As targeted therapies get ever more precise, Deerfield unveils $50M bet on a Harvard professor's chemistry insights
Behind the seemingly simple concept of targeted cancer therapies is the drug developer’s headache that the target is always changing. Each generation of kinase inhibitors may be ostensibly hitting the same oncogene, but in addition to blocking the wildtype oncogene, they must now also address the mutations that have developed along the way, spurring resistance to current drugs.
The more those target kinases evolve, too, the more they could resemble off-target kinases you don’t want to bind. So each iteration requires more selectivity — sometimes down to differences of a few atoms.
Matthew Shair believes chemistry can evolve fast enough to provide an answer.
By utilizing structure-based drug design — by now a familiar tool in small molecule development — his biotech startup, Nuvalent, has spent the past couple of years on two compounds that target the tumor drivers ROS1 and ALK for the clinic.
Now that the $50 million in Series A cash has propelled them to the cusp of the clinic, with the first human studies planned for the second half of 2021, the Harvard professor is ready to tease the biotech world with a glimpse of his efforts.
“I see Nuvalent emerging as one of the (if not the) premier companies developing targeted cancer therapeutics,” Cameron Wheeler, a partner at Deerfield who helped start the company and now chairs its board, wrote in an email.
Nuvalent’s approach, Shair told Endpoints News, starts with going to physicians and seeking their input on what properties they want in a drug.
“What hasn’t been possible for instance in the ROS1 space is to have a molecule that works against the known mutants — the known mutations, including ones that are just recently seen in patients and even the ROS1 protein before it’s mutated, so-called wildtype protein,” he said, “and avoiding interacting with an off target called TRK.”
The next step requires a lot of crystal structures and relevant information to understand the mutations as well as the interaction between small molecule and ligand, in order to locate potential drug candidates that sit in the middle of that convoluted Venn diagram.
CEO James Porter has been leading a team of 14 scientists to refine the twin lead programs, ensuring they are precisely tailored to the problem, while applying any insights to a pipeline of other targeted drugs.
While multiple drugs have been approved for ROS1-positive non-small cell lung cancer, patients who have progressed currently have no option beyond first-generation drugs. Similarly, an emerging ALK+ patient population presents a “wide open space” for Nuvalent’s immediate focus.
“We recognize that if we are rigorous with project selection, execution of our programs, we have disciplined decision-making, we can use our skills in chemistry to create some solutions for patients,” he said, adding that Shair has been closely involved with each of the steps as the head scientific advisor.
The two have known each other since Porter became one of the first chemists at Infinity Pharmaceuticals, where Shair was a co-founder.
“Twenty years ago, every company like Ariad and Millennium and Enanta, they had their own mouse facility on site,” Shair reflected. “Because you couldn’t outsource pharmacokinetic studies, you couldn’t outsource in vivo efficacy. Now it’s all outsourceable. And everything — just about everything is outsourceable except for I think the design of the molecules, the design of your clinical trials, the design of your programs. So that’s a huge sea change which has — I like to think about it, it’s democratized drug discovery. It allows a team of 10, 20, 30 people, to put 2 compounds in the clinic. You could never do that 20 years ago.”