AMSTERDAM– The spectacular long-term efficacy achieved with a novel biologic agent for psoriasis in a first-in-humans, proof-of-concept study has raised the prospect of clinical outcomes continuing to ratchet higher in the treatment of moderate-to-severe chronic plaque psoriasis.

How much higher? Six of nine treated patients followed long-term have maintained a PASI 100 response – that is, completely clear – for up to 66 months after a single subcutaneous injection of the agent known for now as BI 655066, Dr. James G. Krueger reported at the annual congress of the European Academy of Dermatology and Venereology.

“For me, this is one of the most interesting features of this proof-of-concept study,” he added. “If this kind of activity is confirmed in the ongoing phase IIb trial, I think this represents the potential for very long-term disease modification. This could become an important agent in the future to treat psoriasis.”

BI 655066 is a monoclonal antibody that specifically targets the p19 subunit of interleukin (IL)-23. Unlike ustekinumab (Stelara), which blocks both IL-23 and IL-12, BI 655066 selectively blocks only IL-23, which Dr. Krueger believes is the central driving force in activating and sustaining the T-cell subsets responsible for the hyperproliferative and inflammatory reactions that define psoriasis.

“This study is all about testing for the specific pathogenic contribution of IL-23 to psoriasis in a first-in-humans study. Our findings really emphasize the importance of IL-23 in driving the key pathways of psoriasis,” observed Dr. Krueger, professor of investigative dermatology and director of the Milstein Medical Research Program at Rockefeller University, New York.

The study included 39 patients with moderate to severe plaque psoriasis. Their baseline PASI was 18, and they averaged more than a 20-year history of psoriasis. Twenty-four patients were randomized 3:1 to a single intravenous injection of BI 655066 at various doses ranging from 0.01 mg/kg to 5 mg/kg or to placebo in order to get an initial sense of the agent’s safety and tolerability.

In the second part of the study, 15 other participants received a single subcutaneous injection: two got placebo and the rest were randomized to BI 655066 at either 0.25 mg/kg or 1.0 mg/kg. Safety and efficacy were assessed at weeks 0, 2, 4, 12, and 24. In addition, skin biopsies were obtained at weeks 0 and 8 for immunohistochemistry studies and RNA sequencing analysis.

By week 12, the PASI 75 response rate in subcutaneous BI 655066 recipients was 87% and the PASI 90 rate was 58%. At week 24, nine patients elected to continue structured prospective follow-up while remaining off treatment, including six PASI 100 responders. Those six PASI 100 responders remained PASI 100 at ongoing follow-up 48-66 weeks after receiving their single dose of the agent.

Biopsy specimens obtained at week 8 showed normalization of the epidermal psoriasiform hyperplasia which had been present at baseline. A normal-looking granular layer had been reestablished. “This looks essentially like the pattern of normal or nonlesional skin,” according to the dermatologist.

RNA sequencing analysis and gene profiling showed normalized production of the IL-23/IL-17-induced proteins that had been strongly overexpressed at baseline, including lipocalin, beta-defensin, and psoriasin.

“The immune axis is turned down. The number of immune cells is way down, although they’re not completely eliminated. With placebo, you still see a psoriasislike pattern of the disease. With blockade of IL-23, most cases have a gene profile like nonlesional skin. This represents a profound cellular and disease modulation,” Dr. Krueger said.

Among all 39 participants, the only serious adverse event deemed possibly treatment related was a 5-minute transient ischemic attack (TIA) episode in a patient on BI 655066. This caught Dr. Krueger’s attention as a possible red flag; however, he noted that more than 200 patients have since received the biologic agent in the ongoing phase IIb trial, with no reported major adverse cardiovascular events.

“I think that TIA may just be bad luck with small numbers,” he added.

Asked what he thinks might explain the remarkably lengthy disease remission seen following a single dose of the biologic, Dr. Krueger offered two possibilities.

“It may be that IL-23 is necessary to sustain pathogenic clones of memory cells in the skin, and as we get rid of it those clones most likely apoptose. And if you’ve sufficiently removed the clones, then you don’t get the expansion. That’s guess one. Guess two would be that we’ve renormalized tolerance mechanisms in some way. Both of these hypotheses can be tested,” according to Dr. Krueger.

The study was funded by Boehringer Ingelheim. Dr. Krueger reported receiving funding from that pharmaceutical company and nearly two dozen others.

bjancin@frontlinemedcom.com

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