Targeted protein degradation: treating inflammatory diseases in a new way
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Targeted protein degradation, or the ability to harness the body’s protein recycling machinery to degrade disease-causing proteins, is emerging as one of the most exciting new therapeutic modalities with broad potential to effectively treat a range of diseases with limited or no known treatment options. The technology has shown the potential to address hard-to-treat cancers. Now, preclinical research presented by Kymera Therapeutics shows the modality may be a powerful and practical means to address inflammation, the underlying driver of many diseases.
Kymera is focusing on a number of key pathways that, to date, have not been effectively targeted with conventional therapeutics, with the potential to deliver truly breakthrough treatments. The first of these targets is IRAK4, a protein known to play a significant role in inflammation mediated by the activation of toll-like receptors (TLRs) and IL-1 receptors (IL-1Rs). While TLR and IL-1R signaling via IRAK4 is involved in immune surveillance, abnormal activation of those pathways is the underlying cause of multiple inflammatory and autoimmune conditions including hidradenitis suppurativa, atopic dermatitis, rheumatoid arthritis, and systemic lupus erythematosus. By removing IRAK4 with a protein degrader, the company expects to effectively address the underlying driver of inflammation in these diseases.
“We are seeing a clear therapeutic advantage for targeted protein degradation of IRAK4 in inflammatory diseases driven by IL-1R/TLR pathways,” said Jared Gollob, CMO, Kymera Therapeutics. “One of the challenges in effectively treating these diseases, is that you have to address not one but two key functions of IRAK4 — its scaffolding and kinase functions, both of which are required for IL-1R/TLR signaling. Inhibitors only address the kinase function. Protein degradation is the only modality that can accomplish both with one drug.” Research presented last October at the meeting of the American College of Rheumatology showed the company’s IRAK4 degrader more effectively blocked the proinflammatory signaling pathways that can lead to autoimmune diseases over conventional kinase inhibitors.
Kymera’s first disease target is a chronic inflammatory skin disease called hidradenitis suppurativa (HS), which affects nearly 1% of the U.S. population. People with HS have painful, draining nodules and abscesses typically in the folds of their skin, accompanied by signs and symptoms of systemic inflammation, including fatigue and depression. The disease is debilitating for those who have it. There are currently few treatment options available — corticosteroids, antibiotics, and surgery. The only FDA approved drug is the anti-TNF antibody Humira, which benefits 25% to 50% of patients with moderate to severe disease, but is not curative.
“A small molecule IRAK4 degrader that can be orally dosed offers a powerful and practical treatment option for HS patients, particularly in a treatment landscape where most of the drugs in development are biologics requiring injections,” said Gollob.
Later this week, Kymera will present findings from ongoing preclinical analyses which show that its oral degraders completely suppress IRAK4 protein expression in the skin and immune cells. The findings also show that daily dosing can inhibit skin inflammation caused by proteins that regulate the body’s immune response (known as cytokines) similar to those involved in HS whose production is triggered by signaling pathways regulated by IRAK4. Though research to date has been in animal models, Kymera plans to initiate a Phase 1 healthy volunteer trial this year, followed by a Phase 2 study in HS in the second half of 2021, providing a path forward to treat not only HS, but other chronic autoimmune conditions as well. The company is also developing degraders against STAT3, a notoriously elusive and undruggable transcription factor that is a key driver of inflammation and fibrosis (beyond many types of cancers) with hopes of targeting chronic diseases like systemic sclerosis, inflammatory bowel disease, and idiopathic pulmonary fibrosis.
“It is a drug hunter’s dream to work on a modality with the potential to completely transform treatment paradigms,” said Nello Mainolfi, Founder, President and CEO of Kymera Therapeutics. “Targeted protein degradation can overcome challenges associated with existing modalities like monoclonal antibodies, RNAi, and other oligo-based therapies, given its ability to not only effectively treat disease, but do so in a way that is practical and broadly accessible to patients.”