As a prerequisite to building a portfolio strategy, the desired R&D outcome, or the target product profile (TPP), has been defined. Based on discussion with various HAT players and experts, a dual strategy is proposed:
1. The first priority is to develop a safe, effective, and practical stage 2 HAT drug to replace current first-line treatments, and to improve and simplify the current case management. The aim is to develop one drug that is effective against both stage 1 and stage 2 of HAT.
2. The second priority is for a very simple stage 1 treatment, to be used at the local health centre level, which in turn could lead to increased access to treatment and coverage of HAT. Depending on the availability of a simple diagnostic, such a drug would allow for mass screening + treatment campaigns in endemic areas, thus preventing disease progression to stage 2 and reducing disease transmission. Each R&D project in the portfolio will be selected, progressed, and managed according to well-defined decision matrices based on these TPPs.
TPP 1: Towards a new stage 1+2 treatment
|Ideal||Acceptable : improvement to current St2 Tx||NECT|
|Effective against stage 1 and 2||Effective against stage 1+2 (used stage 2 only)||stage 1+2 (used stage 2 only)|
|Broad Spectrum (gambiense and rhodesiense)||Efficacy against gambiense only||gambiense|
|Clinical efficacy > 95% at 18 months follow up||clinical efficacy: 96.5% (ITT NECT Study)|
|Effective in melarsoprol refractory patients||effective|
|<0.1% drug related mortality||<1% drug related mortality||1.2% possibly related mortality (NECT Field)|
|Safe during pregnancy and for lactating women||no specific adverse event found in babies born or being breastfed after treatment (NECT Field)|
|Adult and paediatric formulations||DFMO paediatric dosing available + Nifurtimox 5 mg tablets to be cut|
|No monitoring for AEs||Weekly simple lab testing (field testing)||hospitalization required|
|< 7 days p.o. once daily (DOT)||10 days p.o. (up to tid)||7 days IV infusion (bid) + 10 days po (tid)|
|< 7 days i.m. once daily||10 days i.m. once daily|
|Stability in Zone 4 for > 3 years||Stability in Zone 4 for > 12 months||Stability in Zone 4 for > 24 months|
|Cidal||DFMO static + Nifurtimox cidal|
|Multitarget||Unique target (but not uptake via P2-transporter only)|
|< 30 € / course* (only drug cost)||< 100 €* / course||222.5 € / course (in 4 treatments kits; WHO)|
|< 200 €* / course ok if very good on other criteria|
* It is expected that donor agencies will pay this, not patients. Considering that some 20-50,000 patients per year might require treatment, this is still realistic.
TPP 2 : To be developed only if a second stage treatment fails to show efficacy and is already in advanced clinical trials
|Ideal||Acceptable : improvement to current St2 Tx|
|Effective against stage 1||Effective against stage 1|
|Broad spectrum (gambiense and rhodesiense)||Efficacy against gambiense only|
|Clinical efficacy > 95% at 18 months follow up||Clinical efficacy no worse than pentamidine|
|0% drug related mortality||0% drug related mortality|
|≤ 3 days treatment||≤ 7 days treatment|
|Safe during pregnancy, for breastfeeding women and children||Safe during pregnancy, for breastfeeding women and children|
|Adult and paediatric formulations||Adult and paediatric formulations|
|No monitoring for AEs||No monitoring for AEs|
|Single dose p.o. or i.m.||2-3 daily doses p.o. or i.m.|
|(single dose in animal models, long t1/2)|
|Stability in Zone 4 for > 4 years||Stability in Zone 4 for > 2 years|
|Multitarget||1 target but resistance not readily inducible|
|< 10 € / course*||< 30 €* / course|
* A successful campaign also requires a simple field diagnostic being available.
Review of these TPPs will occur on a regular basis through consultation with stakeholders including WHO, HAT control programs in endemic countries, and specifically with physicians and health workers who deal with this disease on a daily basis.