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Table 1 target candidate profile for a new endectocide

From: A discovery and development roadmap for new endectocidal transmission-blocking agents in malaria

TCP-6 criteria at human proof of concept Minimum essential Ideal
Dosing regimen Oral, once monthly three daily doses of < 10 mg/kg Oral, once monthly single dose < 2 mg/kg
Action and clinical parasite reduction ratio from single dose Efficacy of a Hazard ratio at least 4 is delivered upon mosquito feeding 28 days post oral dose (for a use with SMC) Rapid onset of action, within 12 h. Efficacy equal or higher than a hazard ratio of 4 is delivered upon mosquito feeding 30 days post oral dose
Susceptibility to loss of efficacy due to acquired resistance in mosquitoes No fit, fertile insecticide resistant insects in early resistance generation studies, no increase in cuticle thickening or selection for P450s which would reduce susceptibility to other insecticides Idem
Relative efficacy against mosquitoes highly resistant to current insecticides Minimum activity on field An. arabiensis, An. gambiae and An. funestus via membrane feeding including strains with known insecticide resistance Activity on all four major Anopheles species with malaria relevance in Africa
Drug–drug interactions No unsurmountable risks with potential anti-malarial partners, especially those under consideration for SMC No interactions with other anti-malarial, anti-retroviral or tuberculosis medicines
Safety Safety margin > tenfold between therapeutic exposure and NOAEL in preclinical studies, and easily ‘monitorable’ adverse event or biomarker for human studies. Safety margin > 50 fold and easily ‘monitorable’ adverse event. No reprotox safety signal in two animal species (‘Minimum’ for MDA, ‘Ideal’ for SMC).
Formulation Simple and inexpensive to produce, not requiring proprietary methodology or kits; can readily be produced in endemic countries. Simple and inexpensive to produce, not requiring proprietary methodology or kits; can readily be produced in endemic countries. No food effect.
Cost of active ingredient in final medicine Similar to current anti-malarials: ≤ $0.5 for adults, $0.1 for infants under 2 years Similar to older anti-malarials: < $0.25 for adults, $0.05 for infants under 2 years
Estimated stability of final product under Zone IVb conditions (30 °C 75% humidity), in final packaging ≥ 2 years ≥ 3–5 years
  1. TCP-6 criteria for moving a molecule forwards into Phase II
  2. PK, pharmacokinetic; MTD, maximum tolerated dose, NOAEL, no-observed-adverse-effect-level; G6PD, glucose-6-phosphate dehydrogenase