Causal biology is the North Star of R&D, from Karuna to ADC engineering, says BMS’s Plenge

Bristol Myers’ head of research leans into CNS, modality innovation, first vs. best in class, and more on The BioCentury Show

Within the framework of target, modality and path to clinic, causal biology is the axis along which Robert Plenge is building and prosecuting research at BMS. It maps from late stage decisions the company has made, such as the Karuna acquisition, to strategies in early R&D, such as how to innovate in ADCs and extend the modality to new applications. 

Plenge became EVP, chief research officer and head of research at  Bristol Myers Squibb Co. (NYSE:BMY) in July 2023, having joined the company via the Celgene acquisition, where he had been head of the Inflammation & Immunology Thematic Center of Excellence.

On The BioCentury Show, Plenge outlined his view of causal biology as a principal axiom for building an R&D engine to maximize probability of success. It is the foundation for step one — picking the right target — and sets the basis for the second and third tenets of his framework, finding the right therapeutic modality for a mechanism of action, and establishing a clear path to clinical proof of concept.

Plenge says that adhering to human biology isn’t enough. “A lot of people say human biology — and then they’ll say gene expression data, or observation of a target that’s expressed in different ways at the protein level or RNA level. That certainly is human biology but it doesn’t distinguish between a cause and a consequence.”

At its simplest, causal biology means understanding that “perturbing a target will have a desired effect on human physiology that’s relevant for drug research and development.” Often, it involves genetics, but not always. 

For example, BMS’s $14 billion acquisition of Karuna Therapeutics Inc. (NASDAQ:KRTX) centered on lead asset KarXT, a combination of xanomeline and trospium, for treatment of schizophrenia. The therapy has a PDUFA date of Sept. 26. Xanomeline provides antipsychotic effects via central M1/M4 muscarinic agonism. Trospium acts peripherally to block non-selective muscarinic activity, which underlies the adverse effects that had previously prevented companies from pursuing xanomeline. 

The original studies, conducted in Alzheimer’s disease, aimed to improve cognition, but revealed the molecule could improve neuropsychiatric symptoms. After Eli Lilly and Co. (NYSE:LLY) and Novo Nordisk A/S (CSE:NOVO B; NYSE:NVO) abandoned the program because of the adverse event profile, Karuna followed the cause-effect thread established in symptoms of schizophrenia, and worked on combining xanomeline with other agents and optimizing dosing. 

Plenge said KarXT represents part of BMS’s “reentry” into CNS diseases, and the follow-on indications for that therapy will include Alzheimer’s disease psychosis and agitation.

Plenge also discussed how he views first-in-class and best-in-class criteria for programs, why advances in CAR T manufacturing generate efficacy advantages for patients, and how he views the exploding innovation in antibody-drug conjugates, which are rapidly diversifying in form and function.

In cancer, said Plenge, “there are tumor intrinsic mechanisms: oncogenic drivers, cancer vulnerabilities, lineage specific markers that will mark tumor cells. And then there are tumor extrinsic mechanisms: immune cells, the tumor microenvironment. Importantly, it’s the relationship between the two that ultimately drives cancer but also gives a foundation for how to treat those cancers.”

“In the case of ADCs, what we’re really going after are those lineage-specific markers,” he added, which are often on the outside of a cell. “That’s the causal human biology for a cancer cell. Then you say, OK, how do we actually attack that particular marker to kill that cancer cell?”

Because there are a number of different ways to do that, the field is expanding, from basic cytotoxic payloads to targeted protein degraders that can kill the cell in a “different and potentially a safer way,” and beyond that to stimulating the immune response or inducing neoantigens.

“So the ADC is simply a framework to deliver cargo to tumor cells to allow this tumor intrinsic and extrinsic mechanism to play out to hopefully benefit patients.”