A Pill for Psoriasis: The Latest Oral Medications

The chronicity and complexity of psoriasis make the condition both a physical and psychological burden for patients, typically resulting in a reduced quality of life and productivity. However, the growing and changing landscape of psoriasis treatments proves promising. In particular, there has been an increased focus on developing safer and more effective oral therapies, which would provide options for patients for whom topical therapies are not sufficient or effective.

Here, we give a comprehensive overview of the oral medications available to help improve and relieve the negative symptoms of psoriasis, as well as potential new agents under investigation.

New Advances in Oral Therapies on the Market

Methotrexate, cyclosporine, and acitretin are three long-standing oral medications that are considered to be traditional therapy options for psoriasis. Methotrexate, approved by the US Food and Drug Administration (FDA) in 1972, is one of the oldest and most familiar oral medications for treating psoriasis. Similarly, cyclosporine and acitretin have been regularly used in psoriasis treatment since their approval in 1997. However, these drugs have proven to be relatively slow-acting and have a high risk for adverse side effects, especially when taken long-term.

Apremilast, an inhibitor of phosphodiesterase 4, was approved in 2014 for moderate to severe plaque psoriasis and has proven to be effective, tolerable, and relatively safe for patients. Moreover, recent clinical trials have shown exciting advances for the use of apremilast in mild to moderate, genital, and pediatric psoriasis.

As a result of findings from the ADVANCE clinical trial, apremilast was approved by the FDA in 2021 for patients with mild to moderate plaque psoriasis, making it the only oral systemic agent for mild, moderate, and severe psoriasis. ADVANCE, a multicenter, double-blind, placebo-controlled phase 3 trial, is the first to study the efficacy and safety of apremilast 30 mg taken twice daily compared with placebo for patients with mild to moderate psoriasis. For the first 16 weeks, patients were randomized in a 1:1 ratio to receive apremilast or placebo, after which all patients received apremilast 30 mg twice daily until week 32. The results of the study were statistically significant and clinically meaningful by week 16, with more than 21% of the patients randomized to apremilast achieving static Physician Global Assessment (sPGA) scores of 0 or 1 (clear or almost clear) with ≥ 2-point reduction from baseline compared with about 4% in the placebo group. In the apremilast group, the sPGA response rate was significantly greater than placebo as early as week 2. There was also a ≥ 75% reduction in psoriasis-involved body surface area (BSA-75 response), a greater achievement of BSA ≤ 3%, and improvement in the Whole Body Itch Numeric Rating Scale response (≥ 4-point reduction from baseline; baseline score ≥ 4) with apremilast compared with placebo. The safety profile of apremilast in ADVANCE was similar to that of other clinical trials focused on moderate to severe psoriasis. Mild to moderate adverse events (AEs) included diarrhea, headache, and nausea.

The DISCREET study was a 32-week trial in which patients with moderate to severe genital psoriasis were randomized to receive apremilast 30 mg twice daily or placebo for the first 16 weeks and then continued or switched to apremilast for the remainder of the trial. At week 16, 39.6% of patients treated with apremilast achieved a modified sPGA-G (static Physician Global Assessment of Genitalia) score of clear or almost clear compared with 19.5% receiving placebo.

SPROUT is a multicenter, double-blind, placebo-controlled phase 3 study that assessed the safety and efficacy of apremilast for pediatric patients (aged 6-17 years) with moderate to severe plaque psoriasis. Patients were randomized to take apremilast 20 mg twice daily or 30 mg twice daily, depending on body weight, or placebo for 16 weeks. Thereafter, all patients received apremilast until week 52. By week 16, 33% of patients who received apremilast compared with 11% of the placebo group achieved sPGA scores of 0 or 1.

Deucravacitinib: The Most Recently Approved Oral Agent

Deucravacitinib, approved by the FDA in 2022 for moderate to severe psoriasis, acts as a selective tyrosine kinase 2 (TYK 2) inhibitor. It binds to a unique regulatory domain of TYK 2. Two pivotal 52-week, phase 3 trials (POETYK PSO-1 and POETYK PSO-2) demonstrated the efficacy and superiority of deucravacitinib over apremilast in patients with moderate to severe plaque psoriasis. Patients were randomized in a 2:1:1 ratio to receive deucravacitinib 6 mg daily, placebo, or apremilast 30 mg twice daily. In each study by week 16, the primary endpoints of achieving 75% or greater improvement in Psoriasis Area and Severity Index score (PASI 75) and sPGA scores of 0 and 1 were met, and the response rates were significantly higher in the deucravacitinib group compared with the placebo and apremilast groups. In POETYK PSO-1, PASI 75 was achieved by 58.4%, 12.7%, and 35.1% of deucravacitinib, placebo, and apremilast recipients, respectively, and sPGA of 0 or 1 was achieved by 53.6%, 7.2%, and 32.1%. In POETYK PSO-2, the respective proportions of participants who achieved PASI 75 were 53.0%, 9.4%, 39.8%, and proportions of those with an sPGA score of 0 or 1 were 49.5%, 8.6%, 33.9%. The most common AEs were mild to moderate and included nasopharyngitis, upper respiratory tract infection, headache, and nausea, with a few cases of nonserious herpes zoster.

The POETYK PSO-1 and POETYK PSO-2 trials revealed mean changes in lipid levels from baseline to week 16 were minimal and not clinically significant across all groups. This is significant because plaque psoriasis is associated with hypertriglyceridemia and metabolic syndrome, and the frequency of hypertriglyceridemia increases with severity of the condition. Moreover, there were no lipid-related AEs that caused any patients to discontinue deucravacitinib. Diet and lifestyle optimization are recommended by the 2018 AHA/ACC/multisociety cholesterol guideline for most patients with moderate to severe psoriasis who may have metabolic syndrome. Deucravacitinib was relatively well-tolerated and displayed durable efficacy.

This was further demonstrated in the 2-year follow-up study POETYK PSO-LTE, which examined the long-term efficacy and safety of deucravacitinib. Response rates for achieving PASI 75 and sPGA scores of 0 or 1 were 77.7% and 58.7%, respectively, by week 60. In terms of safety, the AEs observed were similar to those in POETYK PSO-1 and POETYK PSO-2 and remained mild to moderate. Although there was a higher incidence of COVID-19 in the long-term study because the trial was conducted during the peak of the pandemic, deucravacitinib was not a risk factor for SARS-CoV-2 infection. Alanine aminotransferase elevations in patients treated with deucravacitinib were not serious, and no patients discontinued treatment as a result of it. The prescribing information indicates the requirement of a laboratory evaluation for tuberculosis screening before drug initiation, as well as the periodic evaluation of triglycerides according to clinical guidelines. In patients with known or suspected liver disease, liver enzymes should be evaluated before and periodically during therapy.

Potential Drugs in the Pipeline

As the armamentarium for psoriasis treatments continues to expand, oral medications in the pipeline are growing increasingly prominent. Results from multiple phase 2 trials of new agents under investigation are encouraging for the future of newer-generation oral psoriasis therapies.

JNJ-2113 is the first oral peptide interleukin-23 (Il-23) inhibitor that selectively targets the Il-23 signaling pathway, which is central to the pathogenesis of psoriasis. FRONTIER 1 was a 24-week phase 2b clinical trial designed to test the safety and efficacy of JNJ-2113 in patients with moderate to severe psoriasis. The multicenter, double-blind, placebo-controlled study randomized adult patients into six treatment groups: 25 mg daily, 25 mg twice daily, 50 mg daily, 100 mg daily, 100 mg twice daily, and placebo. From data presented at the World Congress of Dermatology in 2023, the primary endpoint of PASI 75 was reached by week 16, with a significantly greater percentage of patients in each of the JNJ-2113 groups achieving this result (37.25%-78.6%, depending on the dosage) than in the placebo group (9.3%). Results for achievement of PASI 90 and PASI 100 were similarly positive. In addition, the drug was tolerated well; the most frequent AEs were infection (COVID-19, nasopharyngitis, and upper respiratory tract infection). As a result of the positive findings of FRONTIER 1, a phase 3 clinical trial of JNJ-2113 in treating moderate to severe psoriasis is underway.

EDP1815 is under investigation for the treatment of mild to moderate psoriasis. EDP1815 is a nonliving gut bacterium that resides in the small intestine of humans and acts as an anti-inflammatory agent. A multicenter, double-blind, placebo-controlled, dose-ranging phase 2 trial was conducted to evaluate the efficacy and safety of EDP1815 vs placebo in patients with mild to moderate psoriasis, as well as to determine the optimal dose of EDP1815. Three cohorts received EDP1815 in capsule form to be taken daily in an increasing dosage. Results of the study showed the efficacy of EDP1815 over placebo with 80%-90% probability; cohorts that received EDP1815 achieved a greater mean percentage change in PASI at week 16. In the post-treatment period, during which 83 patients were followed for up to 24 weeks, no flare-ups of psoriasis were observed.

Another potential treatment in the pipeline, KBL697, a probiotic Lactobacillus gasseri, is undergoing a phase 2 trial to test its efficacy and safety vs placebo for patients with moderate plaque psoriasis. Similarly, a phase 2 trial of the oral interleukin-17 antagonist DC-806 intended to treat moderate to severe psoriasis is currently underway, with results expected by about mid-2024.

The development of next-generation oral therapies that are effective, tolerable, and safe in treating the spectrum of psoriasis disease is crucial. These therapies offer greater flexibility in meeting patients' preferences and needs that injectable biologics cannot always offer. Oral systemic medications have been and, hopefully, will continue to be at the forefront of the evolving landscape of psoriasis treatments.

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