New Targeted Molecular Agents Tailor Psoriasis Treatment

Psoriasis, one of the most common immune-mediated diseases, currently affects more than 7.5 million adults ages 20 and older in the U.S.

The cutaneous condition is characterized by the excessive proliferation and abnormal differentiation of keratinocytes and infiltration of the skin by multiple inflammatory cells.

Far from being just a skin-deep condition, it also is a whole-body problem, which left untreated has systemic inflammatory effects that can raise the risk of cardiovascular disease, stroke, joint damage, and possibly some cancers.

“While the prevalence of psoriasis in the United States is likely stable, increased awareness of the disease, both in medical and public sectors, may result in more patients seeking care and ultimately being diagnosed and treated for the condition,” said Amit Garg, MD, of the Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York.

“We are diagnosing this skin condition more often in our clinic, and it runs a very close second to eczema in prevalence,” added Danilo C. Del Campo, MD, of the Chicago Skin Clinic.

Therapeutic Shift

“If you have to have psoriasis, today is a much better time to have it, since treatment has shifted away from traditional topicals and broader immune suppressants to more targeted molecular therapy,” Garg told MedPage Today.

“The development of first-, second-, and third-generation biologic and small-molecule therapies has allowed us to clear or almost clear a high proportion of patients with moderate to severe psoriasis, and the degree of efficacy has been unprecedented,” he added.

For more limited areas of involvement, new steroid-free topical therapies are also highly effective, he noted.

“Twenty years ago we focused mainly on shutting down symptoms with more generalized immune suppressants like prednisone, methotrexate, and cyclosporine,” Del Campo said. “But over the past two decades, there’s been a renaissance of research in the area and we’ve been able to fine-tune and personalize treatment by targeting elements in the immune system and their subunits with agents like interleukin blockers and Janus kinase and tyrosine kinase inhibitors. And there are many more targets waiting to be discovered.”

Nicholas Brownstone, MD, of Temple University Hospital in Philadelphia, told MedPage Today that “psoriasis used to be considered the result of hyperproliferation of the epidermis, but in the past 10 years we’ve realized it’s linked to immune dysregulation via upregulation of the T helper cell 1 (Th1) pathway, with the master culprit cytokine behind this being interleukin [IL]-23.”

Recently developed medications home in on the etiological roots of psoriatic disease by targeting these immune components and their molecular signaling pathways, especially the IL-17/23 pathogenic axis.

The pre-psoriatic immune cascade triggers the activation of Th1 and Th7, as well as the secretion of other contributory inflammatory cytokines, such as tumor necrosis factor (TNF), IL-21, and IL-22. These cytokines activate keratinocytes and produce antimicrobial peptides, cytokines, and chemokines, thereby amplifying inflammation. Multiple agents targeting TNF-α, IL-23, and IL-17 have shown therapeutic efficacy.

New Topicals and Systemics

“Injectable biologic cytokine inhibitors for IL-17 and -23 are generally the most effective at clearing psoriasis,” said Garg. “Inhibitors of small molecules including prostaglandin esterase and kinases, which are administered orally, also offer safe and effective options for patients with moderate to severe disease.”

“We’re beginning to see penetration into the landscape by biologic biosimilars that inhibit TNF,” he added. Novel topical treatments are also proving effective.

One of the latter is tapinarof (Vtama), a first-in-class small-molecule receptor antagonist of aryl hydrocarbon (AhR), a transcription factor in the immune system. AhR modulates expression of IL-17 and skin barrier proteins and binds and activates AhR, thereby reducing skin inflammation, normalizing the skin barrier, lessening oxidative stress, and regulating immune cell gene expression.

Response to tapinarof in patients with moderate to severe disease was 35.4% in one phase III trial and 40.2% in another, but adverse effects such as headache, upper respiratory infections, and nasopharyngitis occurred.

Roflumilast (Zoryve) is a highly selective topical phosphodiesterase-4 (PDE4) inhibitor, whose oral form treats chronic obstructive pulmonary disease. The PDE4 enzyme upregulates pro-inflammatory signals and decreases anti-inflammatory signals.

In the DERMIS-1 and DERMIS-2 phase III trials, statistically significantly greater percentages of roflumilast-treated patients than vehicle-treated patients had Investigator Global Assessment (IGA) success at week 8 (P<0.001 for both):

• DERMIS-1: 42.4% vs 6.1%
• DERMIS-2: 37.5% vs 6.9%

The agent also produced significant improvements in the Psoriasis Area and Severity Index (PASI), and is being studied in foam formulation for scalp and body psoriasis.

The newest FDA-approved biologic is the monoclonal antibody bimekizumab (Bimzelx), which uniquely blocks both the IL-17A and IL-17F subunits, while other IL-17 antagonists block only IL-17A (ixekizumab [Taltz] and secukinumab [Cosentyx]) or IL-17 receptor A (brodalumab [Siliq]).

In the phase III BE READY trial, 91% of 349 patients receiving this rapid-onset medication achieved a PASI score of 90 at week 16 compared with 1% of 86 patients receiving placebo. In addition, 93% of patients on bimekizumab achieved an IGA score of 0 or 1 compared with 1% of patients on placebo. Responses were maintained through week 56.

“But liver enzymes need to be checked, and there’s a risk of fungal infections such as oral candidiasis,” cautioned Brownstone.

In the phase III POETYK PSO-1 trial, response rates with deucravacitinib (Sotyktu), an oral, selective, allosteric tyrosine kinase 2 inhibitor, were significantly higher compared with placebo or apremilast (Otezla) for PASI 75: 58.4%, 12.7%, and 35.1%, respectively. Efficacy improved beyond week 16 and was maintained through week 52.

At 3 years, extended data with deucravacitinib showed clinical response rates of 73.2% for PASI 75, 48.1% for PASI 90, and 54.1% for static Physician’s Global Assessment, all with a consistent safety profile.

Although adalimumab (Humira) is not a new biologic per se, several biosimilars of this TNF inhibitor have been approved for the management of adult plaque psoriasis.

Challenges

Overall, the average treatment responses look similar across the newer targeted agents, so factors such as speed of onset, comorbidities, and the presence of psoriatic arthritis can help to fine-tune treatment choice amid a growing array of options.

Always top of mind in treatment selection is the concurrent presence of inflammatory joint disease, liver disease, and bowel disease, and history of malignancy and infections. Speed and durability are also factors in the selection equation, as is ease of access, according to Garg.

“In 2024, it’s wonderful to be able to offer patients a number of safe and effective treatment options for different types of psoriasis and the spectrum of their severities,” he said. “We partner with patients in choosing the best treatment options based on type and severity of psoriasis, comorbidity profiles, convenience of use, and cost.”

The task facing dermatologists in this option-rich therapeutic environment, he noted, is to learn more about predicting which treatments will be most effective for a particular type of psoriasis in any given individual — “that is to say, personalized medicine.”

Del Campo added that “ultimately, what we want to do is find an off-switch that will achieve long-term remission or cure so we no longer have to treat.”

One of the therapeutic avenues in the future may well be genetic therapy, he said. “In the meantime, we need to look at drug delivery. How do we get the safest medicine into patients in the easiest and simplest way possible?”

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