DISCUSSION
This series of dermal safety trials with tapinarof cream 1% in healthy volunteers was conducted in accordance with FDA guidelines for new topical drugs.12,13 The trials demonstrated no evidence of clinically significant cumulative irritation, sensitization, or phototoxic or photoallergic potential with tapinarof. In the cumulative skin irritation trial, tapinarof was classified as having "slight potential for very mild cumulative irritation" with repeated dosing for 21 days under exaggerated conditions with occlusive dressing of approximately 0.2 mL of tapinarof cream 1% per patch. In the skin sensitization trial, tapinarof was non-sensitizing, with no participants requiring re-challenge. No photoallergic responses were observed in the photoallergy trial and there was no indication of phototoxicity in the phototoxicity trial, suggesting a low risk for photoallergy and phototoxicity with application of tapinarof under standarduse conditions.
Overall, a low incidence of AEs was reported across the trials and none was considered related to tapinarof. This is consistent with the safety profile observed in 18 tapinarof clinical trials in over 2200 participants, including the phase 2b psoriasis15 and atopic dermatitis7 trials, two 12-week pivotal psoriasis trials (PSOARING 1 and 2),10 and the PSOARING 3 long-term extension trial,11 in which tapinarof cream 1% QD was well tolerated and showed no increased risk of AEs with long-term use.11 Notably, the dermal safety trials reported here found no evidence of drug sensitization. In phase 3 pivotal trials conducted in adults with psoriasis, treatment-related TEAE of contact dermatitis was reported in 3.8% (PSOARING 1) and 4.7% (PSOARING 2) of adults receiving tapinarof cream 1%.10
Interestingly, in participants experiencing contact dermatitis, the distribution was limited to focal areas and was not uniformly seen at all sites of application of tapinarof. This latter observation, together with the fact that reapplication of tapinarof after resolution of contact dermatitis did not uniformly re-elicit this AE, suggests that the observed dermatitis does not represent allergic contact dermatitis to tapinarof. This is further supported by the results of the skin sensitization study in which no positive patch tests results were observed in any of the healthy volunteers. This highlights the importance of conducting dermal safety trials in healthy adults and indicates that the AE of contact dermatitis observed in PSOARING 1 and 2 may have been associated with the underlying pathophysiological processes of psoriasis. Alternatively, the contact dermatitis events observed in the PSOARING phase 3 program may represent a phenotypic switch. This switch has been previously reported in patients with plaque psoriasis treated with biologic therapy. It has been proposed that targeting T helper (Th) 1 and Th17 cytokines could induce a shift to a Th2-dominated immune response and result in an atopic dermatitis phenotype.16
Tapinarof cream 1% once-daily may provide a first-in-class, nonsteroidal, topical therapeutic option for patients with psoriasis and AD that is highly effective and well tolerated. The safety profile of tapinarof represents a substantial advantage over other topical products such as corticosteroids, retinoids, and vitamin D analogs, which have restrictions on duration of use and site/ extent of application.2,3 In adults with plaque psoriasis, tapinarof cream 1% QD demonstrated highly statistically significant and clinically meaningful efficacy in two identical, double-blind, randomized, controlled, phase 3 trials (PSOARING 1 and 2),10 and a long-term, open-label, phase 3 trial (PSOARING 3).11 A clinical program comprising 2 pivotal phase 3 trials (ADORING 1 and 2) and a long-term extension trial (ADORING 3) is planned to evaluate the safety and efficacy of tapinarof cream 1% QD in children and adults with AD.
Overall, a low incidence of AEs was reported across the trials and none was considered related to tapinarof. This is consistent with the safety profile observed in 18 tapinarof clinical trials in over 2200 participants, including the phase 2b psoriasis15 and atopic dermatitis7 trials, two 12-week pivotal psoriasis trials (PSOARING 1 and 2),10 and the PSOARING 3 long-term extension trial,11 in which tapinarof cream 1% QD was well tolerated and showed no increased risk of AEs with long-term use.11 Notably, the dermal safety trials reported here found no evidence of drug sensitization. In phase 3 pivotal trials conducted in adults with psoriasis, treatment-related TEAE of contact dermatitis was reported in 3.8% (PSOARING 1) and 4.7% (PSOARING 2) of adults receiving tapinarof cream 1%.10
Interestingly, in participants experiencing contact dermatitis, the distribution was limited to focal areas and was not uniformly seen at all sites of application of tapinarof. This latter observation, together with the fact that reapplication of tapinarof after resolution of contact dermatitis did not uniformly re-elicit this AE, suggests that the observed dermatitis does not represent allergic contact dermatitis to tapinarof. This is further supported by the results of the skin sensitization study in which no positive patch tests results were observed in any of the healthy volunteers. This highlights the importance of conducting dermal safety trials in healthy adults and indicates that the AE of contact dermatitis observed in PSOARING 1 and 2 may have been associated with the underlying pathophysiological processes of psoriasis. Alternatively, the contact dermatitis events observed in the PSOARING phase 3 program may represent a phenotypic switch. This switch has been previously reported in patients with plaque psoriasis treated with biologic therapy. It has been proposed that targeting T helper (Th) 1 and Th17 cytokines could induce a shift to a Th2-dominated immune response and result in an atopic dermatitis phenotype.16
Tapinarof cream 1% once-daily may provide a first-in-class, nonsteroidal, topical therapeutic option for patients with psoriasis and AD that is highly effective and well tolerated. The safety profile of tapinarof represents a substantial advantage over other topical products such as corticosteroids, retinoids, and vitamin D analogs, which have restrictions on duration of use and site/ extent of application.2,3 In adults with plaque psoriasis, tapinarof cream 1% QD demonstrated highly statistically significant and clinically meaningful efficacy in two identical, double-blind, randomized, controlled, phase 3 trials (PSOARING 1 and 2),10 and a long-term, open-label, phase 3 trial (PSOARING 3).11 A clinical program comprising 2 pivotal phase 3 trials (ADORING 1 and 2) and a long-term extension trial (ADORING 3) is planned to evaluate the safety and efficacy of tapinarof cream 1% QD in children and adults with AD.
CONCLUSION
In conclusion, these dermal safety trials demonstrate no evidence
of clinically meaningful cumulative irritation, sensitization, or
phototoxic or photoallergic potential with tapinarof cream 1%
in healthy adults.
