Benvitimod (Tapinarof)

J Invest Dermatol . 2017 Oct;137(10):2110-2119

Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans[Pubmed: 28595996]

Tapinarof (GSK2894512) is a naturally derived topical treatment with demonstrated efficacy for patients with psoriasis and atopic dermatitis, although the biologic target and mechanism of action had been unknown. We demonstrate that the anti-inflammatory properties of tapinarof are mediated through activation of the aryl hydrocarbon receptor (AhR). We show that tapinarof binds and activates AhR in multiple cell types, including cells of the target tissue-human skin. In addition, tapinarof moderates proinflammatory cytokine expression in stimulated peripheral blood CD4+ T cells and ex vivo human skin, and impacts barrier gene expression in primary human keratinocytes; both of these processes are likely to be downstream of AhR activation based on current evidence. That the anti-inflammatory properties of tapinarof derive from AhR agonism is conclusively demonstrated using the mouse model of imiquimod-induced psoriasiform skin lesions. Topical treatment of AhR-sufficient mice with tapinarof leads to compound-driven reductions in erythema, epidermal thickening, and tissue cytokine levels. In contrast, tapinarof has no impact on imiquimod-induced skin inflammation in AhR-deficient mice. In summary, these studies identify tapinarof as an AhR agonist and confirm that its efficacy is dependent on AhR.

J Invest Dermatol . 2017 Oct;137(10):2110-2119.

Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans[Pubmed: 28595996]

Tapinarof (GSK2894512) is a naturally derived topical treatment with demonstrated efficacy for patients with psoriasis and atopic dermatitis, although the biologic target and mechanism of action had been unknown. We demonstrate that the anti-inflammatory properties of tapinarof are mediated through activation of the aryl hydrocarbon receptor (AhR). We show that tapinarof binds and activates AhR in multiple cell types, including cells of the target tissue-human skin. In addition, tapinarof moderates proinflammatory cytokine expression in stimulated peripheral blood CD4+ T cells and ex vivo human skin, and impacts barrier gene expression in primary human keratinocytes; both of these processes are likely to be downstream of AhR activation based on current evidence. That the anti-inflammatory properties of tapinarof derive from AhR agonism is conclusively demonstrated using the mouse model of imiquimod-induced psoriasiform skin lesions. Topical treatment of AhR-sufficient mice with tapinarof leads to compound-driven reductions in erythema, epidermal thickening, and tissue cytokine levels. In contrast, tapinarof has no impact on imiquimod-induced skin inflammation in AhR-deficient mice. In summary, these studies identify tapinarof as an AhR agonist and confirm that its efficacy is dependent on AhR.

Am J Clin Dermatol . 2022 Jan;23(1):83-91.

Tapinarof Cream 1% for Extensive Plaque Psoriasis: A Maximal Use Trial on Safety, Tolerability, and Pharmacokinetics[Pubmed: 34713415]

Background: Tapinarof is a novel topical therapeutic aryl hydrocarbon receptor modulating agent in development for the treatment of psoriasis and atopic dermatitis. Objective: This multicenter, open-label trial assessed the safety, tolerability, pharmacokinetics (PK), and efficacy of tapinarof cream 1% once daily (QD) under maximal use conditions in extensive plaque psoriasis. Methods: Adults with a baseline Physician Global Assessment (PGA) score of ≥ 3 and body surface area (BSA) involvement ≥ 20% received tapinarof cream 1% QD for 29 days. Safety and tolerability assessments included adverse events (AEs) and local tolerability scales. PK parameters were calculated using non-compartmental analysis. Efficacy assessments included change in PGA, Psoriasis Area and Severity Index score, and %BSA affected. Results: Twenty-one patients were enrolled. Common AEs were folliculitis, headache, back pain, and pruritus (none led to discontinuation). Tapinarof plasma exposure was low, with the majority of concentrations being below detectable limits. At day 29, 14 patients (73.7%) had a ≥ 1-grade improvement in PGA score and six patients (31.6%) had a ≥ 2-grade improvement; four patients (21.1%) achieved treatment success (PGA 0 or 1 and ≥ 2-grade improvement). Conclusion: Tapinarof cream 1% QD was well tolerated, with limited systemic exposure and significant efficacy at 4 weeks in patients with extensive plaque psoriasis. ClinicalTrials.gov Identifier

N Engl J Med . 2021 Dec 9;385(24):2219-2229.

Phase 3 Trials of Tapinarof Cream for Plaque Psoriasis[Pubmed: 34879448]

Background: Tapinarof cream is a topical aryl hydrocarbon receptor-modulating agent under investigation for the treatment of psoriasis. Tapinarof modulates the expression of interleukin-17 and the skin-barrier proteins filaggrin and loricrin. Methods: We conducted two identical phase 3 randomized trials of tapinarof in patients with mild-to-severe plaque psoriasis. Adults with a baseline Physician's Global Assessment (PGA) score of 2 (mild) to 4 (severe) (on a scale from 0 to 4, with higher scores indicating more severe psoriasis) and a percent of total body-surface area affected of 3 to 20% were randomly assigned in a 2:1 ratio to use tapinarof 1% cream or vehicle cream once daily for 12 weeks. The primary end point, PGA response, was a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points at week 12. Secondary efficacy end points at week 12 were a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI) score, a PGA score of 0 or 1, the mean change from baseline in the percent of body-surface area affected, and a reduction of at least 90% in the PASI score. Patient-reported outcomes were the mean changes from baseline to week 12 in the proportion of patients who had a decrease of at least 4 points in the Peak Pruritus Numeric Rating Scale (PP-NRS) score (range, 0 [no itch] to 10 [worst imaginable itch]), the PP-NRS total score, the Dermatology Life Quality Index total score, and the Psoriasis Symptom Diary score. Results: In trials 1 and 2, a total of 692 and 674 patients, respectively, were screened, with 510 and 515 patients being enrolled. A PGA response occurred in 35.4% of the patients in the tapinarof group and in 6.0% of those in the vehicle group in trial 1 and in 40.2% and 6.3%, respectively, in trial 2 (P<0.001 for both comparisons). Results for secondary end points and patient-reported outcomes were generally in the same direction as those for the primary end point. Adverse events with tapinarof cream included folliculitis, nasopharyngitis, contact dermatitis, headache, upper respiratory tract infection, and pruritus. Conclusions: Tapinarof 1% cream once daily was superior to vehicle control in reducing the severity of plaque psoriasis over a period of 12 weeks but was associated with local adverse events and headache. Larger and longer trials are needed to evaluate the efficacy and safety of tapinarof cream as compared with existing treatments for psoriasis.

Int J Mol Sci . 2020 Dec 10;21(24):9412.

IL-24 Negatively Regulates Keratinocyte Differentiation Induced by Tapinarof, an Aryl Hydrocarbon Receptor Modulator: Implication in the Treatment of Atopic Dermatitis[Pubmed: 33321923]

Skin barrier dysfunction, including reduced filaggrin (FLG) and loricrin (LOR) expression, plays a critical role in atopic dermatitis (AD) development. Since aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, mediates keratinocyte differentiation, it is a potential target for AD treatment. Recently, clinical studies have shown that tapinarof, an AHR modulator, attenuated the development of AD. To examine the molecular mechanism involved in this, we analyzed tapinarof-treated normal human epidermal keratinocytes (NHEKs). Tapinarof upregulated FLG and LOR mRNA and protein expression in an AHR-dependent manner. Tapinarof also induced the secretion of IL-24, a cytokine that activates Janus kinase (JAK)-signal transducer and activator of transcription (STAT), leading to the downregulation of FLG and LOR expression. Knockdown of either IL-24 or STAT3 expression by small interfering RNA (siRNA) transfection augmented the upregulation of FLG and LOR expression induced by tapinarof, suggesting that inhibition of the IL-24/STAT3 axis during AHR activation supports the improvement of skin barrier dysfunction. Furthermore, tapinarof alone could restore the downregulation of FLG and LOR expression induced by IL-4, a key cytokine of AD, and its combination with JAK inhibitors enhanced this effect. These findings provide a new strategy for treating AD using AHR modulators and JAK inhibitors.

J Am Acad Dermatol . 2021 Mar;84(3):624-631.

A phase 2b, randomized clinical trial of tapinarof cream for the treatment of plaque psoriasis: Secondary efficacy and patient-reported outcomes[Pubmed: 32446832]

Background: Tapinarof cream is a topical therapeutic aryl hydrocarbon receptor modulating agent under investigation for treatment of psoriasis and atopic dermatitis. Methods: In a phase 2b, double-blind, vehicle-controlled study, adults with plaque psoriasis were randomized to tapinarof cream 0.5% or 1% once or twice daily or vehicle once or twice daily for 12 weeks with 4-week follow-up. Efficacy outcomes included Physician Global Assessment (PGA) scores, change in PGA and total target lesion grading scores, and proportion of patients achieving ≥50%, ≥75%, and ≥90% reductions in the Psoriasis Area and Severity Index scores from baseline (PASI50, PASI75, and PASI90). Results: At week 12, improvements were observed in all tapinarof groups vs vehicle in PGA response, change in PGA and total target lesion grading scores, PASI50 (71%-92% vs 10%-32%), PASI75 (46%-65% vs 5%-16%), and PASI90 (18%-40% vs 0%); all differences were statistically significant with tapinarof 1% once daily. Tapinarof responses were apparent from week 2, with significant efficacy at week 8 maintained through week 16. Most adverse events were mild or moderate. Limitations: The analyses reported require confirmation in larger prospective studies. Conclusions: Tapinarof may represent an important advance in the development of topical medicines for treatment of psoriasis.

Arch Pharm Res . 2013 Jul 17.

Antioxidant and anticancer activity of 3,5-dihydroxy-4-isopropylstilbene produced by Bacillus sp. N strain isolated from entomopathogenic nematode[Pubmed: 23861102]

3,5-Dihydroxy-4-isopropylstilbene is a natural phytoalexin and was first identified as bacterial secondary metabolites. The aim of this study is to investigate in vitro antioxidant and anticancer activity of 3,5-dihydroxy-4-isopropystilbene purified from the cell free culture filtrate of Bacillus sp. N strain associated with rhabditid entomopathogenic nematode. Antioxidant activity was evaluated by five separate methods: free radical scavenging, reducing power assay, chelating effects on ferrous ions, NBT superoxide radical scavenging assay and hydroxyl radical scavenging activity. The stilbene recorded powerful antioxidant activity at various antioxidant systems in vitro. The superoxide radical scavenging (92.1 %) and hydroxyl radical scavenging (83.4 %) activities of the stilbenes at 100 μg/ml were higher than the butylated hydroxyanisole, the known antioxidant agent. Anticancer activity of stilbene was tested against breast cancer (MDAM B-231), cervical cancer (HeLa), lung cancer (A 549), colon cancer (HTL 116) cell lines using MTT method. The induction of apoptosis was studied by morphological analysis, apoptotic cell staining, caspase 3 activation assay and cell cycle analysis using flow cytometry. Stilbene induced significant morphological changes and DNA fragmentation associated with apoptosis in HeLa cells. Acridine orange/ethidium bromide stained cells indicated apoptosis induction by stilbene. Up-regulation of caspase 3 activity was also found in cells treated with stilbene. Flow cytometry analysis showed an increase in the percentage of apoptotic cells in sub G0 phase (2.4 % in control plates to 11.4 % in 25 μg/ml of stilbene) confirming the stilbene induced apoptosis. The results of the present study showed that stilbene demonstrated a strong antioxidant and anticancer effects. These suggest that stilbene may be used as possible natural antioxidant and anticancer agents to control various human diseases.

Microbiology (Reading) . 2005 Aug;151(Pt 8):2543-2550.

The gene stlA encodes a phenylalanine ammonia-lyase that is involved in the production of a stilbene antibiotic in Photorhabdus luminescens TT01[Pubmed: 16079333]

Photorhabdus is a genus of Gram-negative bacteria from the family Enterobacteriaceae. Members of Photorhabdus have a complex life cycle during which the bacterium has a pathogenic interaction with insect larvae whilst also maintaining a mutualistic relationship with nematodes from the family Heterorhabditidae. During growth in the insect, Photorhabdus bacteria produce a broad-spectrum antibiotic identified as 3,5-dihydroxy-4-isopropylstilbene (ST). The biochemical pathway responsible for the production of this antibiotic has not been characterized. In this report, a mutant strain of Photorhabdus luminescens subsp. laumondii TT01, BMM901, has been isolated, by transposon mutagenesis, that is unable to produce the ST antibiotic. Using in silico studies, feeding experiments and biochemical analyses, it is shown that the gene mutated in this strain, stlA, encodes phenylalanine ammonia-lyase (PAL). PAL catalyses the non-oxidative deamination of l-phenylalanine to trans-cinnamic acid and the enzyme is ubiquitous in plants, where it is involved in the production of phenylpropanoids such as lignin and phytoalexins. However, this is the first report of PAL activity in a member of the Proteobacteria.

J Invest Dermatol . 2017 Oct;137(10):2110-2119

Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans[Pubmed: 28595996]

Tapinarof acts through AhR to reduce inflammation in IMQ-treated mice. AhR-sufficient mice on a C57Bl/6 background exhibit a reduced clinical score after treatment with Tapinarof or 6-formylindolo(3,2-b)carbazole (FICZ). In contrast, AhR KO mice do not respond to the anti-inflammatory effects of Tapinarof. FICZ is used as a comparator in these studies and yields similar results, with dramatically reduced inflammatory responses in wild-type, but not AhR KO mice