Biologics Maintain Benefits Long-term in Plaque Psoriasis

Miriam E. Tucker

March 06, 2016

Washington, DC — New long-term data for two third-generation biologics demonstrate their durability in both efficacy and safety for the treatment of moderate to severe plaque psoriasis.

The UNCOVER-3 trial showed favorable results at 60 weeks for ixekizumab (Eli Lilly & Co), whereas secukinumab (Cosentyx, Novartis) maintained superiority vs ustekinumab (Stelara, Johnson & Johnson) at 52 weeks in the CLEAR study.

We're in the third generation of biologics, and we're getting better and better and better. Dr Andrew Blauvelt

"The development of biologics has gradually been improving in efficacy as well as safety over the last 15 years," said Andrew Blauvelt, MD, president of Oregon Medical Research Center in Portland, who was the principal investigator for both trials. "We're in the third generation of biologics, and we're getting better and better and better."

The results of both studies were presented here at the American Academy of Dermatology (AAD) 74th Annual Meeting.

As reported by Medscape Medical News in January 2015, secukinumab was the first fully human interleukin 17A (IL-17A) inhibitor approved in the United States to treat moderate to severe plaque psoriasis. It was also recently approved for the treatment of psoriatic arthritis and ankylosing spondylitis in both the United States and the European Union.

Ixekizumab, which also targets IL-17A, is expected to receive approval soon from the US Food and Drug Administration for the treatment of psoriasis.

By targeting IL-17, both secukinumab and ixekizumab exert a more specific blocking effect on psoriasis-associated inflammation than does ustekinumab, which targets IL-12 and IL-23. However, all three biologic agents represent an advance over the older tumor necrosis factor alpha inhibitors infliximab, etanercept, and adalimumab, Dr Blauvelt told Medscape Medical News. They are more effective and less likely to result in severe infection, he explained.

But cost is a problem, he acknowledged, noting that for the 20% to 30% of patients who require systemic treatment, payers will often require physicians to first prescribe a nonbiologic agent such as methotrexate.

"The cost of biologics is very high. Payers are under pressure to get patients on the older therapies," he said.

UNCOVER-3 at Week 60

Lilly's phase 3 trial, for which 12-week results were previously published in the Lancet, initially randomly assigned 1346 patients with moderate to severe plaque psoriasis to receive placebo, etanercept 50 mg twice weekly, or 80 mg ixekizumab every 4 weeks or every 2 weeks after an initial 160-mg starting dose.

After the first blinded 12 weeks, all patients were entered into open-label treatment with ixekizumab every 4 weeks. Disease severity was assessed using the static Physician Global Assessment and percentage improvement in the Psoriasis Area Severity index (PASI).

A total of 722 patients were continuously treated with ixekizumab from week 0 to week 60. "We see very little falloff from week 12," said Dr Blauvelt, commenting on the number of patients who achieved PASI 75.

The number of patients achieving PASI 90 actually increased from the prior blinded period of the study, as did the number of patients achieving PASI 100.

Table 1. Outcomes at 12 Weeks and 60 Weeks by Initial Dosing Group

  Initial 4-Week Dosing Group Initial 2-Week Dosing Group
Outcome 12 Weeks 60 Weeks 12 Weeks 60 Weeks
PASI 75, % 84.2 79.5 87.3 83.4
PASI 90, % 65.3 71.0 68.1 73.2
PASI 100, % 35.0 37.7 52.1 55.3
Static Physician Global Assessment, % 75.4 72.8 80.5 74.5

Regarding safety, Dr Blauvelt said, "We haven't revealed 60th-week safety data, but it's good news, in that there are no unexpected safety signals that were not seen with initial therapy."

"The overall rate of coming completely clear is incredibly high. This is something we never thought was achievable," session moderator Joel M. Gelfand, MD, medical director of the Clinical Studies Unit and associate professor of dermatology at the University of Pennsylvania, Philadelphia, told Medscape Medical News. "But it's hard to know what the true duration of results is," adding that some studies suggest falloff rates of 5% to 10% per year, for various reasons including efficacy.

"They're incredibly effective drugs, but will patients be clear at 5 to 10 years, or will many have recurrence of disease over time? It's a very high efficacy sustained over a year, but we need more data for the real endpoint, whether people are in control for 2, 4, or 5 years," said Dr Gelfand.

At 1 Year, Secukinumab Still Bests Ustekinumab

Diamant Thaçi, MD, from the Comprehensive Center for Inflammation Medicine, University Hospital Schleswig-Holstein, in Lübeck, Germany, presented the 52-week data from the multicenter, double-blind head-to-head CLEAR study, The 16-week results from the study were published last year.

A total of 676 subjects were randomly assigned in a 1:1 ratio to a subcutaneous injection of secukinumab 300 mg or ustekinumab per label. The primary end point was the proportion achieving PASI 90.

Table 2. Outcomes at 16 and 52 Weeks

  Secukinumab Ustekinumab P Value
PASI 90 (%)      
 16 weeks 79.0 57.6 <.0001
 52 weeks 76.2 60.6 <.0001
PASI 100 (%)      
 16 weeks 44.3 28.4 <.0001
 52 weeks 45.9 35.8 <.05

Also superior for secukinumab at 52 weeks were the number of patients achieving scores of 0 or 1 on the Dermatology Life Quality Index, at 71.6% vs 59.2% for ustekinumab (P = .0008). In addition, the number achieving investigator global assessment 2011 modified version scores of 0 (clear) or 1 (almost clear) were 80.4% vs 65.0% (P < .0001) for secukinumab and ustekinumab, respectively.

Adverse event rates at 52 weeks were similar between the two groups. Nonfatal serious adverse events occurred in 9.6% with secukinumab and 8.5% with ustekinumab. Discontinuations resulting from adverse events were also similar between the two groups (10% vs 9%). In all, the safety profile was consistent with that reported in secukinumab pivotal phase 3 studies, said Dr Thaçi.

The findings look excellent, but one drawback to secukinumab is the number of injections patients need to receive, at once monthly vs every 3 months after initial dosing, Dr Gelfand told Medscape Medical News.

"I think it's an interesting finding that you can do even better than an already-excellent drug on the market over a 1-year period of time," he said. "It's really exciting, but the ultimate question is, Does the patient want to inject themselves so often? The one that didn't do as well still did very well with fewer injections."

Also, he added, if a patient had to stop the drug for lack of insurance or other reasons, "it's likely that ustekinumab patients would have a slower recurrence of disease than secukinumab, because it's known to have a longer effect."

Dr Gelfand added, "The area under the curve overall looks better for secukinumab, but it's a lot more shots. The question in real practice is, if you have to come in and out of therapy, what's the overall benefit from the patient's perspective if they have to stop taking it?"

Dr Blauvelt has served as a scientific consultant and clinical study investigator for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen Ortho Biotech, Merck, Novartis, Pfizer, and Sandoz. Dr Thaçi has served as a consultant, served as an advisory board member, and/or received honoraria for lecturing for AbbVie, Amgen, Biogen-Idec, Celgene, Eli Lilly, Janssen-Cilag, Leo Pharma, MSD, Novartis, Pfizer, Regeneron, and Sanofi. Dr Gelfand has consulted for or received grant funding and/or honoraria from AbbVie, Amgen, Celgene Corporation, Coherus Biosciences (Data Safety Monitoring Board), Eli Lilly and Company, Elsevier Inc, Janssen Pharmaceuticals Inc, Leo Pharma Inc, Merck & Co, Inc (Data Safety Monitoring Board), Novartis Pharmaceuticals Corp, Pfizer Inc, Regeneron, and Sanofi US Services.

American Academy of Dermatology (AAD) 74th Annual Meeting. Presented March 5, 2016.


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