Dose escalation randomised study of efmarodocokin alfa in healthy volunteers and patients with ulcerative colitis

Abstract

Background: The interleukin-22 cytokine (IL-22) has demonstrated efficacy in preclinical colitis models with non-immunosuppressive mechanism of action. Efmarodocokin alfa (UTTR1147A) is a fusion protein agonist that links IL-22 to the crystallisable fragment (Fc) of human IgG₄ for improved pharmacokinetic characteristics, but with a mutation to minimise Fc effector functions.

Methods: This randomised, phase 1b study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat intravenous dosing of efmarodocokin alfa in healthy volunteers (HVs; n=32) and patients with ulcerative colitis (n=24) at 30-90 µg/kg doses given once every 2 weeks or monthly (every 4 weeks) for 12 weeks (6:2 active:placebo per cohort).

Results: The most common adverse events (AEs) were on-target, reversible, dermatological effects (dry skin, erythema and pruritus). Dose-limiting non-serious dermatological AEs (severe dry skin, erythema, exfoliation and discomfort) were seen at 90 μg/kg once every 2 weeks (HVs, n=2; patients, n=1). Pharmacokinetics were generally dose-proportional across the dose levels, but patients demonstrated lower drug exposures relative to HVs at the same dose. IL-22 serum biomarkers and IL-22-responsive genes in colon biopsies were induced with active treatment, and microbiota composition changed consistent with a reversal in baseline dysbiosis. As a phase 1b study, efficacy endpoints were exploratory only. Clinical response was observed in 7/18 active-treated and 1/6 placebo-treated patients; clinical remission was observed in 5/18 active-treated and 0/6 placebo-treated patients.

Conclusion: Efmarodocokin alfa had an adequate safety and pharmacokinetic profile in HVs and patients. Biomarker data confirmed IL-22R pathway activation in the colonic epithelium. Results support further investigation of this non-immunosuppressive potential inflammatory bowel disease therapeutic.

Trial registration number: NCT02749630.

Keywords: gene expression; interleukins; intestinal microbiology; ulcerative colitis.

Figure 1

Study design. UC, ulcerative colitis.

Figure 2

Pharmacokinetics (PK) of efmarodocokin alfa. PK in (A) all HV cohorts and (B) all UC patient cohorts. PK comparisons between HV and UC patients dosed at 60 µg/kg, given (C) once every 4 weeks and (D) once every 2 weeks. *Cohort F, 90 ug/kg every 2 weeks in HV, was discontinued either after the second dose (n=3) or third dose (n=3) due to dermatological dose-limiting adverse events (DLAEs). HV, healthy volunteers; UC, ulcerative colitis.

Figure 3

Serum biomarker response to efmarodocokin alfa. Percent change from baseline over time in serum REG3A levels in (A) HVs and (B) patients with UC and in serum CRP levels in (C) HVs and (D) patients with UC. Cohort F, 90 ug/ kg Q2W in HV, was discontinued either after the second dose (n=3) or third dose (n=3) due to dermatological dose-limiting adverse events (DLAE). CRP, C reactive protein; HVs, healthy volunteers; UC, ulcerative colitis.

Figure 4

Patient plots of modified Mayo Clinic Score (mMCS) at baseline, week 4 and week 12 in the (A) placebo cohort; (B) cohort C; (C) cohort E and (D) cohort K.

Figure 5

Effects of efmarodocokin alfa on stool frequency, Robarts Mayo Endoscopic Score (RMES) and rectal bleeding in different dose cohorts. Scores here were part of the modified Mayo Clinic Score presented in figure 4.

Figure 6

Histological scores in patients with ulcerative colitis at baseline and following treatment with efmarodocokin alfa as measured by (A) Geboes Score; (B) Nancy Index (C) Robarts Histologic Index. UC, ulcerative colitis.

Figure 7

Effects of efmarodocokin alfa on gene expression and microbiota. Expression of IL-22 signature genes (A) DMBT1 and (B) MUC1 in the colon of HV and patients. Expression is shown at baseline, and after efmarodocokin alfa treatments. Each sample point is a donor, and the y-axis shows normalised expression values from bulk RNAseq as log2(nRPKM). (C) Shannon Diversity for the microbiota of HV and patients with UC at baseline before administration of study drug. (D) The Spearman correlation coefficient (ρ) for Log₂ FC in abundance from baseline (treatment effect) in HV vs Log₂ FC in abundance between UC and HV at baseline (dysbiosis effect). (E) Spearman correlation coefficient (ρ) of treatment effect in patients with UC vs dysbiosis effect. For C–E, faecal microbiota (16S rRNA gene sequencing), faecal microbiota (WMS) and mucosal microbiota (16S rRNA gene sequencing) are depicted. For C, p value was determined by t-test. Note that data from study days >43 in the HV cohort receiving the 90 µg/kg every 2 weeks dosing regimen were omitted due to early termination. HV, healthy volunteers; UC, ulcerative colitis; WMS, whole metagenome sequencing.