Tapinarof cream 1% in plaque psoriasis: a profile of its use

Tapinarof (VTAMA®) cream 1%, a topical, non-steroidal, aryl hydrocarbon receptor agonist, presents a valuable addition to the therapy options for topical treatment of plaque psoriasis in adults. In the pivotal 12-week, randomized, double-blind, vehicle-controlled, phase 3 PSOARING 1 and PSOARING 2 trials, once-daily tapinarof cream 1% was shown to be efficacious in reducing the severity of plaque psoriasis. Furthermore, evidence from an open-label extension study shows that continuous and intermittent use of tapinarof cream 1% for up to 1 year has durable on-treatment efficacy with a substantial remittive effect off treatment. Tapinarof cream 1% was generally well tolerated, with few patients discontinuing treatment in the pivotal trials due to adverse events, and with no new safety signals identified with longer-term treatment. Post-marketing real-world data and/or active-controlled studies to compare tapinarof cream 1% with other topical treatments used for plaque psoriasis would be of interest. Plaque psoriasis, an inflammatory skin disease, can have considerable negative impacts on physical as well as psychological well-being. Most commonly, plaque psoriasis is treated with topical medications, including corticosteroids. While generally efficacious (particularly in the short term), many of the currently used topical medications are restricted in the length of time and/or in the regions of the body that they can be used. Tapinarof (VTAMA®) cream 1% is a first-in-class, non-steroidal, topical therapy which received US Food and Drug Administration approval in 2022 for use in the treatment of plaque psoriasis in adults. As demonstrated in two 12-week, vehicle-controlled, phase 3 trials, once-daily tapinarof cream 1% reduces the severity of plaque psoriasis. Evidence from a 40-week extension study showed that the efficacy is durable and, furthermore, that the therapeutic effects of tapinarof cream 1% are maintained for a substantial period off treatment. Tapinarof cream 1% was generally well tolerated, including at the sites of application. Thus, tapinarof cream 1% presents a valuable addition to the therapy options for topical treatment of plaque psoriasis in adults.


What is the rationale for developing tapinarof cream 1% in plaque psoriasis?
Psoriasis is a chronic, immune-mediated skin disease which, in addition to the negative impacts on physical well-being, can be associated with a significant psychological burden [1][2][3]. In the USA, psoriasis affects 3.0% of adults aged ≥ 20 years, although the prevalence varies by race (White, 3.6%; Asian, 2.5%; Hispanic, 1.9%; Black, 1.5%) [4]. Plaque psoriasis, the most prevalent manifestation of the disease (making up ≈ 90% of cases), is characterized by well-demarcated, erythematous, scaly plaques [1,2]. It most commonly affects the extensor surfaces of the elbows and knees, the trunk, the scalp, and intertriginous areas (e.g., axillae, the groin, the intergluteal cleft), but can occur on skin surfaces anywhere on the body and can range from a few lesions to widely generalized disease [1,2].
A range of therapies is available for the treatment of psoriasis, with disease severity being one of the main determining factors in the choice of therapy used [3,[5][6][7]. While systemic or biologic therapies are indicated for the treatment of moderate-to-severe psoriasis in adults [6,7], mild to moderate disease is most commonly treated with topical medications (including corticosteroids, calcineurin inhibitors, vitamin D analogues, retinoids, and others) [5]. Topical medications are also commonly used as adjunctive therapies for patients receiving phototherapy, systemic, or biologic therapy [5].
While topical therapies are generally highly efficacious (particularly for short-term use) and remain the mainstay of psoriasis treatment, many of the currently used topical medications have restrictions in the length of time and/or in the regions of the body that they can be used [5]. Given these limitations, there was an unmet clinical need in the treatment of psoriasis and the search for improved treatments has continued. In this context, one therapeutic target of interest identified for the treatment of psoriasis was the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor which has been found to play a crucial role in skin homeostasis [8].
Tapinarof, an anti-inflammatory compound originally derived from the metabolites of a group of bacterial symbionts of entomopathogenic nematodes, was identified as an AhR agonist and investigated for its potential in the treatment of inflammatory skin diseases, including plaque psoriasis and atopic dermatitis [8]. Supported by the findings of a range of clinical trials, including the pivotal, randomized, double-blind, vehicle-controlled, PSOARING 1 and PSOARING 2 phase 3 trials [9] and the PSOARING 3 openlabel long-term extension trial [10], tapinarof (VTAMA ® ) cream 1% has been approved in the USA and is indicated for the topical treatment of plaque psoriasis in adults [11]. Table 1 provides a summary of the prescribing information for tapinarof cream 1%, under the US label [11]. Consult local prescribing information for further details.

How does tapinarof cream 1% work?
Tapinarof is a first-in-class, non-steroidal, AhR agonist; however, the specific mechanisms of action of tapinarof cream 1% in the treatment of plaque psoriasis have not been fully elucidated [11]. In vitro studies have shown that tapinarof binds to and activates AhR in human skin cells [12]. Furthermore, there is evidence that tapinarof induces gene expression of skin-barrier proteins (e.g., filaggrin) in primary human keratinocytes and also moderates expression of T helper-17-type pro-inflammatory cytokines (including interleukin-17A) [12]. In mouse models of psoriasis, topical tapinarof cream 1% reduced erythema, epidermal thickening, and tissue cytokine levels in AhR-sufficient but not AhR-deficient mice, confirming that the anti-inflammatory properties of tapinarof involve AhR modulation [12].

What are the pharmacokinetic properties of tapinarof?
Tapinarof plasma exposure is low, with the topical application of tapinarof cream 1% once daily under maximal use conditions (in patients with plaque psoriasis affecting ≥ 20% of the body-surface area) resulting in concentrations of tapinarof that, using a sensitive assay, were below the quantifiable limit (< 50 pg/mL) in the majority (68%) of samples [13]. Maximum tapinarof plasma concentrations were reached 2-5 h after application. The highest plasma concentrations were observed on day 1 of treatment, with tapinarof plasma exposure decreasing over time with repeat once-daily application, possibly due to the effect of the drug towards restoring the skin barrier function [13]. Consistently low tapinarof plasma concentrations were also reported in the pivotal 12-week, phase 3 PSOARING 1 and PSOARING 2 trials in patients with plaque psoriasis affecting 3-20% of the body-surface area [9], with > 95% of samples in the pivotal trials having tapinarof concentrations that were below the quantifiable limit [14]. These pharmacokinetic findings suggest a low potential for clinically relevant drug interactions with tapinarof cream 1% once daily [14].
In vitro studies indicate that tapinarof metabolism is hepatic and involves multiple processes, including oxidation, glucuronidation, and sulfation [15]. Oxidative metabolism of tapinarof primarily involves cytochrome P450 (CYP) 1A2 and CYP3A4, with minor contributions from CYP2C9, CYP2C19, and CYP2D6 [15]. Concentrations of the metabolite tapinarof sulfate were below the quantifiable limit (< 10 pg/mL) in all samples in the maximal use study, indicating that unchanged tapinarof is the major circulating component in plasma [13].

What is the efficacy of tapinarof cream 1% in plaque psoriasis?
Once-daily topical tapinarof cream 1% is efficacious in reducing the severity of plaque psoriasis, based on results from two 12-week, multicenter, randomized, double-blind,

Adis evaluation of tapinarof cream 1% in the treatment of plaque psoriasis
A first-in-class, non-steroidal, aryl hydrocarbon receptor agonist indicated for the topical treatment of plaque psoriasis in adults Once-daily application Significantly reduces the severity of plaque psoriasis Has durable on-treatment efficacy and a substantial offtreatment remittive effect Generally well tolerated No US Food and Drug Administration contraindications or restrictions on duration, extent or sites of application vehicle-controlled, phase 3 trials (PSOARING 1 and PSOARING 2) [9]. Furthermore, continuous and intermittent use of tapinarof cream 1% for up to 1 year has durable on-treatment efficacy with a substantial remittive effect off treatment, based on the findings of the open-label extension trial, PSOARING 3 [10]. The tapinarof concentration and dosing frequency used in the phase 3 trials (i.e., 1%, once daily) were selected based on the findings of a 12-week, randomized, vehicle-controlled, phase 2b dose-finding trial (NCT02564042) in 227 adults with plaque psoriasis, with significant efficacy for tapinarof cream 1% once daily also demonstrated in the dose-finding trial [16].
The pivotal PSOARING 1 and PSOARING 2 trials were of identical design and enrolled adults (aged 18-75 years) with chronic plaque psoriasis and stable disease for ≥ 6 months [9]. Eligible participants had a Physician Global Assessment (PGA) score of 2 (mild disease), 3 (moderate disease), or 4 (severe disease), and a body-surface area involvement (excluding the scalp, palms, fingernails, toenails, and soles) of 3-20%. Patients were randomized (2:1) to treatment with tapinarof cream 1% or vehicle cream, with stratification according to baseline PGA score. For study treatment, patients were instructed to apply a thin layer of trial cream to affected areas once daily, including newly appearing lesions and any areas in which psoriasis cleared during the trial. Treatment of fingernail, toenail, palm, sole, and scalp lesions was permitted but not required; efficacy outcomes in the trial did not include assessment of any treatment effect in these areas. Only the trial cream was permitted for the treatment of psoriasis lesions. The use of biologic agents, apremilast, methotrexate, and glucocorticoids was prohibited during the trial and for a minimum period before baseline (five half-lives for biologics, 4 weeks for the other systemic therapies) [9].
The primary endpoint was a PGA response [defined as a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of ≥ 2 points on the 5-point PGA scale] at week 12 [9]. To control for multiplicity, secondary endpoints were tested sequentially in a prespecified hierarchy ( Table 2). Efficacy endpoints were analyzed in the intentto-treat population (n = 510 and 515 in PSOARING 1 and PSOARING 2, respectively), with multiple imputation used to handle missing data [9].
Demographics and clinical characteristics of patients at baseline were generally well balanced across treatment groups in both PSOARING 1 and PSOARING 2 [9]. Across both trials, most (82%) patients had moderate disease (PGA score of 3) at baseline, while 10% had mild disease (PGA score of 2) and 8% had severe disease (PGA score of 4). At baseline, patients had a mean Psoriasis Area and Severity Index (PASI) score of 9 and had disease affecting a mean of 8% of body-surface area [9].
In both PSOARING 1 and PSOARING 2, a significantly (p < 0.001) higher percentage of patients treated with tapinarof cream 1% achieved a PGA response at 12 weeks compared with those treated with vehicle cream (primary endpoint; Table 2) [9]. Results for all secondary endpoints also significantly (p < 0.001) favored tapinarof cream 1% over vehicle cream in both trials (Table 2), including the percentage of patients with a ≥ 75% reduction in the PASI score (PASI 75) from baseline to week 12; the percentage of patients with a PGA score of 0 or 1 at week 12; the mean change in the percent of total body-surface area affected from baseline to week 12; and the percentage of patients with a ≥ 90% reduction in the PASI score (PASI 90) from baseline to week 12 [9].
Patients who completed 12 weeks of treatment in PSOARING 1 or PSOARING 2 were eligible to enter Table 1 Summary of the prescribing information of tapinarof (VTAMA ® ) cream 1% in plaque psoriasis in the USA [11] What is the approved indication for tapinarof cream 1%? Topical treatment of plaque psoriasis in adults How is tapinarof cream 1% available? In tubes containing 60 g of cream; each gram of cream contains 10 mg of tapinarof How should tapinarof cream 1% be administered?
A thin layer of cream should be applied to affected areas once daily Hands should be washed after application (unless the cream is used for treatment of the hands) The cream is not for oral, ophthalmic, or intravaginal use What are the contraindications to the use of tapinarof cream 1%? None How should tapinarof cream 1% be used in special populations? Lactating women Based on animal data, tapinarof may be secreted in breast milk Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for tapinarof cream 1% and any potential adverse effects on the breastfed infant from tapinarof cream 1% or from the underlying maternal condition a Patients entering the trial with, or achieving during the trial, a PGA score of 0 (clear) discontinued treatment and were followed for off-treatment remittive effect (defined as the maintenance of a PGA score of ≤ 1 while off treatment). Clinical assessments were performed every 4 weeks. If disease worsened (defined as reaching a PGA score of ≥ 2), tapinarof cream 1% was restarted and continued until a PGA score of 0 was achieved [10]. Tapinarof cream 1% demonstrated continued and durable efficacy in PSOARING 3, with 312 (40.9%) of the 763 patients achieving a PGA score of 0 (clear from disease) at least once during the trial (79 patients entering the extension trial with a PGA score of 0 and 233 who entered the trial with a PGA score of ≥ 1) [10]. Data from PSOARING 3 also suggest that the maximal treatment effect may not have been reached in the 12-week PSOARING 1 and PSOARING 2 trials. Of the 519 patients who entered PSOARING 3 with a PGA score of ≥ 2, 302 patients (58.2%) achieved a PGA score of 0 or 1 at least once during the extension trial. A substantial off-therapy remittive effect was also observed in PSOARING 3. Among patients entering the extension study with a PGA score of 0 (n = 79), there was a median off-treatment remittive effect of 115 days (95% CI 85-168); 19 (24.1%) of these patients did not require retreatment during the extension trial. For the 312 patients achieving a PGA score of 0 at any time during PSOARING 3, the mean total duration of off-treatment remittive effect was 130 days [10].
Evidence for the efficacy of tapinarof cream 1% in patients with more extensive plaque psoriasis disease is available from a small, 29-day, open-label, phase 2a trial (NCT04042103) [13]. The trial enrolled 21 patients with moderate to severe plaque psoriasis (mean PASI score of 24.65; mean percentage of body-surface area affected of 27.20%). One patient withdrew and one patient was lost to follow-up. Of the 19 patients who completed the trial, 12 patients (63.2%) had moderate disease (PGA score of 3) and seven patients (36.8%) had severe disease (PGA score of 4) at baseline. At the end of the trial (day 29), four patients (21.1%) had a PGA score of 1 (almost clear), nine patients (47.4%) had a PGA score of 2 (mild disease), five patients (26.3%) had a PGA score of 3 (moderate disease), and one patient (5.3%) had a PGA score of 4 (severe disease), with a mean change from baseline in PGA score among these 19 patients of − 1.2 points (p < 0.0001). Additionally, there was a mean change in PASI score from baseline of − 15.14 points (− 59.56% change) and a mean change in the percentage of body-surface area affected from baseline of − 14.44 percentage points (− 49.77% change) [13].

What is the tolerability profile of tapinarof cream 1%?
Topical tapinarof cream 1% once daily was generally well tolerated in clinical trials in patients with plaque psoriasis [9,10,13,16]. In the pivotal, 12-week, vehicle-controlled Table 2 Efficacy of tapinarof cream 1% in plaque psoriasis in the vehicle-controlled PSOARING 1 and PSOARING 2 phase 3 trials [9] BSA body-surface area, PASI Psoriasis Area and Severity Index, PGA Physician Global Assessment, pts patients, wk week *p < 0.001 vs vehicle cream a Endpoints are listed in the prespecified order of hierarchical testing b Primary endpoint; PGA response defined as a PGA score of 0 or 1 and a decrease of ≥ 2 points from baseline at wk 12 c PASI 75 response defined as a ≥ 75% reduction in the PASI score from baseline to wk 12 d PASI 90 response defined as a ≥ 90% reduction in the PASI score from baseline to wk 12  [9]. Based on pooled data from the two trials, the most common TEAEs, occurring in ≥ 1% of tapinarof cream 1% recipients (n = 683) and more frequently than in vehicle cream recipients (n = 342), were folliculitis (20% vs 1%), nasopharyngitis (11% vs 9%), contact dermatitis (7% vs 1%), headache (4% vs 1%), pruritus (3% vs 1%), and influenza (2% vs 1%) [11]. Most TEAEs were mild to moderate in severity [9]. Across the two trials, TEAEs leading to trial discontinuation occurred in 5.7% of tapinarof cream 1% recipients and 0.3% of vehicle cream recipients. Sixteen patients (2.3%) receiving tapinarof cream 1% developed serious TEAEs, none of which were considered to be related to treatment; no serious TEAEs were reported in patients receiving vehicle cream [9]. Tapinarof cream 1% was well tolerated at application sites, with low levels of local irritation reported in the PSOARING 1 and PSOARING 2 trials [9]. With patientreported assessment of burning/stinging and itching on a 5-point scale ranging from 0 (none) to 4 (severe), mean scores were ≤ 2 (mild) across visits in both treatment groups in both trials. Furthermore, mean scores were numerically lower with tapinarof cream 1% than vehicle cream at all visits. Similarly, with investigator-assessment of dryness, erythema, and peeling on the 5-point Local Tolerability Scale [with scores ranging from 0 (no irritation) to 4 (very severe)], mean scores were < 1 (mild) across visits in both treatment groups in both trials, including when the cream was applied to sensitive areas, such as the face and intertriginous areas [9].
Tapinarof cream 1% continued to be generally well tolerated longer term with treatment for up to 52 weeks (including 12 weeks in PSOARING 1 or 2 and up to 40 weeks in PSOARING 3) [10]. The tolerability profile for tapinarof cream 1% in PSOARING 3 was generally consistent with that reported in PSOARING 1 and 2. No new safety signals were identified in the extension trial [10].

What is the current clinical position of tapinarof cream 1% in plaque psoriasis?
Clinical trial data show that once-daily topical tapinarof cream 1% is efficacious and generally well tolerated in the treatment of plaque psoriasis in adults [9,10,13,16]. Furthermore, with evidence that continuous and intermittent use of tapinarof cream 1% has durable on-treatment efficacy, a substantial remittive effect off treatment, and a consistent tolerability profile over longer-term (up to 1 year) treatment [10], tapinarof cream 1% presents a valuable addition to the therapy options for topical treatment of plaque psoriasis in adults.
The pivotal vehicle-controlled PSOARING 1 and PSOARING 2 trials showed that once-daily topical tapinarof cream 1% significantly reduces the severity of plaque psoriasis in adults over a period of 12 weeks [9]. Furthermore, the open-label extension study, PSOARING 3, showed that continuous and intermittent use of tapinarof cream 1% for up to 1 year has durable on-treatment efficacy, with no apparent tachyphylaxis, and a substantial remittive effect off treatment [10]. While the pivotal PSOARING 1 and PSOAR-ING 2 were well designed, one limitation was part of the trial design that restricted the proportion of patients with mild or severe disease to ≈ 10% each [9]. Thus, although the trials included patients with plaque psoriasis across the range from mild to severe disease, ≈ 80% of patients in the trials had moderate disease (PGA score of 3) at baseline, which (at least to some extent) may limit the generalizability of the trial findings [9].
Tapinarof cream 1% is generally well tolerated, with few patients discontinuing treatment during clinical trials due to adverse events [9,10,13,16]. Pharmacokinetic data from patients treated with topical tapinarof cream 1% under maximal use conditions showed that systemic exposure of tapinarof is low [13], which is consistent with the low rates of systemic adverse events observed in clinical trials [14]. Additionally, tapinarof cream 1% was well tolerated at sites of application, with low levels of local irritation reported, including when the cream was applied to sensitive areas such as the face and intertriginous areas [9]. The most common adverse event reported in patients treated with tapinarof cream 1% was folliculitis, reported in clinical trials with an incidence of ≈ 20% [9,10,13,16]; however, folliculitis was mostly mild and infrequently led to treatment discontinuation [17]. The tolerability profile of tapinarof cream 1% with continuous or intermittent treatment for up to 52 weeks was consistent with that derived from the 12-week vehiclecontrolled trials, and no new safety signals were identified with longer-term treatment [10].
Thus, based on these collective findings, tapinarof cream 1% appears to address some of the limitations of other topical medications currently used for the treatment of plaque psoriasis. Notably, tapinarof cream 1% has been approved by the US Food and Drug Administration for the treatment of plaque psoriasis of any severity in adults, without restrictions on duration, extent or sites of use. Activecontrolled trials comparing the efficacy, safety, and tolerability of tapinarof cream 1% with other topical plaque psoriasis therapies, or other comparative data, would be of interest.
A further key aspect affecting the effectiveness of topical medications in the treatment of psoriasis is that of patient adherence to treatment [18]. Based on assessment from patient diaries and the weight of tapinarof tubes used, adherence to tapinarof cream 1% in the phase 3 trials was approximately 90% or higher [9,10]. Furthermore, patient satisfaction data from the PSOARING 3 extension trial indicated generally high patient satisfaction with tapinarof cream 1% [19]. Nonetheless, real-world data will be required to accurately assess the potential impact of factors such as patient adherence on treatment effectiveness for tapinarof cream 1%.