As the therapeutic pipeline for atopic dermatitis (AD) is growing, several agents are coming closer to market. Ahead, we get updates on two promising topical agents: tapinarof and roflumilast. Of note, each is also being investigated to manage psoriasis, as well.
Tapinarof, a therapeutic aryl hydrocarbon receptor modulating agent or TAMA, inhibits the IL-17A and IL-17F pathways implicated in psoriasis and IL-4, IL-5, and IL-13 in atopic dermatitis. Positive data for the topical agent used in psoriasis have been published. (Read more in our July edition, online at PracDerm.com/TAMApso.)
Secondary efficacy and patient-reported outcomes from Dermavant’s Phase 2b randomized clinical trial of tapinarof cream for the treatment of atopic dermatitis were recently reported in The Journal of the American Academy of Dermatology (JAAD). Tapinarof 1% QD demonstrated statistically significant improvement in EASI75 compared to vehicle QD at Week 12. Tapinarof 1% QD demonstrated statistically significant greater reductions from baseline in mean percentage change in BSA compared to vehicle QD at Week 12.
Ahead, Todd Zavodnick, CEO at Dermavant Sciences, which is developing the topical therapy, talks about its potential to treat AD.
Are there any known or theoretical safety risks associated with this type of therapy?
Todd Zavodnick: In the Phase 2b studies for tapinarof for the treatment of psoriasis and atopic dermatitis, most adverse events were reported to be mild or moderate. In the psoriasis study, the most commonly reported adverse events were folliculitis, contact dermatitis, and headache. In the atopic dermatitis study, the most commonly reported adverse events were nasopharyngitis, folliculitis, and atopic dermatitis. While our current studies are ongoing and we won’t have clarity on the safety and tolerability profile until they report out, we have been pleased with overall retention in the studies with over 90 percent of subjects that have completed the pivotal trials electing to enroll in the PSOARING 3 (Long Term Extension Study).
How does this MOA compare or contrast with some of the newer classes of biologics on the market?
Mr. Zavodnick: Most biologics focus very specifically on individual cytokines or receptors in the inflammatory pathways of the various diseases (psoriasis and atopic dermatitis). As a result, and due to the disparate pathophysiology of the disorders, a biologic targeting pathways in psoriasis is typically not amenable to atopic dermatitis or vice versa. Because tapinarof influences both Th17 and Th2 pathways, it has the potential to impact the pathways in both psoriasis and atopic dermatitis, respectively. It is believed that the AhR modulation by tapinarof also increases antioxidant activity via upregulation of Nrf2 and promotes skin barrier restoration through upregulation of a number of epidermal barrier genes, including filaggrin, hornerin, and involucrin. These characteristics illustrate tapinarof’s potential to pivot between these very distinct diseases.
Looking at the early data, what strikes you in terms of the efficacy? Safety?
Mr. Zavodnick: While we remain blinded to the study results, we are pleased with the overall retention rates in the studies (even with the emergence of COVID). We have also witnessed a very high percentage of subjects completing the double-blind portion studies, electing to continue with the open-label extension study. We are looking forward to releasing details of top-line results in the second half of 2020.
Arcutis Biotherapeutics, Inc. is advancing ARQ-151 (topical roflumilast cream) to Phase 3 trials for the treatment of atopic dermatitis bypassing a previously planned Phase 2b AD trial, following meetings with the FDA. ARQ-151 is a once-daily topical cream formulation of roflumilast, a phosphodiesterase type 4 inhibitor (PDE4). PDE4 is an intracellular enzyme that increases the production of pro-inflammatory mediators and decreases production of anti-inflammatory mediators and has been implicated in a wide range of inflammatory diseases including psoriasis, eczema, and chronic obstructive pulmonary disease (COPD).
Arcutis Biotherapeutics is also developing ARQ-252, a potent and highly selective topical small molecule inhibitor of Janus kinase type 1 (JAK1), in adult patients with chronic hand eczema. Topline data from this trial are expected in the second half of 2021.
Ahead, Arcutis CEO Frank Watanabe talks about the potential for roflumilast.
What is the MOA of roflumilast for AD and psoriasis? Are there any other potential applications?
Frank Watanabe: Roflumilast is a once-daily topical cream formulation of a highly potent and selective PDE4 inhibitor (roflumilast) that is under development for atopic dermatitis and psoriasis. Roflumilast has shown greater potency (25-to 300-fold) than the two other FDA-approved PDE4 inhibitors. In addition to the cream formulation, we are also studying a foam version for the treatment of seborrheic dermatitis and scalp psoriasis.
Are there any known or theoretical safety risks associated with this type of therapy?
Mr. Watanabe: Oral roflumilast has been approved by the FDA for treatment to reduce the risk of exacerbations of COPD since 2011. There are more than a million patient years of exposure.
There hasn’t been any evidence of local tolerability issues (burning, stinging). Moreover, there hasn’t been any evidence of side effects typical of oral PDE4 inhibitors, such as nausea, vomiting, or diarrhea
To date, we have treated more than 1,700 patients with topical roflumilast in various clinical trials, and there has been no consistent signals of safety or tolerability issues.
In our Phase 2 proof-of-concept study, we reported:
- Both doses (0.15 and 0.05) of roflumilast cream were well-tolerated.
- 95 percent of subjects on active treatment completed the full study.
- The incidence of treatment-related Treatment Emergent Adverse Events (TEAEs) and application site reactions were low (< 5 percent) and similar between active treatment and vehicle.
- All TEAEs were mild to moderate in severity.
- Among subjects receiving ARQ-151, there was only one Serious Adverse Event (SAE), which was unrelated to treatment, and only one discontinuation due to a TEAE.
- The safety and tolerability of ARQ-151 in atopic dermatitis is particularly important given that most AD subjects are young children.
How does this MOA compare or contrast with some of the newer treatments for AD and PsO on the market?
Mr. Watanabe: Nearly all AD subjects who receive prescription therapy will be treated with a topical agent. Recall that AD is a disease that occurs predominantly in little kids and tends to be more extensive than psoriasis, with at least 20 to 30 percent body surface area being typical, and >50 percent BSA not unusual.
Also, because AD is a skin barrier defect, there is an increased risk of systemic exposure, even with topical treatment.
The major competition for us includes topical steroids and topical calcineurin inhibitors.
Chronic use of topical steroids is problematic, especially in young children, due to potential adrenal axis suppression and the risk of growth retardation, as well as local steroid side effects like skin thinning. Also, many parents are reluctant to use steroids on their children.
Topical calcineurin inhibitors (Elidel and Protopic) are generally less effective than steroids, are frequently irritating, and both have boxed warnings for lymphoma, which creates significant concerns for many parents.
Crisaborole (Eucrisa) is also a topical PDE-4 inhibitor and is indicated for the treatment of AD. Crisaborole’s affinity for the 4 different PDE-4 isotypes is 100- to 300-fold weaker than ARQ-151, potentially explaining its lack of efficacy in psoriasis and rather modest efficacy in AD. Furthermore, it burns/stings and is irritating upon application, and is an ointment (which patients prefer less than creams) that requires twice daily application.
In terms of novel agents in development for atopic dermatitis, other than topical roflumilast, the topical JAK inhibitors are the other notable topical agents in development. Topical JAK inhibitors are very effective in AD, but there are there are significant safety concerns that are likely to severely limit their use, especially in children.
In terms of novel agents in development for psoriasis, other than topical roflumilast, the topical AHR agonist tapinarof is the other notable topical agent in development. Tapinarof has demonstrated efficacy in psoriasis comparable to topical roflumilast, but has shown much poorer tolerability, in articular high rates of folliculitis and contact dermatitis in the area of drug application.
Also Worth Noting: Difamilast Moves Forward
Medimetriks Pharmaceuticals, Inc. is moving forward with its MM36 (difamilast) Atopic Dermatitis Development Program following a meeting with the FDA. Medimetriks is now preparing to conduct a single pivotal trial in the US for MM36, which will be supported by data from already-completed Phase 3 trials conducted in Japan.
MM36 (difamilast) is a novel, nonsteroidal, highly selective PDE4 inhibitor being developed as a topical treatment for atopic dermatitis (AD).
Looking at the early data, what strikes you in terms of efficacy and safety?
Mr. Watanabe: It’s clear from the POC study that the drug works in AD. Interestingly, the vehicle also works really well. AD responds to emollients, and we have a very emollient vehicle.
The primary endpoint was absolute change from baseline, and on that, we just missed statistical significance, albeit showing clear signs of efficacy.
The POC study was small (136 patients ages 12 and above), and if it had been slightly larger we likely would have reached statistical significance on the primary endpoint.
It’s clear, though, that there’s an effect and if you look at all the other endpoints, we hit statistical significance, for example on the 72 percent reduction from baseline on the EASI in patients treated with topical roflumilast. Half of patients treated with topical roflumilast had an EASI-75, and a half of patients treated with roflumilast got to IGA of clear almost clear—results that are comparable to a topical JAK or mid-potency steroid.
Both doses (0.15 and 0.05) of roflumilast cream were well-tolerated; 95 percent of subjects on active treatment completed the full study.