Leveraging genetic insights throughout the drug discovery pipeline

Robert M. Plenge, MD, PhD, senior vice president in research and early development, and head of the immunology, cardiovascular, fibrosis and global health research team at Bristol Myers Squibb, discusses leveraging genetic insights in drug discovery.

Illustration of scientists studying genetics

Drug development and discovery is a long game. It demands patience and innovative thinking as well as years of iterative lab work, an ever-evolving search for mechanisms underlying human illnesses and deep pockets. Recent leaps made in genetics and genomics improve the probability that one among thousands of promising compounds aimed at many possible targets in the human body will make it from preclinical studies through clinical trials, hurdle a rigorous approval stage and go on to gain traction within a broad market for biopharmaceuticals.

Robert M. Plenge, MD, PhD, is senior vice president in research and early development, and head of the immunology, cardiovascular, fibrosis and global health research team at Bristol Myers Squibb (BMS). According to his deft blog Plenge Gen, his mission, which is developing medicines that matter to people struggling with many diseases, is driven by a deep understanding of causal human biology through tools such as genetics. Here he answers our questions about the real-world impact of genetics on drug discovery, his rule of three Ms and novel therapeutic modalities on the rise.

Interview edited and condensed for clarity

Where do things stand in terms of the real-world impact that genetics is having on biopharmaceutical R&D?

I think there is a growing realization that human genetics can increase the probability of success of the drug discovery and development process. There are some general numbers that people throw around — about a twofold increase in the probability of success if a target has human genetic support — but there’s a range of values. It may be even higher, especially for rare genetic diseases where the underlying etiology is precisely known, such as cystic fibrosis and hemoglobinopathies like sickle cell disease and thalassemia. For more complex, common diseases where you might have a genetic signal, but you don’t really understand details of the mechanism, it might increase probability of success a bit, but probably not twofold and certainly not higher.

In most infectious diseases, there is a germline genetic component, but it’s really about targeting the infectious organism itself. And cancer is less about germline genetics and more about the tumor and the tumor microenvironment. So, let’s remove those two categories of diseases and just look at everything else, including therapeutic areas such as cardiovascular diseases, immunological diseases, fibrotic diseases and neurological diseases.

There have been some good examples in the cardiovascular area, specifically around disorders of cholesterol and cholesterol metabolism. One of the most often cited examples is for a genetic target called PCSK9. That discovery from 2003 led in just over 10 years to an approved drug. It’s one of the better, more modern examples of human genetics leading to a target and ultimately to approval of a drug that was really driven by the genetic observation, rather than something else.

A second good example, and this is actually in our BMS pipeline, is a target called TYK2, which has very strong genetic support from rare and common genetic diseases. The clinical trials are ongoing for a small molecule allosteric inhibitor of TYK2, so we don’t yet know if this will lead to a drug approval. The drug is in phase II for psoriasis with data published in New England Journal of Medicine about a year and a half ago.

If you have a genetically validated target, what are the key approaches or frameworks critical to leveraging genetic insights through the downstream R&D process?

In order to turn a genetic discovery into a true clinical study in a drug discovery program, you need to address the three Ms: mechanism, magnitude and markers. By mechanism, I mean the ability to understand the underlying genetic perturbation — and therefore, how you turn that mechanism into a therapeutic hypothesis, and match a particular modality to that mechanism. So, for example, do you want to inhibit the target? Activate the target? Or do something more complex than inhibiting or activating?

The second part is magnitude: how much do you want to inhibit or activate the target? Because a medicine might be activating or inhibiting, but do you want to do it completely? Or partially? And if partially, how much do you think you need in order to see benefit?

And then markers are important as well. In clinical studies, we measure both clinical outcomes and also biomarkers that show us whether the drug that showed promise in a preclinical model is actually doing what we think it should do in human subjects.

For every genetic discovery it's important to address mechanism, magnitude and markers. I think understanding how to address the three Ms at a very early stage in a drug discovery program — that is, years before it ever goes into humans — will lead to an increased probability of success that an idea will turn into an approved medicine.

How are novel therapeutic modalities accelerating the applications of genomics in drug development?

Traditionally the drug discovery field has used small molecules and monoclonal antibody-based approaches to make new medicines. So, a small molecule is something that might inhibit the enzymatically active site of a protein, for example — turn it on and off — whereas an antibody may neutralize a protein that circulates in the blood and basically prevent it from performing its function altogether. Many of the drugs that are approved today fall into one of these categories: small molecules or monoclonal antibodies. These two modalities will continue to be very important for genetically-driven drug discovery.

But what is particularly exciting are new modalities that allow us to match the underlying genetic mechanism with a new way of perturbing a target. So, for example, it's now possible to inhibit RNA with nucleic acid approaches, such as antisense oligonucleotides (ASOs) or RNA interference (RNAi). It may also be possible to inhibit RNA with a small molecule. There are approaches to degrading proteins that weren't possible before: not just inhibiting the protein, but actually binding to and degrading the protein completely. This affects other aspects of the protein that may be important in its function, such as the ability of a protein to serve as a scaffold inside of a cell.

There are also living cell therapies, which do much more than just act on one protein or one target. These are actually living cells that can be infused into individuals. They can have a wide variety of functions, including the secretion of molecules from that cell which may kill other cells in a very specific manner. This cell therapy is being used for different types of blood cancers, for example.

There’s a burgeoning set of modalities, which are at a nascent stage but showing promise. Several have actually led to approved drugs. I think we’re going to continue to see these types of modalities matched to genetic mechanisms become a very powerful force in the years to come.

– Francesca Coltrera

Continue the conversation on Twitter by connecting with us @HMS_ExecEd or with Dr. Plenge @rplenge.

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