TABLE 1.

Clinical trials on efficacy and safety of tapinarof

Study	Drug	Design	Outcomes	Results	Safety
NCT04042103 27 (Phase IIa, multicenter, open‐label trial)	Tapinarof 1% cream QD	‐ 21 participants (adults) with: ‐plaque psoriasis ‐PGA ≥3 ‐BSA ≥20% ‐ 19 participants completed the trial ‐ Tapinarof cream 1% applied QD for 29 days. There was no restriction on the area of application	Primary: Evaluate the safety, tolerability, efficacy (PGA, PASI and BSA) and PK of tapinarof cream 1% QD Secondary: Exclude clinically relevant effects of tapinarof cream 1% QD on the QT interval	Improvement in PGA score on day 29: ≥ 1‐grade: 14 patients (73.7%) ≥ 2‐grade: 6 patients (31.6%) PGA 0 or 1 and ≥2‐grade: 4 patients (21.1%) PASI: Mean day 1: 24,65 Mean day 29: 15,14 PASI75: 7 patients (36.8%) % BSA: Mean day 1: 27,20 Mean day 29: 14,44	Treatment‐emergent adverse effects Folliculitis (19%) Headache (19.0%) Others: Back pain Pruritus Contact dermatitis
Robbins et al 29 (Phase II, randomized, double‐blind, vehicle‐controlled study‐NCT02564042)	Tapinarof 0.5% or 1% cream QD or BID	227 patients aged 18–65 with: ‐Stable plaque psoriasis (≥6 months) ‐BSA ≥1%–≤15% ‐PGA score ≥2 Randomized in 6 arms (1:1:1:1:1:1, 12 weeks): 1% tapinarof BID (n = 38) 1% tapinarof QD (n = 38) 0.5% tapinarof b.i.d (n = 38) 0.5% tapinarof QD (n = 38) Vehicle b.i.d (n = 38) Vehicle QD (n = 38) 175 patients completed the trial	Primary % of patients with a PGA score of 0 or 1 at week 12 ≥2‐grade improvement in PGA score from baseline Secondary % patients achieving PASI 75 Mean change in PASI and BSA Changes in PGA Evaluation of adverse effects	PGA response at week 12: Higher (p = 0.05) in tapinarof groups 65%–1% b.i.d 56%–1% QD 46%–0.5% b.i.d 36%–0.5% QD PASI 75 at week 12: Higher (p = 0.05) in tapinarof groups 65%–1% b.i.d 56%–1% QD 46%–0.5% b.i.d 46%–0.5% QD 16%—vehicle b.i.d 5%—vehicle QD Mean reduction in %BSA at week 12: Tapinarof group: 3.6%–4.9% Vehicle group: 1%–1.6%	Treatment‐emergent adverse events: 68%–1% b.i.d 53%–1% QD 58%–0.5% b.i.d 45%–0.5% QD 24%—vehicle b.i.d 26% vehicle QD Mild‐to‐moderate intensity Most common: Folliculitis, contact dermatitis, application site dermatitis, application site, irritation, allergic dermatitis, headache, monocyte count decrease (1 case in vehicle group) Discontinuation: 10% tapinarof groups 1% vehicle groups. Due to contact dermatitis and application site dermatitis
Stein Gold L et al 30 (Multicenter, phase IIb, double blinded, randomized, vehicle‐controlled study)		227 patients aged 18–65 with: ‐plaque psoriasis ‐BSA ≥1% ‐ ≤15% ‐PGA ≥2 Randomized 1:1:1:1:1:1 received for 12 weeks: ‐Tapinarof cream 0.5% or 1% QD or BID ‐vehicle cream QD or BID	Efficacy outcomes: PGA response Change in mean PGA Total target lesion grading scores % patients achieving PASI50, PASI75, and PASI90.	PGA response: Higher in all tapinarof cream groups compared with vehicle group Mean improvements in PGA scores from baseline: Higher in all tapinarof groups compared to vehicle. Total target lesion grading Higher reductions in total target lesion grading scores from baseline were observed in all tapinarof groups beginning at week 2. PASI50, PASI75, and PASI90 Higher responses starting at week 2 compared to vehicle cream, and superior efficacy maintained until week 12 and 4 weeks after the treatment	Treatment‐emergent adverse effects Mild‐to‐moderate in severity Tolerability scores: Patient: Score of 0 or 1—none or slight application site burning/stinging and itching during 12 weeks Investigator: Predominantly 0 (no irritation) through 12 weeks No skin atrophy
	Tapinarof 1% cream 0.5% or 1% cream QD or BID	4 weeks of follow up
PSOARING 131 NCT03956355 (Phase III, multicentre, randomized, double blind, vehicle‐controlled trial)	Tapinarof 1% cream QD	−510 patients aged 18–75 with: ‐ mild to severe plaque psoriasis ‐BSA ≥3%–≤20% ‐PGA ≥2 2 arms (2:1, 12 weeks): −1% Tapinarof cream QD (n = 340) ‐Vehicle cream QD (n = 170)	Primary PGA response: PGA score of 0 or 1 and a decrease of ≥2–5 points at week 12 Secondary Changes in the baseline of BSA, PGA score of 0 or 1, PASI 75 and PASI 90 at week 12.	Primary: 35.4%—Tapinarof arm (p < 0,001 vs vehicle) 6%—Vehicle arm Secondary: PASI 75 36.1%—Tapinarof arm (p < 0.001 vs. vehicle) 10.2%—Vehicle arm PGA score of 0 or 1 37.8%—Tapinarof arm 9.9%—Vehicle arm (p < 0,001 vs vehicle) BSA changes −3.5%—Tapinarof arm (p < 0,001 vs vehicle) −0.2%—Vehicle arm PASI 90 18,8%—Tapinarof arm (p < 0,001 vs vehicle) 1,6%—Vehicle arm	Treatment‐emergent adverse effects Tapinarof arm: 50.3% Vehicle arm: 22.4% Most common: folliculitis, contact dermatitis, headache, pruritus
PSOARING 231 NCT03983980 (Phase III, multicentre, randomized, double blind, vehicle‐controlled trial)	Tapinarof 1% cream QD	515 patients aged 18–75 with: ‐Plaque psoriasis ‐ BSA ≥3%–≤20% ‐ PGA score ≥2 2 arms (2:1, 12 weeks): −1% Tapinarof cream QD (n = 343) ‐Vehicle cream QD (n = 172)	Primary PGA response: PGA score of 0 or 1 and a decrease of ≥2–5 points at week 12 Secondary Changes in the baseline of BSA, PGA score of 0 or 1, PASI 75 and PASI 90 at week 12.	Primary: 40.2%—Tapinarof arm (p < 0.001 vs. vehicle) 6.3%—Vehicle arm Secondary: PASI 75 47.6%—Tapinarof arm (p < 0,001 vs vehicle) 6.9%—Vehicle arm PGA score of 0 or 1 43,6%—Tapinarof arm (p < 0,001 vs vehicle) 8.1%—Vehicle arm BSA changes −4.2%—Tapinarof arm (p < 0,001 vs vehicle) −0.1%—Vehicle arm PASI 90 20.9%—Tapinarof arm (p < 0,001 vs. vehicle) 2.5%—Vehicle arm	Treatment‐emergent adverse effects Tapinarof arm: 54.5% Vehicle arm: 26.2% Most common: folliculitis, contact dermatitis, headache, pruritus
PSOARING 332 (multicenter, open label, extension study)	Tapinarof 1% cream QD	763 patients that had completed 12 weeks' treatment with tapinarof or vehicle in PSOARING 1 or 2 18–75 years with chronic plaque psoriasis, stable for at least 6 months before randomization %BSA affected of ≥3% and ≤ 20% (excluding scalp, palms, soles, fingernails, and toenails), and (PGA score of 2 (mild), 3 (moderate), or 4 (severe) at screening)	Safety Incidence and frequency of AEs, patient‐ and investigator‐assessed local tolerability, vital signs, physical examinations, and laboratory tests Efficacy PGA = 0 at any time during the trial; the total duration of remittive effect; the median duration of remittive effect in patients entering with PGA = 0; and the proportion of patients entering the trial with PGA≥2 who achieved a response (PGA = 0 or 1) at any time during the trial	Efficacy 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 remittive effect off‐therapy for patients achieving PGA = 0 was 130.1 days.	Safety 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%). Tolerability >90% of patients showed no irritation at all visits Good tolerability on sensitive and intertriginous skin. Patient‐reported burning/stinging and itching was low by 86%–92% of patients over 40 weeks
		Patients entering with PGA = 0 discontinued treatment and were monitored for remittive effect (maintenance of a PGA score of 0 or 1 while off therapy) Patients entering with PGA≥1 were instructed to apply tapinarof 1% QD	Tolerability Local tolerability was evaluated using a patient reported 5‐point scale of 0 (none) to 4 (strong/severe) for burning/stinging and itching, and an investigator‐assessed 5‐point scale of 0 (no irritation) to 4 (very severe) for dryness, erythema, and peeling

Abbreviations: AE, adverse event; BID, twice daily; BSA, body surface area; PASI, Psoriasis Area and Severity Index; PASI75 ≥ 75% improvement in Psoriasis Area and Severity Index; PASI90 ≥ 90% improvement in Psoriasis Area and Severity Index; PGA, Physician's Global Assessment; QD, once daily.