Hidradenitis suppurativa patients have suffered enough—a new wave of targeted medicines, hopefully at some point, will enter the market. Perhaps a new disruptive therapy is on the horizon? A Cambridge, MA-based biotechnology venture is advancing the field of protein degradation, accessing the body’s innate protein recycling machinery to degrade dysregulated, disease-causing proteins. Powered by Kymera Therapeutics’ Pegasus™, a game-changing integrated degradation platform, the company recently demonstrated that oral dosing of its IRAK4 degraders completely suppressed IRAK4 protein expression in skin and immune cells and inhibited cutaneous inflammation. According to the company, the data supports the development of its degraders for chronic inflammatory and autoimmune diseases, including the company’s first named inflammation/immunology disease indication—hidradenitis suppurativa (HS).
TrialSite News, in keeping with its mission to break down the complex and simplify clinical research, provides a basic question and answer breakdown below.
What is the Pegasus Platform & its Connection to Protein Degradation?
A powerful drug discovery engine, Kymera, focuses on the body’s natural mechanism known as “proteasomal degradation” for disposing of unwanted proteins. As they note on their website, during this process, ubiquitin, a small, regulatory molecule found in almost all human cells, attaches to a protein and signals the protein transport machinery to ferry it to the proteasome for degradation and disposal.
Targeting protein degradation, which harnesses this ubiquitin-proteasome machinery to completely remove disease-causing proteins, is viewed by many as the most promising new therapeutic modality since CRISPR gene editing and RNAi therapeutics. It involves designing small molecules with two active ends: one that binds to the target protein of interest and the other to the right E3 ubiquitin ligase.
Kymera takes a systematic and rational approach to designing these molecules using the Pegasus™ platform. By continually increasing the understanding of how protein degradation works, researchers can accelerate access to novel E3 ligase biology and binders, becoming more effective in identifying druggable targets likely to benefit from therapeutic intervention and hence discover and develop potent and specific drugs in a disease agnostic manner.
Who is Kymera Therapeutics?
Founded in 2016, they are a Cambridge, MA-based venture that is trying to harness this process of protein degradation as a therapy. They employ about 50 FTEs. Their Pegasus platform is employed to get rid of disease-causing proteins.
Kymera Therapeutics is a hot venture already having raised $95 million according to Crunchbase in an A and B Series.
Elite investors have poured money into this potentially disruptive biotech play, including Lilly Ventures, Amgen Ventures, 6 Dimensions Capital, Bessemer Venture Partners, Pfizer Ventures, MRL Ventures Fund, Sanofi Ventures, Hatteras Venture Partners and Aju IB Investment.
The venture was founded by Nello Mainolfi, who got his start at Novartis Institutes for Biomedical Research, leading teams to identify multiple novel potential medicines that have entered clinical development across a series of disease areas. Prior to Novartis, Mainolfi was Entrepreneur in Residence at Atlas Venture and had previously led discovery research at Raze Therapeutics. He was trained at Imperial College London and the Scripps Research Institute in California.
Partnerships with Big Pharma?
Kymera Therapeutics has put together discovery partnerships with major big pharma such as GlaxoSmithKline. Moreover, Kymera inked a strategic collaborative deal with Vertex Pharmaceuticals to discover and develop targeted protein degradation medicines for serious diseases.
Their lead candidate addresses IRAK4, a key component of a signaling pathway implicated in the pathophysiology of multiple diseases, including inflammatory and autoimmune diseases and cancers. They note on their website that a key challenge in addressing IRAK4 centers on the challenge that researchers must target both its scaffolding and kinase functions to effectively block signaling. Conventional kinase inhibitors affect only the kinase function. Targeted protein degradation is the only way to effectively address both functions with one drug.
They report that pre-clinical studies of their novel small molecule degraders evidence complete suppression of IRAK4, reversing inflammation in human cells and disease models superior to kinase inhibitors. Also, in MYD88-driven B cell lymphomas, pre-clinical research reveals highly selective degradation of IRAK4 and tumor regression both alone and in combination with BTK inhibition. Visit their pipeline page for some informative content.
As Kymera seeks to progress its first target into HS, they will undoubtedly need to file an IND. What does their talent look like? They recently promoted their founder to CEO—a good choice as he will keep an eye on the visionary prize. They recently hired an experienced VP of Clinical Operations, Jeff Davis, who has a solid 15 years of relevant experience. Importantly, they have a pedigreed Chief Medical Officer in Jared Gollob who spent a decade at hot biotech venture Alnylam Pharmaceuticals. Their VP/Head of Discovery, Chris De Savi, an industry vet, spent 15 years at AstraZeneca. A review of other FTEs reveals a super talented, highly experienced team. They are well situated to execute, we believe.
Who are some of their Competitors focusing on Protein Degradation Strategies?
Cedilla Therapeutics, another Cambridge, MA venture secured $56 million in a Series A round as well as Watertown-based C4 Therapeutics which announced its protein degradation model with a Series A funding of $73 million. Publicly traded Arvinas, based in New Haven, CT, commenced clinical research for its experimental protein degradation therapies for prostate and breast cancers.
TrialSite News is super interested in disruptive, highly effective new therapies for Hidradenitis suppurativa (HS). Although still early days, they recently presented the early success of their degraders for chronic inflammatory and autoimmune diseases, including their first target—HS. They recently presented this research at the 9th European Hidradenitis Suppurativa Foundation Scientific Conference in Athens, Greece. The findings hopefully will make their way into an IND approval and, thereafter, clinical trials.