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Table 2 TPP-1 profiles for treatment of children or adults infected with malaria

From: New developments in anti-malarial target candidate and product profiles

Parameter to be demonstrated for the combination in clinical evaluation Minimum essential Ideal
Rate of onset of action At least one component acts immediately; fever clearance at 24 h Both components act immediately; fever clearance at 24 h
Proportional reduction in parasite load Capable of achieving >12 log10 unit reduction in asexual blood-stage load; >95% patients free from parasites with from one to three doses >12 log10 unit reduction in asexual blood-stage load in >95% patients with a single dose
Parasite-free (day 7), including patients from areas with known drug-resistance to current first-line medications 100% 100%
Clinical efficacy (ACPR at day 28 or later; per protocol) >95% PCR-corrected, in a per-protocol population; on day 28; non-inferior to standard of care >95% PCR-corrected, in a per-protocol population, on days 42–63; non-inferior to standard of care
Transmission blocking Not required per se, but must not display detrimental drug–drug interactions with low-dose (0.25 mg/kg) primaquine Combination should prevent clinical transmission, with no oocysts found in mosquitoes used in direct feeding or ex vivo experiments 15 days post treatment dose, without the need for low-dose primaquine
Relapse prevention: prevents the relapse of P. vivax, and by inference P. ovale. Not required per se, but must not display drug–drug interactions with a relapse-preventing dose of 8-aminoquinoline Confirmation in clinical studies (6 months in South America, Ethiopia and SE Asia, and the Pacific Ocean, potentially 24 months in India, Pakistan and Afghanistan)
Bioavailability/food effect Predicted to be >30% for each molecule/ less than threefold (likely will be known by this stage) Predicted to be >50% for each molecule/none (likely will be known at this stage
Drug-drug interactions No unmanageable risk in terms of solid state or PK interactions No risks in terms of solid state or PK interactions
Dosing regimen Oral, two or three doses Oral, once
Safety and tolerability Few and manageable drug-related SAEs (serious adverse events), or adverse events leading to exclusion from study in phase III No drug related SAEs; minimal drug-related AEs; no enhanced risk, no risk of hemolysis in subjects with reduced G6PD activity
Pregnancy Not contra-indicated in second or third trimester Not contra-indicated in second or third trimester, no suggestion of embryo-fetal toxicity in first trimester in preclinical species
Formulations Co-formulated tablets or equivalent, with taste-masking (if needed) for pediatrics Co-formulated tablets for adults. Dispersible or equivalent with taste masking (if needed) for pediatrics
Cost of treatment course <$3.00 for adults and <$1.00 for infants younger than 2 year, benchmarked against the most expensive ACT ($3; ASMQ, artesunate/mefloquine) ≤$1.00 for adults, $0.25 for infants under 2 years, benchmarked against the cheapest ACT ($1)
Shelf life of formulated product (ICH guidelines for Zone IVa, b; combination only) ≥2 years ≥5 years
Susceptibility to loss of efficacy due to acquired resistance Low: active against all known clinical strains. No evidence of transmissible resistant parasites in clinical development Low: active against all known clinical strains. No evidence of transmissible resistant parasites in clinical development