stilbenes and Psoriasis

Tapinarof is a topical, aryl-hydrocarbon receptor agonist that has recently received FDA-approval for the treatment of psoriasis. This novel therapeutic has also been shown to be effective for atopic dermatitis and is currently in phase 3 for this indication. Beyond good efficacy and fast onset of action in patients with psoriasis, the clinical response to tapinarof is notable for durable remission or near remission, maintained for an average of 130 days beyond treatment discontinuation in patients with psoriasis in phase 3 studies. Tapinarof is usually well tolerated but can induce a follicular inflammatory reaction and dermatitis in some patients. This narrative review covers the historical development of this molecule, safety and efficacy data from clinical trials conducted with various topical formulations, and practical considerations derived from our 15 years of clinical trial experience with the drug.

Topics: Dermatitis, Atopic; Humans; Psoriasis; Resorcinols; Stilbenes

Psoriasis is a chronic, immune-mediated, multisystem, inflammatory dermatological condition that is persistent and relapsing. Topical treatments are first line agents for mild to moderate plaque psoriasis. With proven efficacy and safety, topical corticosteroids are often used, although adverse effects and limitations for use exist. Tapinarof (Vtama®), a novel topical aryl hydrocarbon receptor modulating drug, was approved by the US Food and Drug Administration for the treatment of plaque psoriasis in adults in May 2022. A literature search of PubMed, MEDLINE, and ClinicalTrials.gov was conducted using the following keywords: tapinarof, psoriasis, GSK2894512. Articles published before January 2023 were included in this review. This review describes the preclinical and clinical studies demonstrating the efficacy and safety of tapinarof, its place in therapy, and relevance to patient care. Kalabalik-Hoganson J, Nogid A, Frey K. A review of tapinarof: novel topical treatment for plaque psoriasis in adults. J Drugs Dermatol. 2023;22(8):761-765. doi:10.36849/JDD.7481.

Topics: Adult; Chronic Disease; Dermatologic Agents; Humans; Psoriasis; Resorcinols; Stilbenes; Treatment Outcome

Since its introduction in 1952, topical glucocorticosteroids remain the initial and long-term treatment option for various forms of inflammatory dermatitis. A number of non-steroidal topicals for treating inflammatory dermatoses have been developed in the recent decades (such as topical calcineurin inhibitors, vitamin D analogues, and phophodiesterase-4 inhibitors), but none had the combination of broad therapeutic range, relatively rapid onset of action, high tolerability, and wide-spread clinical success; this allowed topical glucocorticosteroids to remain the mainstay of therapy. This situation has shifted dramatically, with three non-steroidal new molecular entities, each with completely different mechanisms of action, receiving approval of the Food and Drug Administration (FDA) in the past year. Topical ruxolitinib, a Janus kinase (JAK) inhibitor, was approved by the FDA in September 2021 for atopic dermatitis, and was the subject of the first report in this review series. Subsequently, topical tapinarof, an aryl hydrocarbon receptor modulating agent, was approved by the FDA in May 2022 for treating plaque psoriasis, and is the focus of this present report. Finally and the most recently, topical roflumilast, a highly potent phosphodiesterase-4 inhibitor, received FDA approval in July 2022 for treating plaque psoriasis, and is reviewed in the third and final report in this series. In addition to their unique mechanisms of action and spectra of activity, each of these agents has unique clinical characteristics, including degree of efficacy, rapidity of onset of efficacy, potential remittive effects, and safety and tolerability profiles. In short, in this three-part series, we reviewed and summarized the data surrounding each agent, providing a comprehensive overview which would allow dermatologists to confidently and appropriately integrate them into treatment paradigms.

Topics: Dermatitis, Atopic; Humans; Psoriasis; Resorcinols; Stilbenes; United States

Psoriasis is a chronic immune-mediated skin disease with a significant impact on patients' quality of life. Mild-to-moderate forms of the disease usually require long-term topical treatment, but prolonged use of corticosteroids and vitamin D analogues is limited by adverse effects. With further understanding of psoriasis pathogenesis, new molecules are emerging aiming to fulfil these clinical needs. Tapinarof, an aryl hydrocarbon receptor modulator, has completed a phase III study and demonstrated good efficacy results, even in long treatment courses, with a favourable safety profile. It additionally appears to have a promising remitting effect as patients presented with an average relapsing time of over 3 months. Roflumilast, a phosphodiesterase type 4 inhibitor, also underwent a phase III study with significant lesion improvement and notable pruritus management, and with no reported side effects. Roflumilast was evaluated as an option for intertriginous areas with good outcomes in a small sample, but larger trials are required. The Janus kinase-signal transducer and activator of transcription pathway has been targeted in recent clinical investigations with promising options, currently with brepocitinib pending phase IIb results. Ongoing preclinical studies involving interleukin-2 inhibition, RNA modulators and amygdalin analogues may lead to forthcoming clinical trials. New topical drugs are successfully emerging and future research comparing them to classical options will dictate their clinical role in the treatment of psoriasis.

Topics: Administration, Topical; Aminopyridines; Amygdalin; Benzamides; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclopropanes; Dermatologic Agents; Humans; Interleukin-2; MicroRNAs; Nitriles; Phosphodiesterase 4 Inhibitors; Piperidines; Psoriasis; Pyrazoles; Pyrimidines; Resorcinols; Stilbenes

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%.. 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.. 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.

Topics: Dermatologic Agents; Humans; Psoriasis; Resorcinols; Stilbenes

Tapinarof cream 1% (VTAMA

Topics: Adult; Dermatitis, Atopic; Humans; Psoriasis; Resorcinols; Stilbenes

Tapinarof, a novel, first-in-class, small-molecule topical therapeutic aryl hydrocarbon receptor (AhR)-modulating agent, is in clinical development for the treatment of psoriasis and atopic dermatitis. The efficacy of tapinarof in psoriasis is attributed to its specific binding and activation of AhR, a ligand-dependent transcription factor, leading to the downregulation of proinflammatory cytokines, including interleukin 17, and regulation of skin barrier protein expression to promote skin barrier normalization. AhR signaling regulates gene expression in immune cells and skin cells and has critical roles in the regulation of skin homeostasis. Tapinarof-mediated AhR signaling underlies the mechanistic basis for the significant efficacy and acceptable tolerability observed in early-phase clinical trials of tapinarof cream in the treatment of psoriasis.

Topics: Basic Helix-Loop-Helix Transcription Factors; Clinical Trials as Topic; Gene Expression Regulation; Humans; Interleukin-17; Keratinocytes; Oxidative Stress; Psoriasis; Receptors, Aryl Hydrocarbon; Resorcinols; Skin; Skin Absorption; Stilbenes

Psoriasis is a chronic inflammatory autoimmune disease that can be initiated by excessive activation of endosomal toll-like receptors (TLRs), particularly TLR7, TLR8, and TLR9. Therefore, inhibitors of endosomal TLR activation are being investigated for their ability to treat this disease. The currently approved biological drugs adalimumab, etanercept, infliximab, ustekinumab, ixekizumab, and secukizumab are antibodies against effector cytokines that participate in the initiation and development of psoriasis. Several immune modulatory oligonucleotides and small molecular weight compounds, including IMO-3100, IMO-8400, and CPG-52364, that block the interaction between endosomal TLRs and their ligands are under clinical investigation for their effectiveness in the treatment of psoriasis. In addition, several chemical compounds, including AS-2444697, PF-05387252, PF-05388169, PF-06650833, ML120B, and PHA-408, can inhibit TLR signaling. Although these compounds have demonstrated anti-inflammatory activity in animal models, their therapeutic potential for the treatment of psoriasis has not yet been tested. Recent studies demonstrated that natural compounds derived from plants, fungi, and bacteria, including mustard seed,

Topics: Aminoquinolines; Animals; Anti-Inflammatory Agents, Non-Steroidal; Curcumin; Cytokines; Dermatitis; Endosomes; Humans; Imiquimod; Indazoles; Isonicotinic Acids; Mice; Psoriasis; Resveratrol; Signal Transduction; Skin; Stilbenes; Toll-Like Receptor 7; Toll-Like Receptor 8; Toll-Like Receptor 9; Toll-Like Receptors

Tapinarof is a novel topical therapeutic aryl hydrocarbon receptor modulating agent in development for the treatment of psoriasis and atopic dermatitis.. 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.. 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.. 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).. 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 NCT04042103.

Topics: Dermatologic Agents; Humans; Psoriasis; Resorcinols; Severity of Illness Index; Skin Cream; Stilbenes

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.. 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.. 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.. 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. (Funded by Dermavant Sciences; PSOARING 1 and 2 ClinicalTrials.gov numbers, NCT03956355 and NCT03983980, respectively.).

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Contact; Double-Blind Method; Female; Headache; Humans; Intention to Treat Analysis; Interleukin-17; Male; Middle Aged; Patient Reported Outcome Measures; Psoriasis; Receptors, Aryl Hydrocarbon; Resorcinols; Severity of Illness Index; Skin Cream; Stilbenes

Tapinarof cream is a topical therapeutic aryl hydrocarbon receptor modulating agent under investigation for treatment of psoriasis and atopic dermatitis.. 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).. 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.. The analyses reported require confirmation in larger prospective studies.. Tapinarof may represent an important advance in the development of topical medicines for treatment of psoriasis.

Topics: Adolescent; Adult; Aged; Canada; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Japan; Male; Middle Aged; Patient Reported Outcome Measures; Psoriasis; Resorcinols; Severity of Illness Index; Skin Cream; Stilbenes; Treatment Outcome; United States; Young Adult

Benvitimod cream, a novel synthetic small molecule, was effective in treating mild-to-moderate plaque psoriasis. We conducted a phase III clinical trial to assess the efficacy and safety of benvitimod cream in patients with mild-to-moderate plaque psoriasis.. We randomly assigned 686 patients (2:1:1) to receive 1% benvitimod cream, 0.005% calcipotriol ointment or placebo twice a day for 12 weeks. The primary efficacy end points were the percentage of patients with a 75% or greater reduction from baseline in the psoriasis area and severity index (PASI 75) score and with a score of 0 or 1 in static physician's global assessment (sPGA) at week 12.. The results showed that 50.4% of patients in the benvitimod group achieved PASI 75, which was significantly higher than that in the calcipotriol (38.5%, P < 0.05) and placebo (13.9%, P < 0.05) groups. The proportion of patients achieving an sPGA score 0 or 1 was 66.3% in the benvitimod group and 63.9% in the calcipotriol group, which were both significantly higher than that in the placebo group (34%, P < 0.05). In the long-term follow-up study, 50.8% of patients experienced recurrence. After retreatment with 1% benvitimod, 73.3% of patients achieved an sPGA score of 0 or 1 again at week 52. Adverse events included application site irritation, follicular papules, and contact dermatitis. No systemic adverse reactions were reported.. During this 12-week study, benvitimod cream was demonstrated with high effectiveness and safety in patients with mild-to-moderate plaque psoriasis.. Chinese Clinical Trial Registry (ChiCTR), ChiCTR-TRC-13003259; http://www.chictr.org.cn/showprojen.aspx?proj=6300.

Topics: Double-Blind Method; Follow-Up Studies; Humans; Ointments; Psoriasis; Resorcinols; Severity of Illness Index; Stilbenes; Treatment Outcome

There is a significant need for novel, safe, and efficacious topical treatments for psoriasis.. We assessed the safety and efficacy of tapinarof in a new cream formulation at 2 concentrations and with 2 application frequencies in adults with psoriasis.. Double-blind, vehicle-controlled, randomized, 6-arm trial (1:1:1:1:1:1) in adults, with psoriasis with body surface involvement ≥1% and ≤15% and Physician Global Assessment (PGA) score ≥2 at baseline. Primary endpoint included PGA of 0 or 1 at week 12 and a 2-grade improvement from baseline. Additional analyses included assessment of ≥75% improvement of Psoriasis Area and Severity Index and mean percent change in Psoriasis Area and Severity Index and body surface area involvement.. Treatment success defined by PGA 0 or 1 and a 2-grade improvement at week 12 was statistically significantly higher (at a .05 significance level) in the tapinarof groups (65% [1% twice daily], 56% [1% once daily], 46% [0.5% twice daily], and 36% [0.5% once daily]) than in the vehicle groups (11% [twice daily] and 5% [once daily]) and was maintained for 4 weeks posttreatment. Treatment-emergent adverse events were more frequent in patients treated with tapinarof (85/152, 56%) than vehicle (19/75, 25%) and mild-to-moderate in intensity. Severe treatment-emergent adverse events were reported in all tapinarof groups except the 0.5% once daily group.. Large confirmation trials are needed.. Tapinarof cream is efficacious and well tolerated in adult patients with psoriasis.

Topics: Adolescent; Adult; Aged; Body Surface Area; Dermatologic Agents; Double-Blind Method; Humans; Middle Aged; Psoriasis; Resorcinols; Severity of Illness Index; Skin Cream; Stilbenes; Young Adult

GSK2894512 is a topically delivered investigational drug being developed for treatment of atopic dermatitis and psoriasis.. To investigate, in a phase I clinical trial, the spatial biodistribution and residency of GSK2894512 within the epidermis and dermis of healthy human participants noninvasively using fluorescence lifetime imaging microscopy (FLIM).. Two topical drug formulations containing GSK2894512 1% were applied to the right and left forearms of six participants for seven consecutive days, followed by seven days of observation for residency. FLIM images were obtained daily throughout the study, approximately every 24 h. During the treatment phase of the study, images were collected from each participant pretreatment, reflecting the residual dose from the previous day. Three punch biopsies from each participant of one formulation was obtained from the treated region during the post-treatment follow-up period between days 8 and 14 for comparison with FLIM results.. Cellular and subcellular features associated with different epidermal and dermal layers were visualized noninvasively, down to a depth of 200 μm. Results yielded three-dimensional maps of GSK2894512 spatial distribution and residency over time. This fluorescence data provided a marker that was used as a monitor for day-to-day variance of drug presence and residency postapplication.. The results suggest FLIM could be a viable alternative to skin biopsies without the usual patient discomfort and limitations, thereby enabling the direct measurement of skin distribution through longitudinal monitoring. These results are the first step in establishing the unique capabilities that multiphoton imaging could provide to patients through noninvasive drug detection.

Topics: Administration, Cutaneous; Adult; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Dermatologic Agents; Dermis; Epidermis; Healthy Volunteers; Humans; Intravital Microscopy; Male; Microscopy, Fluorescence, Multiphoton; Psoriasis; Resorcinols; Skin Cream; Stilbenes; Tissue Distribution; Young Adult

To investigate the time-dose-response relationship of benvitimod cream after topical administration in patients with mild and moderate psoriasis vulgaris for dosage regimen exploring.. 36 patients with mild and moderate psoriasis vulgaris were randomly assigned to receive 0.5%, 1.0%, 1.5%, and 0% (placebo) benvitimod cream of 30 g/1.7 m2 twice daily for 6 weeks. The primary efficacy outcome was the proportion of patients achieving more than 75% change of the psoriasis area and severity index (PASI 75) from baseline. A longitudinal Emax model was established using the NONMEM method, and then applied to try to find an appropriate dose for following trials.. In the final time-dose-response model, the primary outcome at week 6 of PASI 75 of the 0.5%, 1.0%, and 1.5% benvitimod cream was 31%, 63%, and 75%, respectively, demonstrating that the 1.0% benvitimod cream was an appropriate dose for the next trial. The time parameters of ET50 and ET90 were 15 and 69 days for 1.0% benvitimod cream, indicating that the maximum efficacy of PASI change rate was obtained at approximately week 10. The accuracy of PASI change rate by extrapolation prediction was limited at week 10, so the treatment period should be longer in future trials.. The established dose-response model could well describe the relationship between PASI change rate and doses of benvitimod cream in patients with mild and moderate psoriasis vulgaris. This modeling approach may help choose 1.0% benvitimod cream twice daily as a dosage regimen in following clinical trials.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Ointments; Psoriasis; Resorcinols; Stilbenes

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.. 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.. 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.. Benvitimod cream, at single doses of up to 30 mg, is well tolerated by healthy subjects. Following topical application, systemic absorption was negligible.

Topics: Administration, Cutaneous; Adult; Anti-Inflammatory Agents, Non-Steroidal; Chromatography, Liquid; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Psoriasis; Resorcinols; Skin Cream; Stilbenes; Tandem Mass Spectrometry

Psoriasis is a systemic inflammatory immune-mediated skin disease. Recently a relationship with metabolic syndrome in terms of psoriasis severity and response to therapy was observed.. We performed an open-label randomized controlled study to evaluate the role of a nutraceutical containing Q10 coenzyme, Krill-oil, lipoic acid, resveratrol, Vitis vinifera seed oil, vitamin E and selenium in addition to etanercept therapy for patients affected by psoriasis and metabolic syndrome. Forty patients were enrolled and divided into two arms, one receiving only etanercept, one other receiving also the neutraceutical. After a period of 3 months (T1) a second evaluation of the considered parameters was performed.. At T1 statistically significant differences were detected in HDL cholesterol and triglycerides values both comparing the two arms and in the nutraceutical arm.. Our results show that the dietary addiction of the nutraceutical to the etanercept therapy in patients affected by both psoriasis and metabolic syndrome could help to restore the normal lipid profile.

Topics: Adult; Animals; Antioxidants; Biomarkers; Body Mass Index; Cholesterol, HDL; Dietary Fats, Unsaturated; Dietary Supplements; Etanercept; Euphausiacea; Female; Follow-Up Studies; Humans; Immunoglobulin G; Immunosuppressive Agents; Male; Metabolic Syndrome; Middle Aged; Psoriasis; Receptors, Tumor Necrosis Factor; Resveratrol; Seeds; Selenium; Severity of Illness Index; Stilbenes; Thioctic Acid; Treatment Outcome; Triglycerides; Tumor Necrosis Factor-alpha; Ubiquinone; Vitamin E; Vitis

There is a need for the development of novel non-steroidal topical drugs for the treatment of psoriasis.. To assess the efficacy and safety of topical 1.0% WBI-1001 in patients with mild to moderate plaque psoriasis.. A total of 61 patients with 1-10% body surface area (BSA) covered with plaque psoriasis and a physician's global assessment score (PGA) of 2-4 were randomized (2:1) to receive either 1% WBI-1001 in a cream formulation or placebo, applied twice daily for 12 weeks. Efficacy was evaluated using PGA, BSA and Psoriasis Area and Severity Index (PASI). The primary endpoint was the change from baseline (Day 0) in PGA at week 12.. The improvement in PGA at week 12 was 62.8% for patients randomized to WBI-1001 when compared with 13.0% for patients randomized to placebo (P<0.0001). At week 12, the proportion of patients who achieved a PGA of clear or almost clear and the mean improvement in BSA were 67.5% and 79.1%, respectively, for patients randomized to WBI-1001, when compared with 4.8% (P<0.0001) and an increase of 9.4% (P<0.0001), respectively, for patients randomized to placebo. More application site adverse drug reactions were observed in patients randomized to WBI-1001 than in those randomized to placebo. These adverse drug reactions were all mild or moderate in intensity.. Topical WBI-1001 induces rapid and significant improvement in patients with plaque psoriasis.

Topics: Administration, Topical; Dermatologic Agents; Double-Blind Method; Humans; Placebos; Psoriasis; Resorcinols; Severity of Illness Index; Stilbenes

Topics: Humans; Psoriasis; Resorcinols; Stilbenes

Topics: Child; Emollients; Female; Humans; Psoriasis; Resorcinols; Stilbenes

Topics: Dermatitis, Atopic; Dermatologic Agents; Humans; Interleukin-33; Keratinocytes; Psoriasis; Receptors, Aryl Hydrocarbon; Resorcinols; Stilbenes

Tapinarof cream 1% once daily, an aryl hydrocarbon receptor-modulating agent, was significantly more efficacious than vehicle and well tolerated in two 12-week phase 3 trials in adults with mild to severe plaque psoriasis.. To assess long-term safety, efficacy, remittive effect, durability of response, and tolerability of tapinarof.. Patients completing the 12-week trials were eligible for 40-weeks' open-label treatment and 4-weeks' follow-up. Treatment was based on the Physician Global Assessment (PGA) score. Patients entering with PGA≥1 received tapinarof until PGA = 0. Patients with PGA = 0 discontinued tapinarof and were monitored for remittive effect. Patients with PGA≥2 were re-treated until PGA = 0.. Overall, 91.6% (n = 763) of eligible patients enrolled; 40.9% of patients achieved complete disease clearance (PGA = 0), and 58.2% entering with PGA≥2 achieved PGA = 0 or 1. Mean duration of off therapy remittive effect for patients achieving PGA = 0 was 130.1 days. No new safety signals were observed. Most frequent adverse events were folliculitis (22.7%), contact dermatitis (5.5%), and upper respiratory tract infection (4.7%).. Open-label; no control; may not be generalizable to all forms of psoriasis; remittive effect/response rate potentially underestimated.. Efficacy improved beyond the 12-week trials, with a 40.9% complete disease clearance rate, ∼4-month off therapy remittive effect, durability on therapy, and consistent safety.

Topics: Adult; Emollients; Humans; Psoriasis; Receptors, Aryl Hydrocarbon; Resorcinols; Stilbenes

Topics: Dermatologic Agents; Drug Combinations; Humans; Psoriasis; Resorcinols; Stilbenes; Treatment Outcome

VTAMA

Topics: Clinical Trials, Phase III as Topic; Double-Blind Method; Humans; Psoriasis; Randomized Controlled Trials as Topic; Resorcinols; Severity of Illness Index; Skin Cream; Stilbenes; Treatment Outcome

Topics: Administration, Topical; Humans; Psoriasis; Resorcinols; Stilbenes

Resveratrol was shown to exert anti-inflammatory effects in experimental models of psoriasis. Several natural oligomers of resveratrol have been extracted from plants. We investigated the antipsoriatic activity of topical administration of resveratrol oligomers and explored the effect of the number of resveratrol subunits on skin absorption to establish the structure-permeation relationship (SPR). Three oligomers, ε-viniferin (dimer), ampelopsin C (trimer) and vitisin A (tetramer), extracted from Vitis thunbergii root were compared to the resveratrol glycoside polydatin. Delivery to porcine skin was assessed in vitro using the Franz cell. Keratinocytes activated with imiquimod (IMQ) were utilized to evaluate cytokine/chemokine inhibition. Topical application of resveratrol and oligomers was characterized in vivo by assessing cutaneous absorption, skin physiology, proinflammatory mediator expression, and histopathology in IMQ-treated mice. Skin deposition decreased as the molecular size and lipophilicity of the permeants increased. Resveratrol exhibited highest absorption, followed by ε-viniferin. The monomers resveratrol and polydatin exhibited higher flux across skin than the larger oligomers. In silico modeling revealed the permeants that strongly interacted with stratum corneum (SC) lipids exhibited lower transport to viable skin and the receptor compartment. In vitro, resveratrol and its derivatives had comparable ability to inhibit IMQ-induced IL-1β, IL-6, and CXCL8 secretion in activated keratinocytes. In vivo, topically applied ε-viniferin accumulated at higher levels than resveratrol (0.067 versus 0.029 nmol/mg) in psoriasis-like mouse skin with impaired barrier capacity. Topical ε-viniferin alleviated psoriasiform symptoms and reduced IL-23 secretion (by 58% vs. 37%) more effectively than resveratrol. ε-Viniferin has potential as an anti-inflammatory agent to prevent or treat psoriasis.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Benzofurans; Chemistry, Pharmaceutical; Chemokines; Cytokines; Flavonoids; Glucosides; Inflammation Mediators; Keratinocytes; Mice; Phenols; Plant Extracts; Psoriasis; Resveratrol; Skin Absorption; Stilbenes; Swine

There is a need for new and effective topical treatment options for psoriasis. Recent phase I and II clinical trials have demonstrated efficacy of the novel nonsteroidal drug tapinarof to treat mild to moderate plaque psoriasis. Tapinarof is an aryl hydrocarbon receptor (AHR) agonist that induces antioxidant, immunomodulatory and epidermal differentiation regulation pathways. In this review, we examine the current preclinical and clinical studies with a focus on the mechanism of action, pharmacokinetics, safety and efficacy of tapinarof to treat psoriasis.

Topics: Administration, Topical; Clinical Trials as Topic; Humans; Psoriasis; Receptors, Aryl Hydrocarbon; Resorcinols; Stilbenes

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.

Topics: Administration, Topical; Animals; Basic Helix-Loop-Helix Transcription Factors; Cells, Cultured; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Humans; Inflammation; Mice; Psoriasis; Receptors, Aryl Hydrocarbon; Resorcinols; Skin; Stilbenes

The polyphenol resveratrol has anti-inflammatory effects in various cells, tissues, animals and human settings of low-grade inflammation. Psoriasis is a disease of both localized and systemic low-grade inflammation. The Sirtuin1 enzyme thought to mediate the effects of resveratrol is present in skin and resveratrol is known to down regulate NF-κB; an important contributor in the development of psoriasis. Consequently we investigated whether resveratrol has an effect on an Imiquimod induced psoriasis-like skin inflammation in mice and sought to identify candidate genes, pathways and interleukins mediating the effects.. The study consisted of three treatment groups: A control group, an Imiquimod group and an Imiquimod+resveratrol group. Psoriasis severity was assessed using elements of the Psoriasis Area Severity Index, skin thickness measurements, and histological examination. We performed an RNA microarray from lesional skin and afterwards Ingenuity pathway analysis to identify affected signalling pathways. Our microarray was compared to a previously deposited microarray to determine if gene changes were psoriasis-like, and to a human microarray to determine if findings could be relevant in a human setting.. Imiquimod treatment induced a psoriasis-like skin inflammation. Resveratrol significantly diminished the severity of the psoriasis-like skin inflammation. The RNA microarray revealed a psoriasis-like gene expression-profile in the Imiquimod treated group, and highlighted several resveratrol dependent changes in relevant genes, such as increased expression of genes associated with retinoic acid stimulation and reduced expression of genes involved in IL-17 dependent pathways. Quantitative PCR confirmed a resveratrol dependent decrease in mRNA levels of IL-17A and IL-19; both central in developing psoriasis.. Resveratrol ameliorates psoriasis, and changes expression of retinoic acid stimulated genes, IL-17 signalling pathways, IL-17A and IL-19 mRNA levels in a beneficial manner, which suggests resveratrol, might have a role in the treatment of psoriasis and should be explored further in a human setting.

Topics: Aminoquinolines; Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Gene Expression Regulation; Humans; Imiquimod; Interleukins; Male; Mice; Psoriasis; Resveratrol; Signal Transduction; Stilbenes

Benvitimod is a newly synthesized non-steroid small molecule being developed as a candidate drug for the treatment of inflammatory skin diseases. Here a rapid, sensitive and specific high performance liquid chromatography-tandem mass spectrometry (LC/ESI/MS/MS) method was developed for the determination of benvitimod in human plasma. The samples were alkalified with disodium tetraborate firstly, and then extracted by methyl tert-butyl ether. Fluorophenyl-benvitimod was used as internal standard (I.S.). Chromatographic separation was performed on an Ultra C(18) column (150mm×2.1mm, 5.0μm). The mixed mobile phase delivered at 300μl/min was CH3CN/H2O, 76.65:23.35 (v/v), containing 0.2mmol/L NH(4)COOH. Detection and quantitation was performed by electrospray ionization (ESI) and multiple reaction monitoring (MRM) in the negative ion mode. The most intense [M-H](-) MRM transition of benvitimod at m/z 253.1→211.0 was used for benvitimod quantitation and the transition at m/z 270.9→229.2 was used to monitor I.S. The calibration curve was linear within the concentration range of 0.1-10.0ng/mL (r>0.99). The lower limit of quantification (LLOQ) was 0.1ng/mL. The extraction recovery was above 80%. The accuracy expressed as relative error (RE) was less than 1.03%. The intra- and inter-day precisions were less than 11.81%. The freeze-thaw stability was also investigated and it was found that both benvitimod and the I.S. were quite stable. This method is especially useful for the pharmacokinetic study of benvitimod.

Topics: Administration, Topical; Anti-Inflammatory Agents, Non-Steroidal; Chromatography, High Pressure Liquid; Drug Stability; Humans; Psoriasis; Randomized Controlled Trials as Topic; Reproducibility of Results; Resorcinols; Sensitivity and Specificity; Stilbenes; Tandem Mass Spectrometry