zunsemetinib (ATI-450) / Aclaris 
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  • ||||||||||  zunsemetinib (ATI-450) / Aclaris
    Journal:  Discovery of a Novel p38?-MK2 Complex Inhibitor as a Potential Choice for Autoimmune Diseases. (Pubmed Central) -  Jan 12, 2025   
    Here, we carried out a series of optimizations on CDD-450, aiming to enhance inhibition of the p38?-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.
  • ||||||||||  zunsemetinib (ATI-450) / Aclaris
    Inhibition of p38? MAPK-MK2 axis alleviate inflammatory response in various inflammation-related disease models (Exhibit Hall F1; Poster Board Number: B866) -  Mar 29, 2024 - Abstract #IMMUNOLOGY2024IMMUNOLOGY_1454;    
    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.
  • ||||||||||  zunsemetinib (ATI-450) / Aclaris
    Phase classification, Enrollment change, Trial completion date, Trial termination, Trial primary completion date:  Study of ATI-450 vs Placebo in Patients With Moderate to Severe Psoriatic Arthritis (clinicaltrials.gov) -  Feb 15, 2024   
    P2,  N=47, Terminated, 
    141-A is currently under IND-enabling studies and P1 trial is planned in early 2025. 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
  • ||||||||||  zunsemetinib (ATI-450) / Aclaris
    Phase classification:  ATI-450 vs Placebo in Patients With Moderate to Severe Hidradenitis Suppurativa (HS) (clinicaltrials.gov) -  Dec 22, 2023   
    P2,  N=95, Completed, 
    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 Phase classification: P2a --> P2
  • ||||||||||  zunsemetinib (ATI-450) / Aclaris
    Loss of MAPKAPK2 Enhances cGAS-STING-IFN (Room 8) -  Aug 22, 2023 - Abstract #ASTRO2023ASTRO_1821;    
    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-IFN
  • ||||||||||  zunsemetinib (ATI-450) / Aclaris
    Trial completion date, Trial primary completion date:  Study of ATI-450 vs Placebo in Patients With Moderate to Severe Psoriatic Arthritis (clinicaltrials.gov) -  Jun 7, 2023   
    P2a,  N=70, Recruiting, 
    Recruiting --> Active, not recruiting Trial completion date: Jun 2023 --> Apr 2024 | Trial primary completion date: Jun 2023 --> Apr 2024
  • ||||||||||  zunsemetinib (ATI-450) / Aclaris, ulixertinib (BVD-523) / BioMed Valley Discoveries
    TNF-MK2 signaling drives protective autophagy following MAPK pathway inhibition in pancreatic cancer (Section 15; Poster Board #20) -  Mar 14, 2023 - Abstract #AACR2023AACR_6095;    
    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.
  • ||||||||||  zunsemetinib (ATI-450) / Aclaris
    Clinical, P2a data, Journal:  Selective Inhibition of the MK2 Pathway: Data From a Phase IIa Randomized Clinical Trial in Rheumatoid Arthritis. (Pubmed Central) -  Jan 7, 2023   
    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.
  • ||||||||||  zunsemetinib (ATI-450) / Aclaris
    Enrollment closed:  ATI-450 vs Placebo in Patients With Moderate to Severe Hidradenitis Suppurativa (HS) (clinicaltrials.gov) -  Oct 26, 2022   
    P2a,  N=70, Active, not recruiting, 
    This suggests that targeting the MK2 pathway mitigates the tachyphylaxis observed with p38 MAPK inhibitors in RA and supports further exploration. Recruiting --> Active, not recruiting
  • ||||||||||  irinotecan / Generic mfg.
    Journal:  The MK2/Hsp27 axis is a major survival mechanism for pancreatic ductal adenocarcinoma under genotoxic stress. (Pubmed Central) -  Mar 31, 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 In this study, we aimed to identify and characterize resistance mechanisms to a FIRINOX chemotherapy regimen (a combination of 5-fluorouracil, irinotecan, and oxaliplatin) because it is the most aggressive regimen currently used clinically for patients with PDAC...In an autochthonous PDAC mouse model, the MK2 inhibitor ATI-450 decreased PDAC development and progression...[Figure: see text].
  • ||||||||||  zunsemetinib (ATI-450) / Aclaris
    A Trial of MK2 Inhibitor ATI-450 in Patients with Moderate-Severe Novel Coronavirus Disease 2019 (COVID-19) (Area J, Hall F (North Building, Exhibition Level), Moscone Center) -  Feb 19, 2022 - Abstract #ATS2022ATS_3080;    
    Blood drawn at baseline and end of treatment demonstrated relative reductions in IL-6, IL-8, TNFα, and G-CSF in the ATI-450 arm compared to placebo (discussed in a separate abstract).ConclusionsOur phase 2, double-blind, randomized controlled trial demonstrated that ATI-450 is safe and well tolerated in an acutely ill patient population. Furthermore, we observe a relative- reduction (incremental to dexamethasone) in IL-6, IL-8, TNFα, and G-CSF in patients treated with ATI-450 over placebo.Table 1:
  • ||||||||||  zunsemetinib (ATI-450) / Aclaris
    Enrollment change, Trial completion date, Trial termination:  Study of ATI-450 in Patients With Cryopyrin-Associated Periodic Syndrome (CAPS) (clinicaltrials.gov) -  Apr 22, 2021   
    P2a,  N=1, Terminated, 
    These results support further study of ATI-450 in immunoinflammatory diseases in phase 2 trials. N=10 --> 1 | Trial completion date: Jun 2021 --> Feb 2021 | Recruiting --> Terminated; Due to patient enrollment challenges stemming from the COVID-19 pandemic, Aclaris has decided to focus its efforts and resources on other immuno-inflammatory diseases.
  • ||||||||||  zunsemetinib (ATI-450) / Aclaris
    Enrollment closed, Enrollment change, Trial primary completion date:  A Trial of Aclaris Therapeutics, Inc. (ATI)-450 in Patients With Moderate-severe Novel Coronavirus Disease 2019 (COVID-19) (clinicaltrials.gov) -  Apr 4, 2021   
    P2,  N=20, Active, not recruiting, 
    N=10 --> 1 | Trial completion date: Jun 2021 --> Feb 2021 | Recruiting --> Terminated; Due to patient enrollment challenges stemming from the COVID-19 pandemic, Aclaris has decided to focus its efforts and resources on other immuno-inflammatory diseases. Recruiting --> Active, not recruiting | N=36 --> 20 | Trial primary completion date: Jul 2021 --> Feb 2021
  • ||||||||||  ATI-450 / Aclaris
    Journal:  Substrate-based kinase activity inference identifies MK2 as driver of colitis. (Pubmed Central) -  Apr 19, 2020   
    Treatment of mice with active colitis with ATI450, an orally bioavailable small molecule inhibitor of the MK2 pathway, reduced inflammatory signaling in the colon and alleviated the clinical and histological features of inflammation. These studies establish MK2 as a therapeutic target in IBD and identify ATI450 as a potential therapy for the disease.
  • ||||||||||  ATI-450 / Aclaris
    Journal:  Selective inhibition of the p38α MAPK-MK2 axis inhibits inflammatory cues including inflammasome priming signals. (Pubmed Central) -  Jun 20, 2019   
    CDD-450 also accelerated TNF-α and IL-6 mRNA decay, inhibited inflammation in mice with cryopyrinopathy, and was as efficacious as global p38α inhibitors in attenuating arthritis in rats and cytokine expression by cells from patients with cryopyrinopathy and rheumatoid arthritis. These findings have clinical translation implications as CDD-450 offers the potential to avoid tachyphylaxis associated with global p38α inhibitors that may result from their inhibition of non-MK2 substrates involved in antiinflammatory and housekeeping responses.