Nonsteroidal topical treatments for psoriasis, atopic dermatitis

Promising topical agents for psoriasis and/or atopic dermatitis (AD) that are commercially available or in late-stage development include tapinarof, JAK inhibitors, phosphodiesterase (PDE) inhibitors and combination products with novel patient-friendly vehicles.

In dealing with inflammatory dermatoses, says George Han, M.D., Ph.D., a patient’s desire for nonsteroidal topical treatments fits into an overall trend toward products perceived as natural. He is an assistant professor of dermatology at the Icahn School of Medicine at Mount Sinai in New York.

RELATED: Optimizing management of atopic dermatitis

However, he noted, patients should beware of Internet “miracle” products. When a colleague had a purported herbal cream brought in by a patient analyzed, its main ingredient was clobetasol.

Fortunately, says Dr. Han, an increasing number of nonsteroidal treatments for psoriasis and AD are becoming available. For starters, he says, many dermatologists are excited about tapinarof.

“Technically it is a natural product, which may satisfy picky patients who only want natural remedies,” he says. 

Tapinarof is a small molecule produced by bacteria that live off of nematodes.

MULTIFACETED MECHANISMS
In AD, which is expected to be tapinarof’s first indication, the drug has posted efficacy numbers more impressive than those of the PDE4 inhibitor crisaborole.

“One of the knocks on crisaborole is that while it has a useful place in our non-steroidal armamentarium, the separation between the medication and the vehicle isn’t that great, whereas with tapinarof you’re seeing a much larger delta between the active ingredient and the placebo control vehicle.”

In an early eczema trial, tapinarof achieved investigator global assessment (IGA) reductions of 43% and 56% in treated patients, vs. 15% for placebo.¹

An aryl hydrocarbon agonist, tapinarof inhibits many proinflammatory mediators associated with cutaneous infl ammation, including interferon gamma, TNF-alpha, interleukin (IL)-6 and IL-17.1 Additionally, tapinarof has been shown to enhance skin barrier function, which is a helpful feature in AD.²

“It is an intriguing molecule,” Dr. Han says. “If you look closely at the atopic dermatitis trials, the vast majority of patients who responded to treatment remained clear one month later. There are many reasons to believe that tapinarof will be helpful in more than one infl ammatory skin condition due to its broad eff ect on pro-inflammatory cytokines.”

In phase 2 psoriasis trials, 53% of tapinarof-treated patients achieved IGA 0/1 (with a two-point improvement from baseline) at week 12, versus 24% for placebo.³ Treatment-emergent adverse events aff ected 56% of the tapinarof group, versus 41%
for placebo. Most adverse events were mild.

“Those are the best numbers we’ve seen for any nonsteroidal treatment so far,” says Dr. Han.

Assuming tapinarof earns FDA approval, he says, it will bring the first truly novel mechanism to the eczema and psoriasis
markets in quite some time.

LP0133/JTE-052 inhibits JAK 1-3 and tyrosine kinase (Tyk) 2. In a phase 2 AD trial, various concentrations yielded modified eczema area and severity index (mEASI) reductions between 41.7% and 72.9%, vs. 12.2% for placebo (P < 0.001 for all analyses).⁴

RELATED: JAK Inhibitors Offer Multiple Applications

“Topical JAK inhibitors are going to be interesting because not only are we looking for efficacy in eczema and psoriasis, but those drugs might also get a lot of play in other dermatologic conditions such as alopecia areata and vitiligo, for which we lack an efficacious topical treatment outside of steroids. However, these conditions are also a little more diffi cult to design trials around, especially alopecia areata, which has a high rate of spontaneous recovery.”

One such medication, he adds, failed to meet primary endpoints due to high rates of treatment response in the vehicle treatment group.

Finding the right JAK inhibitor and formulating it into an effective topical vehicle has also proven challenging, he says, partly because some JAK inhibitors’ molecular heft is not ideal for topical application. Topical JAK inhibitors may debut in four to five years, Dr. Han estimates. 

In AD, he adds, crisaborole ointment appears equivalent to a lower-mid-potency steroid.

“Some proportion of patients experience burning and stinging. I find that if you give crisaborole ointment to a patient who’s having a severe eczema flare who has already been scratching their skin, they’re the ones who are prone to burning and stinging.”

For such patients, he starts with a stronger topical steroid for two weeks.

“Once you calm down the initial severe flare, they’re more likely to be able to maintain on crisaborole, and you optimize the safety and maximize the efficacy of the product in this way,” he says.

Thin-skinned areas such as the periocular area also tend to experience burning and stinging, says Dr. Han. He therefore recommends avoiding crisaborole ointment in such areas during acute disease flares, or refrigerating it or mixing it with a
moisturizer to improve tolerability.

“It has good efficacy and is an important part of the long-term treatment arsenal. We need more nonsteroidal topical anti-inflammatory medications like crisaborole to come to market,” Dr. Han says.

Although Pfizer is no longer pursuing a psoriasis indication for crisaborole ointment, Dr. Han sometimes uses it for inverse psoriasis.

“We want to avoid a steroid in areas such as skin folds that are prone to striae or cutaneous atrophy,” he says. “The medication has some utility there.”

COMBINATIONS FOR PSORIASIS
In psoriasis, says Dr. Han, there is room for combinations of existing agents with innovative vehicles. With calcipotriol-betamethasone diproprionate foam (Enstilar, LEO Pharma), he says, a mean Psoriasis Area and Severity Index (PASI) reduction of 73% was reported in phase 3 trials, but this data must be interpreted carefully because mean baseline PASI scores were between six and 10, reflecting a more moderate patient than in most trials of biologics.^5,6

“Enstilar is a very effective product. What’s novel is that the foam formulation super-saturates the active ingredients on the skin, so there is a higher concentration of drug delivered. We find that it works well in tough-to-treat places. It’s something I reach for when somebody who’s on a biologic has a couple of stubborn plaques.”

Patients also like the once-daily formulation, Dr. Han adds. 

Halobetasol propionate-tazarotene lotion (Duobrii, Ortho Dermatologics) combines a potent steroid and a retinoid for synergistic effects. Halobetasol helps suppress tazarotene-induced irritation, Dr. Han explains, while tazarotene helps prevent steroid-induced skin atrophy. He likes that the product demonstrated safety when tested in near-continuous use for one year (with maximum continuous exposure to 24 weeks).⁷

“That provides some comfort regarding longterm treatment that we currently do not have with such a strong steroid,” Dr. Han says. 

The product also may have off-label indications such as AA and vitiligo, he says, where previous combinations of retinoids and anti-inflammatories have shown some synergy. Halobetasol propionate 0.01% lotion (Bryhali, Ortho Dermatologics) has shown similar efficacy to halobetasol 0.05% cream.⁸

“And Bryhali is as efficacious in a oncedaily, rather than twice-daily, application,” Dr. Han says. He has been using a fair amount of halobetasol 0.01% in psoriasis and other topical steroid-responsive skin conditions. 

“I take heart in the fact that it was tested and approved in a longer treatment course - eight weeks of continuous use. People sometimes forget that some of the early topical clobetasol and betamethasone diproprionate studies had hypothalamic-pituitary-adrenal axis suppression in around 50% of patients, and you’re not supposed to use those longer than two weeks at a time,” he says.

Betamethasone diproprionate emollient spray (Sernivo, Promius Pharma) appears to have modest efficacy, similar to generic betamethasone diproprionate, says Dr. Han. In a 351-patient randomized clinical trial, 19% of patients met the endpoint of IGA zero or one, including a twopoint improvement from baseline, vs. 2.3% for placebo.⁹ However, the spray showed good tolerability-13.6% of patients who used a betamethasone lotion comparator experienced burning/stinging, versus 4.1% with the spray (P = 0.006).

Additionally, a calcipotriene-betamethasone cream formulation (MC2-01, MC2 Therapeutics) that has completed phase three psoriasis trials offers a novel vehicle that is says to improve drug delivery partly through a novel oil-in-water dispersion that results in a cosmetically elegant vehicle. MC2 Therapeutics is expected to file a new drug application this year. ƒ

 

Disclosures:

Dr. Han has been an advisor for Intraderm, Janssen, UCB and Eli Lilly; an investigator for MC2 Therapeutics; a speaker for Sun Pharma; an investigator and speaker for Pfizer; and an advisor and speaker for Sanofi Regeneron.

References:

Meeting
George Han MD. “New and Upcoming Topicals in Psoriasis and Atopic Dermatitis,” Atlantic Dermatological Conference. May 5, 2019. New York.

1. Bissonnette R, Poulin Y, Zhou Y, et al. Effi cacy and safety of topical WBI-1001 in patients with mild to severe atopic dermatitis: results from a 12-week, multicentre, randomized, placebo-controlled double-blind trial. Br J Dermatol.2012;166:853-860.

2. Smith SH, Jayawickreme C, Rickard DJ, et al. Tapinarof is a natural AhR agonist that resolves skin inflammation in mice and humans. J Invest Dermatol.2017;137:2110-2119.

3. Peppers J, Paller AS, Maeda-Chubachi T, et al. A phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of atopic dermatitis. J Am Acad Dermatol. 2019;80:89-98.e3.

4. Nakagawa H, Nemoto O, Igarashi A, Nagata T. Efficacy and safety of topical JTE-052, a Janus kinase inhibitor, in Japanese adult patients with moderate-to-severe atopic dermatitis: a phase II, multicentre, randomized, vehicle-controlled clinical study. Br J Dermatol. 2018;178:424-432.

5. Stein Gold L, Lebwohl M, Menter A, Villumsen J, Rosen M, Koo J. Aerosol foam formulation of fixed combination calcipotriene plus betamethasone dipropionate is highly efficacious in patients with psoriasis vulgaris: pooled data from three randomized controlled studies. J Drugs Dermatol. 2016;15:951-957.

6. Kim ES, Frampton JE. Calcipotriol/betamethasone dipropionate foam: a review in plaque psoriasis. Drugs. 2016;76:1485-1492.

7. Lebwohl MG, Sugarman JL, Gold LS, et al. Long-term safety results from a phase 3 open-label study of a fi xed combination halobetasolpropionate 0.01% and tazarotene 0.045% lotion in moderate-to-severe plaque psoriasis. J Am Acad Dermatol. 2019;80:282-285.

8. Kerdel FA, Draelos ZD, Tyring SK, Lin T, Pillai R. A phase 2, multicenter, double-blind, randomized, vehicle-controlled clinical study to compare the safety and efficacy of a halobetasol propionate 0.01% lotion and halobetasol propionate 0.05% cream in the treatment of plaque psoriasis. J Dermatolog Treat.2019;30:333-339.

9. Fowler JF Jr, Hebert AA, Sugarman J. DFD-01, a novel medium potency betamethasone dipropionate 0.05% emollient spray, demonstrates similar efficacy to augmented betamethasone dipropionate 0.05% lotion for the treatment of moderate plaque psoriasis. J Drugs Dermatol. 2016;15:154-162.