SAR444656 / Kymera Therap, Sanofi - LARVOL DELTA

Development and validation of an LC-MS/MS method for the novel PROTAC KT-474 in rat and mouse plasma: Application to dose-dependent pharmacokinetics and metabolite identification in mice. (PubMed, J Chromatogr B Analyt Technol Biomed Life Sci) - "Pharmacokinetic studies in mice demonstrated that KT-474 exhibited a nonlinear pharmacokinetic profile up to an oral dose of 10 mg/kg, with oral bioavailability ranging from 16.93% to 25.08%. Collectively, these findings provide a comprehensive characterization of the pharmacokinetic and metabolic properties of KT-474 and support its further clinical development."

Journal • PK/PD data • Preclinical • Inflammation • Targeted Protein Degradation • IRAK4

PROTAC-mediated regulation of programmed cell death: From molecular mechanisms to therapeutic breakthroughs. (PubMed, Innovation (Camb)) - "Currently, over 30 PROTAC candidates have entered clinical trials, including the estrogen receptor (ER) degrader ARV-471 for breast cancer and the IRAK4 degrader KT-474 for inflammatory diseases, both showing remarkable efficacy in overcoming drug resistance. These efforts will establish PROTACs as groundbreaking solutions for intractable diseases, with their precise control of PCD pathways opening new therapeutic avenues. The technology's ability to selectively modulate cell death mechanisms positions it as a transformative approach in precision medicine."

Journal • Review • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BCL2 • ER • GPX4 • IRAK4 • RIPK1 • RNF114 • STING

Structural basis for selective and potent degradation of IRAK4 by KT-474. (PubMed, Nat Commun) - "Moreover, the structure provides insight into the selective degradation profile of KT-474. Our results offer important insights into the mechanism of action of KT-474 and highlight the value of cryo-EM structures in the optimization of protein degraders."

Journal • Atopic Dermatitis • Dermatitis • Dermatology • Hidradenitis Suppurativa • Immunology • Inflammation • Targeted Protein Degradation • CRBN • DDB1 • IRAK4

Design, Synthesis, and Evaluation of Nucleolin-Bridged, MDM2-Recruiting IRAK4 Degraders for the Treatment of Autoimmune Diseases. (PubMed, J Med Chem) - "Here, we designed and synthesized a series of nucleolin (NCL)-bridged, MDM2-recruiting PROTAC degraders by conjugating oridonin (Ori) with Zimlovisertib (Zim). Notably, Ori-Zim-6 exhibited superior anti-inflammatory activity compared to the reference degrader KT-474. These findings establish Ori-Zim-6 as an orally available IRAK4 degrader for the treatment of autoimmune diseases."

Journal • Dermatology • Immunology • Inflammation • Psoriasis • Targeted Protein Degradation • IRAK4 • NCL

Developmental Toxicology Profile of the IRAK4 Degrader KT-474. (PubMed, Toxicol Sci) - "Structural similarities of the CRBN-binding portion of these degraders to IMiDs (e.g., thalidomide) have raised safety concerns due to potential degradation of CRBN neosubstrates implicated in teratogenicity, such as SALL4. Deep IRAK4 degradation by KT-474 in primary rat cells, rabbit PBMCs, and a range of tissues provides confidence in the appropriateness of the animal species tested. Taken together, these data clearly differentiate KT-474 from IMiDs, support that CRBN-mediated teratogenicity seen with IMiD drugs is neosubstrate-driven, and demonstrate that structure-based design can generate highly selective degraders devoid of teratogenic risk."

Journal • Targeted Protein Degradation • CRBN • IRAK4 • SALL4

ADVANTA: Phase 2 Study of SAR444656 in Adult Participants With Moderate to Severe Atopic Dermatitis (clinicaltrials.gov) - P2 | N=70 | Terminated | Sponsor: Sanofi | Trial completion date: Aug 2026 ➔ Nov 2025 | Active, not recruiting ➔ Terminated; Sponsor decision. Not related to safety concern.

Trial completion date • Trial termination • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

ZEN: A Phase 2 Study to Evaluate the Efficacy and Safety of SAR444656 Compared With Placebo in Adult Participants With Moderate to Severe Hidradenitis Suppurativa (clinicaltrials.gov) - P2 | N=70 | Terminated | Sponsor: Sanofi | Trial completion date: Jul 2026 ➔ Nov 2025 | Active, not recruiting ➔ Terminated; Sponsor decision. Not related to safety concern.

Trial completion date • Trial termination • Dermatology • Hidradenitis Suppurativa • Immunology

ZEN: A Phase 2 Study to Evaluate the Efficacy and Safety of SAR444656 Compared With Placebo in Adult Participants With Moderate to Severe Hidradenitis Suppurativa (clinicaltrials.gov) - P2 | N=70 | Active, not recruiting | Sponsor: Sanofi | N=156 ➔ 70 | Trial primary completion date: Jun 2026 ➔ Oct 2025

Enrollment change • Trial primary completion date • Dermatology • Hidradenitis Suppurativa • Immunology

ADVANTA: Phase 2 Study of SAR444656 in Adult Participants With Moderate to Severe Atopic Dermatitis (clinicaltrials.gov) - P2 | N=70 | Active, not recruiting | Sponsor: Sanofi | N=200 ➔ 70 | Trial primary completion date: Jul 2026 ➔ Oct 2025

Enrollment change • Trial primary completion date • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

Discovery and Characterization of SIM0711: a Potent and Selective IRAK4 PROTAC with Improved Efficacy and Safety (ACR Convergence 2025) - "SIM0711 was benchmarked against KT-474 (an IRAK4 PROTAC) and PF-06650833 (a selective kinase inhibitor). These findings support SIM0711 as a potential best-in-class IRAK4 PROTAC for the treatment of a range of autoimmune diseases. Its robust IRAK4 degradation, superior anti-inflammatory efficacy, and favorable pharmacological profile highlight its strong therapeutic potential. IND submission is expected by Q3 2025."

Clinical • Immunology • Inflammation • Targeted Protein Degradation • CXCL8 • IL1R1 • IL6 • IRAK4 • TLR4 • TLR7 • TLR8 • TLR9

Discovery and characterization of SIM0711, a potent and selective IRAK4 PROTAC with Enhanced Efficacy and Safety (EADV 2025) - "Its activity was compared with either the benchmark IRAK4 PROTAC (KT-474) or the benchmark IRAK4 inhibitor (PF-06650833). These findings establish SIM0711 as a best-in-class IRAK4 PROTAC with the potential to treat a wide range of autoimmune and inflammatory diseases. Its robust IRAK4 degradation, superior anti-inflammatory efficacy, and favorable drug properties support its further development, with an IND submission anticipated in H2 2025."

Clinical • Dermatitis • Immunology • Inflammation • Targeted Protein Degradation • CXCL8 • IL1R1 • IL33 • IL5 • IL6 • IRAK4

Degradation of IRAK4 for the treatment of lipopolysaccharide-induced acute lung injury in mice. (PubMed, Front Pharmacol) - "Additionally, a lipopolysaccharide-induced acute inflammatory mouse model was established, and KT-474 displayed significant therapeutic benefits in vivo compared to kinase inhibitors. Therefore, these findings highlight the therapeutic potential of IRAK4 degrader for the treatment of acute lung injury."

Journal • Preclinical • Acute Lung Injury • Inflammation • Pneumonia • Respiratory Diseases • IRAK4

ADVANTA: Phase 2 Study of SAR444656 in Adult Participants With Moderate to Severe Atopic Dermatitis (clinicaltrials.gov) - P2 | N=200 | Active, not recruiting | Sponsor: Sanofi | Recruiting ➔ Active, not recruiting

Enrollment closed • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

ZEN: A Phase 2 Study to Evaluate the Efficacy and Safety of SAR444656 Compared With Placebo in Adult Participants With Moderate to Severe Hidradenitis Suppurativa (clinicaltrials.gov) - P2 | N=156 | Active, not recruiting | Sponsor: Sanofi | Recruiting ➔ Active, not recruiting

Enrollment closed • Dermatology • Hidradenitis Suppurativa • Immunology

IRAK4 Targeting: A Breakthrough Approach to Combat Hidradenitis Suppurativa. (PubMed, Biologics) - "This paper comprehensively reviews IRAK4 and its family members' physiological functions, systematically examines the IRAK family's roles in the IL-1R/TLR pathway, with a focus on IRAK4, analyzes IRAK4's specific role in HS, strengthening the theoretical basis for using IRAK4-targeted drugs. The text also covers representative drugs of the major biologics currently used in the treatment of HS and describes the IRAK4 inhibitor Zimlovisertib and the IRAK4 degrader KT-474, along with a discussion of the current status of drugs that inhibit IRAK4 in the treatment of HS and the challenges they face."

Journal • Review • Dermatology • Hidradenitis Suppurativa • Immunology • Pain • IL1R1 • IRAK4

Kymera Therapeutics Announces Sanofi IRAK4 Collaboration Update (GlobeNewswire) - "Sanofi has informed Kymera that KT-485/SAR447971, an oral, highly potent and selective development candidate targeting IRAK4 for immuno-inflammatory diseases that Kymera has discovered and characterized through preclinical studies, has been selected to advance into clinical studies. Following extensive preclinical work supporting its robust development potential, KT-485 is being prioritized for development under the companies’ existing IRAK4 collaboration, and is expected to advance into Phase 1 testing next year. Based on the planned development of KT-485, Sanofi will not advance KT-474....In conjunction with its plans to advance KT-485, Sanofi also communicated its decision to exercise its participation election right for the IRAK4 target under the terms of the companies’ collaboration agreement. Under the agreement, Kymera achieved a $20 million milestone in the second quarter of 2025 related to preclinical activities associated with KT-485."

New P1 trial • Pipeline update • Immunology • Inflammation

DISCOVERY AND CHARACTERIZATION OF SIM0711, A POTENT AND SELECTIVE IRAK4 PROTAC WITH ENHANCED EFFICACY AND SAFETY (EULAR 2025) - "Its activity was compared with either the benchmark IRAK4 PROTAC (KT-474) or the benchmark IRAK4 inhibitor (PF-06650833). These findings establish SIM0711 as a best-in-class IRAK4 PROTAC with the potential to treat a wide range of autoimmune and inflammatory diseases. Its robust IRAK4 degradation, superior anti-inflammatory efficacy, and favorable drug properties support its further development, with an IND submission anticipated in H2 2025."

Clinical • Dermatitis • Immunology • Inflammation • Targeted Protein Degradation • CXCL8 • IL1R1 • IL33 • IL5 • IL6 • IRAK4

BGB-45035, a highly potent IRAK4 degrader with differentiated MOA, demonstrates strong and sustained anti-inflammatory effects in murine models of autoimmune diseases (IMMUNOLOGY 2025) - "We have developed BGB-45035, a highly selective and potent IRAK4 degrader to completely inhibit IRAK4 function, which demonstrated superior performance compared to KT-474 (Kymera/Sanofi). Additionally, in a therapeutic mouse model of MC903-induced atopic dermatitis, BGB-45035 achieved deeper IRAK4 degradation in both tissue and peripheral compartments, along with improved efficacy and reduced inflammatory biomarkers. These data highlight the best-in-class potential of BGB-45035 to effectively block various immune cell functions and induce long-lasting effects to treat inflammatory and autoimmune diseases.Keywords: Cells Th1/Th2 Cells; Diseases Autoimmunity; Processes Inflammation; Tissues Skin"

Preclinical • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • IL1R1 • IL33 • IRAK4

Kymera Therapeutics Announces First Quarter 2025 Financial Results and Provides a Business Update (GlobeNewswire) - "In partnership with Sanofi, two Phase 2b dose-ranging clinical trials for the treatment of HS and AD are ongoing with primary completion expected in the first half of 2026 for HS and mid-2026 for AD."

Trial status • Atopic Dermatitis • Hidradenitis Suppurativa • Immunology

BGB-45035 a selective IRAK4 CDAC demonstrated fast IRAK4 degradation and strong signaling inhibition and superior efficacy in preclinical disease models (IMMUNOLOGY 2025) - "Furthermore, BGB-45035 demonstrated better efficacy than KT-474 in IL-33-induced skin inflammatory disease model with stronger inhibition of ear IL-5 and Th2 cells in ear draining lymph node. These data enlightened the contribution of faster and deeper degradation to robust biological effects of IRAK4 degraders.Keywords: Animals Rodent; Processes Inflammation; Tissues Skin"

Preclinical • Dermatitis • Dermatology • Immunology • Inflammation • Psoriasis • CRBN • CXCL1 • IL1R1 • IL33 • IL5 • IRAK4

Discovery and characterization of SIM0711 a potent and selective IRAK4 PROTAC with enhanced efficacy and safety (IMMUNOLOGY 2025) - "In comparison to benchmark PROTAC KT-474, SIM0711 induced near-complete IRAK4 degradation in diverse primary human immune cells and stromal cell lines, demonstrating faster degradation kinetics in THP-1 cells and primary human monocytes in vitro. Furthermore, SIM0711 demonstrated improved bioavailability, favorable PK/PD characteristics, and good safety profiles across multiple species. Taken together, these data support the further development of SIM0711 as a potential BIC IRAK4 PROTAC for treating a range of inflammatory and autoimmune diseases with expected IND submission in H2 2025.Keywords: Animals Rodent; Cells Monocytes/Macrophages; Diseases Autoimmunity; Molecules Protein Kinases/Phosphatases; Processes Inflammation"

Clinical • Dermatitis • Immunology • Inflammation • Targeted Protein Degradation • CXCL8 • IL1R1 • IL33 • IL5 • IL6 • IRAK4

Pharmacokinetics and Pharmacodynamics of KT-474, a Novel Selective Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) Degrader, in Healthy Adults. (PubMed, Clin Transl Sci) - P1 | "KT-474 demonstrated robust IRAK4 degradation in blood, with mean reductions of up to 98% observed at the 50-200 mg QD doses, as well as inhibition of ex vivo induction of a broad array of cytokines and chemokines by stimulants lipopolysaccharides and R848. Analysis of the relationship between plasma KT-474 concentration and IRAK4 reduction in blood indicated that plasma concentrations of 4.1-5.3 ng/mL would yield 80% IRAK4 reductions."

Clinical • Journal • PK/PD data • Inflammation • IRAK4

Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) Degraders for Treating Inflammatory Diseases: Advances and Prospects. (PubMed, J Med Chem) - "The most advanced IRAK4-selective degrader, KT-474 (SAR444656), significantly reduced inflammatory biomarker levels in patients and demonstrated high safety and tolerability. This perspective introduces and discusses the physiological biology of IRAK4, its associated diseases, and the current development of IRAK4 degraders, thereby offering insights into future research directions."

Journal • Review • Inflammation • IRAK4

Kymera Therapeutics Outlines Key 2025 Objectives and Strategy to Advance Industry Leading Portfolio of Oral Immunology Programs (GlobeNewswire) - "Key upcoming KT-474 milestones: Collaborate with Sanofi to advance the KT-474/SAR444656 (IRAK4) Phase 2b dose-ranging clinical trials in HS and AD, with primary completion expected in the first half of 2026 for HS and mid-2026 for AD. Key upcoming pipeline disclosures: Kymera plans to announce the next immunology program, a first-in-class development candidate addressing an undrugged transcription factor, in the first half of 2025, and initiate clinical testing in early 2026."

Commercial • New molecule • Trial primary completion date • Atopic Dermatitis • Hidradenitis Suppurativa

Kymera Therapeutics Announces Third Quarter 2024 Financial Results and Provides a Business Update (GlobeNewswire) - "In October, Kymera initiated dosing in the Phase 1 healthy volunteer clinical trial evaluating single and multiple ascending doses of KT-621, a potent and selective oral degrader of STAT6. The Phase 1 trial will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of KT-621 compared to placebo. The Company expects to report Phase 1 data in the first half of 2025....Hidradenitis Suppurativa (ZEN trial): The study has been expanded from 99 to 156 patients. Previously, the trial included one active dose of KT-474 as well as placebo. The study will now include an additional dose. The estimated primary completion date for the ZEN trial is now in the first half of 2026.; Atopic Dermatitis (ADVANTA Trial): The study has been expanded from 115 to 200 patients. Previously, the trial included two active doses of KT-474 as well as placebo. The study will now include an additional dose. The estimated primary completion date for the ADVANTA trial is now in the middle of 2026."

P1 data • Trial completion date • Trial status • Atopic Dermatitis • Dermatitis • Dermatology • Hidradenitis Suppurativa • Immunology • Inflammation