Safety, Pharmacokinetics, and Causal Prophylactic Efficacy of KAF156 in a Plasmodium falciparum Human Infection Study

Abstract

Background: KAF156 is a novel antimalarial drug that is active against both liver- and blood-stage Plasmodium parasites, including drug-resistant strains. Here, we investigated the causal prophylactic efficacy of KAF156 in a controlled human malaria infection (CHMI) model.

Methods: In part 1, healthy, malaria-naive participants received 800 mg KAF156 or placebo 3 hours before CHMI with P. falciparum-infected mosquitoes. In part 2, KAF156 was administered as single doses of 800, 300, 100, 50, or 20 mg 21 hours post-CHMI. All participants received atovaquone/proguanil treatment if blood-stage infection was detected or on day 29. For each cohort, 7-14 subjects were enrolled to KAF156 treatment and up to 4 subjects to placebo.

Results: KAF156 at all dose levels was safe and well tolerated. Two serious adverse events were reported-both resolved without sequelae and neither was considered related to KAF156. In part 1, all participants treated with KAF156 and none of those randomized to placebo were protected against malaria infection. In part 2, all participants treated with placebo or 20 mg KAF156 developed malaria infection. In contrast, 50 mg KAF156 protected 3 of 14 participants from infection, and doses of 800, 300, and 100 mg KAF156 protected all subjects against infection. An exposure-response analysis suggested that a 24-hour postdose concentration of KAF156 of 21.5 ng/mL (90% confidence interval, 17.66-25.32 ng/mL) would ensure a 95% chance of protection from malaria parasite infection.

Conclusions: KAF156 was safe and well tolerated and demonstrated high levels of pre- and post-CHMI protective efficacy.

Clinical trials registration: NCT04072302.

Keywords: Plasmodium falciparum; chemoprophylaxis; human infection studies; malaria; prevention.

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.

KAF156 study design. Study design for part 1 pre-CHMI dosing of 800 mg KAF156 or placebo (top panel) and part 2 post-CHMI dose de-escalation dosing (bottom panel). Pipettes indicate blood collection for parasite density assessment, red drops indicate blood collection for PK assessments, and blue hearts indicate ECGs. Protocol-defined treatment criteria were (1) 2 consecutive positive qRT-PCR results in an afebrile participant with at least 1 of the results ≥250 estimated parasites/mL or (2) 1 positive qRT-PCR result in a febrile participant, or (3) 1 positive thick blood smear in a febrile or otherwise symptomatic participant. In this paper, day 0 is the day of CHMI. Abbreviations: CHMI, controlled human malaria infection; ECG, electrocardiogram; PK, pharmacokinetics; qRT-PCR, quantitative reverse transcription–polymerase chain reaction.

Figure 2.

Kaplan-Meier analysis of qRT-PCR–defined safety and efficacy thresholds. Time-to-event analysis for the protocol-defined primary efficacy and treatment threshold (A) and the alternative (B). The y-axis represents the percentage of participants who had not reached the treatment definition of (A) 2 consecutive positive qRT-PCR results including 1 result ≥250 estimated parasites/mL (all participants were treated based on this treatment definition) or (B) a single qRT-PCR positive result ≥250 estimated parasites/mL. Days are numbered post-CHMI. Log-rank (Mantel-Cox) test for treatment groups vs placebo control. *P < .05, ****P < .0001. Abbreviations: CHMI, controlled human malaria infection; est. p, estimated parasites; qRT-PCR, quantitative reverse transcription–polymerase chain reaction.

Figure 3.

KAF156 concentration-time profiles and exposure–response relationship. A, Individual subject data from the PK analysis set of parts 1 and 2 are shown. Dotted lines indicate subjects who developed protocol-defined malaria infections; solid lines indicate those with no demonstrated blood-stage infection. KAF156 800-mg cohort data from parts 1 and 2 are pooled. Note that none of the subjects treated with 20 mg KAF156 had measurable drug beyond 24 hours. The KAF156 limit of quantification was 5 ng/mL. The shaded region denotes the 21.5-ng/mL threshold. B, Logistic regression with 90% confidence limits for protocol-defined Plasmodium 18S rRNA biomarker positivity (2 consecutive positives including 1 result ≥250 estimated parasites/mL) against KAF156 20, 50, and 100 mg 24-hours postdose concentration as predictor (PK analysis set). Partial exposure profile is shown to magnify the curvature of logistic model PK data from both parts pooled together. The model could not be fitted for part 1 separately due to no malaria infection in the active treatment group. Abbreviations: PK, pharmacokinetics; rRNA, ribosomal RNA.