AT THE EADV CONGRESS
GENEVA (FRONTLINE MEDICAL NEWS) – Can potent, highly efficacious biologic therapy induce longstanding remission of moderate to severe plaque psoriasis following discontinuation of all treatment?
The answer appears to be yes, in a minority of patients, based on results of a long-term extension study of two pivotal phase 3 clinical trials of secukinumab (Cosentyx), Mark G. Lebwohl, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
This 2-year extension study provides the first double-blind, long-term evidence regarding the natural history of psoriasis following discontinuation of a contemporary potent targeted therapy.
The results are exciting because spontaneous remission of moderate to severe psoriasis is rare; psoriasis typically reverts to baseline severity following discontinuation of treatment. In the extension study, though, 21% of patients who achieved a 75% reduction in the Psoriasis Area Severity Index (PASI 75) response on secukinumab at the 300-mg dose for 52 weeks and were then crossed over double-blind to placebo remained continuously relapse-free after 12 months on placebo, and 10% remained relapse-free at 2 years, at which point they were unblinded and put back on secukinumab. No psoriasis therapies were permitted during the placebo phase.
Those findings are particularly impressive because participants in the two pivotal trials of secukinumab combined for the treatment withdrawal extension study – ERASURE and FIXTURE – had a mean 14- and 16-year history of psoriasis at baseline.
“Secukinumab appears to have modified the course of chronic moderate to severe psoriasis, despite intervening late in its course. Treating patients early is expected to have an even greater potential for disease modification,” commented Dr. Lebwohl , the Sol and Clara Kest Professor and chair of the department of dermatology at Icahn School of Medicine at Mount Sinai, New York.
That hypothesis is under investigation in the ongoing multinational STEPin trial (Study of the Efficacy of Early Intervention With Secukinumab 300 mg s.c. [subcutaneous] Compared to Narrow-band UVB in Patients With New-onset Moderate to Severe Plaque Psoriasis). STEPin involves about 200 patients with newly diagnosed disease not previously treated with systemic agents or phototherapy.
Dr. Lebwohl focused on the 120 patients in the extension study who had a PASI 75 response to secukinumab at the 300-mg dose and the 100 patients with a PASI 75 response to the 150-mg dose who, after 52 weeks on the fully human anti-interleukin-17A monoclonal antibody, were crossed over double-blind to placebo for 2 years or until relapse occurred. Patients were assessed monthly during the extension study.
Relapse was defined as loss of 50% of the maximum PASI improvement achieved while on secukinumab. The relapse-free rate was better in patients who had been on secukinumab 300 mg than in those on 150 mg. At 1 year on placebo, 21% of patients formerly on secukinumab at the higher dose remained free of relapse, as did 10% at 2 years. In contrast, the 1- and 2-year relapse-free rates in the group formerly on secukinumab 150 mg were lower at 14% and 6%, respectively, even though everyone in the extension study had a PASI 75 response when they went off treatment.
The mean baseline PASI score in the ERASURE and FIXTURE trials was 23. Among patients who remained relapse-free for 1 year, the mean PASI score was dramatically lower, at 0.7; among those in remission for 2 years, it was 0.4.
Importantly, the longer a patient’s history of psoriasis, the less likely a long-term relapse-free experience, the dermatologist observed.
A separate mechanistic study in a different group of psoriasis patients provided a likely explanation for the long relapse-free period seen off therapy in some patients in the extension study. The mechanistic study entailed transcriptional analysis of psoriasis-related genes in lesional and nonlesional skin before and after 1 year of treatment with secukinumab 300 mg. The major finding: 85% of the upregulated genes and 75% of downregulated genes in lesional skin pretreatment reverted to normal levels in healed lesional skin post treatment.
Moreover, global mRNA expression for key genes involved in the interleukin-23/interleukin-17 inflammatory cytokine pathway closely resembled healthy skin following treatment with secukinumab. This is evidence of profound molecular normalization, Dr. Lebwohl said.
These secukinumab studies were sponsored by Novartis. Dr. Lebwohl reported having no personal financial conflicts of interest, although his department receives research funding from Novartis and numerous other pharmaceutical companies.