SAR444656 / Kymera Therap, Sanofi - LARVOL DELTA

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

ADVANTA: Phase 2 Study of SAR444656 in Adult Participants With Moderate to Severe Atopic Dermatitis (clinicaltrials.gov) - P2 | N=200 | Recruiting | Sponsor: Sanofi | N=115 ➔ 200 | Trial completion date: Feb 2025 ➔ Aug 2026 | Trial primary completion date: Jan 2025 ➔ Jul 2026

Enrollment change • Trial completion date • Trial primary completion date • 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 | Recruiting | Sponsor: Sanofi | N=99 ➔ 156 | Trial completion date: Mar 2025 ➔ Jul 2026 | Trial primary completion date: Feb 2025 ➔ Jun 2026

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

Discovery of the First Clinical Protein Degrader for the Treatment of Autoimmune Indications: Orally Bioavailable and Selective IRAK4 Degrader KT-474. (PubMed, J Med Chem) - "IRAK4 inhibitors have been sought for the treatment of a host of diseases, however, recent evidence suggests a protein degradation approach might have advantages over an inhibitor. This viewpoint summarizes the discovery of KT-474─a selective and orally bioavailable interleuken receptor-associated kinase 4 proteolysis-targeting chimera in Phase 2 clinical trials for autoimmune indications."

Journal • Immunology • Targeted Protein Degradation • IRAK4

Discovery of KT-474─a Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases. (PubMed, J Med Chem) - "This molecule successfully completed phase I studies in healthy adult volunteers and patients with atopic dermatitis or hidradenitis suppurativa. Phase II clinical trials in both of these indications have been initiated."

Journal • Atopic Dermatitis • Dermatitis • Dermatology • Hidradenitis Suppurativa • Immunology • Oncology • IL1R1 • IRAK4

Interleukin 1 Receptor-Associated Kinase 4 is Overexpressed in Hidradenitis Suppurativa Skin and Correlates with Inflammatory Biomarkers. (PubMed, J Invest Dermatol) - P=N/A | "Multiple inflammatory mediators were upregulated in HS lesional skin, correlating with IRAK4 overexpression. These data confirm the significance of the IL-1R/TLR pathway in the pathogenesis of HS and provide support for ongoing clinical studies evaluating KT-474 in the treatment of HS."

Biomarker • IO biomarker • Journal • Dermatology • Hidradenitis Suppurativa • Immunology • Inflammation • Pain • IRAK4

Kymera Announces Expansion of KT-474 (SAR444656) HS and AD Phase 2 Studies Following Interim Review of Safety and Efficacy (GlobeNewswire) - "Kymera Therapeutics...announced that following a review of preliminary KT-474 safety and efficacy data by an Independent Data Review Committee, Sanofi has informed Kymera that it intends to expand the ongoing Hidradenitis Suppurativa (HS) and Atopic Dermatitis (AD) Phase 2 trials to more rapidly progress towards pivotal studies....'We look forward to sharing further information as it is available, including trial designs and updated timing for the expanded Phase 2 data readouts'."

Clinical protocol • DSMB • Atopic Dermatitis • Hidradenitis Suppurativa

Kymera Therapeutics Announces First Quarter 2024 Financial Results and Provides a Business Update (BioSpace) - "Enrollment is ongoing in the two randomized, placebo-controlled Phase 2 trials being conducted by Sanofi, evaluating KT-474 for the treatment of hidradenitis suppurativa (HS) and atopic dermatitis (AD). Topline data is expected to be reported in the first half of 2025."

Enrollment status • P2 data • Atopic Dermatitis • Hidradenitis Suppurativa • Immunology

ADVANTA: Phase 2 Study of SAR444656 in Adult Participants With Moderate to Severe Atopic Dermatitis (clinicaltrials.gov) - P2 | N=115 | Recruiting | Sponsor: Sanofi | Trial completion date: May 2026 ➔ Feb 2025 | Trial primary completion date: Apr 2026 ➔ Jan 2025

Trial completion date • Trial primary completion date • 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=99 | Recruiting | Sponsor: Sanofi | Trial completion date: Sep 2026 ➔ Mar 2025 | Trial primary completion date: Aug 2026 ➔ Feb 2025

Trial completion date • Trial primary completion date • 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=99 | Recruiting | Sponsor: Sanofi | Trial completion date: Mar 2025 ➔ Sep 2026 | Trial primary completion date: Feb 2025 ➔ Aug 2026

Trial completion date • 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=115 | Recruiting | Sponsor: Sanofi | Trial completion date: Feb 2025 ➔ May 2026 | Trial primary completion date: Jan 2025 ➔ Apr 2026

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

ADVANTA: Phase 2 Study of SAR444656 in Adult Participants With Moderate to Severe Atopic Dermatitis (clinicaltrials.gov) - P2 | N=115 | Recruiting | Sponsor: Sanofi | Not yet recruiting ➔ Recruiting

Enrollment open • 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=99 | Recruiting | Sponsor: Sanofi | Not yet recruiting ➔ Recruiting

Enrollment open • Dermatology • Hidradenitis Suppurativa • Immunology

Kymera Therapeutics Announces First Patient Dosed in Phase 2 Atopic Dermatitis Clinical Trial of KT-474 (SAR444656), a First-in-Class, Investigational IRAK4 Degrader, Generating a $15 Million Payment from Sanofi (GlobeNewswire) - "Topline Phase 2 data from both the AD and HS trials expected in the first half of 2025....Kymera Therapeutics...today announced that the first patient has been dosed in the randomized Phase 2 clinical trial (ADVANTA) evaluating KT-474 (SAR444656) in AD, generating a $15 million milestone payment under its collaboration with Sanofi....Sanofi is conducting Phase 2 KT-474 studies in both AD and HS....Study completion dates for both trials are projected in the first quarter of 2025."

P2 data • Trial completion date • Trial status • Atopic Dermatitis • Hidradenitis Suppurativa

Kymera Therapeutics Announces Publication of Phase 1 Trial Results for KT-474 (SAR444656), a First-in-Class IRAK4 Degrader, in Nature Medicine (Yahoo Finance) - P1 | N=154 | NCT04772885 | Sponsor: Kymera Therapeutics, Inc. | "Kymera Therapeutics, Inc...today announced that results from the positive Phase 1 clinical trial from its lead program, KT-474 (SAR444656), a potent, highly selective, orally bioavailable IRAK4 degrader, were published in Nature Medicine. The results showed a reduction of disease-relevant inflammatory biomarkers in the blood and skin of HS and AD patients associated with improvement in skin lesions and symptoms....The publication also highlights preclinical data on KT-474, including the first publication of the compound’s chemical structure."

P1 data • Preclinical • Atopic Dermatitis • Hidradenitis Suppurativa • Immunology

IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial. (PubMed, Nat Med) - P1 | "These results, from what, to our knowledge, is the first published clinical trial using a heterobifunctional degrader, provide initial proof of concept for KT-474 in HS and AD to be further confirmed in larger trials. ClinicalTrials.gov identifier: NCT04772885 ."

Clinical • IO biomarker • Journal • P1 data • Atopic Dermatitis • Dermatitis • Dermatology • Hidradenitis Suppurativa • Immunology • Infectious Disease • Inflammation • IRAK4

Kymera Therapeutics Announces First Patient Dosed in Phase 2 Hidradenitis Suppurativa Clinical Trial of KT-474 (SAR444656), a First-in-Class, Investigational IRAK4 Degrader, Generating $40 Million Payment from Sanofi (GlobeNewswire) - "Kymera Therapeutics...announced that the first patient has been dosed in the randomized Phase 2 clinical trial in hidradenitis suppurativa (HS) evaluating KT-474 (SAR444656), a first-in-class, investigational IRAK4 degrader. The Phase 2 study will evaluate the efficacy, safety, pharmacokinetics, and biological effects of KT-474 compared with placebo in adult patients with moderate to severe HS. Kymera’s partner Sanofi is conducting the Phase 2 study in HS, and has initiated a second randomized Phase 2 trial in AD. Under the terms of the collaboration, dosing of the first patient in the HS trial generated a milestone payment of $40 million. Dosing of the first patient in the AD trial will also generate a milestone payment to Kymera....The dosing of the first patient in the Phase 2 Atopic Dermatitis (AD) clinical trial is expected later this quarter."

Financing • Trial status • Atopic Dermatitis • Hidradenitis Suppurativa