zunsemetinib (ATI-450) / Aclaris - LARVOL DELTA

Defining The Molecular Pathways Of MK2-Driven Cell Motility, Invasion, And Tumor Metastasis In Head And Neck Squamous Cell Carcinoma (MHNCS 2026) - "Finally, to validate the phenotypic and proteomic findings from the murine model, MK2 was targeted in metastatic human HNSCC cells (HN31, FaDu) using both siRNA-mediated knockdown and pharmacologic inhibitors currently in clinical trials (ATI450, CC-99677). Through unbiased molecular analysis and corroboration in metastatic human HNSCC lines, we identified novel mechanisms through which MK2 may drive cancer cell migration, invasion and metastasis. Further delineation of these MK2-regulated signaling cascades will expand our understanding of HNSCC locoregional/distant spread and validate MK2 and its related proteins as therapeutic targets for patients with metastatic disease."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • JPT1 • MET

Title: Pharmacological Inhibition of MK2 reduces head and neck squamous cell carcinoma (HNSCC) spheroid growth in microphysiological systems (MPS). (MHNCS 2026) - "Inhibition of MK2 activity by the inhibitor pf3604422 (10 mM) or ATI-450 (10 mM) caused spheroid growth to be reduced compared to non-treated controls... In summary, we have developed an ex vivo MPS that recapitulates our published in vivo findings and demonstrate here that MK2 inhibition can delay tumor spheroid growth and migration. We intend to use the murine MPS model to bridge our understanding between the mouse metastases data and our human models by examining a variety of cellular combinations. This is in-line with the FDA mandate to reduce the use of in-vivo models and replace with microphysiological systems, our murine and patient-derived MPS' will help to bridge a pre-clinical gap allowing us to model tumor cell migration-invasion and metastases process as well as drug screen novel anti-cancer therapeutics using an ex vivo 3D model."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

TNFR-MK2 Signaling Drives Autophagy and Resistance to KRAS/MAPK Inhibition in Pancreatic Cancer Free (AACRPanCa 2025) - "These findings reveal a novel TNFR-MK2–UPR–autophagy axis that facilitates tumor cell survival under therapeutic pressure.Therapeutically, combining the MK2 inhibitor ATI-450 with MEK, ERK, or KRAS inhibitors resulted in more effective tumor suppression in human PDAC xenograft models compared to monotherapy...Targeting MK2 in combination with existing inhibitors disrupts this protective mechanism and enhances treatment efficacy. These results provide strong rationale for the clinical evaluation of MK2 inhibitors in combination therapy regimens for PDAC patients."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BECN1 • KRAS • MAPKAPK2 • TNFA

Phase I trial of MK2 inhibitor in combination with mFOLFIRINOX for untreated metastatic pancreatic ductal adenocarcinoma. (ASCO 2025) - P1 | "Funded by Pancreatic SPORE (P50 CA272213), Aclaris Clinical Trial Registration Number: NCT06648434 Background: Zunsemetinib (also known as ATI-450) is an investigational small molecule inhibitor targeting MAPK-Activated Protein Kinase (MAPKAPK2, or MK2)...Pre- and post-treatment serum samples will also be collected for the analysis of inflammatory cytokines. Clinical Trial Registration: NCT06648434"

Combination therapy • Metastases • P1 data • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • BECN1 • MAPKAPK2

MK2 Inhibitor in Combination With mFOLFIRINOX for Untreated Metastatic Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P1 | N=51 | Recruiting | Sponsor: Washington University School of Medicine | Not yet recruiting ➔ Recruiting

Enrollment open • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CA 19-9

Zunsemetinib in Combination With Capecitabine in Patients With Hormone Receptor-Positive and HER2-Negative Metastatic Breast Cancer With Bone Metastasis (clinicaltrials.gov) - P1/2 | N=152 | Recruiting | Sponsor: Washington University School of Medicine | Not yet recruiting ➔ Recruiting

Enrollment open • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

MK2 Inhibitor in Combination With mFOLFIRINOX for Untreated Metastatic Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P1 | N=51 | Not yet recruiting | Sponsor: Washington University School of Medicine | Trial completion date: Dec 2029 ➔ Mar 2030 | Initiation date: Dec 2024 ➔ Mar 2025

Trial completion date • Trial initiation date • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Discovery of a Novel p38α-MK2 Complex Inhibitor as a Potential Choice for Autoimmune Diseases. (PubMed, J Med Chem) - "Here, we carried out a series of optimizations on CDD-450, aiming to enhance inhibition of the p38α-MK2 complex and improve pharmacokinetic properties...Evaluation in the Lewis rat adjuvant-induced arthritis model showed that compound 36 had a robust inflammation inhibitory effect and joint repair ability. Currently, compound 36 is being considered for preclinical development as a potential treatment for inflammatory diseases."

Journal • Immunology • Oncology • Rheumatology • IL6

MK2 Inhibitor in Combination With mFOLFIRINOX for Untreated Metastatic Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P1 | N=51 | Not yet recruiting | Sponsor: Washington University School of Medicine

Combination therapy • Metastases • New P1 trial • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Inhibition of p38α MAPK-MK2 axis alleviate inflammatory response in various inflammation-related disease models (IMMUNOLOGY 2024) - "141-A potently reduced various cytokine production (TNFα, IL-1β, IL-6, IL-8 and IL-17) in human peripheral blood mononuclear cells (PBMC) and displayed excellent efficacy in adjuvant-induced arthritis (AIA), psoriasis and MSU-induced air pouch rat models with 1/6 of the systematic exposure of CDD450. The compound exhibits favorable physicochemical and pharmacokinetic properties, along with an excellent preclinical toxicity profile, which may enhance therapeutic efficacy without causing side effects. 141-A is currently under IND-enabling studies and P1 trial is planned in early 2025."

Dermatology • Immunology • Inflammation • Psoriasis • Rheumatology • ATF2 • CXCL8 • IL17A • IL1B • IL6 • TNFA

Zunsemetinib in Combination With Capecitabine in Patients With Hormone Receptor-Positive and HER2-Negative Metastatic Breast Cancer With Bone Metastasis (clinicaltrials.gov) - P1/2 | N=138 | Not yet recruiting | Sponsor: Washington University School of Medicine

Combination therapy • New P1/2 trial • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

Study of ATI-450 vs Placebo in Patients With Moderate to Severe Psoriatic Arthritis (clinicaltrials.gov) - P2 | N=47 | Terminated | Sponsor: Aclaris Therapeutics, Inc. | Phase classification: P2a ➔ P2 | N=70 ➔ 47 | Trial completion date: Apr 2024 ➔ Dec 2023 | Recruiting ➔ Terminated | Trial primary completion date: Apr 2024 ➔ Dec 2023; Sponsor decision

Enrollment change • Phase classification • Trial completion date • Trial primary completion date • Trial termination • Immunology • Inflammatory Arthritis • Psoriatic Arthritis • Rheumatology • Seronegative Spondyloarthropathies

ATI-450 vs Placebo in Patients With Moderate to Severe Hidradenitis Suppurativa (HS) (clinicaltrials.gov) - P2 | N=95 | Completed | Sponsor: Aclaris Therapeutics, Inc. | Phase classification: P2a ➔ P2

Phase classification • Dermatology • Hidradenitis Suppurativa • Immunology

Aclaris Therapeutics Reports Third Quarter 2023 Financial Results and Provides a Corporate Update (GlobeNewswire) - "Psoriatic Arthritis (ATI-450-PsA-201): This Phase 2a placebo-controlled trial to investigate the efficacy, safety, tolerability, PK and PD of zunsemetinib (50 mg twice daily) in patients with moderate to severe psoriatic arthritis (PsA) is ongoing. Aclaris continues to expect topline data in the first half of 2024."

P2a data • Trial status • Immunology • Psoriatic Arthritis

Aclaris Therapeutics Announces Top-line Results from 12-Week Phase 2b Trial of Oral Zunsemetinib (ATI-450) for Moderate to Severe Rheumatoid Arthritis and Provides Corporate Update (GlobeNewswire) - P2b | N=251 | NCT05279417 | Sponsor: Aclaris Therapeutics, Inc. | "Aclaris Therapeutics, Inc...today announced top-line results from a Phase 2b study of zunsemetinib (ATI-450), an investigational oral MK2 inhibitor, in subjects with moderate to severe rheumatoid arthritis....In the trial, patients administered either the 20mg or 50mg dose did not meet the primary endpoint of ACR20 response or any of the secondary efficacy endpoints at 12 weeks, including ACR50 response, ACR70 response, and DAS28-CRP. There was no notable differentiation between zunsemetinib and placebo across any measures of efficacy at week 12....Based on the overall program results, Aclaris will discontinue further development of the ATI-450 program, including halting enrollment of Aclaris’ ongoing Phase 2a trial of zunsemetinib in psoriatic arthritis."

Discontinued • P2b data • Immunology • Psoriatic Arthritis • Rheumatoid Arthritis

ATI-450 Plus MTX Versus Placebo Plus MTX in Patients With Moderate to Severe Active RA (clinicaltrials.gov) - P2 | N=251 | Completed | Sponsor: Aclaris Therapeutics, Inc. | Active, not recruiting ➔ Completed

Trial completion • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CRP

Investigating the Role of MK2 in Head and Neck Squamous Cell Carcinoma Growth, Metastasis and STING Pathway Activation. (PubMed, Int J Radiat Oncol Biol Phys) - "HNSCC tumor MK2 inhibition enhances RT-mediated micronuclei formation and subsequent cGAS-STING-IFNβ1 levels. Loss of HNSCC MK2 leads to increased CD4-CD8 T-cell infiltration into the tumor and this effect is enhanced following RT. Targeting tumor MK2 may facilitate improved tumor control."

Journal • Head and Neck Cancer • Infectious Disease • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4 • CD8 • IFNB1 • MAPKAPK2 • STING

Aclaris Therapeutics Completes Enrollment in Phase 2b Study of ATI-1777 for Mild to Severe Atopic Dermatitis (ATI-1777-AD-202) (GlobeNewswire) - "Aclaris Therapeutics, Inc...today announced the completion of enrollment into ATI-1777-AD-202, its Phase 2b trial of its investigational topical 'soft' Janus kinase (JAK) 1/3 inhibitor, ATI-1777, in patients with mild to severe atopic dermatitis. Aclaris anticipates releasing top-line efficacy, safety and other preliminary data from this trial around the end of this year....'With this achievement, we are positioned for a very exciting year end for our two lead assets, first with the data read-out of our Phase 2b trial of zunsemetinib (ATI-450) in rheumatoid arthritis expected in November, followed by the top-line results of the ATI-1777 trial expected around year end.'"

Enrollment closed • P2b data • Atopic Dermatitis • Immunology • Rheumatoid Arthritis

Loss of MAPKAPK2 Enhances cGAS-STING-IFNß1 Pathway Activation in Head and Neck Squamous Cell Carcinoma (ASTRO 2023) - "Selected drug studies using the MK2 inhibitor, ATI-450, were performed with RT... HNSCC tumor MK2 inhibition enhances RT-mediated micronuclei formation and subsequent cGAS-STING-IFNß1 levels. Loss of HNSCC MK2 leads to increased CD4-CD8 T-cell infiltration into the tumor and this effect is enhanced following RT. Targeting tumor MK2 may facilitate improved tumor control"

Head and Neck Cancer • Infectious Disease • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4 • CD8 • MAPKAPK2 • STING

ATI-450 Plus MTX Versus Placebo Plus MTX in Patients With Moderate to Severe Active RA (clinicaltrials.gov) - P2 | N=251 | Active, not recruiting | Sponsor: Aclaris Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CRP

Aclaris Therapeutics Completes Enrollment in Phase 2b Study of Oral Zunsemetinib (ATI-450) for Moderate to Severe Rheumatoid Arthritis (ATI-450-RA-202) (GlobeNewswire) - "Aclaris Therapeutics, Inc...announced the completion of enrollment into ATI-450-RA-202, its Phase 2b trial of oral zunsemetinib in patients with moderate to severe rheumatoid arthritis (RA). Aclaris expects to announce top-line efficacy, safety and other preliminary data from this trial in the fourth quarter of this year."

Enrollment closed • Immunology • Inflammation • Rheumatoid Arthritis • Rheumatology

Study of ATI-450 vs Placebo in Patients With Moderate to Severe Psoriatic Arthritis (clinicaltrials.gov) - P2a | N=70 | Recruiting | Sponsor: Aclaris Therapeutics, Inc. | Trial completion date: Jun 2023 ➔ Apr 2024 | Trial primary completion date: Jun 2023 ➔ Apr 2024

Trial completion date • Trial primary completion date • Immunology • Inflammatory Arthritis • Psoriatic Arthritis • Rheumatology • Seronegative Spondyloarthropathies • CRP

TNF-MK2 signaling drives protective autophagy following MAPK pathway inhibition in pancreatic cancer (AACR 2023) - "The combination of MK2 inhibitor ATI-450 and ERK inhibitor ulixertinib was more effective in curbing the growth of PDAC patient-derived xenograft in vivo and prolonged the survival of autochthonous PDAC mice (KPC model). Overall, our study provided novel insights on the mechanisms that drive protective autophagy following MAPK pathway inhibition and a rationale and feasible therapeutic combination that can be tested in clinical trials for PDAC patients."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BECN1 • KRAS • TNFRSF1A

ATI-450 Plus MTX Versus Placebo Plus MTX in Patients With Moderate to Severe Active RA (clinicaltrials.gov) - P2 | N=240 | Recruiting | Sponsor: Aclaris Therapeutics, Inc. | Trial completion date: May 2023 ➔ Sep 2023 | Trial primary completion date: Apr 2023 ➔ Aug 2023

Trial completion date • Trial primary completion date • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CRP

ATI-450 vs Placebo in Patients With Moderate to Severe Hidradenitis Suppurativa (HS) (clinicaltrials.gov) - P2a | N=95 | Completed | Sponsor: Aclaris Therapeutics, Inc. | Active, not recruiting ➔ Completed

Trial completion • Dermatology • Hidradenitis Suppurativa