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SAN FRANCISCO -- Almost twice as many patients with chronic plaque psoriasis responded to treatment with an interleukin-23 (IL-23) inhibitor as compared with an IL-12/23 inhibitor, a small randomized trial showed.

After 12 weeks of follow-up, 77.1% of patients treated with BI-655066 (90 mg plus 180 mg doses) had 90% improvement in the Psoriasis Area and Severity Index (PASI-90) versus 40% of patients treated with ustekinumab (Stelara). BI-655066 demonstrated a rapid onset of action, as about 70% of patients had 50% improvement (PASI-50) by 4 weeks, increasing to more than 90% at 8 weeks.

Severe and serious adverse events occurred infrequently with the investigational BI-655066 and ustekinumab, K. Alexander Papp, MD, PhD, of in Waterloo, Ontario, reported here at the American Academy Dermatology meeting.

"What we see from this study is hope that there is another therapy that will be very effective in treating psoriasis, not just for the short term but the long term," Papp told 名媛直播. "They are preliminary results, but we actually have very high efficacy, and we see a very quiet safety signal."

"We're going to need more patients. We're going to need longer-term studies. At this point, we can say that it is something that holds a great deal of promise," he added.

But the results make a strong case for IL-23 as the key player in psoriasis, as opposed to both IL-12 and 23, he acknowledged.

"The results are so spectacular that it's unlikely that blockade of IL-12 really has much of a role to play," Papp said. "Until we actually do the study, looking at IL-12 blockade, we won't know for sure. Certainly, it's very compelling evidence at this point to suggest that it is really IL-23 and that are the key pathways in driving psoriasis.

"That means that, in terms of future therapeutic development, looking at other compounds for treating psoriasis, more and more focus on that pathway and the variety of intracellular and interleukin mechanisms of expressing inflammation in psoriasis will be pursued."

IL-23 versus IL-12/23

IL-23 has been recognized as a major factor in the etiology and pathogenesis of psoriasis, and recent therapeutic development has focused on inhibition of the inflammatory cytokine. Among other pro-inflammatory activities, IL-23 activation stimulates production of other cytokines, including IL-17 and IL-22, both of which directly affect skin inflammation.

IL-12 and IL-23 are members of the same cytokine family, and their relative contributions to psoriasis pathogenesis have been a source of intense research and debate for several years. Some authorities have argued that inhibition of both IL-12 and IL-23 results in more complete control of the inflammatory pathway. Some recent evidence has suggested that IL-23 has the predominate role in psoriasis.

BI-655066 selectively inhibits the p19 fragment of IL-23, effectively blocking production of both IL-17 and IL-22. Ustekinumab inhibits both IL-12 and IL23.

Papp reported findings from a randomized phase II trial involving patients with chronic moderate-to-severe plaque psoriasis. Patients were randomized to one of three doses of BI-655066 (18, 90, or 180 mg) or to ustekinumab.

Patients randomized to the lowest dose of BI-655066 received a single active dose at baseline and placebo injections at weeks 4 and 16. The remaining three groups received three injections of active therapy.

The primary endpoint was the proportion of patients achieving PASI 90 at week 12 in the 90- and 180-mg BI-655066 groups combined versus ustekinumab. Secondary endpoints included PASI 50, PASI 75, PASI 100, and the Static Physician Global Assessment (sPGA).

The primary analysis occurred after 12 weeks of follow-up, but the trial will continue for 48 weeks.

Primary Results

Investigators in the multicenter trial enrolled and randomized 166 patients, 157 of whom completed the first 12 weeks of treatment and follow-up. Baseline PASI averaged about 20, about a fourth of the patients had psoriatic arthritis, and about a fourth had prior exposure to a tumor necrosis factor inhibitor.

The results showed that 64 of 83 patients in the 90- and 180-mg BI-655066 groups met the primary endpoint of PASI 90 at week 12, as compared with 16 of 40 in the ustekinumab arm. In the 18-mg BI-655066 group, 14 of 43 (32.6%) patients had achieved PASI 90 by week 12.

Papp reported that the 90-mg group (P=0.0013), the 180-mg group (P<0.0001), and the two groups combined (P<0.0001) had significantly higher PASI 90 rates as compared with the ustekinumab group.

Reviewing the secondary efficacy endpoints, Papp showed that more than 90% of BI-655066 patients in the combined analysis achieved PASI 50 by 8 weeks and maintained the response to week 24. About 90% of the patients in the combined group met criteria for PASI 75 by week 12 and maintained that response to week 24.

Patients randomized to 180 mg of BI-655066 maintained the PASI 90 response to 24 weeks in about 90% of cases, whereas the PASI 90 rate in the 90-mg group began to decline after week 16.

PASI 100 -- complete clearance of lesions -- was achieved by 61% of the 180-mg group at week 20 and by 53% of the 90-mg group, as compared with 30% of the ustekinumab group.

Favorable Safety Data

The most commonly reported adverse events with BI-655066 were nasopharyngitis (about 25%) and headache (5% to 10%). Nasopharyngitis was reported most frequently in the ustekinumab group (7.5%).

One patient each in the 90-mg and 180-mg BI-655066 groups had severe adverse events, 14 patients in the two groups combined had adverse events considered drug related, and two patients in the 90-mg group versus none in the 180-mg group had serious adverse events. One patient in the 90-mg group discontinued treatment because of adverse events.

Severe, drug-related, and serious adverse events occurred in two, seven, and one patient, respectively, in the ustekinumab group, and one patient stopped treatment because of adverse events.

Though compelling, the results require confirmation in larger trials, said Michael Siegel, PhD, research director for the National Psoriasis Foundation. He also cautioned overinterpretation of the trial's implications for future therapeutic development.

"It is exciting ... that we are understanding immune signaling pathways better and better with time and that selectively targeting the 'right' pathway can have such value for our patients," Siegel told 名媛直播 by email. "But psoriasis has so many variables, presents in so many unique ways, and responds differently to different treatments in different people.

"So I would not want to give up on any one treatment that may work well for many people because another good option has entered the market. I want our patients and providers to have as many options as possible to choose from when treating each individual case."

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