II-079 Simon Koele

Model-informed trial design for the malaria transmission blocking antibody TB31F

Simon Koele1, Merel Smit2, Matthew McCall2, Matthijs Jore2, Will Stone3, Teun Bousema2, Rob ter Heine1

1 Department of Pharmacy, Radboud Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands 2 Department of Medical Microbiology and Radboud Center for Infectious Diseases, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands 3 Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, Keppel Street, London, UK

Introduction: TB31F is a transmission-reducing monoclonal antibody targeting a highly conserved epitope of the malaria gametocyte [1]. A previous study in healthy adults show that TB31F is well tolerated and reduced malaria transmission over the trial duration (84days) [2]. TB31F concentrations were predicted to persist at concentrations capable at blocking the malaria transmission for 4/5 months [3]. Demographically targeted TB31F administration was previously predicted to be highly effective at reducing the malaria burden [3]. The TB31F-Mali study, therefore, aims to establish the tolerability and activity of TB31F in a target population of naturally infected Malian children (aged 10-18). To minimize the burden and invasiveness while maximizing information we investigated the optimal study design for assessing exposure-response relationships within the target population, demonstrate complete transmission blockade, and identify the optimal time points for direct skin feeding assays (DSF) to determine their transmission-blocking activity.

Methods: A representative virtual population consisting of children between 10-18 years was constructed using WHO weight/height for age distributions. A correction was applied to accurately simulate the weight distribution of children in Africa [4]. It was assumed that 75% of all included children were aged between 10-15 years.

A previously published pharmacokinetic-pharmacodynamic model was scaled to the pediatric population, which was used to simulate exposures of TB31F following 30mg, 50mg, or 100mg SC administration [3]. In total 2000 individual concentration-time curves were simulated per dose. As a sensitivity analysis, the clearance in the target population was set 20% higher compared to the healthy volunteers, to account for potentially increased protein metabolism e.g. due to malnutrition and inflammation. Two dosing groups were selected; one that is predicted to fully block malaria transmission and one that provides exposures similar to the EC50 of the exposure-response derived in the healthy volunteer study (2.18 mg/L) [3].

Predicted individual TB31F exposures were subsequently used to describe the oocyst count over time using a previously published PD model. Baseline oocyst count data from Mali were used to represent the mosquito infectivity and oocyst distribution in the target population (ClinicalTrials.gov, NCT05081089) [3]. For each simulated clinical trial, 90 participants were randomized to receive either 100mg SC TB31F, 30mg SC TB31F, or placebo. All participants had DSF on day 0 (pre-dose), and participants in the control group or 100mg SC group also had DSF performed at day 5 to demonstrate complete inhibition of malaria transmission. To determine the EC50 of the malaria transmission reducing activity, the 30mg SC dosing group was analyzed at three different DSF time points: day 1, day 2, or day 3. Day 5 was not considered for DSF experiments, as the systemic exposure on day 5 is expected to result in near-maximum blockage in almost all individuals and is, thus, less informative for estimation of the EC50. A total of 1000 clinical trials were simulated for each of the three designs. The bias and precision of the EC50 parameter were determined and summarized using the stochastic simulation and estimation [5, 6].

Results: Median (5th-95th percentile) TB31F concentrations following a 100 mg SC dose at day 5 were 15.8 (8.78 – 29.4) and 15.3 mg/L (8.57 – 28.7) with 20% increased clearance. A full blockage of malaria transmission is expected at this concentration. Median (5th-95th percentile) TB31F concentrations following a 30 mg SC dose at day 1 were 2.04 mg/L (1.10 – 4.00) and 2.03 mg/L (1.09-3.98) with 20% increased clearance, similar to the EC50 of the transmission reducing activity in the healthy volunteer study (2.18 mg/L).

The bias and precision of determining the EC50 were determined at 0.033 mg/L and 10.5% for day 1, versus -0.0094 mg/L and 10.8% for day 2, and -0.0090 mg/L and 12.5% for day 3, respectively. Performing DSF at day 1 had slightly better precision in determining the EC50 compared to the other strategies  and was, therefore, selected as DSF timepoint.

Conclusions: Simulations showed plasma concentrations associated with a full blockage of malaria transmission are expected at a 100mg SC dose, and a 30mg SC dose resulted in plasma concentrations similar to the EC50 determined in the healthy volunteer study. Increased clearance had little effect on the TB31F plasma concentrations at up until day 5 after dose. DSF assays provided the most information on estimating the EC50 when performed at day 1. In conclusion, model-informed clinical trial design aided in dose selection, minimized clinical trial burden, and improved confidence in the selection of DSF time points.

References:

  1. Kundu, P., et al., Structural delineation of potent transmission-blocking epitope I on malaria antigen Pfs48/45. Nature Communications, 2018. 9(1): p. 4458.
  2. van der Boor, S.C., et al., Safety, tolerability, and Plasmodium falciparum transmission-reducing activity of monoclonal antibody TB31F: a single-centre, open-label, first-in-human, dose-escalation, phase 1 trial in healthy malaria-naive adults. Lancet Infect Dis, 2022. 22(11): p. 1596-1605.
  3. Challenger, J.D., et al., Modeling the Impact of a Highly Potent Plasmodium falciparum Transmission-Blocking Monoclonal Antibody in Areas of Seasonal Malaria Transmission. J Infect Dis, 2023. 228(2): p. 212-223.
  4. Wasmann, R.E., et al., Constructing a representative in-silico population for paediatric simulations: Application to HIV-positive African children. Br J Clin Pharmacol, 2021. 87(7): p. 2847-2854.
  5. Lindbom, L., J. Ribbing, and E.N. Jonsson, Perl-speaks-NONMEM (PsN)–a Perl module for NONMEM related programming. Comput Methods Programs Biomed, 2004. 75(2): p. 85-94.
  6. Beal, S.L., et al., NONMEM users guides. NONMEM Project Group, University of California, San Francisco, 1992.

Reference: PAGE 32 (2024) Abstr 11188 [www.page-meeting.org/?abstract=11188]

Poster: Methodology - Study Design

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