Founder and Chief Technology Officer Nello Mainolfi told BioWorld that Kymera Therapeutics Inc. will disclose more in the months ahead about its lead compound, which sits at "the juncture between oncology and inflammation" and has been widely implicated in hematological cancers as well as other conditions. Meanwhile, the Cambridge, Mass.-based firm's $65 million series B round will push that prospect into the clinic and advance the pipeline of other candidates in cancer and immunology. So far, the Pegasus protein degradation platform has yielded preclinical data packages that support drug-like properties of Kymera's assets as well as differentiated pharmacology, Kymera said.
The company's method leverages the body's innate protein degradation and recycling machinery, the ubiquitin-proteasome system, to knock down disease-causing proteins regardless of their function. The effect is distinct from conventional small-molecule therapeutics, which are limited largely to inhibitory actions. About a year ago, six quarters after its inception, the firm raised $30 million in a series A financing. (See BioWorld, Oct. 31, 2017.)
Behind the approach is a thesis "basically saying the body is not recognizing the malfunctioning protein to be a problem because it's probably not due to its hyperregulation or misfolding, but due to a different activity," Mainolfi said. "What we can do is say to the body, 'Look, we know that this protein is not doing the job it should do for the health of the cell,' and so we direct, using a small molecule, the E3 ligase of the ubiquitin proteasome system to recognize that protein [as] bad in that moment and to be degraded. We use a well-oiled machine in a targeted way by using small molecules to inform the cell of this protein that is not working in a natural and healthy way."
The approach is "transformative," he said, because it's so specific and selective. Dysregulated and misfolded proteins are easily recognized by the ubiquitin system, but "many diseases are actually not driven by that," he said. "They're driven by misfiring, activation of the protein through external insults."
Because the technology focuses on pathways rather than targets, it can be applied to every major human organ system. Recognizing its constraints as a small company, Kymera initially focused its resources on oncology, autoimmunity and immuno-oncology. "This is a disease and protein type-agnostic technology," Mainolfi said. "Of course, if you know that there is a protein that is disease-causing, and is not well-served by small-molecule drug discovery" or other approaches – and if researchers suspect that knocking out the protein will be effective – "that's where you want to use targeted protein degradation," he said.
"We all know the huge unmet medical need" in cancer, Mainolfi said. "What we've decided to do, which I think is a little bit different than what's been done in the space, is to look beyond oncology." Taking aim at cancer "is almost an obvious first step for a new modality with huge potential," he said, "but because we're such believers in this potential, we assume this technology will work out [elsewhere], and so we've been thinking, 'What are the other diseases, the other pathologies clinically that have not been solved for by other technologies?'"
Until now, researchers have "been limited [by] technologies to really only drug about 15 percent of the known proteome," Mainolfi said, noting that with his firm's method, "we're basically only allowing something that is bound to happen but [cause it] to happen in a targeted way." Kymera "likes to work on clinical problems – problems where there is, in principle, a high level of validation but in practice, an inability to use current drug discovery technologies."
The company appreciates pathways that have been validated either with strong human genetics data or human pharmacological findings.
GSK, Pfizer interested in concept
The protein-degradation methodology "has been residing in academia for the first 15 years out of 20," Mainolfi said. "In the past five years or so, and it's mostly in the past two or three years, there has been quite a bit of activity in small companies and large pharma. Our position is that we want to be the go-to company in targeted protein degradation," whether for investors or collaborators, in academic settings or at big pharma firms, he said.
In April, Kymera entered a two-year discovery pact with London-based Glaxosmithkline plc. Under the terms, GSK and Kymera will work together on a limited number of protein degradation targets of mutual interest to discover drug candidates and will work together on finding new E3 ligases. Each company retained the right to use certain insights gained in the deal for its own programs.
Pharma demonstrated its interest in protein degradation at the start of this year when New Haven, Conn.-based Arvinas LLC's PROTAC (PROteolysis TArgeting Chimeras) platform drew a potential $830 million multiyear research collaboration and license agreement with Pfizer Inc., of New York, which is providing up-front cash along with milestone payments as development and commercialization goals are hit with candidates using the PROTAC approach. The tie-up with Pfizer covers discovery and clinical work with PROTAC candidates in multiple therapeutic areas, including cancer. Under the terms, Arvinas will drive discovery efforts, and Pfizer will be accountable for clinical development and commercialization of any products that may result. Arvinas could collect tiered royalties based on global sales. (See BioWorld, Jan. 4, 2018.)
6 Dimensions Capital, Bessemer Venture Partners and Pfizer Ventures co-led the Kymera series B with participation by MRL Ventures Fund, Sanofi Ventures, Hatteras Venture Partners and Aju IB Investment, plus Kymera's series A investors. Wei Li of 6 Dimensions Capital, Andrew Hedin of Bessemer and Elaine Jones of Pfizer Ventures will join Kymera's board.