Treatment options for psoriasis expanding

Miami Beach, Fla. - Key trends among topical treatments for psoriasis include the potential reformulation of systemic therapies into topical form, the search for steroid alternatives and the optimization of vehicles, an expert says.

“Overall, there are exciting innovations in drug mechanisms for psoriasis on the horizon,” says Neal Bhatia, M.D., dermatologist in private practice in Long Beach, California and an associate professor of dermatology at the Harbor University of California Los Angeles Medical Center. He spoke recently at the South Beach Symposium.

“The old way we understood psoriasis was that there were just two components: a thick epidermis and inflammation,” he says.

Standard therapies targeted these problems; for example, salicylic acid and urea attempt to impact epidermal turnover, and steroids regulate the inflammation.

‘Losing the battle’

However, Dr. Bhatia says, microscopic analysis reveals that psoriasis consists of inflammation, along with neutrophils, in the stratum corneum; plus lymphocytes and dendritic cells throughout the epidermis and dermis.

“So there’s inflammation swimming throughout the entire process. And when physicians treat with ‘just steroids,’ they’re losing the battle in terms of treating the whole process. Steroids can inhibit the barrier and impair differentiation. What is needed in psoriasis is to slow down the irregular turnover of keratinocytes, which we now know is controlled by IL-17, -22 and -23,” he says.

Phosphodiesterase (PDE) and Janus activated kinase (JAK) inhibitors theoretically work further upstream than agents affecting IL-17, -22 and -23, he says.

“Rather than just blocking the actions of IL-17, -22 and -23, these treatments are trying to block those enzymes, so that those cytokines aren’t made in the first place,” Dr. Bhatia says.

The oral PDE4 inhibitor apremilast (Celgene), which inhibits cyclic adenosine monophosphate (cAMP), is in phase 3 trials for psoriasis and other chronic inflammatory diseases. It was approved in March 2014 for adult patients with active psoriatic arthritis and is pending FDA approval for psoriasis sometime this year.

Among JAK inhibitors, tofacitinib (Pfizer), which is approved for rheumatoid arthritis, is being developed in topical form for psoriasis.

Similarly, INCB 18424/ruxolitinib (Novartis), a selective inhibitor of JAK1 and JAK2, inhibits various cytokines involved in signaling of the Th1 and Th17 pathways. In an unpublished phase 2b study, ruxolitinib 1 percent cream achieved a mean psoriasis area severity index (PASI) reduction of 40 percent, versus 1 percent for placebo (Ortiz-Ibanez K, Alsina MM, Munoz-Santos C. Actas Dermosifiliogr. 2013;104(4):304-310).

Next: Trend toward topicals

Topical trend

The foregoing projects exemplify an exciting trend - the reformulation of systemic therapies into topical form, Dr. Bhatia says. These medications should prove much more patient-friendly than injectable or infusion-based treatments, he says, while bringing the benefits of powerful therapies - based on a deeper understanding of the psoriasis etiology – to small surface areas in patients with mild-to-moderate psoriasis.

Other topical treatments under development include the following:

• LAS41004 (Allmiral) - This nonsteroidal agent has completed four phase 2 studies in psoriasis;

• M518101 (Maruho) - As of March 2014, the developer of this vitamin D3 analogue was recruiting patients for a phase 3 study in psoriasis;

• Calcipotriene-betamethasone diproprionate under patch occlusion - In a 35-patient study, psoriatic lesions treated with the occlusive hydrogel patch showed statistically significant improvement versus unoccluded lesions (P=0.0008; Patel T, Bhutani T, Busse KL, Koo J. Cutis. 2011;88(3):149-154);

• Topical methotrexate (MediQuest) - As of early 2014, this product had completed a phase 2b trial for nail psoriasis, but no results have been released (http://apps.who.int/trialsearch/trial.aspx?TrialID=ISRCTN62739763);

• Rose Bengal (Provectus) - In a phase 2c study, all three treatment arms (0.002 percent, 0.005 percent, 0.01 percent) showed improvement over the vehicle arm, with the low dose (0.002 percent) providing uniformly consistent improvement for all Psoriasis Severity Index (PSI) efficacy parameters over the treatment interval, Provectus states. Additionally, 23 to 29 percent of treated subjects achieved complete or nearly complete resolution of all PSI component symptoms (erythema, induration and desquamation), versus no subjects in the vehicle arm;

• Topical vitamin B12 - Dr. Bhatia says this option could draw significant interest down the road as a psoriasis treatment, depending upon what research reveals regarding its mechanism of action.

Meanwhile, development of the mitogen-activated protein kinase kinase (MEK) inhibitor E6201 (Eisai) has been discontinued, according to Eisai. Similarly, despite successful completion of phase 2 trials in psoriasis, Anacor has suspended development of the boron-based topical agent AN 2728 for this indication as the company instead focuses on atopic dermatitis, according to the company.

Next: The right vehicle, the right application

Finding the right vehicle

Therapeutically, Dr. Bhatia also sees an emphasis on using the right vehicle in the right application. In this regard, a new desoximetasone 0.25 percent spray (Topicort, Taro), approved in April 2013, showed impressive clearance rates in its pivotal study (Kircik L, Lebwohl MG, Del Rosso JQ, et al. J Drugs Dermatol. 2013;12(12):1404-1410), he says.

“But more important is the versatility of the spray.” Like clobetasol spray, Dr. Bhatia says, patients can apply desoximetasone spray to the scalp, legs and hard-to-reach areas.

Regarding vitamin D, he says, calcitriol or natural vitamin D has proven less irritating and slightly more efficacious than calcipotriene, which is synthetic. Traditionally, he adds, dermatologists also use topical vitamin D to promote differentiation. However, Dr. Bhatia says, rather than being keratolytic, vitamin D analogs and retinoids actually regulate transcription, partly by inhibiting IL-2, -6 and -8, along with interferon and granulocyte-macrophage colony stimulating factor (Laws PM, Young HS. Expert Opin Pharmacother. 2010;11(12):1999-2009). “When the actions of those cytokines are slowed down, it can re-stimulate differentiation to a point where keratinocytes will behave normally again.”

Additionally, “One of the big knocks against vitamin D in the psoriasis marketplace was that people thought it didn’t work. But we must define what ‘work’ means. Vitamin D will not put out the fire of an acute outbreak,” he says.

Rather, Dr. Bhatia says vitamin D improves long-term outcomes by changing proliferation and skin cell turnover rates. Regarding calcipotriene in particular, many studies show that in combination regimens with topical steroids, phototherapy or lasers, it improves patients’ response versus those treatments alone.

An ‘unfair assessment’

Over time, topical vitamin D alone isn’t enough to prevent an eruption, he says. When this happens, adding steroids typically resolves the eruption quickly, giving patients the impression that steroids work and vitamin D doesn’t.

“That’s an unfair assessment. You won’t see vitamin D fail unless it’s over the long run. When vitamin D is doing its job, you don’t notice it,” Dr. Bhatia says.

A six-week study that pitted calcipotriene ointment versus fluocinonide ointment showed that both treatments achieved similar improvements in investigator global assessments at week two, but calcipotriene posted statistically significant advantages at weeks four and six (Bruce S, Epinette WW, Funicella T, et al. J Am Acad Dermatol. 1994;31(5 Pt 1):755-759). “That reinforces the concept of not just treating, but keeping the process under control,” he says.

Among retinoids, tazarotene provides the advantage of being very specific for binding and interacting with both retinoic acid receptors (RARs) and retinoid X receptors (RXRs), Dr. Bhatia says.

“This is why traditionally, tazarotene has had some impact on psoriasis versus other retinoids,” he says. Adapalene provides similar advantages, although its vehicle was designed not for psoriasis, but for acne, he says.

Disclosures: Dr. Bhatia is a consultant, investigator and/or speaker for Anacor, Aqua, Bayer, Dusa, Ferndale, Galderma, Leo, Novartis, Promius, Quinnova and Valeant.