Vividion Therapeutics Inc. CEO Diego Miralles told BioWorld that $82 million in new series B money will propel research to "clinical proof of concept in at least one of the three lead programs, if not more" as the company – just over a year after sealing a pact worth $101 million up front that brought Celgene Corp. aboard as a collaborator – pulled off an oversubscribed round with its partner on board.
Miralles declined to be specific about the programs but said one is "a large, multidomain adaptor protein. These are notoriously impossible to drug conventionally." Another is a transcription factor, representing an "extremely fertile" prospect. And the third is an E3 ligase, member of a large family involved in degrading proteins. Each bears "a very strong biological rationale, but they are simply inaccessible," he said, or have been so far. What's more, the three programs "are completely independent of each other, and the ones that come behind as well, so there's no intrinsic risk," he said. "In many companies, they really pound on one pathway or one target, so everything is connected. If that doesn't work, it falls like a house of cards."
San Diego-based Vividion's approach finds novel pockets on proteins and identifies small-molecule ligands to them, so that strategies such as direct inhibition, allosteric modulation and targeted degradation can be deployed to make the discoveries pay. The firm's main push has been in oncology and immunology, but the platform offers "enormous breadth and we can go after targets across any aspect of biology," Miralles said. "It's completely agnostic to the function of the protein. We can detect interaction between a small molecule and a protein regardless of what the protein is. We can detect an interaction with an enzyme as much as we can with a transcription factor." Also, the technology can screen all proteins in a cell at the same time. "We don't need to purify, isolate or express a protein," he said. "That's, I would say, one of the special sauces of Vividion. Not only do you know what small molecules interact with the target, but equally important, you know what target interacts with what molecule. Therefore, you understand the selectivity of that molecule across the whole human proteome," which lets Vividion identify what he calls "golden eggs," or targets with the most promise.
With Celgene, of Summit, N.J., Vividion is pursuing a handful of small molecules against targets for a range of oncology, inflammatory and neurodegenerative indications. Terms of the arrangement call for four years of work, with Celgene potentially extending the pact for another payment, the amount of which the companies left unspecified. The pair is advancing small molecules that function through the ubiquitin proteasome system, modulating specific protein levels for therapeutic benefit. (See BioWorld, March 8, 2018.)
Vividion's deal with Celgene, deliberately crafted as target-based, left plenty of leeway for Vividion's own research using the platform. "Outside of those predetermined targets, it's our space," Miralles said. About the possibility of more such deals and about dealmaking in general, "you have to be pragmatic," he said. "You want to keep as your own as much as possible, but what is possible is determined by how you can build an organization. I pay tremendous attention to the culture of the company, making sure that all employees are fully engaged and have ownership of the programs," a situation that "establishes limits about how much the company can grow and how rapidly," he said. The purpose of reaching proof of concept with one or more of the three lead programs is not to find a partner, he added, but to create a value inflection point and raise more money. "We want to build a company for the ages," he said. "We're doing what we say."
Opening the window
Vividion pulled down $50 million in series A cash at the start of 2017. Founded in 2014, the firm is based on work that started with scientist Ben Cravatt, chair of the Department of Chemical Physiology at The Scripps Research Institute (TSRI), whose efforts focused on getting beyond the conventional target-centric approach that typically nets a limited number of hits and leads. (See BioWorld, Feb. 2, 2017.)
Work by Cravatt and his team at TSRI, published in 2013 in Nature, demonstrated a method of widening that net by developing a way to find ligands – the binding partners – for proteins previously believed unreachable therapeutically. Using a fragment-based ligand discovery approach, researchers attached those fragments to molecules that bind covalently to the amino acid cysteine. It turned out that the human proteome contains many "ligandable" cysteines, including in proteins not shown previously to interact with small molecules. Cravatt's efforts led to more research into targets that could be engaged by ligands, and the possible mapping thereof. Chemistry from TSRI scientists Phil Baran and Jin-Quan Yu entered the mix.
Genetic findings have sent increasingly more would-be targets down the pike, Miralles noted, which brought about methods such as gene therapy, cell therapy and nucleic acid approaches. "Small molecules kind of fell behind, and seemed to have reached a plateau of things they could drug – mostly enzymes, receptors and channels," he said. Vividion aims to change that, and he uses phrases such as "opening the window" and "raising the ceiling" in small-molecule research that could enable global reach vs. biologics.
The series B round was led by Nextech Invest, with participation from new investors BVF Partners, Casdin Capital, Mubadala Ventures, Trinitas Capital, Mirae Asset Capital, Altitude Life Science Ventures and Alexandria Venture Investments. Along with Celgene, other existing investors who joined the round included Arch Venture Partners, Versant Ventures and Cardinal Partners.