Kymera Therapeutics Inc. CEO Laurent Audoly told BioWorld that his firm's deal with Vertex Pharmaceuticals Inc. "signals to the sector how protein degradation is broadly deployable across many diseases. We're going way beyond oncology and immunology."

Cambridge, Mass.-based Kymera is collecting $70 million up front, which includes an equity investment, from Vertex as part of the four-year collaboration to develop small-molecule protein degradation agents against multiple targets. Mark Nuttall, chief business officer, said Kymera will use its Pegasus platform to develop protein degraders, "clinic-ready molecules, and then Vertex has the option to bring them in-house." Kymera could reap more than $1 billion if research, development, regulatory and commercial milestones are met for up to six programs optioned. Vertex, of Boston, will pay tiered royalties on any products that reach the market. The milestone payments "do get bigger [as development goes along] but I would say they are nicely balanced throughout," he said, adding that the terms provide "lots of flexibility for both parties if the collaboration is being productive." The duration and number of targets may be increased.

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. Six quarters after its inception, the firm raised $30 million in a series A financing, and another $65 million came via the series B round last November. (See BioWorld, Oct. 31, 2017, and Nov. 14, 2018.)

Kymera focuses on identifying the right E3 ligases and targets by learning how cells regulate and dispose of unwanted proteins, from ligase binding and tagging (ubiquitination) to degradation by the proteasome. Designed to address interleukin-1 receptor-associated kinase 4 (IRAK4), lead compound KYM-001 is slated to enter the clinic next year. IRAK4 is a key component of a signaling pathway implicated in the pathophysiology of many diseases, including cancer, autoimmune and inflammatory disorders. Kinase inhibitors have been developed to address the target, but with limited efficacy. Unlike conventional kinase inhibitors, the Kymera degrader removes both the kinase and scaffolding function of IRAK4 to block myddosome signaling and make the tumor back off. The myddosome is a complex of proteins characterized by the presence of Myd88.

Kymera also has in the works STAT3 (transcription factor), which works in the JAK/STAT pathway, at the preclinical stage. CEO Audoly noted that the firm has "a number of additional projects that are nicely cadenced so that every six to 12 months we can introduce a new drug candidate into clinical development."

Piper Jaffray analyst Edward Tenthoff, in a report related to Vertex's deal with Kymera, called protein degradation "a burgeoning field" and noted that Vertex has "actively partnered other novel technologies" such as those pursued by Crispr Therapeutics AG, of Zug, Switzerland, which has dosed the first beta-thalassemia patient with CTX-001 and expects to report data by around the end of this year. There's also a pact with Moderna Therapeutics Inc., of Cambridge, Mass., in messenger RNA research. Vertex paid Moderna $20 million in cash as part of its up-front commitment and made a $20 million investment in the form of a note convertible to equity. The investment will provide Vertex with an ownership stake in Moderna, and the deal includes development and regulatory milestone payments of up to $275 million, including $220 million in approval and reimbursement rewards, as well as tiered royalty payments on future sales.

Therapies emerging from CRISPR and RNA efforts are "biologically exceptionally potent and effective" but bring delivery challenges, said Kymera's founder and chief scientific officer (CSO), Nello Mainolfi. "The potential with protein degradation is that you can do the same – at least with RNA therapeutics, CRISPR is a little bit different – with a small molecule," he said. "You can make it into a pill and give it to a patient and it will go into each organ or tissue that it needs to go into."

Going narrow, going wide

Last month at the American Association for Cancer Research meeting in Atlanta, Kymera offered encouraging preclinical data for KYM-001. Myd88-activating mutations occur in 30% to 40% of patients with activated B-cell (ABC)-like diffuse large B-cell lymphoma (DLCBL), the company pointed out. The study assessed the antitumor activity of Kymera's approach in human ABC DLCBL cell lines in vitro and in tumor xenograft models in vivo, alone and in combination with the Bruton tyrosine kinase inhibitor Imbruvica (ibrutinib, Pharmacyclics LLC/Johnson & Johnson).

Kymera also has a two-year discovery agreement with London-based Glaxosmithkline plc, with the pair collaborating on a limited number of protein degradation targets of mutual interest to discover drug candidates. The companies aim to find novel E3 ligases, and each company bears the right to use certain insights gained for its own programs.

CSO Mainolfi said "the principles are the same" across protein-degradation efforts but technical methods and features may not be. "Many companies are built for expanding academic technology into a biotech venture, but we were built with the idea of making drugs," he said. "We were focused on how to take this modality into the clinic as soon as possible," and began with that idea in mind. "Especially in the pharma world, where there are very sophisticated and experienced drug hunters, our approach resonates," he said.

Work with Vertex has been quietly ongoing in parallel with Kymera's pipeline efforts, CEO Audoly said, and his company intends to take aim at "genetically well-defined populations [in cancer] where we can go quickly into the clinic and demonstrate proof of concept" as well as larger indications such as rheumatoid arthritis. "There will be opportunities down the road, in part driven by the continued success of our efforts, to contemplate different options on how we can have the biggest impact for patients," he said. "Whether that's us by ourselves, or us in some other configuration, we'll just have to see."

Among others at work in the protein-degradation space include New Haven, Conn.-based Arvinas Inc., the Yale University spinout that in March began dosing with ARV-110 in a phase I study in men with metastatic castrate-resistant prostate cancer. The candidate emerged from Arvinas' protein-degraders platform called PROTAC, a rough acronym for "proteolysis-targeting chimera." PROTAC therapies work by recruiting an E3 ligase to tag the target protein for ubiquitination and degradation through the proteasome.

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