Lilly and Janssen Announce Latest Phase 2 Clinical Results of IL-23 Inhibitors Mirikizumab and Guselkumab in Crohn’s Disease at UEG Week 2020

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The 28th United European Gastroenterology Week (UEG Week 2020) virtual conference was held from October 11 to 13, 2020. At this conference, Eli Lilly and Johnson & Johnson respectively announced the latest results from Phase 2 clinical studies of their IL-23 inhibitors, mirikizumab and Tremfya® (generic name: guselkumab), for the treatment of Crohn’s disease (CD). CD is an inflammatory bowel disease (IBD) characterized by abdominal pain, diarrhea, fever, and weight loss, and can lead to intestinal obstruction, fibrosis, and other complications. IL-23 is a cytokine that plays a key role in various autoimmune diseases.

Mirikizumab is a humanized IgG4 monoclonal antibody that selectively binds to the p19 subunit of interleukin-23 (IL-23). It is currently under development for the treatment of various immune-mediated diseases, including Crohn’s disease (CD), psoriasis, and ulcerative colitis. Tremfya is a fully human monoclonal antibody targeting the IL-23 p19 subunit. First approved in July 2017, it was the first selective IL-23 inhibitor to receive regulatory approval. In China, Tremfya was approved in Hong Kong in November 2018 and on the Chinese mainland in December 2019 for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy.

mirikizumab：

Sustained symptom improvement and reduced intestinal inflammation

Results from the Phase 2 SERENITY study demonstrated that 52 weeks of mirikizumab treatment led to sustained symptom improvement and significant reduction in intestinal mucosal inflammation in patients with moderately to severely active Crohn’s disease (CD). These data reinforce the ongoing evaluation of mirikizumab for the treatment of CD in the pivotal Phase 3 VIVID program.

SERENITY is a multicenter, randomized, parallel-group, double-blind, placebo-controlled Phase 2 study conducted in patients with moderately to severely active Crohn’s disease (CD). The study spans 52 weeks, comprising a 12-week induction period and a 40-week maintenance period, and is evaluating the safety and efficacy of multiple dosing regimens and two administration routes (intravenous [IV] and subcutaneous [SC]). During the induction period, patients were randomized into four treatment groups to receive either placebo or one of three doses of mirikizumab (200 mg, 600 mg, or 1000 mg) via IV. At Week 12, patients who demonstrated endoscopic improvement were randomized to receive either IV or SC mirikizumab. Patients who did not show endoscopic improvement or who had been randomized to the placebo group during induction were randomized to receive IV mirikizumab.

In May 2019, Eli Lilly reported the primary endpoint results:At Week 12 of treatment, a higher proportion of patients in the mirikizumab group achieved clinical response and clinical remission compared with those in the placebo group. New data presented at this conference showed that the study met multiple key secondary endpoints at Week 52, including endoscopic response (defined as a ≥50% reduction from baseline in the Simple Endoscopic Score for Crohn’s Disease [SES-CD]), patient-reported outcome (PRO) remission (defined as an average daily stool frequency ≤2.5, abdominal pain score ≤1, and no worsening from baseline), and endoscopic remission (defined as an SES-CD <4 for ileocolonic disease, an SES-CD <2 for isolated ileal disease, and no individual subscore >1).Among these, endoscopic response and PRO remission are two important treatment goals for CD.

Specific data are as follows: (1) Endoscopic response: Nearly 60% of patients achieved an endoscopic response, with 58.5% in the randomized intravenous (IV) administration group and 58.7% in the subcutaneous (SC) administration group. (2) Patient-reported outcome (PRO) remission: More than 45% of patients achieved PRO remission, with 46.3% in the IV administration group and 45.6% in the SC administration group. (3) Subset analysis showed that among patients who achieved an endoscopic response at Week 12, 69.6% in the IV group (n=23) and 66.7% in the SC group (n=24) also maintained an endoscopic response at Week 52; among patients who achieved endoscopic remission at Week 12, 50.0% in the IV group (n=6) and 64.3% in the SC group (n=14) also maintained endoscopic remission at Week 52. (4) Safety data indicated that among patients who showed endoscopic improvement at Week 12, one patient in each group discontinued treatment due to adverse events (AEs). The incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) was similar between the IV and SC groups. The most common TEAEs were nasopharyngitis (4.9% in the IV group, 13% in the SC group), headache (7.3% in the IV group, 8.7% in the SC group), and arthralgia (7.3% in the IV group, 13% in the SC group).

Tremfya：

Effective Induction of Clinical and Endoscopic Improvement

Interim analysis data from the Phase 2 GALAXI 1 study demonstrated that, at Week 12 of treatment in patients with moderately to severely active Crohn’s disease (CD), Tremfya yielded significant improvements in key clinical and endoscopic outcome measures compared with placebo, with a safety profile consistent with its approved indications. Currently, Tremfya is not approved for the treatment of CD. The data presented herein represent the first results evaluating Tremfya for the treatment of moderately to severely active CD. Although substantial progress has been made in the clinical management of CD, a subset of patients does not benefit from any currently approved therapies targeting the mechanisms underlying CD symptoms. These initial data confirm that all three doses of Tremfya produced significant responses in key clinical and endoscopic outcome measures.

GALAXI 1 is a double-blind, placebo-controlled, multicenter Phase 2 dose-ranging study evaluating the efficacy and safety of Tremfya in patients with moderately to severely active Crohn’s disease (CD) who have had an inadequate response to or intolerance of conventional therapy (corticosteroids, immunosuppressants) and/or biologics (TNF antagonists). In this study, patients will receive treatment for up to 3 years. The study includes an active comparator group receiving Stelara (generic name: ustekinumab). Stelara is the first biologic agent globally that selectively targets both IL-12 and IL-23 and has been approved for the treatment of adult patients with CD.

The interim analysis reported the 12-week treatment outcomes for the first 250 patients. Approximately 50% of these patients had previously failed biologic therapy, and their baseline disease characteristics were consistent with moderately to severely active Crohn’s disease (CD) (mean Crohn’s Disease Activity Index [CDAI] score, 306.6; median Simple Endoscopic Score for Crohn’s Disease [SES-CD], 11.0). In the study, patients were randomly assigned in a roughly equal ratio to five treatment groups, including three Tremfya dose groups (200 mg, 600 mg, and 1200 mg administered intravenously [IV] at Weeks 0, 4, and 8), a Stelara group (6 mg/kg IV at Week 0 and 90 mg subcutaneously [SC] at Week 8), and a placebo group.

Results showed:At Week 12, compared with the placebo group, each Tremfya dose group (200, 600, and 1200 mg IV) demonstrated a significant reduction in CDAI from baseline (least squares mean changes: -154.1, -144.3, and -149.5, respectively; placebo: -36.0; all p<0.001). Compared with the placebo group, the proportion of patients achieving clinical remission (CDAI <150) was significantly higher in each Tremfya dose group: 54.0%, 56.0%, and 50.0%, respectively, versus 15.7% in the placebo group (p<0.001). Among patients who had failed conventional therapy, 61.6% in the Tremfya combination therapy group and 18.5% in the placebo group achieved clinical remission at Week 12. Among patients who had previously failed biologic therapy, 45.5% in the Tremfya combination therapy group and 12.5% in the placebo group achieved clinical remission at Week 12.

Furthermore, at Week 12, a significantly higher proportion of patients treated with Tremfya achieved clinical response (p<0.001), Patient-Reported Outcome (PRO)-2 remission (p<0.001), clinical biomarker response (p<0.001), and endoscopic response (p<0.001) compared with placebo-treated patients. Endoscopic healing is an important outcome for long-term disease control; 37.3% of patients in the Tremfya combination therapy group achieved endoscopic response after 12 weeks of induction therapy, compared with 11.8% in the placebo group (p<0.001).

The safety profile of Tremfya is consistent with the indications previously established through clinical trials. During the 12-week treatment period, the adverse events (AEs) observed were generally similar between the treatment groups and the placebo group. The incidence rates of serious adverse events in the various Tremfya dose groups and the placebo group were 4%, 4%, 2%, and 4%, respectively; the rates of serious infections were 2%, 0%, 0%, and 0%, respectively. There were no reports of death, active tuberculosis, severe allergic reactions, or malignancies among patients treated with Tremfya.

Reference Sources:

1.Mirikizumab Shows Continued Symptom Improvement and Reduction of Intestinal Inflammation in Patients with Crohn's Disease in 52-Week Phase 2 Trial

2.TREMFYA (guselkumab) Induces Clinical and Endoscopic Improvements in Patients with Moderately to Severely Active Crohn's Disease based on Interim Results from Phase 2 Study