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 24Â h | Both components act immediately; fever clearance at 24Â h |
Proportional reduction in parasite load | Capable of achieving >12Â log10Â unit reduction in asexual blood-stage load; >95% patients free from parasites with from one to three doses | >12Â log10Â 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 |