Safety and efficacy of meplazumab in healthy volunteers and COVID-19 patients: a randomized phase 1 and an exploratory phase 2 trial

Abstract

Recent evidence suggests that CD147 serves as a novel receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Blocking CD147 via anti-CD147 antibody could suppress the in vitro SARS-CoV-2 replication. Meplazumab is a humanized anti-CD147 IgG₂ monoclonal antibody, which may effectively prevent SARS-CoV-2 infection in coronavirus disease 2019 (COVID-19) patients. Here, we conducted a randomized, double-blinded, placebo-controlled phase 1 trial to evaluate the safety, tolerability, and pharmacokinetics of meplazumab in healthy subjects, and an open-labeled, concurrent controlled add-on exploratory phase 2 study to determine the efficacy in COVID-19 patients. In phase 1 study, 59 subjects were enrolled and assigned to eight cohorts, and no serious treatment-emergent adverse event (TEAE) or TEAE grade ≥3 was observed. The serum and peripheral blood C_max and area under the curve showed non-linear pharmacokinetic characteristics. No obvious relation between the incidence or titer of positive anti-drug antibody and dosage was observed in each cohort. The biodistribution study indicated that meplazumab reached lung tissue and maintained >14 days stable with the lung tissue/cardiac blood-pool ratio ranging from 0.41 to 0.32. In the exploratory phase 2 study, 17 COVID-19 patients were enrolled, and 11 hospitalized patients were involved as concurrent control. The meplazumab treatment significantly improved the discharged (P = 0.005) and case severity (P = 0.021), and reduced the time to virus negative (P = 0.045) in comparison to the control group. These results show a sound safety and tolerance of meplazumab in healthy volunteers and suggest that meplazumab could accelerate the recovery of patients from COVID-19 pneumonia with a favorable safety profile.

Fig. 1

Flow chart of the phase 1 trial (a) and exploratory phase 2 trial (b)

Fig. 2

a Mean drug concentration–time profile on peripheral blood cells of healthy subjects in single-dose cohorts; b mean drug concentration–time profile on peripheral blood cells of healthy subjects in the multiple-dose cohort; c mean RO%-time profile on peripheral blood cells of healthy subjects in single-dose cohorts; d mean RO%–time profile on peripheral blood cells of healthy subjects in the multiple-dose cohort. Means and standard deviations are presented

Fig. 3

a Time to virus-negative conversion. The P value was calculated by Cox regression analysis, and P value 0.045 and HR 0.374, 95% CI [0.143–0.978]). The median of time to negative was 3 days (95% CI [1.5–4.5]) for the meplazumab cohort and 13 days (95% CI [6.5–19.5]) for the control cohort. b Analysis of time to discharge. The P value was determined using Cox regression analysis. c Distribution of case severity in severe and critical patients. The P values were from Ordinal regression. The P value comparing between baseline (Day 0) and each time point was shown on the top of the column, and the P value comparing between meplazumab and control at Day 28 was shown on the line

Fig. 4

a Chest imaging analysis. The P values comparing meplazumab and control at Days 7, 14, 21, and 28 were from Ordinal regression; b chest CT image, transverse chest CT images from a 65-year-old male patient showing bilateral large flaky ground-glass shadows, and consolidation on the baseline period. On Day 22, the intrapulmonary lesions were significantly absorbed and dissipated by meplazumab add-on treatment

Fig. 5

The proportion of patients regarding lymphocyte count and CRP concentration. The proportion of patients (% patients) with or without normal lymphocyte count (a) and CRP concentration (b). The P value comparing between baseline (d0) and each time point was determined by McNemar’s test, shown on the top of the column