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Dermatologists can expect to see highly effective systemic and oral therapeutic options for psoriasis and psoriatic arthritis added to their toolbox.
Maui, Hawaii - The introduction of biologic therapies inhibiting tumor necrosis factor-alpha (TNF-alpha) resulted in a new treatment paradigm for psoriasis. Next, understanding of the molecular immunopathogenesis of psoriasis led to the introduction of a treatment targeting interleukin-12/23 (IL-12/23). Soon, dermatologists can expect to see their toolbox of highly effective systemic therapeutic options enriched by several new agents with novel mechanisms of action, according to presentations at the recent 2014 MauiDerm meeting.
“The number of biologic agents approved for the treatment of moderate-to-severe chronic plaque psoriasis will likely double within the next few years. In addition, small molecule agents are on the horizon that will address the need for oral therapeutic alternatives,” says Craig L. Leonardi, M.D, who is clinical professor of dermatology, Saint Louis University, St. Louis. At MauiDerm, He discussed emerging systemic therapies for psoriasis.
IL-17 is the target for three biologic agents that have advanced into phase 3 clinical trials, and results from 52 weeks of follow-up in three phase-3 studies have been reported for one of those agents: secukinumab (Novartis), a human IgG1 monoclonal IL-17A antibody.
In a placebo-controlled study (ERASURE) evaluating secukinumab doses of 150 mg and 300 mg, PASI 75 response rates in the secukinumab groups reached a peak at week 16 (~80 and 90 percent) as did the proportions of patients achieving a rating of clear or almost clear in the Investigators Global Assessment (~60 and 75 percent). The treatment benefit achieved with an induction regimen was maintained through week 52 with secukinumab injections given every four weeks.
Similar efficacy results were achieved in two other secukinumab phase 3 studies. One of the latter trials (FIXTURE) included etanercept as an active control. In the comparator study, patients showed a more rapid response to secukinumab versus etanercept (three versus eight weeks) to achieve a PASI 50 and greater number of patients achieving PASI 90 (72.4 versus 41.5 percent) while the outcomes achieved in the etanercept group surpassed those seen in the pivotal trials for the TNF-alpha inhibitor.
The results for patients treated with secukinumab were far superior, Dr. Leonardi says. The third secukinumab phase 3 trial (SCULPTURE) compared fixed-interval (Q4 weeks) maintenance dosing with an “retreatment-as-needed” regimen. Data from follow-up to week 52 showed fixed interval therapy with SEC 300 mg and 150 mg Q4 weeks sustained significantly greater PASI 75, 90 and 100 clearance rates over one year compared to “retreatment-as-needed,” reaffirming that “retreatment as needed” is not a good regimen for any biologic, Dr. Leonardi says.
“Safety data from the phase 3 studies have not been released, but secukinumab was well-tolerated overall in the phase 2 trials,” he notes.
Ixekizumab (Eli Lilly) is another anti-IL-17 monoclonal antibody that is also being investigated in phase 3 studies comparing it with etanercept. Based on outcomes from a phase 2 dose-ranging study, Dr. Leonardi characterized ixekizumab as “another high-performance, skin clearing drug.” In that trial where almost 150 patients were randomized to placebo or ixekiaumab 10 mg, 25 mg, 75 mg, or 150 mg, about 80 percent of patients receiving either of the two highest ixekizumab doses achieved a PASI 75 response.
“Ixekizumab also had a remarkable safety profile in the phase 2 study where there were no serious adverse events,” Dr. Leonardi adds.
Brodalumab (Amgen) also targets the IL-17 pathway, but it is an anti-IL-17-receptor antibody that blocks the activity of IL-17E and IL-17C in addition to IL-17A. Phase 3 studies of brodalumab include two trials comparing it with ustekinumab. In a phase 2 study, brodalumab also showed impressive efficacy, and patients followed to week 96 in an open-label extension had good long-term maintenance of their clinical response. However, Dr. Leonardi observes that the latter report analyzed data only from patients who remained on treatment rather than in an intent-to-treat cohort.
Oral small molecules are also part of the investigational pipeline of intracellular therapies for psoriasis. Apremilast (Celgene), an intracellular phosphodiesterase-4 inhibitor that modulates the production of a multiple inflammatory mediators in activated immune cells, is currently under review at the Food and Drug Administration.
Results from a phase 3 study (ESTEEM 1) showed that 33 percent of patients treated with apremilast 30 mg BID achieved a PASI 75 response by week 16 compared with 5.3 percent of placebo-treated controls; the PASI 75 response rate was slightly higher among patients who had received no prior systemic or biologic therapy (~36 to 39 percent), but only about 17 percent among those who had been on a biologic agent before.
Apremilast-treated patients also had improvements in assessments of nail and scalp disease and had significantly greater benefits than placebo-treated controls in analyses of itch severity and quality of life scores.
The safety review showed gastrointestinal (GI) side effects were the most common adverse events in the apremilast group, where rates of diarrhea and nausea were 19 and 16 percent, respectively. Only two (0.4 percent) apremilast-treated patients reported severe diarrhea or nausea.
Providing an update on treatments for psoriatic arthritis, Arthur Kavanaugh, M.D., professor of medicine, University of California, San Diego, reviewed data from a phase 3 study of apremilast and a phase 2 study investigating brodalumab. The apremilast NDA for psoriatic arthritis is also undergoing FDA review. In one Phase 3 study enrolling about 500 patients with active psoriatic arthritis despite use of DMARDs and biologic agents (PALACE-1), 45 percent of patients treated with apremilast 30 mg BID were ACR20 responders at week 24 compared with 13 percent of placebo-treated controls; ACR50 and ACR70 response rates for the apremilast group were 22 percent and 12 percent, respectively. Rates of laboratory abnormalities were similarly low in the apremilast and placebo groups.
Dr. Kavanaugh referred to the efficacy data as demonstrating “solid responses” and noted the possibility that apremilast might be approved with a reduced need for laboratory monitoring compared with methotrexate.
“However, it remains to be seen what the FDA decides on that point, and the role of apremilast will also be determined by its cost,” Dr. Kavanaugh says.
Phase 3 studies of brodalumab are about to get underway and will compare doses of 140 mg and 210 mg against placebo. In a phase 2 study, the ACR20 responder rate for patients treated with brodalumab 140 mg every two weeks was 37 percent at week 12 and 51.1 percent at week 24.
Disclosures: Dr. Leonardi and Dr. Kavanaugh are consultants, investigators, and/or speakers for multiple companies that market and that are developing treatments for psoriasis.