Model-informed target product profiles of long-acting-injectables for use as seasonal malaria prevention

Abstract

Seasonal malaria chemoprevention (SMC) has proven highly efficacious in reducing malaria incidence. However, the continued success of SMC is threatened by the spread of resistance against one of its main preventive ingredients, Sulfadoxine-Pyrimethamine (SP), operational challenges in delivery, and incomplete adherence to the regimens. Via a simulation study with an individual-based model of malaria dynamics, we provide quantitative evidence to assess long-acting injectables (LAIs) as potential alternatives to SMC. We explored the predicted impact of a range of novel preventive LAIs as a seasonal prevention tool in children aged three months to five years old during late-stage clinical trials and at implementation. LAIs were co-administered with a blood-stage clearing drug once at the beginning of the transmission season. We found the establishment of non-inferiority of LAIs to standard 3 or 4 rounds of SMC with SP-amodiaquine was challenging in clinical trial stages due to high intervention deployment coverage. However, our analysis of implementation settings where the achievable SMC coverage was much lower, show LAIs with fewer visits per season are potential suitable replacements to SMC. Suitability as a replacement with higher impact is possible if the duration of protection of LAIs covered the duration of the transmission season. Furthermore, optimising LAIs coverage and protective efficacy half-life via simulation analysis in settings with an SMC coverage of 60% revealed important trade-offs between protective efficacy decay and deployment coverage. Our analysis additionally highlights that for seasonal deployment for LAIs, it will be necessary to investigate the protective efficacy decay as early as possible during clinical development to ensure a well-informed candidate selection process.

Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling study

“…We performed this analysis by replicating protective efficacy outcomes from a randomised non-inferiority trial of dihydroartemisinin-piperaquine (DHA-PPQ) to SP-AQ, 26 following the approach described by Burgert and colleagues. 27 SP-AQ’s protective efficacy against clinical case incidence was extracted from Zongo and colleagues. 26 For each SMC modelling approach (blood stage only, dominant blood stage, and dominant liver stage), we used OpenMalaria to perform in-silico clinical trials for a wide range of model parameter values.…”

“…Our analysis then applied a mathematical framework for predicting determinants of intervention impact and defining minimum drug profile criteria. This framework has been previously described, 28 and was demonstrated in a proof-of-concept study 27 (as summarised in appendix 1.4). In brief, we used the individual-based malaria transmission model to simulate scenarios over a wide range of input values for intervention coverage and drug initial efficacy and duration of protection.…”

“…To capture next-generation SMC’s likely protective effect against liver stage parasites, we modelled the intervention’s protective effect as a probability of preventing liver stage infection that decays over time, in combination with five days of blood and liver stage parasite clearance from the start of SMC administration. This approach, which was based on a previously calibrated model of SP-AQ, 24 has two key parameters: duration of protection, driven by the drug’s elimination half-life and EC 50 , and; initial probability of preventing infection, driven by the drug’s maximal effect E max . By modelling the intervention’s protective effect over time, we could translate a drug’s pharmacokinetics or pharmacodynamics to its expected public health impact.…”

Modelling to inform next-generation medical interventions for malaria prevention and treatment

“…Currently very little is known about the PK/PD relationship of monoclonal antibodies. Previous modelling has shown that the protection of an anti-infective malaria monoclonal over time, informed by PK/PD data and models, is an important driver of public health impact 10 . Unlike vaccines, where immune correlates of protection are challenging to define, mAbs offer the potential to provide early PK/PD evidence.…”

Accelerated development of malaria monoclonal antibodies

“…Modeling has highlighted the importance of the pharmacodynamics of seasonal injectable interventions requiring sustained high levels of protection for the duration or longer of the transmission season to achieve non-inferiority to seasonal malaria chemoprevention. 8 …”