NEW ORLEANS – Apremilast, tofacitinib, and a drug for now known as AMG-627 are three novel investigational medications for psoriasis worth keeping an eye on.
The efficacy of these three agents is beyond question, ranging from good to great. Whether they ultimately reach the market will depend upon the answers to tolerability and safety questions that should be provided in phase III clinical trials, Dr. Bruce E. Strober said at the annual meeting of the American Academy of Dermatology.
Dr. Bruce E. Strober
Here's the low-down on these exciting agents, several of which also are being developed for rheumatoid arthritis and other autoimmune diseases, according to Dr. Strober of New York University.
• Apremilast. This oral small molecule inhibitor of phosphodiesterase type 4 is now entering phase III testing for psoriasis.
"You might see this drug on the market in 3-4 years," the dermatologist said.
By inhibiting phosphodiesterase type 4, apremilast curbs formation of multiple cytokines important in inflammatory pathways, including interleukins-12 and -17 as well as tumor necrosis factor–alpha. These pathways are important not only in the pathophysiology of psoriasis, but also for rheumatoid arthritis and other autoimmune diseases as well. For this reason, apremilast's developer, Celgene, is interested in pursuing other indications in addition to psoriasis.
A 16-week, double-blind, placebo-controlled, phase II study conducted in 352 patients with moderate-to-severe plaque-type psoriasis showed an unequivocal dose-response relationship. A 75% reduction from baseline in Psoriasis Area and Severity Index scores, or PASI 75, occurred in 41% of patients randomized to 30 mg of apremilast b.i.d., 29% on 20 mg b.i.d., 11% on 10 mg b.i.d., and 5.7% on placebo.
Tolerability issues came up in this study, especially in patients on the highest dose of apremilast. One-third of them reported headaches, 18% nausea, 16% urinary tract infections, and 16% diarrhea, all rates substantially higher than in controls. The discontinuation rate in the highest-dose group was 14%, compared with 6% in controls.
Nevertheless, this is an oral drug with enough efficacy that it might find a role as first-line therapy after a failure on topical therapy, Dr. Strober predicted.
"It's left to be seen in phase III how safe it is, but I think there will be a place for such an intermediately acting small molecule. Keep your eyes open for this one," he continued.
• Tofacitinib. This oral Janus kinase (JAK) inhibitor just underwent a name change. It was formerly known as tasocitinib. Like apremilast, it's now entering phase III testing for psoriasis.
Tofacitinib is best thought of a broadly acting immunosuppressive agent. By inhibiting JAK kinase, it's likely to affect transcription of genes important in inflammation, red blood cell development, and innate and adaptive immunity. Tofacitinib is also under study for rheumatoid arthritis and other immunologic diseases.
In a 12-week, phase IIb study of 197 patients, psoriasis patients randomized to tofacitinib at 15 mg b.i.d. achieved a 67% PASI 75, compared with a PASI 75 of 41% with 5 mg b.i.d., 25% with 2 mg b.i.d., and 2% for placebo.
Dr. Strober predicted that Pfizer will take the 5 mg b.i.d. dosing forward into phase III because it provides the best combination of efficacy and safety. Dose-related safety issues that emerged in the phase IIb study were a slight reduction in hemoglobin, a decrease in neutrophil count that normalized during the course of the study, and increases in both HDL cholesterol and LDL cholesterol.
"This is a drug that in all likelihood will require monitoring by clinicians during therapy," he concluded.
• AMG-627. This Amgen drug blocks the interleukin-17 receptor. In contrast, Novartis and Lilly are working on drugs that block interleukin-17m which is believed to be a pivotal cytokine in the pathogenesis of psoriasis.
AMG-627 is not as far along the developmental pipeline as apremilast and tofacitinib, but the early clinical studies make one thing clear, in Dr. Strober's view: "The efficacy of this approach will be fairly unequalled. It will come down, as usual, to the safety of the class."
Dr. Strober disclosed that he serves as an investigator for, and consultant to, Pfizer, Amgen, and other pharmaceutical companies having an interest in psoriasis treatment.