Vertex Pharmaceuticals will use Orum Therapeutics’ dual-precision targeted protein degradation (TPD²®) technology platform to discover targeted conditioning agents for use with gene editing therapies, the companies said today, through a collaboration that could generate up to $945 million-plus for the degrader antibody conjugate (DAC) developer.
Orum has granted Vertex rights to conduct research using its TPD² approach to developing DACs, next-generation versions of antibody-drug conjugates (ADCs) which use antibodies to precisely deliver small molecule targeted protein degrader payloads to cancer cells and other targeted biological therapies.
Following a research period for each target, Vertex will have the option to obtain a worldwide, exclusive license to research, develop, manufacture, and commercialize DACs developed with Orum’s TPD² technology for that target.
Vertex has agreed to pay Orum $15 million upfront, plus option payments and milestones potentially totaling up to $310 million per target for up to three targets—up to $930 million total—as well as tiered royalties on potential future global annual net sales. Vertex has agreed to oversee all research, development, and commercialization for the collaboration.
The collaboration comes at a time when researchers across industry and academia are seeking less toxic alternatives to busulfan as a bone conditioning regimen, a crucial component of cell and gene therapy protocols. That effort is of keen interest to Vertex, which made history last December when Casgevy® (exagamglogene autotemcel, or “exa-cel”), which the company co-developed with CRISPR Therapeutics, became the first-ever CRISPR-based gene editing therapy to win FDA approval to treat sickle cell disease (SCD), followed a month later by agency approval of Casgevy to treat transfusion-dependent beta thalassemia.
“You can view this collaboration in the context of looking for more targeted and safer conditioning agents,” Sung Joo Lee, PhD, Orum’s CEO and founder, told GEN Edge. “Before getting this genetic treatment Casgevy, these patients need a preconditioning agent, and that traditionally has been chemotherapy. What we’re targeting through this collaboration is to replace that chemotherapy with a more targeted conditioning agent, using our degrader ADC approach or TPD2 approach.”
Overcoming limitations
According to Orum, TPD² is designed to merge TPD with the precision of ADC technology, while overcoming the limitations of each. Because TPDs are typically small molecules that indiscriminately enter many cells throughout the body, Orum drives localization to specific cells by covalently attaching protein degraders to antibodies.
Orum’s approach addresses what it has pinpointed as three critical limitations of conventional targeted protein degrader product candidates:
- Efficacy—The company says it can enhance the potency of protein degraders up to one thousand-fold through its antibody-mediated delivery approach.
- Safety—Antibody-coupled degraders are inactive until they are internalized and released from the antibody. But internalization depends on binding to specific cell surface antigens, reducing the exposure of non-targeted cells to the effects of the protein degrader.
- Pharmacokinetics and pharmacodynamics—Orum says its coupling of small molecule protein degraders to antibodies leads to increases in payload half-life and drug exposure.
“The beauty of using our kind of degrader approach is that most preconditioning agents are based on chemo, and a lot of them are DNA-damaging agents. Our degrader payloads are still very potent but do not damage the DNA,” Lee said. “Because they do not damage the DNA, it doesn’t require the cell to be actively dividing, so it can also induce apoptosis in non-dividing cells, which is a very good fit for a targeted conditioning agent for a gene therapy.”
The Vertex collaboration is Orum’s second partnership with a big-name biopharma giant. In September 2023, Orum sold its early clinical phase program to develop ORM-6151 to Bristol Myers Squibb (BMS) for $100 million upfront and an additional up to $80 million in milestone payments. The companies have declined to disclose additional details of their partnership to develop ORM-6151, a first-in-class, anti-CD33 antibody-enabled G1 to S phase transition 1 protein (GSPT1) degrader initially developed by Orum to treat acute myeloid leukemia (AML) and other CD33-expressing malignancies.
BMS has since renamed ORM-6151 as BMS-986497, which is now under study in a Phase I trial (NCT06419634) designed to assess the drug’s safety, tolerability, drug levels, and drug efficacy in participants with relapsed or refractory AML or myelodysplastic syndrome (MDS). The study is also designed to determine a recommended dose for later-phase trials of BMS-986497. The study’s estimated primary completion date is February 1, 2027.
“They (BMS) are definitely the leader in developing AML drugs. And we thought our approach was a very innovative and effective approach for AML patients. That was, I think, one of the reasons that the partnership came to fruition last year,” Lee said.
Two clinical candidates
ORM-6151 is one of two Orum-developed candidates in clinical phases. The other is ORM-5029, a first-in-class drug candidate designed to selectively deliver catalytic GSPT1 protein degraders to human epidermal growth factor receptor 2 (HER2)-expressing tumor cells via antibody targeting. ORM-5029 is now being evaluated in a Phase I first-in-human trial (NCT05511844) in up to 90 participants with HER2-expressing advanced solid tumors. The study consists of dose escalation and dose expansion parts.
“We hope to provide an update sometime next year,” Lee said.
Both clinical candidates have been developed using Orum’s GSPT1 platform, which applies the company’s TPD² approach designed to leverage ADCs to precisely deliver and target intracellular proteins for degradation leading to cancer cell death.
The rest of Orum’s pipeline consists of four preclinical candidates, all in discovery phases:
- ORM-1023, a TPD2 GSPT1 candidate being developed to treat small cell lung cancer (SCLC) and neuroendocrine tumor (NET) by targeting an undisclosed target.
- ORM-1153, another a TPD2 GSPT1 candidate whose indications and target are both undisclosed.
- IO-0001, a PD-1 targeting candidate being developed for unspecified multiple indications, developed through the company’s targeted protein stabilizers (TPS2) Casitas B lymphoma-b (Cbl-b) platform. Orum’s TPS2 approach uses proprietary Cbl-b inhibitor payloads conjugated to immune cell- or tumor cell-targeting antibodies.
- PROTAb-0001, a candidate whose multiple indications and target are both undisclosed, developed using the TPD2 PROTAb platform.
PROTAb is an ADC-friendly traceless linker platform designed to enable stable conjugation of the glutarimide ring of the cereblon-based degraders (glue or heterobifunctional) to an antibody, without requiring any modification to the degrader’s chemical structure. The linker undergoes rapid hydrolysis upon targeted delivery and intracellular triggering, thus unleashing the active degrader, achieving a seamless and what Orum says is a traceless release of the payload.
Team commitment
How soon before Orum’s preclinical candidates enter the clinic?
“Hopefully as soon as possible, but it’s hard to predict the future. However, our team is committed to progressing these projects,” Lee said. “And the extra $15 million in our bank, that definitely would help accelerate that.”
Since last year, Lee said, Orum has steadily grown its workforce to accelerate development of its internal projects. Orum’s operations are split between Daejeon, South Korea, and the Boston suburb of Lexington, MA. Orum has about 40 full-time equivalent employees between both locations,
Lee served as Sanofi’s head of research for its Asia-Pacific R&D operation before leaving to establish Orum in 2016. Privately held Orum has raised more than $120 million in funding since its launch.
“We really wanted to focus on difficult, undoable targets using antibody technology. That was the beginning of Orum’s innovation, and that evolved into, ‘Let’s deliver catalytic payloads like degraders on an antibody,’ because the existing ADCs were either DNA damaging agents or they’re tubulin inhibitors,” Lee recalled.
“What we’re doing by our DAC approach is, we want to diversify the ADC field away from those 2 MOAs [mechanisms of action] by delivering targeted degraders. And we thought that degraders were great because first of all, you can target multiple different target proteins of interest using degraders. Second, you don’t need a whole lot of them, because they’re catalytic once they get into the cell,” Lee added. “That’s how we got into the field, and it’s already been many years. So that kind of put us in the first mover position. And now, we’re recognized as a leader in this field.”
