Tapinarof cream for the topical treatment of plaque psoriasis in adults.

INTRODUCTION: Plaque psoriasis, a chronic immune-mediated skin disorder, is characterized by well-demarcated erythematous plaques with silvery scales. This condition stems from complex interactions between genetic predisposition, immune dysregulation, and environmental triggers. Tapinarof downregulates the cytokine IL-17, diminishes the inflammatory infiltrate, and provides antioxidant properties while enhancing the expression of skin barrier proteins. AREAS COVERED: This review begins by assessing tapinarof's mechanism in treating plaque psoriasis. Subsequently, it examines the effectiveness and safety of tapinarof 1% cream in adult patients. EXPERT OPINION: Tapinarof 1% cream, which works by activating the aryl hydrocarbon receptor, is an FDA-approved treatment for adult plaque psoriasis. This therapy introduces a novel, nonsteroidal method for addressing inflammation and skin barrier issues, potentially serving as an alternative to conventional treatments. The once-daily, convenient cream formulation and favorable safety profile may enhance patient adherence, which is often poor with topical treatments. Tapinarof also maintains disease clearance for a mean of 4 months after treatment cessation.

Benvitimod inhibits MCM6-meditated proliferation of keratinocytes by regulating the JAK/STAT3 pathway.

BACKGROUND: Benvitimod (Tapinarof), as a small-molecule topical therapeutical aryl hydrocarbon receptor (AHR)-modulating agent, is in clinical development for treating psoriasis and atopic dermatitis. Benvitimod reduces proinflammatory cytokines in psoriasis by specifically binding and activation of AHR. However, whether benvitimod can inhibit keratinocyte proliferation remains unclear. Minichromosome maintenance protein 6 (MCM6) is a key element of the prereplication complex (pre-RC) assembly which is one of the essential steps in the initiation of DNA replication for cell proliferation. OBJECTIVES: This study aimed to determine whether benvitimod could reduce the excessive proliferation of psoriatic keratinocytes by inhibiting MCM6. METHODS: We examined the inhibitory effect of benvitimod on MCM6-mediated proliferation of keratinocytes by HaCaT cells in vitro and an IMQ-induced psoriatic model of mice in vivo. RESULTS: Epidermal MCM6 expression was enhanced in the skin lesions of psoriatic patients. The experiments further revealed that MCM6 was required for the proliferation of keratinocytes and governed by the IL-22/STAT3 pathway. In addition, the antiproliferation effect of benvitimod is achieved by the inhibition of p-JAK1 and p-JAK2, which further restrained the activation of STAT3 in keratinocytes. Lastly, benvitimod could repressed imiquimod-induced skin lesions and the expression of epidermal MCM6 and p-STAT3 in mice. Moreover, knockdown of AHR in keratinocytes enhanced the activation of JAK1 and JAK2. CONCLUSION: The findings reveal that benvitimod could decrease MCM6-mediated proliferation of keratinocytes by affecting the JAK/STAT3 pathway, thereby serving as a new treatment modality for psoriasis.

Benvitimod for the treatment of psoriasis: A systematic review and meta-analysis of randomized controlled trials.

Benvitimod is a topical drug that has recently been approved for mild to moderate psoriasis and atopic dermatitis. The drug has just completed phase 3 trials for psoriasis, which calls for a systematic update of current evidence on the efficacy and safety of this drug. We searched MEDLINE (PubMed), EMBASE, Science Direct, International Clinical Trials Registry Platform (ICTRP), Cochrane Central Register of Controlled Trials, and Google Scholar for all available randomized controlled trials concerning the topic. We included six randomized controlled trials evaluating the efficacy of benvitimod 1.0% with a total of 1925 patients. Our meta-analysis demonstrated that more patients in the benvitimod group achieved physician global assessment score of 0 or 1 (RR 6.53, 95% CI 4.39-9.71), psoriasis area and severity index (PASI) 75 (RR 4.34, 95% CI 2.96-6.36), PASI 90 (RR 8.83, 95% CI 5.22-14.95) and body surface area reduction (MD -3.85, 95% CI -4.83, -2.88) than placebo at week 12. Patient-reported outcomes were also analyzed, yielding a significant benefit in the benvitimod group for peak pruritus numerical rating scale (PP-NRS) score (MD -1.20, 95% CI -1.98, -0.42), ≥4-point decrease in PP-NRS score (RR 1.58, 95% CI, 1.24-2.03) and dermatology life quality index score (MD -2.54, 95% CI -4.00, -1.07). There was a significantly higher incidence of adverse events in the benvitimod group compared to placebo (RR 1.98, 95% CI 1.73-2.27), while the risk was found to be non-significant for serious adverse events. Benvitimod is an effective treatment of psoriasis as compared to a placebo. However, more large-scale, high-quality trials are needed to comment on the safety of this drug.

Activation of aryl hydrocarbon receptor ameliorates rosacea-like eruptions in mice and suppresses the TLR signaling pathway in LL-37-induced HaCaT cells.

BACKGROUND: Toll-like receptor (TLR) 2, along with some chemokines, were found to be overexpressed in rosacea patients. Aryl hydrocarbon Receptor (AhR) activation inhibited the inflammatory responses triggered by TLR activation. The current study was conducted to evaluate the underlying mechanisms of AhR activation in rosacea models. MATERIALS AND METHODS: Seven-week-old female BALB/c mice received twice daily intradermal injections of LL-37 for 2 consecutive days. Thirty minutes after the second LL-37 injection, 1% or 0.5% AhR agonist benvitimod was administrated topically once per day for 3 consecutive days. HaCaT cells were treated with different concentrations of LL-37 and benvitimod, and were further infected with lentivirus to over-express TLR2. Expressions of TLR2, CCL5, CXCL9, CXCL10 and CXCL11 were evaluated using qRT-PCR, Western Blot or ELISA. RESULTS: AhR activation ameliorated LL-37-induced rosacea-like eruptions in mice by reductions in redness scores, redness areas and dermal inflammatory cell infiltrates. Elevated expressions of TLR2 and chemokines (CCL5, CXCL9, CXCL10 and CXCL11) following LL-37 treatment were decreased by AhR activation. In HaCaT cells receiving LL-37, TLR2 and the four chemokines were up-regulated, and levels of these chemokines were further enhanced after over-expressing TLR2. At 8 h after an administration of 10 µM benvitimod, gene expressions of TLR2 and the four chemokines in LL-37 treated HaCat cells were decreased, while their protein expressions were decreased for 24 h. CONCLUSION: AhR activation is beneficial in treating rosacea in a LL-37-induced rosacea mouse model and involves a suppression of the TLR signaling pathway in an HaCaT cell model of rosacea.

Characterization and determination of benvitimod, an unknown risk substance in cosmetics, using nuclear magnetic resonance spectroscopy and HPLC-MS/MS.

Ultrahigh-performance liquid chromatography-tandem high-resolution mass spectrometry, combined with preparative chromatography and nuclear magnetic resonance spectroscopy, a new method for identifying unknown risk substance structures in cosmetics has been established. Moreover, HPLC-MS/MS was developed for the determination of benvitimod in cosmetics. The sample was collected in ultrahigh-performance liquid chromatography-tandem high-resolution mass spectrometry, and the molecular formula of the unknown was obtained as C17 H18 O2 . After preparative chromatography enrichment and purification, the enriched compound was scanned by nuclear magnetic resonance spectroscopy, and the chemical structure of the unknown compound was confirmed to be benvitimod. Subsequently, the separation was determined in multiple reaction monitoring mode. The results showed that the linearity of benvitimod was good in the range of 1-100 µg/L with a correlation coefficient r2  > 0.999; the limits of detection and quantification were 0.02 mg/kg and 0.067 mg/kg; the precision and stability were good; and the average recoveries were 104.2%, 108.2%, and 108.7% for low, medium, and high spiked concentrations, respectively. Forty batches of cosmetics were screened, of which two batches were detected with the illegal addition of benvitimod at 2.48 and 3.13 g/kg. The method effectively solved the loopholes in regulation and provided a research basis for the qualitative identification of structurally unknown compounds in cosmetics.

Aryl hydrocarbon receptor/nuclear factor E2-related factor 2 (AHR/NRF2) signalling: A novel therapeutic target for atopic dermatitis.

Aryl hydrocarbon receptor (AHR)/nuclear factor-erythroid 2-related factor 2 (NRF2) modulation is emerging as novel targets in the treatment of atopic dermatitis and other inflammatory skin disorders. Agonist activation of this pathway has downstream effects on epidermal barrier function, immunomodulation, oxidative stress reduction and cutaneous microbiome modulation. Tapinarof, a dual agonist of the AHR/NRF2 signalling pathway, has shown promise in phase 2 trials for atopic dermatitis. In this review, we summarize current knowledge of the AHR/NRF2 pathway and implications in skin disease process. We also review the therapeutic potential of current AHR agonists and propose future directions to address knowledge gaps.

Application of benvitimod on psoriasis: A systematic review and meta-analysis of randomized controlled trials. A systematic review of benvitimod on psoriasis.

BACKGROUND: We conducted this systematic review to clarify the efficacy and safety of benvitimod on psoriasis. METHODS: We searched the databases of PubMed, China National Knowledge infrastructure, Cochrane Library, Embase, Web of science to identify randomized controlled trials (RCTs) of benvitimod on psoriasis up to April 2021. RESULTS: Five RCTs of benvitimod on psoriasis were included. A total of 1237 patients were included. 0.5% or 1.0% benvitimod was applied topically once or twice a day. More patients in benvitimod group achieved PASI 90, PASI 75, PASI 50 and BSA reduction than placebo at Week 12. More patients in benvitimod group achieved PGA 0 or 1 than placebo since Week 6. There were no statistical significances in efficacies of benvitimod at different concentrations and frequencies. CONCLUSIONS: Benvitimod was effective and safe for psoriasis. More RCTs with high qualities are needed to further verify the current conclusion.

An overview of benvitimod for the treatment of psoriasis: a narrative review.

INTRODUCTION: The most frequently prescribed first-line treatment for limited (mild-to-moderate) psoriasis is topical corticosteroids, which are associated with several adverse effects with long term use. Benvitimod is an aryl hydrocarbon receptor immunomodulator that is both efficacious and tolerable for use in patients with mild to severe psoriasis with a body surface area (BSA) range of 1-20%. AREAS COVERED: In this review, the authors conducted a PubMed and Google Scholar search of key words and a review of clinical trials. They discuss the targeted mechanism of action for psoriasis, efficacy and safety profile of topical benvitimod, and its indications. Benvitimod affects key regulators of psoriasis, including proinflammatory markers and skin barrier proteins. Benvitimod is well-tolerated in patients with mild to severe plaque psoriasis. Treatment-emergent adverse events (TEAEs) include pruritus, contact dermatitis, and folliculitis; however, the majority of TEAEs were mild to moderate in severity, and most resolved without further treatment. A limitation of this study includes a small number of trials due to the dr' novelty. EXPERT OPINION: Benvitimod may serve as a good alternative for psoriatic patients who desire a nonsteroidal topical option. The usefulness of benvitimod may be limited by prior authorizations that discourage healthcare providers from prescribing the medication and poor outcomes.

New and Emerging Topical Therapies for Psoriasis and Atopic Dermatitis.

Psoriasis and atopic dermatitis represent two of the most common skin conditions seen by both primary care and specialist dermatology. The prevalence of psoriasis in North America is 2 to 4 percent, and it is estimated to cost more than $3 billion per year to treat this condition. Atopic dermatitis has an estimated 15 to 30 percent lifetime prevalence in children and an 8 to 10 percent lifetime prevalence in adults. Both diseases have a significant impact on patient quality of life, as well as associated psychological, social, and economic consequences. While systemic therapies are available for both, the majority of patients with each condition are treated with topical therapies alone, with varying degrees of efficacy and patient satisfaction. As such, there is both need and an incentive to develop new treatments for these two conditions. In this paper, we review new and emerging topical therapies for psoriasis and atopic dermatitis.

Effects of benvitimod on levels of interleukin-4 and -10, interferon-γ and transforming growth factor-βin patients with atopic dermatitis / 中华皮肤科杂志

Objective To detect levels of interleukin?4(IL?4), IL?10, interferon?γ(INF?γ)and transforming growth factor?β(TGF?β)in the culture supernatant of peripheral blood mononuclear cells (PBMCs)from patients with atopic dermatitis(AD), and to evaluate regulatory effects of benvitimod on these cytokines. Methods PBMCs were isolated from 20 AD patients and 20 healthy controls. Then, PBMCs from AD patients were equally divided into 4 groups to be cultured with phosphate?buffered saline (PBS group), 400 nmol/L benvitimod solution (benvitimod group), 250 nmol/L dexamethasone solution (dexamethasone group) and 10 nmol/L tacrolimus solution (tacrolimus group), respectively. Enzyme?linked immunosorbent assay(ELISA)was performed to detect levels of IL?4, IL?10, INF?γand TGF?βin the culture supernatant of PBMCs. Results Compared with healthy controls, patients with AD showed significantly higher level of IL?4(83.4 ± 12.2 vs. 44.3 ± 5.7 pg/ml, P0.05). Compared with PBS, 400 nmol/L benvitimod could decrease the expression of IL?4(50.2 ± 10.1 vs. 83.3 ± 12.2 pg/ml, P 0.05)and INF?γ(9.56 ± 5.1 vs. 12.5 ± 2.3 pg/ml, P>0.05), but increase the expression of TGF?β(203.6 ± 15.3 vs. 178.9 ± 17.4 pg/ml, P>0.05)by PBMCs. In addition, no significant differences in the expression of IL?4, IL?10, INF?γ or TGF?β were observed between the benvitimod group and dexamethasone group or tacrolimus group(all P>0.05). Conclusion Benvitimod can regulate the expression of IL?4, IL?10, INF?γand TGF?βby PBMCs in patients with AD.

Randomized, double-blind, placebo-controlled, multiple-dose study of the safety, tolerability and pharmacokinetics of benvitimod, a candidate drug for the treatment of psoriasis.

WHAT IS KNOWN AND OBJECTIVE: Benvitimod is a newly synthesized non-steroidal small molecule, aimed at the treatment for psoriasis. Several trials have demonstrated that benvitimod improves plaque psoriasis. However, its maximum tolerated dose and pharmacokinetic characteristics have not been reported on. The goals of this study were to evaluate the safety, tolerability and pharmacokinetics of benvitimod after topical administration in healthy subjects. METHODS: This phase I trial in healthy subjects was designed as a randomized, double-blind, placebo-controlled, ascending-dose study. After screening and randomization, 56 volunteers received benvitimod (0·5-2·0%) or placebo cream once or twice daily. Doses were escalated from 5 to 30 mg daily in six cohorts. Safety and tolerability were appraised by monitoring adverse events and laboratory parameters. Benvitimod concentrations were measured using liquid chromatography-tandem-mass spectrometry. RESULTS AND DISCUSSION: Exposure to benvitimod did not result in electrocardiographic or clinical laboratory changes. Doses up to 30 mg were well tolerated. All adverse events were mild. Adverse effects at the application site were observed in subjects randomized to benvitimod 5 mg q.d and b.i.d, but there were no observable dose effects in the dose-range evaluated. Benvitimod was detected in fewer than 5% of the plasma samples. WHAT IS NEW AND CONCLUSIONS: Benvitimod cream, at single doses of up to 30 mg, is well tolerated by healthy subjects. Following topical application, systemic absorption was negligible.

Effect of pH value of pretreatment environment of plasma samples on matrix effects in HPLC-MS/MS analysis of stilbene compounds / 中国药学杂志

OBJECTIVE: To evaluate the effects of the pH condition in which the plasma samples were prepared on the matrix effects of HPLC-MS/MS analysis of stilbene compounds.

Effect of benvitimod on allergic contact dermatitis in BALB/c mice / 中华皮肤科杂志

Objective To evaluate the efficacy of benvitimod on allergic contact dermatitis (ACD) in a mouse model of allergic contact dermatitis.Methods Acute and chronic ACD models were established respectively in 42 BALB/c mice through 2,4-dinitrofluorobenzene (DNFB) sensitization and challenge.Then,the BALB/c mice were equally divided into 7 groups with 6 mice in every group:normal control group receiving no treatment,five treatment groups topically treated with 0.1％ dexamethasone solution,0.1％ tacrolimus (FK506) solution,0.5％ benvitimod solution,1.0％ benvitimod solution and 2.0 ％ benvitimod solution respectively,and dehydrated alcohol group treated with dehydrated alcohol only.All the drug solutions were topically applied at 24 and 36 hours after the last challenge in the murine models of acute ACD which were sacrificed at 48 hours,and twice daily from day 7 to 21 after the initial sensitization in the murine models of chronic ACD which were sacrificed on day 21 after the first topical treatment.Ear tissues were obtained from these mice and subjected to measurement of ear thickness and weight,as well as pathological examination and evaluation of inflammatory infiltrate by hematoxylin-eosin (HE) staining.The safety of these drugs was also estimated at the end of treatment.Results In the murine models of acute ACD,benvitimod showed no obvious therapeutic effect at 24 hours,with no significant differences in bilateral difference in ear thickness or weight between the three benvitimod groups and dehydrated alcohol group (all P ＞ 0.05).Meanwhile,in the murine models of chronic ACD,benvitimod markedly decreased the swelling degree of ears,with significant differences between the three benvitimod groups (0.5％,1.0％ and 2.0％) and dehydrated alcohol group in bilateral difference in ear thickness ((71.50 ± 3.15) × 10-3 mm,(75.50 ± 3.02) × 10-3 mm and (69.50 ± 2.59) × 10-3 mm vs.(91.83 ± 2.04) × 10-3 mm,all P＜ 0.01) and weight ((2.33 ± 0.45) mg,(2.30 ± 0.57) mg and (2.38 ± 0.27) mg vs.(3.73 ± 0.33) mg,all P ＜ 0.01) after 3 weeks of treatment.The inflammatory infiltration in ear tissue was significantly attenuated in murine models of both acute and chronic ACD by the three concentrations of benvitimod compared with dehydrated alcohol (all P ＜ 0.01).Conclusions Topical benvitimod can inhibit chronic ACD in mice induced by 2,4-DNFB,but exhibits no obvious effect on acute ACD.No apparent local adverse effects were observed during the treatment with benvitimod in these mice.