Open Access

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

  • Jeremy N. Burrows1,
  • Stephan Duparc1,
  • Winston E. Gutteridge2,
  • Rob Hooft van Huijsduijnen1View ORCID ID profile,
  • Wiweka Kaszubska1,
  • Fiona Macintyre1,
  • Sébastien Mazzuri3,
  • Jörg J. Möhrle1 and
  • Timothy N. C. Wells1Email author
Malaria Journal201716:151

https://doi.org/10.1186/s12936-017-1809-9

Published: 18 April 2017

The original article was published in Malaria Journal 2017 16:26

Erratum to: Malar J (2017) 16:26 DOI 10.1186/s12936-016-1675-x

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

Parameter to be demonstrated for the combination in clinical evaluation

Minimum essential

Ideal single exposure chemoprotection

Drug product

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

Oral, once per week; injectable once per 3 months

Oral once per month; injectable less frequently than once per 3 months

Rate of onset of action

For asexual blood-stage action—slow onset (>48 h)

 

Clinical efficacy

≥95% protective efficacy and non-inferior to Standard of Care

≥98% protective efficacy and non-inferior to Standard of Care

Transmission blocking

No

Yes

Bioavailability/food effect

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

No risks in terms of solid state or PK interactions

Safety and tolerability

Few and manageable drug-related SAEs in phase III and IV

No drug-related SAEs; minimal drug-related AEs that do not result in study exclusion

Use in patients with reduced G6PD activity

Testing not required; no enhanced risk in mild–moderate G6PD deficiency

No enhanced risk

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 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

TCP-1 criteria at human proof of concept

Minimum essential

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

Rapid clearance of parasites at least as fast as mefloquine (≤72 h from the highest burdens) and projected >106-fold reduction in parasites

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

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

Clinical efficacy against all known resistance (3-day dosing)

Clinical efficacy against all known resistance (single dose)

Drug–drug interactions

No unsurmountable risks with potential anti-malarial partners

No interactions with other anti-malarial, anti-retroviral or TB medicines

Safety

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

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

Measured—no enhanced haemolysis risk from testing in SCID mice engrafted with human blood from volunteers with reduced G6PD activity; clinical confirmation

Measured—no enhanced haemolysis risk in subjects with reduced G6PD activity, with clinical confirmation

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

Cost of active ingredient in final medicine

Similar to current medication: ≤$0.5 for adults, $0.1 for infants under 2 years

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

≥3–5 years

Notes

Declarations

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Authors’ Affiliations

(1)
Medicines for Malaria Venture
(2)
Neglected Infectious Diseases Consulting
(3)
FSG

Reference

  1. Burrows JN, Duparc S, Gutteridge WE, Hooft van Huijsduijnen R, Kaszubska W, Macintyre F, Mazzuri S, Möhrle JJ, Wells TNC. New developments in anti-malarial target candidate and product profiles. Malar J. 2017;16:26. doi:10.1186/s12936-016-1675-x.View ArticlePubMedPubMed CentralGoogle Scholar

Copyright

© The Author(s) 2017

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