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
Cidal Cidal
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.