AT THE EADV CONGRESS
VIENNA (FRONTLINE MEDICAL NEWS) – The investigational interleukin-23 p-19 subunit inhibitor tildrakizumab achieved PASI 90 improvement rates approaching 60% in patients with moderate to severe plaque psoriasis at week 28 of the pivotal phase III reSURFACE 1 and reSURFACE 2 trials, Kristian Reich, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
Moreover, the PASI 100 rate at week 28 in the two clinical trials was 24% with tildrakizumab, a humanized monoclonal antibody, at the 100-mg dose and 30% at 200 mg.
It was at these highest efficacy thresholds that the p-19 inhibitor really separated itself from etanercept (Enbrel) in reSURFACE 2, where the two biologics went head-to-head in randomized fashion. Patients on etanercept had a PASI 90 rate at week 28 of 31%, roughly only half that of tildrakizumab at the higher dose.
“One of the highlights of this meeting with regard to the management of psoriasis is that for the first time we’re seeing phase III data for p-19 inhibitors. The hope – the promise – of the p-19 inhibitors is that, similar to the IL-17a inhibitors, they’ll bring more patients to a PASI 90 response. We are seeing that, and there will be more p-19 inhibitors to come,” said Dr. Reich, professor of dermatology at Georg-August-University in Gottingen, Germany, and a partner at Dermatologikum Hamburg.
Guselkumab was the other IL-23 p-19 inhibitor that was a featured attraction at the EADV congress, with 48-week outcomes presented from the 837-patient, pivotal phase III VOYAGE 1 trial. Although caution is always warranted in comparing results across clinical trials because of differences in study populations, guselkumab achieved better top-end efficacy numbers than did tildrakizumab: a PASI 90 of 73.3% at 16 weeks and 80.2% at 24 weeks, along with PASI 100 responses of 34.4% at 16 weeks and 44.4% at 24 weeks.
“I believe there will be characteristics of the new drugs beyond efficacy that will come into play when making treatment decisions: Is dosing every 8 weeks or every 12 weeks? What is the price? What is the outcome after 1 year? I think it’s too early to close the book in trying to understand what these different drugs do, but these phase III results do give us the insight that IL-23 p-19 is actually the sweet spot in psoriasis. By targeting it we are able to keep the disease under control with drugs that are very convenient to use,” Dr. Reich said.
He added that his psoriasis patients really appreciate the convenience of quarterly as opposed to more frequent dosing of biologics, and he does, too.
reSURFACE 1 is a 64-week, randomized, phase III trial conducted in the United States, Canada, and Europe in which 772 patients were randomized 2:2:1 to tildrakizumab at 100 mg or 200 mg or to placebo. reSURFACE 2 is a 64-week trial in which 1,090 patients were randomized 2:2:1:2 to tildrakizumab at 100 mg or 200 mg, placebo, or etanercept at 50 mg twice weekly for the first 12 weeks and once weekly thereafter. At week 12 in both trials, patients on placebo were rerandomized to tildrakizumab at 100 or 200 mg for the duration. Participants averaged a baseline Psoriasis Area and Severity index score of 20, a body weight of 88 kg, and disease involvement over 31% of their body surface area.
Tildrakizumab was dosed in a regimen that’s the same as for ustekinumab (Stelara), which inhibits IL-12 as well as IL-23: one subcutaneous injection at baseline, another 1 month later, and every 12 weeks thereafter.
Dr. Reich presented results of the two pivotal trials through week 28. The coprimary efficacy endpoints in both studies were the PASI 75 response and proportion of subjects with a Physician’s Global Assessment (PGA) score of 0 or 1, meaning clear or minimal disease, compared with placebo at week 12. In hindsight, he said, those were not the best endpoints to have employed.
“We have here a drug that takes a little while to get to full throttle. The primary endpoint selected here at week 12 does not show efficacy data that really separates tildrakizumab from a drug like Stelara. But at week 28 you move toward levels of PASI 90 and PASI 100 response that we really want to see,” the dermatologist said.
Combining the results of reSURFACE 1 and 2, the PASI 75 response rate at week 12 – after only two doses – was 63% in the 100-mg arm and 64% at 200 mg. But the rates kept climbing thereafter such that by week 28 the PASI 75 rates were 77% and 78%.
Fifty-seven percent of patients on tildrakizumab at 100 mg had a PGA score of 0 or 1 at week 12, as did 6% of placebo-treated controls. By week 28, 66% of patients on the lower dose of the p-19 inhibitor had a PGA of 0 or 1. Rates in patients on tildrakizumab at 200 mg were 57% and 66% at 12 and 28 weeks, respectively.
Rates of adverse events of special interest in new biologic agents, including severe infections, malignancies, and major cardiovascular events, were similarly low across all study arms.
“My feeling is that looking at week 12 and week 28 safety data is of limited value. All I can say here is that through week 28 in these two studies I don’t see a safety signal. But for me, the real insight will have to come from larger studies with longer follow-up,” Dr. Reich said.
Asked why he thinks tildrakizumab is a slow starter, with only middling efficacy at the 12-week mark before subsequently picking up steam, he said it’s probably not a matter of the wrong doses being selected for reSURFACE 1 and 2, since the outcomes with 100 and 200 mg are fairly similar. More likely, the monoclonal antibody takes a bit longer to bind to its target and neutralize it than do some of the other biologics.
“It could be that if you dosed tildrakizumab at weeks 0, 2, and 8 as induction therapy you’d hit the mark at 12 weeks,” he added.
The reSURFACE trials are funded by Sun Pharma and Merck. Dr. Reich reported having received research grants from and serving as a consultant to Merck and numerous other pharmaceutical companies interested in new treatments for inflammatory skin diseases.