Speeding Drug Development With Innovative Technology

Marcelo Bigal, MD, PhD, chief executive officer, Ventus Therapeutics, discusses a drug discovery platform called ReSOLVE and speaks broadly about how innovations in technology can facilitate faster, more efficient drug development.

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Welcome back to PopHealth Perspectives, a conversation with the Population Health Learning Network where we combine expert commentary and exclusive insight into key issues in population health management and more. 

In this episode, Dr Marcelo Bigal discusses how innovative technology can be used to accelerate drug development.

Hello. Thanks for having me here. My name is Marcelo Bigal. I am a neurologist with a PhD in neuroscience. I'm currently the CEO of Ventus Therapeutics, a company based in Massachusetts and Montreal. 

I spent the first half of my career in academia working on topics related to population health, including the prevalence and disability of pain conditions, chronic migraine, and neurological disorders.

What challenges have scientists historically faced when it comes to developing drugs for diseases?

There are so many challenges, but I think they can be described in terms of trades. Do we want to go after diseases that have known targets but lots of therapeutic options, or diseases where the targets are not known and need to be defined? Do we need to have biological validation before we start going into the disease, or do we take chances from the very beginning? 

But more recently, the most fundamental challenge is that the best accepted modality for therapy that patients have are small molecules. The tablets and pills we take every day, vitamins, hypertension medications, contraceptive pills—they're always small molecules. 

So the current trade is the population likes them, trusts them, don't have a problem in using them, and they can be part of a cost control initiative; however, most of the proteins currently in need of being drugged for new diseases seem to be unreachable by small molecules. There is a trade between a modality that the public trusts vs different modalities such as RNA, CRISPR, and stem cell therapies, and this trade is frightening for many. 

It doesn’t have to be like that, because most of the proteins that seem unable to be drugged by small molecules actually are. It is just that we don't find an angle to drug them.

And how can new technology be used to bridge these gaps?

There are several technologies that are used to bridge this gap. But the technology we use, a platform that we developed called ReSOLVE, tries to identify if the proteins have pockets to be drugged that are invisible to the naked eye. 

Let's think about Alzheimer disease. We want to clear the brain of amyloid protein. If you think about the amyloid protein being the size of a bowling ball, a small molecule would have the size of a ping pong ball. To disrupt this massive protein, we have to find a pocket in the protein, like a lock for a key. Everything that has a visible pocket has been drugged already. That's why we can treat cholesterol and hypertension. That's why we have contraceptive pills. The targets that truly matter today don't show an obvious pocket, but in reality, they do have pockets.

Why is that we don't see pockets? First, when we go after a protein, the protein is moving. Think about Pac-Man, where the Pac-Man is opening and closing the mouth and turning around and twisting. Proteins do the same thing, and they have several conformations, or several stages of their movement. Sometimes, the pockets are available in one of these conformations but not in the others. So, first, we must have the technology to look at all the conformations, not just one. 

Second, the protein is in water. The protein is inside the cell, and the cell is water. When the protein has a pocket, very often, water occupies the pocket, and the pocket looks invisible and flat. But if we remove this water and try to mimic the chemical properties that water has, our molecule will find its way to the pocket. 

To summarize, technology can help by making small molecules, which are the preferred modality by the public, useful again in finding their way to elusive proteins, by doing 2 things: A) by mapping every single conformation, and B) by accounting for the effects of water on identifying the pocket.

Where do you see the future headed as we continue to make advancements in drug development?

There are several challenges. Once we identify proteins of relevance for important diseases, we find that what we call a single disease is indeed multiple diseases. What we call Alzheimer disease represents several subsets of patients that have different problems that converge to the same clinical presentation, which we call Alzheimer disease. I think the first challenge in the future comes with precision medicine, identifying to which patient we should give a particular medication. 

With precision medicine, we will unfold an incredible area of evolution, but we create a new challenge, which is that if the medications we create no longer go to the masses but rather to subsets of patients that are more likely to benefit, how do we make the medication affordable? Developing medications is very, very expensive, and we are doing it in a more precise way. We need to develop technologies to compress the development of medications, to make it faster, to make it more precise. And regulatory agencies must adjust as well and get rid of unnecessary requirements that make drug development long and more expensive than it needs to be. 

Ultimately, it comes down to the point that medications will be developed based on very well-defined biology using modalities such as small molecules that patients like, for the subsets of patients that can benefit but not for all the others that wouldn't, in a way that is affordable. Right now, we don't try to achieve many of these steps, so medications end being useful only for a subset, very pricey, and often unaffordable.

Is there anything else that we missed today that you would like to add?

Another important challenge we face nowadays is the mistrust of science. As we saw in the COVID-19 pandemic, scientists carried very little weight, meaning it didn't matter what they said. Some people thought scientists were wrong and they knew better. This created an environment where people don't trust each other. 

We don't trust that scientists are doing their best to identify better ways of treating with new medications, that drug developers are doing their best to provide something meaningful to society, that medications were properly developed and aim to achieve more than profit. Medications aim to achieve a common good as well. 

When you asked me, "what are the challenges? And how do you think that we can make advancements?" I think science will make the advancements, but we will need to close the gap between public mistrust and science so we can benefit from these advancements.

Thanks for tuning in to another episode of PopHealth Perspectives. For similar content or to join our mailing list, visit populationhealthnet.com.

This transcript has been edited for clarity.