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Mirikizumab effective in Crohn’s induction
SAN DIEGO — Patients with Crohn’s disease treated with mirikizumab for induction therapy experienced improvements to clinical and endoscopic outcomes, according to research presented at Digestive Disease Week.
Bruce E. Sands, MD, of the Icahn School of Medicine at Mount Sinai, said agents that target the interleukin-23 pathway, like mirikizumab, have shown efficacy in CD. The drug has also shown success in treating ulcerative colitis and psoriasis.
“Mirikizumab is a humanized immunoglobulin G4 monoclonal antibody, and it binds to the p19 subunit of IL-23,” Sands said in his presentation. “We assessed the safety and efficacy of mirikizumab with a phase 2, multi-center, randomized, parallel-arm, double-blind, placebo-controlled trial in patients with moderate-to-severely active Crohn’s disease.”
Researchers randomly assigned 191 patients to receive either 200 mg (n = 31), 600 mg (n = 32) or 1,000 mg (n = 64) of mirikizumab (LY3074828; Eli Lilly) or placebo (n = 64) intravenously at weeks 0, 4 and 8. Their primary goal was to determine the superiority of mirikizumab over placebo for the induction of endoscopic response — defined as a 50% reduction from baseline in Simple Endoscopic Score for CD (SES-CD) — at week 12. They also included clinical remission and endoscopic remission as secondary outcomes.
At week 12, in which 10.9% of patients achieved endoscopic response (95% CI, 3.3–18.6), response rates were better in all three mirikizumab groups vs. placebo. The 200 mg group experienced a 25.8% response rate (95% CI, 10.4–41.2), the 600 mg group achieved a 37.5% response rate (95% CI, 20.7–54.3) and the 1,000 mg group achieved a 43.8% response rate (95% CI, 31.6–55.9).
Additionally, data showed that patients in the 600 mg and 1,000 mg mirikizumab groups achieved better rates of endoscopic remission (P = .032 and P = .009, respectively) and clinical remission assessed by patient reported outcomes (28.1% and 21.9%, respectively). All three treatment groups showed greater response regarding CD activity index (200 mg: P = .015; 600 mg: P = .001; 1.000 mg: P = .026).
The safety findings of the study were similar to the drug’s previous safety profile, with the frequency of serious and treatment-emergent adverse events in all three treatment arms similar to placebo.
“Mirikizumab treatment resulted in significant improvement in endoscopic findings, significant improvement in patient reported outcomes and Crohn’s disease activity index,” Sands concluded. “We feel that these data support the further development of Mirikizumab for Crohn’s disease.” – by Alex Young
Reference:
Sands B, et al. Abstract 1,003. Presented at: Digestive Disease Week; May 18-21, 2019; San Diego.
Disclosures: Sands reports financial ties to 4D Pharma, Allergan, Sales, Amgen, Arena, Boehringer Ingelheim, Capella Biosciences, Celgene, EnGene, Ferring, Gilead, Janssen, Lilly, Lyndra, MedImmune, Oppilan, Otsuka, Palatin Technologies, Pfizer, Progenity, Rheos Medicine, Seres Therapeutics, Syngery, Takeda, Target Pharmasolutions, Theravance Biopharma, TiGenix, Vivelix and WebMD. Please see the meeting disclosure index for all other authors’ relevant financial disclosures.
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Mirikizumab (LY3074828, Eli Lilly) is a humanized monoclonal antibody binding to the p19 subunit of interleukin-23. Ustekinumab (Stelara, Janssen) also blocks interleukin-23 as well as interleukin-12 by blocking the p40 subunit of IL-23 and IL-12.
We know that ustekinumab is effective and approved in Crohn’s disease, and we are now seeing the development of several IL-23 specific inhibitors by virtue of targeting the p19 subunit that is present in IL-23, but not present in IL-12. This is more selective than ustekinumab and does not affect IL-12.
Why would we want to be more selective? Well, there are some data, which are not very strong, that suggest inhibition of IL-12 may have some additionally potential side effects, including carcinogenesis. But that has not been demonstrated in human trials. So, this is somewhat speculative within humans as far as increased safety.
Nevertheless, selecting IL-23 appears effective in a dose-response between 200 mg and 1,000 mg. We actually do not know if the 1,000 mg dose is providing the optimal response, because we have not seen the response rate level off. In other words, 1,000 mg provided better results than the 600 mg or 200 mg, but we don’t know for instance if going above 1,000 mg would have actually improved things further.
As we anticipated from previous studies with ustekinumab, the inhibition of IL-23 appears to be another very safe therapy with an apparent lower risk for infections than we have seen with TNF inhibitors.
I say apparent, because we do not yet have head-to-head studies between IL-23 and TNF inhibition, but I will point out that there is an ongoing trial comparing ustekinumab with Humira (adalimumab, AbbVie) in Crohn’s disease.