Dr. Richard Langley
The incidence of treatment-emergent antidrug antibodies in the secukinumab arms was 0.4%, and when it occurred, it had no impact on treatment efficacy or safety. Patients on etanercept weren’t tested for the emergence of antidrug antibodies.
Candida infections occurred in 4.7% of patients on secukinumab 300 mg, 2.3% of those on 150 mg, and 1.2% of the etanercept group. All cases in patients on secukinumab were mild or moderate and easily treated. Candida infections are a side effect of special interest because patients with a genetic defect in the IL-17 pathway can develop chronic mucocutaneous candidiasis. A theoretical concern that pharmacologic inhibition of IL-17 might create a big problem in this regard has not materialized.
The other two phase III secukinumab clinical trials presented in Istanbul – ERASURE and SCULPTURE – showed efficacy and safety results similar to those of FIXTURE. Unlike FIXTURE, neither of those trials featured a head-to-head comparison with another biologic.
These were the first completed phase III studies for any of the three biologics in this novel, highly promising class targeting IL-17 in the treatment of psoriasis and other immune-mediated inflammatory diseases. The other two agents in the pipeline targeting IL-17, brodalumab and ixekizumab, remain in ongoing phase III trials.
Because of the pivotal role IL-17 plays in generating inflammatory cytokines downstream, all three drugs are being studied for additional indications beyond psoriasis. For example, secukinumab, an IgG1 human monoclonal antibody, is in phase III clinical trials for psoriatic arthritis, ankylosing spondylitis, and rheumatoid arthritis, and in phase II for muscular sclerosis and asthma.
One audience member asked Dr. Langley for his thoughts regarding the absence of injection-site reactions in the secukinumab-treated patients. He replied that one obvious factor is that secukinumab injections are given much less frequently: once monthly during maintenance therapy as compared to once weekly with etanercept. In any event, he doesn’t consider injection-site reactions to be clinically relevant.
"Injection-site reactions don’t seem to be a major issue with any of the subcutaneous therapies. It has never in 15 years of using different biologics been an issue that’s made me stop treatment for a patient," he added.
Secukinumab was dosed at baseline, again weekly through week 4, then once monthly from week 8 through the study’s end. Etanercept was dosed at 50 mg twice weekly for 12 weeks, then once weekly in accord with the labeling instructions in most countries. Nonresponders at 12 weeks in the placebo arm were at that point randomized to secukinumab at 300 mg or 150 mg. The statistical analysis in FIXTURE was performed by nonresponder imputation.
"Those who are interested in statistics will know that that’s the most rigorous way that you can look at the data, because anybody who drops out of the study, whether they withdraw consent, have a protocol violation, or have an adverse event, even if they were responding at that time, are considered a failure or nonresponder," Dr. Langley explained.
Asked how he sees secukinumab fitting into patient management, Dr. Langley replied, "Most of us are forced to use conventional therapies and phototherapy to get approval for biologics, but after that I think the safety and efficacy of this drug put it right at the top. I could definitely use this drug as a first-line biologic for patients with plain psoriasis without psoriatic arthritis."
Coinvestigator Dr. Kristian Reich, professor of dermatology at Georg-August University in Göttingen, Germany, said he will probably continue to use TNF inhibitors in psoriasis patients with prominent arthritis, where he believes the TNF inhibitors are particularly beneficial, but he anticipates using secukinumab widely in others.
Dr. Bruce E. Strober, another active clinical trial researcher in psoriasis, said he likes what he sees in the IL-17 inhibitor data.
"I predict as a specialty we’ll become very confident in these drugs 5 years from now. A lot of us will be using them as first line in many patients. That’s my prediction. For now, though, I’m a big fan of TNF inhibition," added Dr. Strober, vice chair of dermatology at the University of Connecticut Medical Center, Farmington.
The secukinumab development program is sponsored by Novartis. Dr. Langley, Dr. Reich, and Dr. Strober disclosed having received research grants from and serving as consultants to Novartis and numerous other companies developing biologic agents for psoriasis.