Psoriatic Arthritis: Phase 3 Data Confirm Secukinumab Efficacy

Pam Harrison

October 06, 2015

Selective inhibition of interleukin 17A (IL-17A) with secukinumab improves the signs and symptoms of psoriatic arthritis (PsA) as well as physical function and quality of life out to 52 weeks, according to results from a study published in the October 1 issue of the New England Journal of Medicine.

Data from the phase 3 FUTURE 1 trial thus confirm that IL-17A is a mediator of the PsA disease process.

Philip Mease, MD, from Seattle Rheumatology Associates in Washington, and colleagues found that American College of Rheumatology (ACR) 20 response rates at week 24 were significantly higher, at 50% for patients receiving either 150 or 75 mg secukinumab every 4 weeks compared with 17.3% for placebo controls (P < .001).

The proportion of patients who achieved an ACR50 response was also significantly higher in the secukinumab group at 24 weeks, at 34.7% for the higher-dose group and 30.7% for the lower-dose group compared with 7.4% for placebo controls.

In addition, approximately half of the patients in the active therapy groups had resolution of both dactylitis and enthesitis compared with 15.5% of patients receiving placebo.

Perhaps most important, patients in the secukinumab groups had significantly less radiographic progression, as measured by the change from baseline on the van der Heijde–modified total Sharp score at week 24, than placebo controls (P < .05 for both comparisons).

After a mean exposure of 438.5 days to secukinumab, serious adverse event rates were 11.5 per 100 patient-years for the 150-mg dose and 7.4 per 100 patient-years for the 75-mg dose. Adverse events leading to discontinuation of the study drug occurred in less than 5% of patients and were similar in both dose groups and placebo controls.

"One of the things that is very important to patients is whether or not they will experience disease progression on treatment," Proton Rahman, MD, professor of medicine and rheumatology and associate dean of clinical research, Memorial University, St. John's, Newfoundland, Canada, told Medscape Medical News. "And this data shows that secukinumab does delay radiographic progression, so that's an important feature of the drug."

FUTURE 1 Trial

A total of 606 patients with PsA were enrolled in the FUTURE 1 trial. Patients had active disease on study enrolment, defined as three or more tender joints and three or more swollen joints despite previous treatment with nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, or tumor necrosis factor (TNF) inhibitor therapy.

Patients in both secukinumab groups received an intravenous dose of the drug at 10 mg/kg of body weight at baseline, and again at weeks 2 and 4, followed by subcutaneous secukinumab at either 150 or 75 mg every 4 weeks thereafter. The concomitant use of oral glucocorticoids and methotrexate was permitted during the study interval.

"More than half the patients (53.6%) had psoriasis affecting at least 3% of their body-surface area," the authors note.

Also, 53.5% had dactylitis and 61.4% had enthesitis. More than 70% of patients had not received prior anti-TNF therapy, but 60.7% of them were receiving concomitant methotrexate. A total of 553 patients completed the 24-week evaluation period, and 515 completed the 52-week evaluation period.

As the authors note, significant improvement was seen in a number of secondary endpoints at week 24.

Table 1. Secondary Efficacy Endpoints at Week 24

Endpoint Secukinumab 150 mg Secukinumab 75 mg Placebo
Psoriasis Area Severity Index 75 response 61.1% 64.8% 8.3%
Psoriasis Area Severity Index 90 response 45.4% 49.1% 3.7%
Change from baseline in 28-joint Disease Activity Score–C-reactive protein −1.62 −1.67 −0.77
Change from baseline in Short Form-36 physical component 5.91 5.41 1.82
Change from baseline in Health Assessment Questionnaire Disability Index score −0.40 −0.41 −0.17
Change from baseline in joint structural damage (modified total Sharp score) 0.13 0.02 0.57

At week 24, an ACR20 response in patients who had received no previous anti-TNF therapy was achieved in similar proportions of patients, at about 55% in each of the secukinumab groups compared with 17.5% in the placebo group.

At the same time, among patients whose previous response to anti-TNF therapy was inadequate or who had unacceptable adverse effects, an ACR20 response was reported in similar proportions of patients, at about 39% in both groups of active therapy vs about 17% of the placebo controls, the authors add.

Improvements were, however, smaller among patients receiving secukinumab who had also received prior anti-TNF therapy.

"Clinical benefits in the secukinumab groups were sustained through 52 weeks of therapy," Dr Mease and colleagues point out.

At week 52, for example, an ACR20 response was still being reported in 59.9% of both groups receiving active therapy.

In terms of adverse events, four patients in the secukinumab groups had a stroke, compared with none in the placebo group. "[A]ll these patients were receiving 75 mg of secukinumab," the authors observe.

In addition, two patients had a myocardial infarction: one in each of the secukinumab dosing groups. In contrast, no strokes or myocardial infarctions were observed in the placebo group.

Candida infections were also more common among patients receiving secukinumab than among placebo controls. As the authors note, this is perhaps not surprising, as IL-17 plays a role in host defense against bacterial and fungal infections, particularly at mucosal sites.

No Dose–Response Relationship

"It is noteworthy that there was no apparent dose–response relationship between the two secukinumab groups with respect to efficacy assessments up to week 24," the investigators observe.

This lack of difference may be at least in part a result of the same intravenous loading dose that was given to patients in both dosing groups, they suggest.

"Nowadays with the biologic agents, primarily the anti-TNF inhibitors, patients' expectations from treatment are a lot higher now, and now that the bar has been raised so much higher, patients want an improvement that is similar to what they get with an anti-TNF agent," Dr Rahman said.

However, only two drug classes at the moment provide that magnitude of improvement: the TNF inhibitors and IL-12/23 antibodies, he added.

There are also certain contraindications to the anti-TFN agents, and clinical trials suggest that about 40% of patients who receive an anti-TNF blocker do not meet study criteria for improvement.

"So there's still a large unmet need for patients with PsA," Dr Rahman said. "And secukinumab has characteristics where just about all parts of the disease improve, whether it's the skin, the joints or periarticular features, including dactylitis and enthesitis, so it has a very good profile in terms of global improvement for PsA."

More Excitement

Asked to comment on the study, Jason Kolfenbach, MD, assistant professor of rheumatology, University of Colorado, Denver, told Medscape Medical News that in general, there is more excitement around secukinumab than some of the other new drugs such as oral apremilast for PsA, probably because the data look stronger for secukinumab than for some of the other agents.

"The fact that secukinumab improved dactylitis and enthesitis impressed me too, because that is an endpoint that some of our oral medications don't work well for, and if someone fails an anti-TNF medication, we don't have any other option right now," Dr Kolfenbach said.

Although IL-17A has not been compared head-to-head with any anti-TNF agent, he agreed with Dr Rahman that the rates of improvement reported in the current study are in line with what investigators reported for anti-TNF agents when they first came out.

"We also give a lot of injectable medications in rheumatology, and some of them have to be given once a week, so I think patients will be fine with an injectable they have to give themselves at home every 4 weeks," Dr Kolfenbach added.

The study was funded by Novartis Pharma. Dr Mease has reported serving as an advisory board member or on the speakers bureau for Novartis, UCB Pharma, Merck Sharp & Dohme, Bristol-Myers Squibb, Celgene, and Janssen. Several coauthors reported various financial relationships with Novartis, UCB Pharma, Merck Sharp & Dohme, AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Centocor, Amgen, Pfizer, Roche, Schering-Plough, UCB Pharma, Wyeth, Ablynx, AstraZeneca, GlaxoSmithKline, Novo Nordisk, Consultancy BV, Biogen Idec, Covagen, Crescendo, Genentech, Lilly, Abbott, Augurex, Chugai, Daiichi-Sankyo, Galapagos, Janssen Biologics, Otsuka, Roche, Sanofi-Aventis, and Vertex. Dr Rahman has reported being on advisory boards for Amgen, AbbVie, Celgene, Novartis, Pfizer and Janssen. Dr Kolfenbach has disclosed no relevant financial relationships.

N Engl J Med. 2015;373:1329-1339. Abstract

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