Dr. Alice B. Gottlieb
Other important developments that may bode well for the treatment of psoriasis include data on IL-17 inhibitors, oral and topical janus kinase (JAK) inhibitors, an oral phosphodiesterase inhibitor, several IL-23 blockers, and topical niacin/calcipotriene, according to Dr. Leonardi and Dr. Alice B. Gottlieb of Tufts Medical Center in Boston.
Targeting IL-17
Recent studies have suggested that IL-17A–producing T cells have a crucial role in the pathogenesis of psoriasis, making them a potential treatment target.
In a phase II trial, a fully human IL-17 antibody AIN457 (Novartis) produced clinically meaningful reductions of disease activity at 4 and 12 weeks in 13 of 18 psoriasis patients who were randomized to receive a single 3-mg/kg intravenous infusion of the drug. At study weeks 4 and 12, respectively, the mean PASI score decreased by 58% and 63% in the AIN457 patients, compared with 4% and 9% in placebo patients, the authors wrote (Sci. Transl. Med. 2010;52:52ra72).
The results of a phase I study of another IL-17 drug – Amgen’s AMG 827, which binds to and blocks signaling via the IL-17 receptor – were reported at the EADV meeting. Most of the 16 patients who received a single dose of the fully human monoclonal antibody experienced substantial improvements in psoriasis symptoms. Based on the favorable findings, a phase II study is currently underway.
JAK 3 Inhibitors
The JAK pathways are also believed to have roles in the psoriasis disease cascade and as such have emerged as a treatment target. The four known JAK enzymes – JAK1, JAK2, JAK3, and tyrosine kinase (TYK) 2 – are components of signaling mechanisms used by multiple cytokines and growth factors that trigger dysregulated inflammatory pathways, according to Dr. Gottlieb. Oral and topical inhibitors of JAK are in phase II and III trials and have had promising results so far, she said in an interview.
In a 197-patient, phase II efficacy and safety study, Pfizer’s investigational oral JAK3 inhibitor, tentatively named tasocitinib (CP-690550), produced statistically significant responses at 12 weeks, compared with placebo in adults with moderate to severe psoriasis. The PASI 75 responses for patients randomized to twice daily tasocitinib at 2-mg, 5-mg, and 15-mg doses, respectively, were 25%, 40.8%, and 66.7%, compared with 2.0% for placebo, according to a company-issued statement. Additionally, as early as study week 4, "treatment with 5 and 15 mg twice daily of tasocitinib significantly improved patient-reported health-related quality of life outcomes."
Regarding safety, three patients randomized to tasocitinib treatment experienced a total of five serious adverse events during the study. Additionally, the investigators observed dose dependent decreases in mean neutrophil counts and hemoglobin values and increases in mean LDL, HDL, and total cholesterol levels. A large-scale, phase III trial program, called Oral Psoriasis Treatment (OPT) trials, is currently underway.
Topical JAK inhibitors are also under development, which presumably will avoid some of the complications associated with systemic therapy, according to Dr. Gottlieb, who is involved with investigations of Incyte’s topical JAK1/JAK2 inhibitor, INCB18424, which has demonstrated robust activity and safety in placebo-controlled, multidose, phase IIb trials in patients with mild to moderate psoriasis.
In studies reported by Dr. Gottlieb at last year’s annual meeting of the American Academy of Dermatology, topical application of INCB18424 cream led to significant improvement in the psoriatic lesions of treated patients at day 28, with the total lesion scores decreasing twofold, compared with placebo. "The effects were seen as early as 2 weeks, and they extended through" the study period," she said, noting that immunohistochemical staining and microarray gene analysis data confirmed the improvement in skin histology and the reduction in the psoriatic molecular signature.
Apremilast May Break Ground
Poised to be "the first oral medication with a new mechanism of action for psoriasis in almost 20 years," the phosphodiesterase 4 (PDE4) enzyme inhibitor apremilast (Celgene) demonstrated favorable results in a phase IIb study reported in December 2009 and has recently begun phase III trials, according to Dr. Leonardi.
In the phase IIb trial, 352 patients with moderate to severe plaque-type psoriasis were randomized to receive 10 mg, 20 mg or 30 mg of apremilast twice per day or placebo. Of the apremilast patients, 41% of the 30-mg group, 29% of the 20-mg group, and 11% of the 10-mg group achieved a PASI 75 after 16 weeks, compared with 6% of the placebo group, according a company statement.
A comparison of infection rates showed that infections occurred in 48% of the 30 mg apremilast patients and 33% of the placebo patients. No serious adverse events related to apremilast were reported.