- |||||||||| selonsertib (GS-4997) / Gilead
Design and optimization of potent, selective and brain penetrant Apoptosis signal-regulating kinase 1 (ASK1) inhibitors (In-Person Room (Virtual Room)) - Jan 28, 2022 - Abstract #ACSSp2022ACS_Sp_3387; Our studies, designed to probe the therapeutic value of modulating this pathway in preclinical models of neurological disease, focused on two strategies:A) Deconstruction of the solvent exposed region of known ASK1 Inhibitor Selonsertib (1) followed by macrocyclization of the resulting simplified pharmacophore to afford novel macrocyclic inhibitors (2).B) Optimization of the phenyl group of the same simplified structure with polar 5-membered heterocycles designed to place polar substituents in the solvent exposed area of the protein (3).Despite encouraging results, compound 2 suffered from a poor PK profile and compound 3 was not well tolerated upon chronic dosing. Further optimization of compound 3, to improve in vivo tolerability, resulted in the discovery of (4), a potent and selective ASK1 inhibitor with suitable PK and brain penetration for proof of pharmacology studies.
- |||||||||| selonsertib (GS-4997) / Gilead
Journal: Performance of noninvasive tests of fibrosis among Asians, Hispanic and non-Hispanic Whites in the STELLAR trials. (Pubmed Central) - Jan 26, 2022 P3 Further optimization of compound 3, to improve in vivo tolerability, resulted in the discovery of (4), a potent and selective ASK1 inhibitor with suitable PK and brain penetration for proof of pharmacology studies. In the global phase 3 STELLAR trials, the diagnostic performance of routinely available noninvasive tests for the detection of advanced fibrosis due to NASH was acceptable and similar between White and Asian patients.
- |||||||||| Review, Journal: Emerging Therapies for the Treatment of Non-Alcoholic Steatohepatitis: A Systematic Review. (Pubmed Central) - Dec 25, 2021
To our knowledge, this is the first report on illuminating the related mechanisms of increased GRP78 protein expression in AsO-induced ER stress condition through a novel IRE1α pathway. These novel agents may fill a pharmacotherapy gap in patients with NASH and possibly prevent progression to advanced liver disease.
- |||||||||| selonsertib (GS-4997) / Gilead
Preclinical, Journal: ASK1 Enhances Angiotensin II-Induced Liver Fibrosis In Vitro by Mediating Endoplasmic Reticulum Stress-Dependent Exosomes. (Pubmed Central) - Nov 4, 2021 Human hepatic LX-2 stellate cells were treated with Ang II alone or cotreated with Ang II plus an ASK1 inhibitor (GS-4997) or siRNA-targeting ASK1...The activation of LX-2 cells could be blocked by treating the exosomes with annexin. In summary, we found that ASK1 mediates Ang II-activated ERS in HSCs and the subsequent activation of HSCs, suggesting a promising strategy for treating liver fibrosis.
- |||||||||| Clinical, Review, Journal: Efficacy and safety of drugs for nonalcoholic steatohepatitis. (Pubmed Central) - Sep 19, 2021
Vitamin E has been recommended for patients with NASH without type 2 diabetes mellitus (T2DM), whereas a combination of pioglitazone and vitamin E is recommended for patients with both NASH and T2DM...Some of the drugs are at phase III clinical trials, including obeticholic acid (OCA), Elafibranor, Cenicriviroc, Selonsertib, Resmetirom, Emricasan and Aramchol...Especially, due to the interim positive effect for the improvement of liver fibrosis, OCA has been filling to FDA and is waiting for the final approval for the treatment of NASH. Therefore, it is urgent to review the efficacy and safety of drugs for NASH in current clinical trials.
- |||||||||| sirolimus / Generic mfg.
Review, Journal: Endoplasmic reticulum stress and protein degradation in chronic liver disease. (Pubmed Central) - Sep 3, 2021 In most instances, the degradation of excessive proteins protects cells with ER stress survival from apoptosis. According to the specific functions of protein degradation in chronic liver disease, choosing to promote or inhibit this process is promising as a potential method for treating chronic liver disease.
- |||||||||| selonsertib (GS-4997) / Gilead
Journal: Design, synthesis and biological evaluation of 1H-indazole derivatives as novel ASK1 inhibitors. (Pubmed Central) - Aug 25, 2021 Mechanistic research demonstrated that compound 15 suppresses phosphorylation in the ASK1-p38/JNK signaling pathway in HT-29 cells, and regulates the expression levels of apoptosis-related proteins. Altogether, these results show that compound 15 may serve as a potential candidate compound for the treatment of inflammatory bowel disease (IBD).
- |||||||||| Firsocostat (GS-0976) / Gilead, cilofexor (GS-9674) / Gilead
Journal, Combination therapy: Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis due to NASH. (Pubmed Central) - Aug 11, 2021 In patients with bridging fibrosis and cirrhosis, 48 weeks of CILO/FIR was well tolerated, led to improvements in NASH activity, and may have an anti-fibrotic effect. This combination offers potential for fibrosis regression with longer term therapy in patients with advanced fibrosis due to NASH.
- |||||||||| selonsertib (GS-4997) / Gilead
Preclinical, Journal: Selonsertib Alleviates the Progression of Rat Osteoarthritis: An in vitro and in vivo Study. (Pubmed Central) - Jul 30, 2021 Furthermore, intra-articular injection of Ser could significantly alleviate the surgery induced cartilage damage in rat OA model. In conclusion, our work provided insights into the therapeutic potential of Ser in OA, indicating that Ser might serve as a new avenue in OA treatment.
- |||||||||| selonsertib (GS-4997) / Gilead, Tavalisse (fostamatinib) / Rigel
Journal: Redundant role of ASK1-mediated p38MAPK activation in human platelet function. (Pubmed Central) - Jun 10, 2021 Furthermore, ASK1 and p38 inhibitors had no effect on PLA phosphorylation, TxA formation and platelet aggregation, demonstrating that this pathway is redundant in human platelets. Together, these results demonstrate that ASK1 contributes to TxA formation in murine, but not human platelets and highlight the importance of confirming findings from genetic murine models in humans.
- |||||||||| Review, Journal: Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH)-related liver fibrosis: mechanisms, treatment and prevention. (Pubmed Central) - May 15, 2021
While several promising drug candidates failed in phase 2 or 3 clinical trials (including elafibranor, emricasan and selonsertib), promising results with the farnesoid X receptor agonist obeticholic acid, the pan-PPAR agonist lanifibranor and the chemokine receptor CCR2/CCR5 inhibitor cenicriviroc support the expectation of an effective pharmacological therapy for liver fibrosis in the near future. Tackling NAFLD-associated fibrosis from different directions by combinatorial drug treatment and effective lifestyle changes hold the greatest prospects.
- |||||||||| selonsertib (GS-4997) / Gilead, Firsocostat (GS-0976) / Gilead
[VIRTUAL] A 3D in vitro screening-based discovery approach for selecting and prioritizing NASH drug candidates (Poster area) - Apr 9, 2021 - Abstract #EASLILC2021EASL_ILC_885; Together, these findings suggest that ASK1 inhibitors can potentially be used as a therapeutic strategy for UC. In summary, using this rapid, high-throughput-com- patible 3D NASHmodel for drug candidate efficacy testing represents a promising approach for selection and decision making of the most effective drug candidates to move further in the development.
- |||||||||| selonsertib (GS-4997) / Gilead, Firsocostat (GS-0976) / Gilead, cilofexor (GS-9674) / Gilead
Trial completion: Safety, Tolerability, and Efficacy of Selonsertib, Firsocostat, and Cilofexor in Adults With Nonalcoholic Steatohepatitis (NASH) (clinicaltrials.gov) - Jan 19, 2021 P2, N=220, Completed, Together, these data indicate a possible therapeutic target for PF that involves ASK1/p38 signaling pathway. Active, not recruiting --> Completed
- |||||||||| selonsertib (GS-4997) / Gilead
Journal: Ox-LDL Causes Endothelial Cell Injury Through ASK1/NLRP3-Mediated Inflammasome Activation via Endoplasmic Reticulum Stress. (Pubmed Central) - Jan 6, 2021 Afterwards, ASK1 inhibitor (GS-4997) or endoplasmic reticulum stress (ERS) inhibitor (4-PBA) was used to measure the performance of endothelial cells...Our results suggest that cholesterol efflux from endothelial cells is reduced by ox-LDLs, and these reductions in cholesterol efflux are accompanied by increased NLRP3 inflammasome signaling, ASK1 and higher levels of endoplasmic reticulum stress. Our results suggest this axis as potential targets for treating atherosclerosis.
- |||||||||| selonsertib (GS-4997) / Gilead, Firsocostat (GS-0976) / Gilead, cilofexor (GS-9674) / Gilead
Enrollment closed: Safety, Tolerability, and Efficacy of Selonsertib, Firsocostat, and Cilofexor in Adults With Nonalcoholic Steatohepatitis (NASH) (clinicaltrials.gov) - Oct 28, 2020 P2, N=220, Active, not recruiting, In conclusion, major advances are expected for the treatment of NASH. Recruiting --> Active, not recruiting
- |||||||||| [VIRTUAL] HUMAN IN VITRO 3D NASH MODEL FOR HIGH-THROUGHPUT DRUG EFFICACY TESTING () - Oct 11, 2020 - Abstract #AASLD2020AASLD_546;
Importantly, treatment with anti-NASH drug candidates (Elafibranor, Obeticholic acid, Selonsertib and Firsocostat) affected biochemical endpoints indicative of disease progression and the results were to a large extent in line with clinical observations. In summary, using this 3D NASH model to test novel drug candidates in pre-clinical and clinical development represents a promising approach for selection and decision making of the most effective drug candidates to move further in the development.
- |||||||||| selonsertib (GS-4997) / Gilead
Review, Journal: MAP3K kinases and kidney injury. (Pubmed Central) - Sep 21, 2020 Indeed, the ASK1 inhibitor Selonsertib has undergone clinical trials for diabetic kidney disease...Given their role as upstream regulators of intracellular signaling, MAP3K are potential therapeutic targets in kidney injury, as demonstrated for some of them. However, the role of most MAP3K in kidney disease remains unexplored.
- |||||||||| semaglutide SC once-daily (NN9536) / Novo Nordisk
Journal: Current and new pharmacotherapy options for non-alcoholic steatohepatitis. (Pubmed Central) - Jul 21, 2020 Farnesoid X receptor (FXR) agonist (obeticholic acid [OCA]) significantly ameliorated hepatic fibrosis in NASH stage 2/3 fibrosis in an interim analysis of phase 3 trial...Selonsertib (apoptosis signaling kinase 1 inhibitor), emricasan (an irreversible pan-caspase inhibitor), and simtsuzumab (a monoclonal antibody against lysyl oxidase-like 2) were discontinued because of no efficacy over placebo...Among antidiabetic agents, semaglutide, a novel GLP-1 RA, is ongoing for NASH stage 1-3 fibrosis in a phase 2 trial. Furthermore, the combination of GLP-RA/glucagon receptor agonist and GLP-RA/gastrointestinal peptide agonist are promising future options.
- |||||||||| selonsertib (GS-4997) / Gilead
Phase classification, Enrollment change, Trial completion date, Trial primary completion date, Metastases: MOSAIC: Study to Evaluate the Efficacy and Safety of Selonsertib in Participants With Moderate to Advanced Diabetic Kidney Disease (clinicaltrials.gov) - Jul 9, 2020 P2b, N=289, Active, not recruiting, Furthermore, the combination of GLP-RA/glucagon receptor agonist and GLP-RA/gastrointestinal peptide agonist are promising future options. Phase classification: P3 --> P2b | N=3300 --> 289 | Trial completion date: Dec 2024 --> Aug 2021 | Trial primary completion date: Dec 2024 --> Aug 2021
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