Mirikizumab is the first interleukin (IL) 23p19 to report positive phase 3 results for induction therapy in patients who have moderate to severe ulcerative colitis (UC) and have already been treated with at least one prior therapy.
Compared to placebo, almost a quarter (24.2%) of patients treated with mirikizumab versus 13% of those treated with placebo were in clinical remission at the end of the 12-week LUCENT-1 study. This was the study’s primary endpoint and it was a significant result (P = .00006), study investigator Geert D’Haens, MD, PhD, reported at the 17th congress of the European Crohn’s and Colitis Organisation.
Moreover, mirikizumab met all its secondary endpoints in the trial. At the end of the study almost two-thirds (63.5%) of patients achieved a clinical response (vs. 42.2% in the placebo arm); over one-third (36.3%) exhibited endoscopic remission (vs. 21.1%), and just over a quarter (27.1% vs. 13.9%) showed histologic-endoscopic mucosal improvement, according to a press release. The P values for all comparisons were less than .00001.
Perhaps more importantly from the patient perspective, there was greater symptomatic improvement and less bowel urgency in those treated with mirikizumab versus those randomized to placebo.
“The results confirmed [the] efficacy and safety noted in the phase 2 induction [trials], and supports mirikizumab’s potential as treatment for ulcerative colitis,” said D’Haens, professor of gastroenterology and hepatology at Amsterdam University Medical Centers.
Dominik Bettenworth, MD, who was not involved in the study, said that “the positive results from the LUCENT-1 trial are an important step towards selective IL-23 inhibition as a new mode of action for the treatment of patients with UC.
“This treatment approach has been shown efficacious and launched in other immune-mediated diseases such as psoriasis,” said Bettenworth, a specialist in internal medicine and gastroenterology in Münster, Germany.
“Noteworthy, for the first time in a phase 3 trial in IBD, [bowel] urgency has been assessed as a secondary endpoint – a clinical symptom of particular importance for patients with UC,” he added, noting that regarding safety, “the LUCENT-1 trial further confirms the previously observed overall good safety profile of IL-23 inhibitors.”
About Mirikizumab and LUCENT-1
Mirikizumab is a humanized monoclonal antibody directed against the p19 subunit of IL-23 and is one of several IL23p19 antibodies currently under investigation for the treatment of IBD.
LUCENT-1 was a multicenter, randomized, double-blind, parallel group, placebo-controlled induction study in just over 1,200 patients aged 18-80 years. For inclusion, patients had to have moderately to severely active UC and had to have received at least one prior therapy, but had an inadequate or loss of response to it or been intolerant of it. Baseline data showed that 40% of patients included had been treated with corticosteroids and 24% with immunomodulators, and any current treatment remained unchanged during the study. Biologic treatment had failed in about 40% of patients and any patient taking such therapy had to discontinue it before participating in the trial.
Patients were randomized to receive 300 mg of mirikizumab or matching placebo, given intravenously at weeks 0, 4, and 8. D’Haens noted that randomization had been in a 3:1 ratio and had been stratified according to various factors such as biologic failure status, corticosteroid use, baseline disease activity, and region of the world where the patient was recruited.
Better Results If Biologic Naive
Clinical remission was stringently defined as: Mayo stool frequency subscore of zero or one, with a reduction of one point or greater from baseline; no rectal bleeding; and a Mayo endoscopic subscore of zero to one. When looking at this primary endpoint in terms of whether patients had received prior biologic treatment, there was a higher remission rate at week 12 if patients had not previously been given any biologic therapy than if they had, but rates were still higher than placebo (30.9% vs. 15.8% and 15.2% vs. 8.5%, respectively), according to the press release. The P value was less than .001 for both comparisons although the study was not powered to look at these subgroups of patients.
Similarly, for clinical response – which was a decrease in the modified Mayo score of 2 or more points and at least a 30% decrease from initial values, as well as a decrease in rectal bleeding – there were differences between patients who had (54.6% for mirikizumab vs. 29.7% for placebo) and had not (70.1% vs. 50.3%) received a biologic previously (again, P less than .001 for both comparisons).
“Control of bowel function is one of the most debilitating, or one of the most important features for patients with ulcerative colitis,” D’Haens said when presenting the data on bowel urgency. In the trial there was an improvement in urgency – which was rated by patients – starting as early as week 2, with further improvement seen as the induction period went on.
Mirikizumab Safety Consistent With Other Trials
D’Haens noted that the safety profile of IL23 antibodies was “extremely clean.” As with other trials of mirikizumab, he said, there were similar or lower rates to placebo for many adverse events including any infection (15.1% vs. 14%) and cerebrocardiovascular events (0.6% vs. 0.1%). The overall rate of treatment emergent adverse events was 44.5% vs. 46.1% for mirikizumab and placebo. Notably, there were fewer serious adverse events (2.8% vs. 5.3%.) and discontinuations because of side effects (1.6% vs. 7.2%) in the mirikizumab group.
Are Gastroenterologists Now Spoiled for Choice?
Lots of questions followed D’Haens presentation, many picking up on the high placebo response and remission rates.
“We’ve seen it in a number of trials now,” D’Haens said. “One of the reasons is that patients are allowed to start corticosteroids as late as 2 weeks before randomization,” he observed. In LUCENT-1, half of the patients that were using steroids were receiving a dose of 20 mg of prednisone.
“Now when you start 20 mg of prednisone 2 weeks before randomization that might have an impact on your placebo readout. So I think that’s a lesson for many more trials in the future,” D’Haens said,”
A high placebo response rate was not expected and another hypothesis is that maybe additional clinical support for fatigue that was received may have played a role.
Several delegates asked for guidance on where mirikizumab and other IL-23p19 blockers might now fit in the grand scheme of patient treatment.
“It is really nice to have expanding therapeutic options but how will we choose?” said one in the online Q&A. “Which IL23 antagonist should we be using now?” and “Is ustekinumab obsolete in UC?” asked others.
“I think it’s early days to decide where the field is going,” D’Haens said after his presentation. “We don’t have head-to-head data. In GALAXI, ustekinumab was a reference arm.”
There will be further subanalyses of LUCENT-1 to come, including results from endoscopy and histology investigations, and the maintenance trial LUCENT-2 will also report soon.
“The feeling is that IL23 blockade is more specific, [more] beneficial in inflammatory bowel disease than blocking both IL12 and IL23,” D’Haens said.
D’Haens was an investigator in the LUCENT-1 trial and has acted as an adviser to the study’s sponsor, Eli Lilly, among many other big pharma companies. Bettenworth is on the advisory board or is a consultant for AbbVie, Amgen, Arena, Atheneum, BNG Service GmbH, Bristol Myers Squibb, CED-Service GmbH, Celltrion, Else Kröner-Fresenius-Foundation, Galapagos, Guidepoint, Impulze, Falk Foundation, Ferring, Janssen Cilag, Medical Tribune, MedTriX, MSD, Mylan, Onkowissen, Pharmacosmos, Pfizer, Roche, Sandoz, Takeda, Tetrameros, Thieme, Tillotts Pharma, and Vifor Pharma.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.