Safety and tolerability of non-neutralizing adrenomedullin antibody adrecizumab (HAM8101) in septic shock patients: the AdrenOSS-2 phase 2a biomarker-guided trial

Abstract

Purpose: Investigate safety and tolerability of adrecizumab, a humanized monoclonal adrenomedullin antibody, in septic shock patients with high adrenomedullin.

Methods: Phase-2a, double-blind, randomized, placebo-controlled biomarker-guided trial with a single infusion of adrecizumab (2 or 4 mg/kg b.w.) compared to placebo. Patients with adrenomedullin above 70 pg/mL, < 12 h of vasopressor start for septic shock were eligible. Randomization was 1:1:2. Primary safety (90-day mortality, treatment emergent adverse events (TEAE)) and tolerability (drug interruption, hemodynamics) endpoints were recorded. Efficacy endpoints included the Sepsis Support Index (SSI, reflecting ventilator- and shock-free days alive), change in Sequential-related Organ Failure Assessment (SOFA) and 28-day mortality.

Results: 301 patients were enrolled (median time of 8.5 h after vasopressor start). Adrecizumab was well tolerated (one interruption, no hemodynamic alteration) with no differences in frequency and severity in TEAEs between treatment arms (TEAE of grade 3 or higher: 70.5% in the adrecizumab group and 71.1% in the placebo group) nor in 90-day mortality. Difference in change in SSI between adrecizumab and placebo was 0.72 (CI -1.93-0.49, p = 0.24). Among various secondary endpoints, delta SOFA score (defined as maximum versus minimum SOFA) was more pronounced in the adrecizumab combined group compared to placebo [difference at 0.76 (95% CI 0.18-1.35); p = 0.007]. 28-day mortality in the adrecizumab group was 23.9% and 27.7% in placebo with a hazard ratio of 0.84 (95% confidence interval 0.53-1.31, log-rank p = 0.44).

Conclusions: Overall, we successfully completed a randomized trial evaluating selecting patients for enrolment who had a disease-related biomarker. There were no overt signals of harm with using two doses of the adrenomedullin antibody adrecizumab; however, further randomized controlled trials are required to confirm efficacy and safety of this agent in septic shock patients.

Trial registration: ClinicalTrials.gov NCT03085758.

Keywords: Adrecizumab (HAM8101); Adrenomedullin; Endothelial function; Enibarcimab; Septic shock.

Fig. 1

Patient flowchart. Overall, in 30 sites in four European countries, 459 patients were screened, of which 301 were eligible and randomized (intention-to-treat (ITT) population). Five patients withdrew consent during follow-up and five were lost to follow-up. In both cases, data from these patients was included to maximum extent. For the per-protocol (PP) analysis, seven patients had major protocol deviations, and were excluded and analyses were performed on 294 patients (see Supplement Table 2 for details)

Fig. 2

Adverse events (AE) and Treatment Emergent Adverse Events (TEAEs) by treatment arm in all patients randomized (ITT, n = 301). TEAEs were AEs not present at baseline, or AEs that worsened after start of treatment even if they were present at baseline. AEs (any, serious or death) or TEAEs were similar, between patients randomized to Adrecizumab and placebo. *TEAE, grade 3–5  all severe events according to Common Terminology Criteria for Adverse Events (CTCAE) classification; TEAE, serious  all serious events; TEAE, death  all events that led to death; TEAE, related all events that were categorized as related to Adrecizumab

Fig. 3

Efficacy endpoints in the ITT population—SSI and SOFA score change. A Mean and 95% CI of Sepsis Support Index (SSI) with 14 days follow-up, Adrecizumab combined (blue) and placebo (red) for ITT (p = 0.32, Kruskal–Wallis test, and p = 0.45, two-sample Kolmogorov–Smirnov test). B SOFA score change (points) starting prior Adrecizumab/placebo administration (pre-Investigational Medicinal Products (IMP)) (mean with 95% CI) for ITT (n = 254 with pre-IMP SOFA score available). For each time point the maximum number of patients with available SOFA score data was used. All time points show the same directionality. *p < 0.05 for 24 h change. As the number of missing patients differed between time points, post hoc sensitivity analysis were performed and results shown in supplement Fig. 6

Fig. 4

Efficacy endpoints in the ITT population—hazard ratios (HR) and survival rates. A HR with 95%-CI for 28-day mortality (n = 301) Combined = both doses of adrecizumab + the placebo group as control; 2 mg/kg = treatment arm with 2 mg/kg adrecizumab + the placebo group as control; 4 mg/kg = treatment arm with 4 mg/kg adrecizumab + the placebo group as control. Treatment effects were adjusted for initial severity: baseline bio-ADM (bio-ADM adj.); pre-IMP SOFA score (Score prior adrecizumab administration; SOFA adj.)—to rule out baseline differences affecting the observed mortality reduction. B Kaplan–Meier plot for 28-day mortality: adrecizumab combined and placebo (n = 301)

Fig. 5

Pharmacokinetics by time of blood draw and treatment arm, A geometric means (± Standard Deviation (SD) of free adrecizumab in n = 53 patients (eligible PK analysis set), B means of bio-ADM (± standard error of the mean (SEM)) (all available samples), and C MR-proADM (± standard error of the mean) (all available samples)