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

Abstract

AbstractsRecent 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 Cmax 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.

Incomplete antiviral treatment may induce longer durations of viral shedding during SARS-CoV-2 infection

“…In many clinical trials, the duration of viral shedding has been used as a primary outcome to evaluate the antiviral effect of treatments with lopinavir and ritonavir ( 11 ), hydroxychloroquine ( 38 , 39 ), and meplazumab ( 40 ). Because the viral load of SARS-CoV-2 peaks on or before symptom onset in many patients ( 18 ), and the mean interval between symptom onset and hospitalization is estimated to be 4.64 d ( 41 ), it is expected that antiviral treatments initiated after symptom onset will not shorten the duration of viral shedding.…”

Human Basigin (CD147) Does Not Directly Interact with SARS-CoV-2 Spike Glycoprotein

“…This is in contrast to a previous report which identified basigin as a coreceptor for SARS-CoV-2, showed binding of RBD to spike via SPR assays and ELISA, and showed that meplazumab, an anti-basigin MAb, could neutralize SARS-CoV-2 ( 10 ). The use of an anti-basigin MAb in clinical trials has begun on the basis of the original observation that basigin may be required for host cell entry ( 30 ). We believe that it is necessary to proceed with caution when interpreting the trial data, as further investigation is warranted to determine what role, if any, basigin has in the SARS-CoV-2 invasion process.…”

“…Initial evaluation of meplazumab, an anti-basigin antibody, for treatment of SARS-CoV-2 pneumonia suggested that there could be a benefit ( 30 ). These results are based on small groups ( n = 17 in the treatment group) ( 30 ); as such, it will be necessary to conduct larger clinical studies to confirm this finding.…”

“…Initial evaluation of meplazumab, an anti-basigin antibody, for treatment of SARS-CoV-2 pneumonia suggested that there could be a benefit ( 30 ). These results are based on small groups ( n = 17 in the treatment group) ( 30 ); as such, it will be necessary to conduct larger clinical studies to confirm this finding. If indeed these findings hold, the reported effect could be due to a nonspecific anti-inflammatory effect of basigin blockade, as there have been some reports of a proinflammatory role of basigin in immune signaling ( 32 – 36 ).…”

“…In the context of infectious disease, basigin has also been well characterized as an essential receptor for Plasmodium falciparum invasion into human erythrocytes, during which it is bound by the malaria parasite’s reticulocyte-binding protein homolog 5 (RH5) ( 23 , 24 ). Based on the initial observation that appeared to show that basigin binds to the SARS-CoV-2 spike glycoprotein receptor binding domain (RBD) ( 10 ), clinical trials were initiated investigating an anti-basigin MAb as a therapeutic for COVID-19 ( 30 ) (ClinicalTrials.gov identifier NCT04275245).…”