Kymera’s Next Generation Therapeutics: Protein Degraders. New Way and New Rules for a New Modality.

Innovation That Matters

By Rich Soll, Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx) and WuXi AppTec Content Team

Proteins are essential to proper cellular function. Protein dysfunction, arising from any number of causes, can lead to serious diseases. It is often a struggle to pursue disease-causing proteins using existing modalities such as small molecule inhibitors, therapeutic antibodies, and oligo-based therapeutics, which highlights the need for new therapeutic approaches.

Kymera Therapeutics has been pioneering a novel approach: targeted protein degradation (TPD). This exciting new modality leverages the body’s natural protein recycling system – the Ubiquitin Proteasome System – whose normal function is to degrade proteins when they are no longer needed. Kymera is seeking to harness this system to redirect the cellular process and degrade specific proteins that contribute to a large variety of diseases.

This affinity-based technology was pioneered in the early 2000s, but limitations confined it to academia. Recent advances in the understanding of protein degradation, like the concept of ligandability to E3 ligases, in particular the discovery of small molecules that bind specifically to this class of proteins, have created a surge of interest.

This game-changing development led to the founding of Kymera in 2016. Kymera’s heterobifunctional molecules are designed to catalytically recruit a protein to an E3 ligase and tag it for ubiquitination followed by subsequent degradation. The company uses their innovative Pegasus platform to develop the necessary components to efficiently identify and degrade disease-causing proteins with their proprietary E3 ligase toolbox, state of the art degradation assays, and predictive modeling capabilities.

Kymera emerged from stealth mode in 2017 with a $30M Series A launch backed by Atlas Venture—which co-founded, seeded and incubated the company—along with Lilly Ventures and Amgen Ventures. Kymera raised $65M in Series B financing in November 2018 with investments from a stellar group of big name VCs and corporate venture fund. The company has established pharma partnerships with GSK and Vertex Pharmaceuticals.

Rich Soll and the WuXi AppTec Content Team recently spoke with Mainolfi about Kymera.

Kymera’s target selection strategy is based on unmet medical needs, a high degree of target validation, clear patient stratification hypothesis and the prospect for overcoming the limitations of currently available therapies. 

“Let’s take STAT3 as an example,” said Mainolfi when describing how the company makes its targeting decisions. “The JAK-STAT pathway is one of the most well validated pathways in human biology but the key node (STAT3) hadn’t previously been drugged well. We identified small molecules that could bind to STAT3 and the E3 ligase of interest. We were able to degrade STAT3 fully in cells as well as in vivo, and we now have degraders that are able to degrade STAT3 and fully regress tumor types sensitive to this mechanism in xenograft models.”

In Mainolfi’s view this represents complete success in dissociating binding and function from binding and degradation.

“The beauty of the technology is you can go after proteins that are traditionally not inhibitable by small molecules, but you can still do it with a small molecule based technology,” Mainolfi said. “The end compound can be delivered orally or parenterally.”

The body’s UPS system uses ligases in a very specific, targeted way to ensure that only the desired proteins are degraded. When asked about how Kymera’s Pegasus platform dealt with this difficulty, Mainolfi indicated that there were three key components to the solution.

First, Kymera invested very heavily in building a comprehensive model to understand the fundamental principles of protein degradation to enable the team to predict how changes in molecules would affect various steps of this cascade.

Second was Kymera’s use of novel E3 ligases. This technology in fact allows Kymera to almost completely decouple the natural specificity of E3 ligases to substrate. This process enables them to expand their drug discovery “toolbox” well beyond what is possible with traditional methods.

Third is Kymera’s sharp focus on the properties of their molecules.

“Discovering and developing drugs has always been our priority,” Mainolfi emphasized. “We were able to develop orally active compounds for our drug programs very early on in the process. The Kymera team has vast discovery experience and collectively we developed several drugs now on the market.”

Mainolfi affirmed the effect of protein degradation is different from the traditional protein inhibition approach. He reiterated his company’s commitment to pursuing targets that provide unique or additional value beyond what current methods offer.

“One example in our pipeline is IRAK4. IRAK4 is a protein that can be inhibited in its kinase domain by small molecule kinase inhibitor,” Mainolfi said. “But we have demonstrated that removing the whole protein has a unique and superior phenotype in blocking downstream biology compared to traditional small molecules.” This is only one of the examples in Kymera’s pipeline showing degradation can redesign treatment paradigms.

Mainolfi indicated that Kymera’s rapid progress is a combination of internal effort and external partnership. He described Kymera’s partnership with GSK as a technology collaboration centered around two key areas. First, Kymera utilizes GSK’s DNA-encoded library to identify small molecule binders to targets of interest to Kymera. The second area of the collaboration is jointly identifying new E3 ligases and together finding ligands to these novel E3 ligases.

He also praised Kymera’s collaboration with Vertex; their strategic partnership deal was signed in May 2019. In the agreement the two companies have promised to work together on six targets that Vertex is interested in, with an option for Vertex to license and develop the targets should they prove viable and with Kymera receiving royalties and payments for specific milestones.

“The great thing about the Vertex deal is that it allows us to maintain ownership of our pipeline while expanding our platform impact,” Mainolfi shared. “This helps us further the mission to make Kymera a target and disease agnostic protein degradation company. And Vertex is a great partner, they’re pursuing some really interesting areas of biology and clinical investigation.”

Mainolfi also spoke highly of WuXi’s role as a supporting platform. This allowed Kymera to focus on what it does best while maintaining a small footprint.

“We’ve had a long-standing collaboration with WuXi. Our long-term partnerships with many functions of the WuXi team around chemistry, biology, preclinical safety, etc. have enabled us to make really great progress across several programs.”

Mainolfi indicated that Kymera is aiming to be a fully integrated drug discovery and development company, successfully taking programs from target ID all the way to commercialization.

“We probably cannot achieve this on our own for every program,” Mainolfi admitted. “But we will continue to build our pipeline and work with the appropriate partner when it makes sense. It is important that in 2020 we start clinical investigation of some of our more advanced programs and continue to reach clinical stages with new products each year. We will need to continuously enhance our platform and to be the partner of choice for investors, collaborators, and partners.”

“To further a paradigm shift, we also need to have better target validation and translational models that help reduce risk in the early phases of drug discovery. In addition, I would like to better understand protein folding to better predict small molecule ligandability,” Mainolfi stated. 

Casting his eyes forward into the future, Mainolfi expects that by 2030 many of Kymera’s current early stage technology platforms will be an integral part of the industry. He expects to see targeted protein degradation applied far beyond its current applications in oncology, utilized in the areas of rare disease, immunology, and neuroscience. And he strongly believes that Kymera will have a huge role to play in the future of medicine.

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