Kymera Therapeutics has announced positive results in an early-stage Phase I trial for an investigational drug designed to treat millions of patients experiencing symptoms of chronic inflammation and allergic reactions. This spectrum of targeted conditions, known as Th2 diseases, is characterized by dysregulation of T helper type 2 (Th2) cells in immune response and includes common conditions, such as asthma and atopic dermatitis (AD) or eczema.
The oral drug candidate aims to rival Sanofi and Regeneron’s blockbuster therapy, Dupilumab, which recorded $11.6 billion in global sales in 2023.
The trial tested the safety and efficacy of KT-621, a once-a-day drug which degrades STAT6, a signaling protein crucial in immune response. Results from the 118 healthy volunteer study showed that KT-621 was well tolerated with a safety profile undifferentiated from placebo.
To support proof-of-concept, KT-621 achieved over 90% STAT6 degradation in blood at all doses above 1.5 mg. Additionally, complete STAT6 degradation was achieved in both blood and skin at all doses over 50 mg.
Although the Phase I trial was completed in healthy volunteers who did not experience disease symptoms, KT-621 impacted Th2 biomarkers competitive to Dupilumab with median 37% and 63% reduction in TARC (thymus and activation-regulated chemokine) and Eotaxin-3 respectively, two signaling molecules that play an active role in recruiting immune cells.
Dupilumab, which is taken by more than one million patients, is approved for both eczema and asthma, among other conditions. The treatment is an antibody administered as an injectable biologic that targets the IL-4 receptor upstream of STAT6 to block immune signals for inflammation.
In contrast, Kymera’s targeted protein degradation (TPD) technology uses small molecules to trigger degradation of a disease-relevant protein, in this case STAT6, to achieve a competitive therapeutic effect. In biology, cells clean out misfolded or accumulated proteins via the E3 ubiquitin pathway. TPD involves the tagging of protein targets by small molecule degraders, sometimes called PROTACs (proteolysis targeting chimeras). KT-621 was previewed in a keynote presentation at SLAS 2024 by Juliet Williams, PhD, head of research at Kymera.
Nello Mainolfi, PhD, CEO of Kymera, told GEN that the goal of KT-621 is to expand treatment access to large patient populations who may not be eligible for injectable biologics use. He added that KT-621 demonstrates the first safe and successful targeting of STAT6, an attractive target that has eluded the industry for the past decade, that operates as well as its injectable counterparts.
TBD small molecules have the advantage of not being challenged by logistical considerations faced by injectable biologics, such as cold storage. Catalytic degraders also provide sustained effects over time compared to traditional small molecule inhibitors, whose effects dissipate once the drug is cleared.
Mainolfi said Kymera distinguishes itself as a company that goes after targets that have not yet been drugged with a TBD pipeline fully focused on immunology. Other candidates in Kymera’s pipeline include an IRF5 degrader program announced in May which expands into rheumatic and other autoimmune diseases, including lupus.
The KT-621 Phase Ib trial in moderate and severe AD is actively recruiting with data expected in Q4 of 2025. Additionally, two parallel Phase IIb trials in AD and asthma are planned to start in Q4 of 2025 and Q1 of 2026 respectively.
