Published in:
Open Access 01-12-2017 | Erratum
Erratum to: New developments in anti-malarial target candidate and product profiles
Published in: Malaria Journal | Issue 1/2017
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After publication of the original article [1], the authors wished to submit a number of minor corrections affecting Fig. 2; Tables 3 and 4. Revised versions of these items are published in this erratum.
Fig. 2
Inter-relationships between the two high-level target product profiles (center) with the individual target candidate profiles (left) for molecules that are part of the product. The uses for each product are summarized on the right
Table 3
TPP-2 chemoprotection profiles
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Parameter to be demonstrated for the combination in clinical evaluation
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Minimum essential
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Ideal single exposure chemoprotection
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|---|---|---|
|
Drug product
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For elimination phases at least one of the two compounds also with TCP-4, co-formulated. The other should be a long-lasting blood schizonticide TCP-1
|
For elimination phases both molecules should have TCP-4 activity, co-formulated
|
|
Dosing regimen
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Oral, once per week; injectable once per 3 months
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Oral once per month; injectable less frequently than once per 3 months
|
|
Rate of onset of action
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For asexual blood-stage action—slow onset (>48 h)
|
|
|
Clinical efficacy
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≥95% protective efficacy and non-inferior to Standard of Care
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≥98% protective efficacy and non-inferior to Standard of Care
|
|
Transmission blocking
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No
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Yes
|
|
Bioavailability/food effect
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Predicted or measured >30% for each molecule/<threefold
|
Predicted or measured >50% for each molecule/no significant food effect
|
|
Drug–drug interactions
|
No unmanageable risk in terms of solid state or PK interactions
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No risks in terms of solid state or PK interactions
|
|
Safety and tolerability
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Few and manageable drug-related SAEs in phase III and IV
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No drug-related SAEs; minimal drug-related AEs that do not result in study exclusion
|
|
Use in patients with reduced G6PD activity
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Testing not required; no enhanced risk in mild–moderate G6PD deficiency
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No enhanced risk
|
|
Pregnancy
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Not contra-indicated in second or third trimester
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Not contra-indicated in second or third trimester, no suggestion of embryo-fetal toxicity in first trimester in preclinical species
|
|
Formulations
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Co-formulated tablets or equivalent, with taste-masking for paediatrics if taste is unacceptable to children
Long-lasting formulations for intramuscular or intradermal use with low injection volume
|
Co-formulated tablets for adults. Dispersible or equivalent with taste-masking for paediatrics
|
|
Cost of treatment
|
≤$1.00 for adults, $0.25 for infants under 2 years
Similar to vaccine costs for an injectable
|
Idem
|
|
Shelf life of formulated product (ICH guidelines for Zones III/IV; combination only)
|
≥2 years
|
≥5 years
|
|
Susceptibility to loss of efficacy due to acquired resistance
|
Very low; no cross resistance with partner
|
Very low; no cross resistance and orthogonal mechanism from those used in treatment
|
Table 4
TCP-1 profiles, molecules that clear asexual parasitaemia
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TCP-1 criteria at human proof of concept
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Minimum essential
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Ideal
|
|---|---|---|
|
Dosing regimen; adult/paediatric dose
|
Oral, single dose (predicted) <1000 mg/<250 mg; oral, three doses <400 mg/<100 mg for areas of multidrug resistance
|
Oral, single dose (predicted); <100 mg/25 mg
|
|
Rate of onset of action and clinical parasite reduction ratio from single dose
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Rapid clearance of parasites at least as fast as mefloquine (≤72 h from the highest burdens) and projected >106-fold reduction in parasites
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Immediate and rapid clearance of parasites at least as fast as artesunate; >projected 1012-fold reduction in parasites
|
|
Susceptibility to loss of efficacy due to acquired resistance
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No fit, transmissible drug-resistant parasites identified in CHMI challenge model; identification of combination partner with no cross resistance
|
Very low (similar to chloroquine); no cross-resistance with asexual blood-stage combination partner. Resistance markers investigated
|
|
Relative clinical efficacy from patients in areas known to be resistant to current first line medications
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Clinical efficacy against all known resistance (3-day dosing)
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Clinical efficacy against all known resistance (single dose)
|
|
Drug–drug interactions
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No unsurmountable risks with potential anti-malarial partners
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No interactions with other anti-malarial, anti-retroviral or TB medicines
|
|
Safety
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Therapeutic ratio >tenfold between therapeutic exposure and NOAEL (no adverse effects level) in preclinical studies, and easily ‘monitorable’ adverse event or biomarker for human studies
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Therapeutic ratio >50-fold between therapeutic exposure and NOAEL in preclinical studies and easily ‘monitorable’ adverse event or biomarker for human studies
|
|
G6PD (glucose-6-phosphate dehydrogenase) deficiency status
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Measured—no enhanced haemolysis risk from testing in SCID mice engrafted with human blood from volunteers with reduced G6PD activity; clinical confirmation
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Measured—no enhanced haemolysis risk in subjects with reduced G6PD activity, with clinical confirmation
|
|
Formulation
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Simple and inexpensive to produce, not requiring proprietary methodology or kits; can readily be produced in endemic countries
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Simple and inexpensive to produce, not requiring proprietary methodology or kits; can readily be produced in endemic countries
|
|
Cost of active ingredient in final medicine
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Similar to current medication: ≤$0.5 for adults, $0.1 for infants under 2 years
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Similar to older medications: <$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
|
≥24 months
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≥3–5 years
|
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