zunsemetinib (ATI-450) / Aclaris - LARVOL DELTA

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

Study of ATI-450 Plus Methotrexate (MTX) vs MTX Alone in Patients With Moderate to Severe RA (clinicaltrials.gov) - P2a | N=25 | Completed | Sponsor: Aclaris Therapeutics, Inc. | N=19 ➔ 25

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

Selective Inhibition of the MK2 Pathway: Data From a Phase IIa Randomized Clinical Trial in Rheumatoid Arthritis. (PubMed, ACR Open Rheumatol) - "This is the first clinical study demonstrating that selective mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2) pathway blockade leads to a sustained antiinflammatory effect. This suggests that targeting the MK2 pathway mitigates the tachyphylaxis observed with p38 MAPK inhibitors in RA and supports further exploration."

Clinical • Journal • P2a data • Immunology • Inflammatory Arthritis • Oncology • Rheumatoid Arthritis • Rheumatology • CRP • IL6 • TNFA

A Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Zunsemetinib, an Investigational Oral MK2 Inhibitor, at 80 Mg and 120 Mg Twice Daily Dose Levels in Healthy Subjects (ACR Convergence 2022) - "Multiple oral doses of zunsemetinib (up to 120 mg BID) administered to healthy subjects in this study were generally safe and well tolerated.The exposure was dose proportional over the full dose range tested (10 – 120 mg) following 7 days of BID dosing"

Clinical • PK/PD data • Inflammation • Pain • IL17A • IL1B

ATI-450 vs Placebo in Patients With Moderate to Severe Hidradenitis Suppurativa (HS) (clinicaltrials.gov) - P2a | N=70 | Active, not recruiting | Sponsor: Aclaris Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Dermatology • Hidradenitis Suppurativa

A Phase 2a, Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Zunsemetinib vs Placebo in Patients with Moderate-to-Severe Active Psoriatic Arthritis (clinicaltrialsregister.eu) - P2 | N=70 | Ongoing | Sponsor: Aclaris Therapeutics, Inc.

New P2 trial • Immunology • Inflammatory Arthritis • Musculoskeletal Diseases • Psoriatic Arthritis • Rheumatology • Seronegative Spondyloarthropathies