KT-474 is a first-in-class IRAK4 degrader in development for the treatment of immune-inflammatory diseases with significant patient need, such as hidradenitis suppurativa (HS), atopic dermatitis (AD), and potentially others. IRAK4 is a key protein of the myddosome complex that mediates signaling through IL-1 and toll-like receptors, which play a crucial role in initiating the immune response against invading pathogens. IRAK4 is a scaffolding kinase that acts at the interface of the innate and adaptive immune responses with a variety of functions depending on its kinase activity and scaffolding function. Eliminating IRAK4 completely through degradation impacts both the kinase and scaffolding functions, therefore having the potential to achieve a broad, well-tolerated, anti-inflammatory effect providing a novel therapeutic approach for a variety of immune-inflammatory diseases.

KT-474 (SAR444656) is partnered with Sanofi, who is leading the Phase 2 clinical development program. Kymera has the option to participate in future development and commercialization, and 50/50 profit split, in the United States. Double digit tiered royalties in ROW.

Diseases where the TLR/IL-1 pathway has been implicated in pathogenesis and are potential opportunities: Psoriasis, Generalized Pustular Psoriasis, IBD, Asthma, COPD, SSc ILD, RA, PSA, SLE, OA, PSS, MS, AMD.

STAT6 is an essential transcription factor in the IL-4/IL-13 signaling pathways and the central driver of TH2 inflammation in allergic diseases. Multiple gain of function mutations of STAT6 were identified to cause severe allergic diseases in humans. Dupilumab, an injectable monoclonal antibody that blocks IL-4/IL-13 signaling, is an approved therapy for multiple allergic diseases. STAT6 targeting is therefore supported by both human genetics and clinical pathway validation. STAT6 functions through protein-protein and protein-DNA interactions and it has been challenging to selectively and potently inhibit STAT6 with small molecule inhibitors. However, it is well suited for a targeted protein degradation approach, where a binding event is sufficient to drive degradation. In preclinical studies, KT-621, Kymera’s first-in-class oral STAT6 degrader, demonstrated full inhibition of the IL-4/IL-13 pathway in all relevant human cell contexts with picomolar potency that was superior to dupilumab, and equivalent or superior efficacy to dupilumab in multiple preclinical efficacy studies. In addition, at low oral doses, KT-621 demonstrated near full in vivo STAT6 degradation and was well-tolerated in multiple preclinical toxicity studies.

TYK2 is a member of the JAK family of kinases that binds the IL-12, IL-23 and interferon (IFN) receptors to recruit and phosphorylate STAT transcription factors. A loss of function variant is protective in autoimmune diseases and an allosteric inhibitor of TYK2, as well as biological agents targeting IL-12, IL-23 and Type I IFN, have been approved for the treatment of multiple autoimmune diseases, making TYK2 a highly validated target. TYK2 has a well-established scaffolding function that plays a key role in cytokine receptor surface expression and activation. In preclinical studies, KT-295, Kymera’s first-in-class oral TYK2 degrader, has demonstrated picomolar degradation potency and potent inhibition of the IL-23, IL-12 and Type I IFN pathways while sparing IL-10, showing its potential to recapitulate the biology of human TYK2 loss-of-function mutations. Degradation of TYK2 has the potential to overcome the challenges of small molecule inhibitors, which have limitations due to lack of selectivity, limited target engagement, and/or lack of potent activity against Type I IFN.

KT-333 is a potent, highly selective degrader of STAT3 in development for the treatment of multiple STAT3-dependent pathologies, including hematological malignancies and solid tumors. STAT3 is an undrugged transcription factor activated through a variety of different cytokine and growth factor receptors via Janus kinases (JAKs), as well as through oncogenic fusion proteins and mutations in STAT3 itself. In certain malignant cells, STAT3 activation is set into overdrive, leading to a dampened immune response, tumor progression, and metastasis. STAT3’s role as a cancer driver and tumor microenvironment modulator has been validated in a multitude of studies, making it a strong candidate to target in the treatment of cancer. The Phase 1 clinical trial of KT-333 is designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of KT-333 dosed weekly in adult patients with relapsed and/or refractory lymphomas, leukemias, and solid tumors. Clinical data from the KT-333 Phase 1 trial has shown evidence of STAT3 targeted protein degradation in humans with associated STAT3 pathway inhibition, along with early signs of antitumor activity, highlighting the potential of heterobifunctional degraders for targeting this previously undruggable transcription factor.

KT-253 targets MDM2, the crucial regulator of the most common tumor suppressor, p53. P53 remains intact (wild type) in close to 50% of cancers, meaning that it retains its ability to modulate cancer cell growth. While small molecule inhibitors (SMIs) have been developed to stabilize and upregulate p53 expression, they have been unable to show meaningful clinical benefits of P53 stabilization, with acceptable safety margins, likely due to their inability to overcome a feedback loop that increases MDM2 protein levels when P53 is upregulated. In preclinical studies, KT-253 has shown the ability to overcome the MDM2 feedback loop and rapidly induce cancer cell death with brief exposures, providing the opportunity for an improved efficacy and safety profile. The Phase 1 study of KT-253 will evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics, and clinical activity of KT-253 in patients with relapsed or refractory high grade myeloid malignancies, including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), lymphomas, and solid tumors. KT-253 has achieved clinical proof-of-mechanism in the Phase 1 trial and shown signs of anti-tumor activity in liquid and solid tumor types.