum Therapeutics, Inc., it gave the company time to hold out until its initial public offering (IPO), but it was too small a sum to sway BMS’s asset allocation decision.

Choosing CD123 Over CD33… The Burden on ORM-1153 Grows Heavier

Orum Therapeutics, Inc. is positioning ORM-1153, which it is developing in-house, as a next-generation AML treatment that is an improvement over ORM-6151. Both candidates use the GSPT1 degrader “SMol006” and a beta-glucuronide linker, but they target different antigens: ORM-6151 targets CD33, while ORM-1153 targets CD123.

An Orum Therapeutics, Inc. official stated, “ORM-1153 was developed several years after ORM-6151, and we optimized it by incorporating the lessons we’ve learned during that time,” adding, “Our in-house CD123 antibody was designed to facilitate much more efficient cellular internalization than competing antibodies.”

A high intracellular internalization capacity allows for more efficient delivery of the GSPT1 degrader carried by the antibody into cancer cells. Orum Therapeutics, Inc. explains that it has also reduced unnecessary binding to Fc gamma receptors, thereby lowering the likelihood of the drug entering non-target cells.

CD33, the target selected for ORM-6151, has the advantage of being a clinically validated target in AML. It is widely expressed in the leukemia cells of AML patients, and “Mylotac,” an antibody-drug conjugate (ADC) targeting CD33, has also received approval from the U.S. Food and Drug Administration (FDA). However, since it is also expressed in normal hematopoietic cells, it can cause bone marrow suppression; furthermore, since the level of expression varies depending on the patient or cell type, there is a possibility that cancer cells with low CD33 expression may survive.

In contrast, CD123 is expressed not only on AML blast cells but also on leukemia stem cells, which are identified as a cause of relapse following treatment. Orum Therapeutics, Inc. expects that targeting CD123 will allow for the simultaneous attack on both tumor cells and the cells that serve as the seeds of recurrence. However, since CD123 is also expressed in some normal hematopoietic cells, whether it is a superior target to CD33 must be confirmed through the clinical safety and efficacy of ORM-1153.

In preclinical studies, ORM-1153 demonstrated anticancer activity in patient-derived AML cells and TP53-mutant models. According to the company, no degradative products derived from the antibody were detected in the blood, and good tolerability was confirmed in non-human primate repeat-dose studies. The U.S. Food and Drug Administration (FDA) approved the clinical trial protocol last August, and the company plans to begin a Phase 1 clinical trial involving approximately 42 participants by the end of the year.

However, with both ORM-5029 and ORM-6151 halted in clinical trials, ORM-1153 is now the only candidate among those developed in-house by Orum Therapeutics, Inc. that has been approved to enter clinical trials. Since patient dosing has not yet begun, there are no human safety or efficacy data available.

The fact that all three candidates use the same SMol006 is also a point of market scrutiny. The linkers used, however, differ. ORM-5029 utilized a valine-citrulline linker with an HER2 antibody, whereas ORM-6151 and ORM-1153 employed different antibodies and a beta-glucuronide linker. Since safety and efficacy are determined not only by the payload but also by the target, the antibody, the stability of the linker, and the ability to enter cells, it is difficult to directly apply the toxicity issues of ORM-5029 to ORM-1153. Ultimately, the key question is whether ORM-1153 will demonstrate differentiated safety and efficacy in clinical trials.

The reason for the discontinuation of ORM-6151 is also expected to serve as a benchmark. If the issues were related to SMol006—such as hepatotoxicity—this could pose a challenge for ORM-1153 as well. On the other hand, if the discontinuation was due to efficacy or pharmacokinetic data failing to meet BMS’s standards, ORM-1153—which features improvements in the target and antibody performance—may yield different results.

Since ORM-6151 was sold to BMS through an asset transfer, the rights will not revert to Orum Therapeutics, Inc. even upon contract termination. It is also difficult to guarantee that the relevant clinical data will be shared. However, if such data is provided in the future, it is likely to be useful in refining the safety, pharmacokinetic, and pharmacodynamic characteristics of ORM-1153 and other subsequent DACs.

An Orum Therapeutics, Inc. official stated, “While ORM-6151 was discontinued based on efficacy considerations, ORM-1153 is a compound with an improved target and enhanced antibody internalization capacity, so we expect better results.”