Broadening the Scope of Small Molecules: Ventus Therapeutics

Marcelo Bigal, M.D, Ph.D, is the President and CEO of Ventus Therapeutics. Prior to joining Ventus, he held leadership roles at Teva in specialty medicines; at Labrys, where he led the team that developed fremanezumab; and at Merck. Before joining the industry, Bigal was a faculty member at the Albert Einstein College of Medicine, Department of Neurology, as well as the Director of Research at New England Center for Headache. He holds a Medical Doctorate degree from the College of Medicine and a Ph.D. in neurosciences from the University of São Paulo, Brazil.

In this interview, Dr. Bigal talks about how technological innovation in the field of small molecule drug development has created new opportunities for pursuing undruggable targets, building on the well-established strengths of small molecule medicines.

Pharm Exec: Ventus Therapeutics is focused on addressing biologically validated drug targets that have been elusive to small molecules. What drew you to this mission?

Dr. Marcelo Bigal: Over the course of my career, I found it disheartening that so many compelling and validated drug targets were out of reach and couldn’t be pursued. It was indisputable that these targets play a central role in disease and could bring hope and relief to patients, and yet there simply wasn’t an obvious way to intervene therapeutically because of the lack of a known active site or druggable binding pocket. Because these targets were not addressable with small molecules, drug developers moved on to other drug modalities which lead to an unfavorable trade-off of riskier, more complex new modalities to access de-risked, validated targets. At Ventus, we decided not to trade risks and instead to expand the set of targets amenable to small molecule drug discovery by applying a new generation of advanced technologies. We believe, and our R&D work has shown, that advances in structural biology, molecular modeling and computational chemistry can identify novel ways to pursue small molecule drug discovery against historically elusive targets.

Is small molecule drug innovation experiencing a renaissance, in spite of so much other innovation in biotechnology?

Small molecules continue to be a mainstay in the discovery and development of novel medicines, even as the drug industry has expanded into new promising modalities such as cell therapies, gene therapies, RNAi, CRISPR, and others. In many cases, the pursuit of these modalities has been driven not only out of opportunity, but also out of necessity due to apparent roadblocks preventing small molecule discovery for important drug targets. These newer drug modalities have driven innovation, are carving out their places in the biopharmaceutical landscape and are navigating the expected hurdles of biological limitations and manufacturing challenges. However, these new modalities are often not suitable for treatment of prevalent, non-genetic diseases, and have not yet passed the test of time.

A renaissance is happening in small molecule drug discovery because new technologies and computational techniques are enabling us to explore protein structures, their natural movement, and how water dynamics influence protein dynamics, protein conformations, and druggable pockets. This new information can uncover previously unknown putative small molecule binding sites or novel binding site conformations that point to completely new possibilities for small molecule therapeutics discovery. We can now pursue drug targets that were formerly intractable or very challenging, since we can now identify binding sites that were previously invisible.

We focus on highly validated targets where we can identify druggable pockets that can be pursued with the predictability of small molecules. This opens new space for small molecules to play a larger role in addressing challenging drug targets.

What gives you the confidence and capabilities to take on targets that have historically been considered undruggable?

At Ventus we have created unique opportunities to develop small molecules against historically challenging targets by building two distinct platforms: structural immunology and ReSOLVE™.

Our structural immunology platform consists of proprietary protein engineering and structural biology capabilities that have enabled us to target proteins of the innate immune system. These proteins are inactive as intra-cellular monomers, until activated by molecular patterns suggestive of cellular danger. When activated, these proteins form large oligomeric structures which are extremely challenging to work with in drug discovery. Due to these challenges, past efforts have relied on indirect phenotypic approaches to target these proteins, which is akin to working “in the dark” with long, arduous processes that lead to very limited chemical matter diversity. With our structural immunology capabilities, we now have the ability to elucidate molecular structures of the target protein which enables us to rapidly identify highly potent and functional chemical matter, with high levels of structural diversity. With our structural immunology insights and the discoveries of our scientific founders, we are on the path, in a very short period of time, to build a pipeline of best-in-class compounds for targets of the innate immune system.

Our second approach for reaching challenging drug targets is the ReSOLVE platform, a highly advanced computational capability for small molecule drug discovery. ReSOLVE provides insights into protein structures by combining three powerful and unique abilities: to model protein molecular dynamics, to define all the real conformations that the protein can acquire, and to model the precise dynamic solvation structure at the surface of the protein. With these capabilities, we not only identify novel pockets and conformations, but we can also rapidly screen for compounds that will bind to the various protein conformations in the absence of pre-existing chemical matter. In addition, the ability to model the solvation structure gives us unique insights into the energy drivers of small molecule binding and greatly enhances the speed at which small molecules can be optimized compared to other approaches. The ReSOLVE platform can be applied to targets from any therapeutic area or protein class, enabling Ventus to expand our drug discovery to a broad range of challenging proteins in innate immunity and beyond, including those with roles in inflammatory diseases, oncology and neurology.

How does technology innovation bridge the gap between small molecule medicines and seemingly undruggable targets?

Classic druggable targets, such as enzymes and receptors, have a pocket in their protein structure where the potential intervention point for a small molecule is relatively obvious. In many of these cases, traditional high throughput screening approaches have been able to identify small molecules that bind to these pockets with high affinity and impact protein function. Today, however, most of these straightforward target opportunities have been somewhat depleted for highly validated and sought-after proteins.

The ReSOLVE platform applies advanced computational techniques to uncover binding pockets that are not visible to current technologies, opening new territory for small molecule drug discovery. At its core, ReSOLVE allows us to simultaneously understand protein and solvation dynamics of target proteins, see the spectrum of potential druggable pockets and understand the likelihood they can be bound by a small molecule with a high affinity interaction. The ability to understand how a protein exists in solution is truly breakthrough technology that creates new possibilities for finding binding pockets in challenging targets and rapidly enables virtual screening for small molecules that will bind specifically to the newly identified pockets.

Bridging the gap to bring small molecules to historically elusive targets has benefited from applying advanced computational technologies from other industries. Notably, one of the key advancements in computer chip technology that has enabled the ReSOLVE platform capability is utilization of graphics processing units (GPUs). Twenty years ago, even if a drug developer could conceive of this approach, it was impossible to pursue with the technology of the time; the computing power just didn’t exist. By using GPUs, ReSOLVE represents a break from conventional dogma and brings unprecedented, parallel computing power that derives from the gaming industry. This is in contrast to the central processing unit (CPU) in a computer which can do a wide range of tasks quickly but cannot work quickly in parallel. The parallel processing power of a GPU enables tasks such as machine learning and has become indispensable for the analyses enabled by ReSOLVE. Now, we are steering away from the drug industry’s past perception that important targets were ‘undruggable,’ and blazing a trail towards a renaissance era of small molecule drug discovery.

With so much opportunity, how do you prioritize your drug discovery efforts and create a compelling value proposition across all stakeholders, from investors to physicians and patients?

We are focused on closing the gap between highly validated targets and small molecules, reinforcing my previous assertion that we are on the verge of a small molecule renaissance. Our two platforms at Ventus are examples of ‘product engines’ that rapidly enable the development of novel small molecules against undruggable targets, all with the goal of treating challenging diseases for many patients.

Building value at Ventus started at launch in May 2020, with unique structural biology capabilities to pursue small molecules for innate immune targets. With this initial innate immune focus, Ventus raised a $60 million Series A financing. The company’s R&D efforts grew in multiple directions: first, by advancing three pipeline programs in innate immunity and, second, by developing additional platform capabilities in ReSOLVE which, in turn, enabled two additional pipeline targets, relevant to neurology and immunology.

Based on this broad complement of platform and pipeline assets, Ventus secured a $100 million Series B financing from crossover equity and venture investors in April 2021, less than 12 months after the company’s public launch in 2020. This expedited and upsized financing is a springboard for our future progress. Ventus has rapidly created a pipeline of drug programs by identifying small molecule pockets in important, validated targets, creating opportunities for both partnerships and internal advancement of new medicines. Ultimately, the end goal and value creation is measured by developing high-value medicines.