The FDA granted orphan drug designation to darovasertib, a first-in-class oral, small molecular inhibitor of protein kinase C (PKC), for the treatment of uveal melanoma, on 2 May 2022. Primary uveal melanoma has a high risk of progressing to metastatic uveal melanoma, with a poor prognosis. The activation of the PKC and mitogen-activated protein kinase pathways play an essential role in the pathogenesis of uveal melanoma, and mutations in the G protein subunit alpha q (GNAQ), and G protein subunit alpha11 (GNA11) genes are considered early events in the development of uveal melanoma. Compared to other PKC inhibitors, such as sotrastaurin and enzastaurin, darovasertib is significantly more potent in inhibiting conventional (α, β) and novel (δ, ϵ, η, θ) PKC proteins and has a better tolerability and safety profile. Current Phase I/II clinical trials indicated that darovasertib, combined with the Mitogen-activated protein kinase/Extracellular (MEK) inhibitors, binimetinib or crizotinib, produced a synergistic effect of uveal melanoma. In this article, we summarize the development of drugs for treating uveal melanomas and discuss problems associated with current treatments. We also discuss the mechanism of action, pharmacokinetic profile, adverse effects, and clinical trial for darovasertib, and future research directions for treating uveal melanoma.

BACKGROUND: Septic cardiomyopathy (SCM) has a worse prognosis with mortality rates of up to 70%. Most existing treatment is useless and no specific drug or treatment has been found in patients with myocardial hypofunction.
METHODS: We explored the efficacy of the target drugs (Binimetinib) in SCM model in vivo based on high throughput sequencing and bioinformatics analysis. Firstly, a stable SCM mice model was constructed. Secondly, the hub genes of SCM were clarified by high throughput sequencing and bioinformatics analysis. The related pathways and biological process were revealed by Kyoto encyclopedia of genes and genomes (KEGG) and gene ontology (GO) enrichment analysis. Thirdly, the target drugs of the hub genes were investigated by network pharmacology analysis. Fourthly, the curative effects and hub genes regulatory effects of Binimetinib were demonstrated by SCM mice model. Finally, the regulatory mechanism of the target drugs on the hub genes were analyzed by molecular docking.
RESULTS: 109 CFU/ml P. aeruginosa daubed in wound could establish a stable SCM mice model. Il-6, Il-1β and Tnf were the hub genes of SCM. Immune system process and inflammatory response were the main biological process. Binimetinib was the target drug of IL-6, IL-1β and TNF-α. JUN and NFKB1 were the transcription factor (TFs) of hub genes and Binimetinib had the lowest binding energy with NFKB1.
CONCLUSIONS: A stable SCM model was established by wound P. aeruginosa infection. Tnf, Il-1β, Il-6 were the key genes of SCM. Binimetinib might be a drug for the treatment of SCM by downregulating the hub genes. Its active mechanism might be related to NFKB1.

Recently the phase 3 BEACON trial showed that the combination of encorafenib, cetuximab, and binimetinib versus cetuximab and irinotecan/FOLFIRI improved overall survival in pre-treated patients with metastatic colorectal cancer (mCRC) with BRAF V600E mutation. However, whether the benefits of these therapies justify their high costs has not been estimated in the USA. The purpose of this study was to evaluate the cost-effectiveness of BEC (binimetinib, encorafenib, and cetuximab), EC (encorafenib and cetuximab), and CI/CF (cetuximab with irinotecan or FOLFIRI) in patients with BRAF V600E-mutated mCRC after first- and second-line therapy.
A Markov model was constructed to determine the costs and effects of BEC, EC, and CI/CF on the basis of BEACON trial outcomes data. Health outcomes were measured in life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Deterministic and probabilistic sensitivity analyses characterized parameters influencing cost-effectiveness. Subgroup analyses were conducted as well.
The QALYs gained in BEC, EC, and CI/CF were 0.62, 0.54, and 0.40, respectively. BEC resulted in ICERs of $883,895.73/QALY and $1,646,846.14/QALY versus CI/CF and EC, respectively. Compared with CI/CF, the ICER was $435,449.88/QALY in EC. The most sensitive parameters in the comparison among the three arms were the utilities of progressive disease and progression-free survival. Probabilistic sensitivity analyses showed that the probability of BEC and EC being cost-effective was 0%. In subgroup analyses, the ICER remained above the willingness-to-pay threshold of $150,000 per QALY.
BEC and EC were not cost-effective regimens for patients with pre-treated mCRC with BRAF V600E mutation.