Pharmacy and Poisons Board
Protocol No: ECCT/23/11/01 Date of Protocol: 27-07-2023
Study Title:

A Phase 2a, Multicenter, Open-label, Dose-finding, Dose Escalation Study of Meplazumab in Adult Patients Diagnosed with Uncomplicated Plasmodium falciparum Malaria
Study Objectives:

Objectives

Endpoints

Primary
  • To evaluate the safety of meplazumab in an adult population with uncomplicated, symptomatic P. falciparum infection
  • Incidence and severity of AE
  • Incidence of (number of participants with):
    • Drug-related SAE
    • All-cause SAE
    • Drug-related AESI
    • All-cause AESI
    • Participants discontinuation/ withdrawals due to AE

Secondary
  • To evaluate the efficacy of meplazumab as defined by
    • Early treatment failure
    • Late clinical failure
    • Late parasitological failure
    • Uncorrected ACPR
  • Incidence (number of participants with) of early treatment failure
  • Incidence of late clinical failure
  • Incidence of late parasitological failure
  • Incidence of uncorrected ACPR at Day 28
  • To evaluate PRR
  • PRR at 72h
  • To determine the recrudescence (see Section 9.3.7) and re-infection (see Section 9.3.7)
  • Incidence of (number of participants with) recrudescence and re-infection at Week 4
  • Time to recrudescence and re-infection at Week 4
  • To determine the time to relief of fever
  • FCT at 72h
  • To determine the dose-response trend relationship between 3 dose levels of meplazumab by evaluation of safety, efficacy and ACPR outcomes
  • Dose-response trend relationship between the 3 dose levels of meplazumab, based on change from baseline in the summary of the safety and efficacy outcomes to Week 4
  • To evaluate the pharmacokinetics of meplazumab in serum
  • Meplazumab serum concentration-time profiles and PK parameters including but not limited to Cmax, tmax, AUC(0-last), AUC(0-inf), t½, CL, Vz, and Vss
  • To evaluate immunogenicity following meplazumab administration
  • Frequency of confirmed ADA response, ADA titers, and neutralizing activity

Exploratory
  • To evaluate the efficacy of meplazumab by PCR-corrected ACPR
  • Incidence of (number of participants with) PCR‑corrected ACPR at Week 4
  • To evaluate RO (%) of meplazumab in red blood cells following single dose administration
  • Meplazumab RO%-time profiles, pharmacodynamic parameters determined for RO including but not limited to maximum RO% and duration RO% (RO% half-life)
  • To quantify the levels of complement regulatory proteins, the deposition of complement on  erythrocytes, and serum complement activation in human subjects treated with meplazumab.
  • Cell-surface expression of complement regulatory proteins and presence of complement products measured by flow cytometry; and complement activation measured by ELISA kit
  • To evaluate the relationship between exposure to meplazumab and key efficacy and/or safety parameters
  • Graphical (and statistical, if appropriate) display of exposure versus response

Abbreviations: ACPR=adequate clinical & parasitological response; ADA=anti-drug antibodies; AE=adverse event; AESI=adverse event of special interest; AUC(0‑inf)=area under the concentration‑time curve extrapolated to infinity; AUC(0‑last)=area under the concentration‑time curve to the last quantifiable concentration; CL=systemic clearance; Cmax=maximum concentration; FCT=fever clearance time; polymerase chain reaction PCR=polymerase chain reaction; P. falciparum=Plasmodium falciparum; PRR=parasite reduction rate; RO=receptor occupancy; SAE=serious adverse event; t½=elimination half‑life; tmax=time to Cmax; Vz=volume of distribution; Vss=volume at steady state.

 
Laymans Summary:

Open-Label Study to evaluate the safety of meplazumab in an adult population with uncomplicated, symptomatic P. falciparum infection. Malaria is caused by Plasmodium, a parasite which is transmitted to humans by infected female anopheles mosquitoes (malaria vector). When infected anopheles bites a human, Plasmodium sporozoites in the mosquito’s saliva enter the bloodstream and migrate to the liver, followed by the merozoites reproduction within the hepatocytes. This stage is known as exoerythrocytic phase. Merozoites reproduce and form schizonts, which contain several thousands of merozoites. After the schizonts mature and rupture, merozoites are released into the blood and invade erythrocytes, hence initiating the merozoites reproduction in the erythrocytic phase. Current methods toward malaria elimination usually involve the combination of prevention and treatment. Artemisinin-based combination therapies (ACTs) are currently recommended by the World Health Organization for the treatment of malaria. Antimalarial drugs mainly include drugs to eliminate Plasmodium during the erythrocytic or exoerythrocytic phase. From the 1950s, falciparum malaria has developed general resistance to antimalarial drugs such as chloroquine, and sulfadoxine-pyrimethamine, leading to ineffective malaria control. Plasmodium developed higher resistance to the drugs used in combination in ACTs. Therefore, new antimalarial therapies and drugs are imperative due to the recurrent drug resistance of Plasmodium. Meplazumab, an erythrocytic stage-macromolecular antibody drug, has the potential to control clinical occurrence of falciparum malaria. Meplazumab is a humanized anti-CD147 immunoglobulin G subclass 2 (IgG2) monoclonal antibody with strong affinity to CD147. CD147 is expressed on erythrocyte lineage cells throughout erythroid development, including mature erythrocytes and is the target for Plasmodium merozoites to allow reorientation and subsequent invasion of the erythrocytes.
Abstract of Study:

Protocol Title:

A Phase 2a, Multicenter, Open-label, Dose-finding, Dose escalation Study of Meplazumab in Adult Patients diagnosed with Uncomplicated Plasmodium falciparum Malaria.

Rationale:

Meplazumab, an erythrocytic stage-macromolecular antibody drug, has the potential to control clinical occurrence of falciparum malaria. Meplazumab is a humanized anti-CD147 immunoglobulin G subclass 2 (IgG2) monoclonal antibody with strong affinity to CD147. CD147 is expressed on erythrocyte lineage cells throughout erythroid development, including mature erythrocytes and is the target for Plasmodium merozoites to allow reorientation and subsequent invasion of the erythrocytes. Nonclinical studies have demonstrated that meplazumab binding to CD147 interferes with the receptor‑ligand interaction between CD147 and rhoptry-associated protein 2 (RAP2) of the P. falciparum merozoite and inhibits the formation of parasitophorous vacuoles of P. falciparum thus preventing the invasion of P. falciparum into human erythrocytes. Furthermore, the therapeutic and prophylactic effects of meplazumab were demonstrated in vivo using a human erythrocyte chimeric NOG mouse model, which is considered as an optimal choice for in vivo inhibition efficacy study for human-hosted P. falciparum.

Meplazumab has previously been studied in healthy participants in two Phase 1 studies and has also been evaluated for activity in 2 completed clinical trials in patients diagnosed with coronavirus disease 2019 (COVID‑19). In the safety, tolerability, and pharmacokinetics study in healthy participants, MPZ‑I-01, results demonstrated a high and prolonged receptor occupancy (RO%) of meplazumab at CD147.

This Phase 2a study is designed as a dose escalation trial to assess safety of meplazumab in the target population and to evaluate whether meplazumab is efficacious in treating malaria. The data obtained in this study will be used to determine a recommended meplazumab dose for future Phase 2b and 3 efficacy trials.

Protocol Title:

A Phase 2a, Multicenter, Open-label, Dose-finding, Dose escalation Study of Meplazumab in Adult Patients diagnosed with Uncomplicated Plasmodium falciparum Malaria.

Rationale:

Meplazumab, an erythrocytic stage-macromolecular antibody drug, has the potential to control clinical occurrence of falciparum malaria. Meplazumab is a humanized anti-CD147 immunoglobulin G subclass 2 (IgG2) monoclonal antibody with strong affinity to CD147. CD147 is expressed on erythrocyte lineage cells throughout erythroid development, including mature erythrocytes and is the target for Plasmodium merozoites to allow reorientation and subsequent invasion of the erythrocytes. Nonclinical studies have demonstrated that meplazumab binding to CD147 interferes with the receptor‑ligand interaction between CD147 and rhoptry-associated protein 2 (RAP2) of the P. falciparum merozoite and inhibits the formation of parasitophorous vacuoles of P. falciparum thus preventing the invasion of P. falciparum into human erythrocytes. Furthermore, the therapeutic and prophylactic effects of meplazumab were demonstrated in vivo using a human erythrocyte chimeric NOG mouse model, which is considered as an optimal choice for in vivo inhibition efficacy study for human-hosted P. falciparum.

Meplazumab has previously been studied in healthy participants in two Phase 1 studies and has also been evaluated for activity in 2 completed clinical trials in patients diagnosed with coronavirus disease 2019 (COVID‑19). In the safety, tolerability, and pharmacokinetics study in healthy participants, MPZ‑I-01, results demonstrated a high and prolonged receptor occupancy (RO%) of meplazumab at CD147.

This Phase 2a study is designed as a dose escalation trial to assess safety of meplazumab in the target population and to evaluate whether meplazumab is efficacious in treating malaria. The data obtained in this study will be used to determine a recommended meplazumab dose for future Phase 2b and 3 efficacy trials.

Objectives and Endpoints:

Objectives

Endpoints

Primary
  • To evaluate the safety of meplazumab in an adult population with uncomplicated, symptomatic P. falciparum infection
  • Incidence and severity of AE
  • Incidence of (number of participants with):
    • Drug-related SAE
    • All-cause SAE
    • Drug-related AESI
    • All-cause AESI
    • Participants discontinuation/ withdrawals due to AE

Secondary
  • To evaluate the efficacy of meplazumab as defined by:
    • Early treatment failure
    • Late clinical failure
    • Late parasitological failure
    • Uncorrected ACPR
  • Incidence (number of participants with) of early treatment failure
  • Incidence of late clinical failure
  • Incidence of late parasitological failure
  • Incidence of uncorrected ACPR at Day 28
  • To evaluate PRR
  • PRR at 72h
  • To determine the recrudescence (see Section 9.3.7) and re-infection (see Section 9.3.7)
  • Incidence of (number of participants with) recrudescence and re-infection at Week 4
  • Time to recrudescence and re-infection at Week 4
  • To determine the time to relief of fever
  • FCT at 72h
  • To determine the dose-response trend relationship between 3 dose  levels of meplazumab by evaluation of safety, efficacy and ACPR outcomes
  • Dose-response trend relationship between the 3 dose levels of meplazumab, based on change from baseline in the summary of the safety and efficacy outcomes to Week 4
  • To evaluate the pharmacokinetics of meplazumab in serum
  • Meplazumab serum concentration-time profiles and PK parameters including but not limited to Cmax, tmax, AUC(0-last), AUC(0-inf), t½, CL, Vz, and Vss
  • To evaluate immunogenicity following meplazumab administration
  • Frequency of confirmed anti-drug antibody (ADA) response, ADA titers, and neutralizing activity

Exploratory
  • To evaluate the efficacy of meplazumab by PCR-corrected ACPR
  • Incidence of (number of participants with) PCR‑corrected ACPR at Week 4
  • To evaluate RO (%) of meplazumab in red blood cells following single dose administration
  • Meplazumab RO%-time profiles, pharmacodynamic parameters determined for RO including but not limited to maximum RO% and duration RO% (RO% half-life)
  • To quantify the levels of complement regulatory proteins, the deposition of complement on  erythrocytes, and serum complement activation in human subjects treated with meplazumab.
  • Cell-surface expression of complement regulatory proteins and presence of complement products measured by flow cytometry; and complement activation measured by ELISA kit
  • To evaluate the relationship between exposure to meplazumab and key efficacy and/or safety parameters
  • Graphical (and statistical, if appropriate) display of exposure versus response

Abbreviations: ACPR=adequate clinical & parasitological response; ADA=anti-drug antibodies; AE=adverse event; AESI =adverse event of special interest; AUC(0‑inf)=area under the concentration‑time curve extrapolated to infinity; AUC(0‑last)=area under the concentration‑time curve to the last quantifiable concentration; CL=systemic clearance; Cmax=maximum concentration; FCT=fever clearance time; polymerase chain reaction PCR=polymerase chain reaction; P. falciparum=Plasmodium falciparum; PRR=parasite reduction rate; RO=receptor occupancy; SAE=serious adverse event; t½=elimination half‑life; tmax=time to Cmax; Vz=volume of distribution; Vss=volume at steady state.

Overall Design:

This is a Phase 2a multicenter, open-label, dose-finding, dose escalation study. The study will recruit participants with confirmed P. falciparum infection. Up to 60 participants will be enrolled into 1 of 3 meplazumab dose levels (20 participants /dose level).

Number of Participants:

Up to 60 participants will be enrolled into 1 of 3 meplazumab dose levels (20 participants/dose level).

Intervention Groups and Duration:

Participants will be administered a single intravenous (IV) infusion dose of meplazumab 120±5 minutes on Day 0 and hospitalized for 72 hours after dosing (up to Day 3) to monitor for safety and tolerability of therapy, and to ensure treatment response. During hospitalization, blood sampling for safety, pharmacokinetic (PK), and RO pharmacodynamic (PD) testing at predefined times will be collected as specified per the Schedule of Assessment (SoA). Furthermore, in a subset of first 10 participants/dose level, additional (serial) PK and PD samples will be collected at 1, 2, 4 and 8 hours post end-of-infusion. Up to 3 additional samples may be added to the Day 0-3 serial sample collection period.

If clinically well, participants may be discharged from the clinical unit on Day 3 at the Investigator’s discretion. Participants will return to the study center for follow-up visits on Days 28±2, 56±7, 84±7 and 182±7 (End of Study) for safety, tolerability, PK, PD (RO rate), and immunogenicity assessments as per the SoA (Weeks 4, 8, 12 and 26).

Data Monitoring/Other Committee: Yes