Table 3 TCP-4 as part of a prophylactic combination
General considerations | Minimum essential | Ideal |
|---|---|---|
Dosing regimen; adult/paediatric dose | Injectable: subcutaneous or intra-muscular, once per month, with injection volumes < 0.25 mL per molecule for infants and < 1 mL for adults via a 27 gauge or smaller needle | Injectable: subcutaneous or intramuscular once per 3 months |
Pre-clinical activity | Proven liver schizont stage activity and 100% protective efficacy achieved in vivo, defined as no asexual parasitaemia after 30Â days | Proven liver schizont stage activity and 100% protective efficacy achieved in vivo defined as no asexual parasitaemia after 30Â days |
Susceptibility to loss of efficacy due to acquired resistance | Resistance frequency in culture with erythrocytes < 10−5. Marker identified and no pre-existing resistance determined in the global parasite population | Resistance frequency in culture with erythrocytes < 10−9 |
Clinical protection from infection | >Â 80% protective efficacy (positive parasitaemia) predicted from volunteer infection studies | >Â 95% protective efficacy (positive parasitaemia) predicted from volunteer infection studies |
Drug–drug interactions | No unmanageable risks | No interactions with other antimalarial, anti-retroviral or tuberculosis medicines or oral contraception |
Safety and tolerability | Therapeutic ratio > tenfold between therapeutic exposure and NOAEL in preclinical studies and easily monitorable adverse event or biomarker for human studies. No unacceptable adverse events associated with pain, irritation or inflammation at injection site | Therapeutic ratio > 50-fold between therapeutic exposure and NOAEL in preclinical studies if not monitorable adverse event or biomarker for human studies. No adverse events associated with pain, irritation or inflammation at injection site |
Preclinical DART profile | No signals in EFD and juvenile toxicology studies precluding use in children 6Â months old and during 2nd and 3rd trimester pregnancies | No signals in EFD and juvenile toxicology studies precluding use in infants and women with unknown pregnancy status |
G6PD deficiency status | Therapeutic dose shows minimal change in haemoglobin concentration in subjects with reduced G6PD activity. New candidate drugs show no enhanced haemolytic risk in preclinical model | Measured—no enhanced risk in subjects with reduced G6PD activity |
Injectable formulation | Solutions: soluble in targeted volume based on total dose in clinically acceptable oils Suspensions: particle size controlled to give required compound release profile supporting monthly injection | Idem. Ideal formulation should be delivered in a prefilled injection device for once-in-3-months injection |
Cost of single administration | Molecules consistent with a final product cost of < 5 USD per injection | Molecules consistent with a final product cost of ≤ USD 1 for infants, USD 2 for children, USD 4 for adults |
Projected stability of final product under zone IVb conditions (30 °C, 75% relative humidity) | ≥ 2 years | ≥ 3 years |