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

We used a controlled human malaria infection model to investigate the causal prophylactic efficacy of the imidazolopiperazine antimalarial drug KAF156. KAF156 was safe and well tolerated and demonstrated high levels of protective prophylactic efficacy in this controlled infection model.

In 2018, Plasmodium parasites caused approximately 228 million malaria cases and 405 000 deaths [1]. Prophylactic administration of antimalarial drugs to prevent infection can be beneficial for populations at risk of infection or disease [2, 3]. Current chemoprophylaxis employs either suppressive or causal prophylactic agents. Suppressive prophylactics (ie, mefloquine, doxycycline) primarily kill blood-stage parasites and must be administered for 28 days after the last potential exposure. Causal prophylactic agents (ie, atovaquone-proguanil [Malarone], GlaxoSmithKline, primaquine, tafenoquine) are active against both liver- and blood-stage parasites and can be discontinued 7 days after the last potential exposure. Both atovaquone/proguanil and primaquine require daily administration, whereas tafenoquine is dosed weekly.

KAF156 is in the novel imidazolopiperazine class of antimalarial drugs [4], which is distinct from currently marketed antimalarials and is active against drug-resistant parasites. KAF156 exhibits parasiticidal activity against both liver- and blood-stage parasites [5], shows therapeutic and causal prophylactic activities in mouse models, and blocks transmission of gametocytes to mosquitoes [5]. In adults with acute uncomplicated malaria, KAF156 showed activity against Plasmodium falciparum (Pf) and Plasmodium vivax, including artemisinin-resistant strains [6]. KAF156 is currently being investigated in combination with lumefantrine for therapeutic efficacy [7].

Here, we used a controlled human malaria infection (CHMI) model [8] induced by 5 mosquito bites to evaluate the causal prophylactic efficacy of KAF156 pre- and post-CHMI. CHMI has been used safely in more than 1300 subjects [9] as a reproducible, predictable approach for evaluating drug/vaccine efficacy against Pf.

METHODS

Study Design/Oversight

The prophylactic efficacy, safety, and pharmacokinetics of KAF156 were evaluated in a nonconfirmatory, 2-part, randomized, double-blind, placebo-controlled, single-center study in healthy adult participants by CHMI (Figure 1). Part 1 evaluated a single 800-mg dose of KAF156 administered orally approximately 3 hours before exposure to Pf sporozoite–infected mosquitoes to maximize the chances of observing KAF156 prophylactic efficacy as KAF156 C_max is achieved at approximately 3 hours. After such efficacy was observed in part 1, part 2 used a dose de-escalation strategy with interim analyses and design adaptations among 5 cohorts where single oral doses of KAF156 of 800, 300, 100, 50, or 20 mg were administered approximately 21 hours after CHMI by exposure to Pf-infected mosquitoes to determine if protection was maintained when the time since exposure was longer. Timing also optimized participant and staff availability to coincide on the initial days with procedure-intensive mosquito bite administration followed by frequent pharmacokinetics (PK) and electrocardiogram (ECG) assessments. In parts 1 and 2, patients were planned to be randomized in a 14:4 ratio to receive a single dose of either KAF156 or matching placebo. Upon completion of each cohort, interim analysis was conducted before continuing to the next cohort.

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.

The study was sponsored by Novartis and approved by the Western Institutional Review Board with reliance agreements for the University of Washington and Fred Hutchinson Cancer Research Center (clinicaltrials.gov NCT04072302; https://clinicaltrials.gov/ct2/show/NCT04072302).

Study Population

Participants consisted of healthy males and females (of nonchildbearing potential) recruited from multiple venues and the Seattle Malaria Clinical Trials Center volunteer registry. Planned enrollment was up to 126 subjects (part 1, n~18; part 2, n~108). Eligible participants were aged 18–40 years and in good health as determined by history, physical examination, vital signs, ECG, and laboratory tests at screening. Subjects were required to weigh 50 kg or more with a body mass index (BMI) of 18–30 kg/m². All participants provided written informed consent. Exclusion criteria included history of malaria, residence in a malaria-endemic area for more than 6 months, planned travel outside of the country during the study, previous participation in any malaria vaccine study, contraindications to the study drug or treatment drugs, significant cardiovascular disease risks, and other criteria described in the full protocol (available upon request).

Treatment and Procedures

Following a screening period of up to 60 days, participants who met eligibility criteria were enrolled and exposed to 5 mosquito bites by placing a mosquito-containing cup on their forearms. Mosquito feeding was performed for 5–10 minutes under study staff supervision; the process was repeated as needed until 5 bites were sustained by sporozoite-containing mosquitoes. Participants were domiciled from the day of infection until 48 hours postdose; thereafter, all investigations were on an outpatient basis. Subjects were monitored for signs and/or symptoms of malaria from the day of CHMI until 6 weeks post-CHMI and by quantitative reverse transcription–polymerase chain reaction (qRT-PCR) for evidence of blood-stage infection. If blood-stage infection was detected within 28 days post-CHMI, or if a subject withdrew early, the subject was treated with the Food and Drug Administration (FDA)–approved antimalarial drug atovaquone/proguanil. Treated individuals were required to visit the study site for up to 3 consecutive days postinitiation of atovaquone/proguanil for monitoring and thick blood smears (TBSs) and returned for follow-up at 28, 35, and 42 days post-CHMI. All participants who remained qRT-PCR negative for 28 days post-CHMI were tested by blood smears and received atovaquone/proguanil.

Efficacy and Safety Assessments

The primary efficacy variable was the number of participants who developed blood-stage Pf infection. Infection was detected and quantified by Plasmodium 18S ribosomal RNA (rRNA) qRT-PCR, which quantifies Pf A-type 18S rRNA from whole blood as previously reported [10, 11]. The assay has a lower limit of quantification of 20 parasites/mL. If needed, TBSs were prepared and assessed using an internationally harmonized protocol [12]. The TBSs were used if an individual had a temperature of 38°C or higher or any other time during the study at the discretion of the investigator. If samples were collected for TBSs, a paired sample was collected for qRT-PCR. Blood-stage infection was defined as any of the following: (1) 2 consecutive positive qRT-PCR results in a subject with a temperature less than 38.0°C, including 1 result of 250 or more estimated parasites/mL, or (2) 1 positive qRT-PCR result in a subject with a temperature of 38.0°C or higher, or (3) 1 positive TBS.

Safety assessments consisted of collecting all adverse events (AEs) and serious AEs (SAEs), with their severity and relationship to KAF156, as well as monitoring for pregnancy. Regular assessments included hematology, blood chemistry and urine monitoring, as well as vital signs (including ECG), physical condition, and body weight. Subjects were issued symptom diaries, rulers (to measure bite radius), and thermometers, and were instructed to record all symptoms and measure their body temperature daily from the day after CHMI until 6 days post-CHMI. Subjects continued to monitor symptoms and body temperature from 7 days post-CHMI through completion of atovaquone/proguanil treatment and were to contact study personnel immediately if they noticed moderate or severe symptoms or fever at any time post-CHMI.

Pharmacokinetics

Blood samples (3 mL) for PK evaluation were collected from a forearm vein (direct venipuncture or from an indwelling cannula) into a K₂-EDTA tube at each time point. Plasma was prepared and stored at less than −60°C until analysis. KAF156 was quantified in plasma by a validated liquid chromatography–tandem mass spectrometry method with a lower limit of quantification of 5 ng/mL [13]. Plasma PK parameters were determined using noncompartmental methods using the recorded sampling times with WinNonlin Phoenix, Certara (version 6.4).

Statistical Analysis

The primary endpoint (number of subjects that developed blood-stage Pf infections based on the protocol definition) was modeled using a B-binomial model. The safety analysis set included all subjects who received KAF156. The PK and pharmacodynamics (PD) analyses included all subjects in the safety analysis set with available PK/PD data. The respective infection probabilities for the placebo (p1) and KAF156 (p2) arms were given B prior distributions. The prior distribution for p1 was informative (B, 10.23, 0.43) to reflect the site experience with mosquito-bite CHMI and its ability to achieve blood-stage infection in the absence of treatment, and the prior distribution for p2 was noninformative (B, 1/3, 1/3). The exact forms of these prior distributions were outlined in the Statistical Analysis Plan. Based on the outcome data, the above parameters were estimated by their posterior medians, which were presented along with 90% credible intervals. In addition to the above modeling approach, summary statistics were provided for the incidence rate of blood-stage malaria infection by treatment arm.

Summary statistics of PK parameters were provided by cohort and treatment arm. Exposure–response analysis was performed using a logistic regression model. In the model, various PK parameters were assessed against treatment outcome (ie, as malaria parasite infection negative or malaria parasite infection positive). Parameters included AUC_last, AUC_0-24h, C_max, and KAF156 concentration at 24 hours and 96 hours postdose where the PK exposure parameters had overlapping values for malaria parasite infection–positive and malaria parasite infection–negative cases and could be fitted to the model. The best model was then utilized to predict the threshold exposure cutoff to avoid infection until 28 days post-CHMI with certain degrees of confidence.

RESULTS

Study Participants

From 2014 to 2018, 191 volunteers were screened and 87 healthy participants were enrolled and followed in the study (11 in part 1 and 76 in part 2) (Supplementary Figure 1). With the exception of 1 female participant in the 500-mg KAF156 dose group (part 2), all participants were male (98.7%). Other baseline characteristics can be found in Supplementary Table 1. All participants completed the study except for 1 enrolled participant in the placebo group of part 2.

Efficacy

The primary objective of the study was to assess the prophylactic efficacy of orally administered KAF156 in healthy subjects either before or after exposure to Pf-infected mosquitoes. The incidence of blood-stage malaria infection was assessed for 28 days following CHMI (Table 1). All infections except for one in all cohorts were ultimately defined using the definition of 2 consecutive positive qRT-PCR results including 1 with 250 or more estimated parasites/mL. The one exception relied on investigator discretion after 2 nonconsecutive positive qRT-PCR results were observed. Infection definitions reliant on temperature and/or blood smears were not triggered prior to the qRT-PCR definition for any subject.

Table 1.

Protective Prophylactic Efficacy of KAF156 Compared With Placebo

Treatment	n/M	Observed PE, %	Estimated PE (90% CI)	Prediction Probability, %
Part 1
Placebo	4/4	0	…	…
800 mg	0/7	100	98.6 (80.4 to 100.0)	93.3
Part 2
Placebo	18/18	0	…	…
800 mg	0/9	100	98.9 (84.5 to 100.0)	97.1
300 mg	0/9	100	98.9 (84.5 to 100.0)	97.1
100 mg	0/11	100	99.1 (87.2 to 100.0)	99.2
50 mg	11/14	21.4	20.3 (5.8 to 41.4)	NA
20 mg	14/14	0	0.0 (NA to 9.0)	NA

Abbreviations: CI, Bayesian credible interval; M, total number of subjects with ≥1 valid measurement of the primary endpoint; n, number of subjects with blood-stage malaria infection; NA, not applicable; PE, protective efficacy [= (1 − [infection probability in KAF156 arm/infection probability in placebo arm]) × 100%].

In part 1, all 7 subjects treated with KAF156 (800 mg) were protected against infection, whereas all 4 subjects randomized to placebo reached the protocol-defined Pf infection threshold 7–8 days post-CHMI (Figure 2). In part 2, all subjects treated with placebo or 20 mg KAF156 developed malaria infection as well. However, treatment with 50 mg of KAF156 protected 3 of 14 participants, and higher doses of KAF156 (ie, 100, 300, and 800 mg) protected all participants (Figure 2A). Infection probabilities for each treatment arm were used to derive percent protective efficacy (PE), with a value of 95% or higher considered desirable to establish efficacy for completed cohorts. Based on estimated PE and 90% credible intervals (Table 1), the 800-mg dose prechallenge (part 1) and the post-CHMI doses of 100, 300, and 800 mg (part 2) exceeded the desired PE threshold of 95%.

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.

For incompletely protected groups (20- and 50-mg doses), the time from CHMI to any qRT-PCR positivity of 20 or more estimated parasites/mL and to 1 positive result of 250 or more estimated parasites/mL was also assessed. Compared with placebo groups (which became qRT-PCR positive at ≥20 estimated parasites/mL 7–9 days post-CHMI), KAF156-treated participants demonstrated delayed onset up to 13 days post-CHMI (Supplementary Figure 2). Compared with the most sensitive qRT-PCR threshold and the treatment definition, a threshold of 1 positive qRT-PCR of 250 or more estimated parasites/mL showed the best statistical power to identify differences in time to positivity for incompletely protective doses (Figure 2B).

Safety

Overall, KAF156 was safe and well tolerated with comparable AE profiles in KAF156 recipients and placebo recipients (Supplementary Table 2). There were no deaths or premature discontinuations due to AEs. Two participants in part 2 experienced SAEs. An atrial flutter SAE was reported by 1 subject in the KAF156 300-mg arm, which was not suspected to be related to KAF156. The other SAE was elevated aspartate aminotransferase in 1 subject in the placebo arm. Two additional grade 3–4 AEs were observed that were not considered to be SAEs: grade 4 neutropenia in 1 participant receiving placebo and grade 3 syncope in 1 subject dosed with 20-mg KAF156. In addition, compared with placebo, subjects treated with 800 mg KAF156 in part 2 at 3, 6, and 9 hours post–drug administration exhibited statistically significantly higher QT interval corrected by Fredericia (QTcF) intervals following KAF156 administration with a maximum change of 12.10 milliseconds at 6 hours postdose from baseline (Supplementary Figure 3). However, the clinical relevance of this could not be established because the study was not controlled for ECG measurements; a mean maximum change up to 9.33 milliseconds was observed in the placebo group. These changes were not considered significant compared with placebo in part 1 or in any of the other doses tested in part 2. These changes were consistent with observations in a previous study where QTcF was measured more rigorously [13].

Most AEs were grade 1 or grade 2 (Supplementary Table 2), and there were no dose-related trends observed in AEs. In part 1, the most common AEs were gastrointestinal disorders (nausea, abdominal pain, decreased appetite), nervous system disorders (headache), as well as general disorders (headache) and localized pruritus at the mosquito bite site. In part 2, the most common AEs were headache and fatigue and localized pruritus at the mosquito-bite site. Detailed laboratory AEs are reported in Supplementary Tables 3–6.

Pharmacokinetics and Exposure–Response Relationship

The PK variables for single doses of orally administered KAF156 were derived from the plasma concentration-time data for each participant as summarized in Table 2. No concomitant medications were allowed in the 2 weeks before the study or during the study, except for those required to treat AEs and atovaquone/proguanil for treatment. The concentration-time curves of the individual participants’ profiles for both part 1 and part 2 are shown in Figure 3A. In part 1, a single 800-mg oral dose of KAF156 resulted in mean (± SD) C_max of 1630 ± 446 ng/mL with a median T_max of 2.6 hours. The mean elimination half-life was 54.8 hours. The median T_max was approximately 1 hour for the 3 lower doses (20 mg, 50 mg, and 100 mg) and approximately 3 hours for the 2 higher (300 mg and 800 mg) doses. These data indicated that there was a relationship between increasing KAF156 exposure and its prophylactic efficacy. Based on the correlation coefficient, a KAF156 concentration 24 hours postdose provided the best fit in a logistic regression model to assess the various PK parameters against treatment outcome (Figure 3B). This analysis predicted that a 24-hour postdose KAF156 concentration of 21.5 ng/mL (90% confidence interval [CI], 17.7–25.3 ng/mL) would ensure a 95% chance of preventing qRT-PCR–defined malaria parasite infection within 28 days of CHMI based on observed efficacy.

Table 2.

Pharmacokinetic Variables After Prophylactic KAF156 Dosing

PK Parameter (Units)	Part 1 (pre-CHMI)	Part 2 (Post-CHMI)
	800 mg (n = 7)	800 mg (n = 9)	300 mg (n = 9)	100 mg (n = 12)	50 mg (n = 14)	20 mg (n = 14)
AUC, UG* hours/mL
AUCinf	39.8 ± 8.7 (21.8%)	41.8 ± 10.6 (25.4%)	14.3 ± 4.2 (29.0%)	2.9 ± 0.5 (18.4%)a	…	…
AUClast	38.8 ± 8.4 (21.6%)	40.7 ± 10.1 (24.8%)	13.5 ± 3.8 (27.9%)	2.6 ± 0.7 (27.7%)	0.9 ± 0.6 (68.8%)	0.2 ± 0.1 (31.5%)
AUC0–24	17.0 ± 3.1 (18.4%)	17.7 ± 3.5 (19.9%)	5.2 ± 1.1 (20.3%)	1.2 ± 0.2 (20.3%)	0.5 ± 0.1 (26.6%)	0.2 ± 0.05 (26.6%)
Cmax, ng/mL	1630 ± 446 (27.3%)	1400 ± 297 (21.2%)	478 ± 115 (24.1%)	124 ± 41 (33.5%)	47 ± 16 (34.6%)	18 ± 3 (19.7%)
Tmax, hours	2.62 (2.5–5.6)	2.8 (2.6–5.7)	2.6 (0.9–5.5)	0.9 (0.9–1.0)	0.9 (0.8–5.5)	0.9 (0.8–5.6)
T1/2, hours	54.8 ± 6.2 (11.3%)	53.1 ± 9.9 (18.6%)	69.4 ± 10.6 (15.2%)	49.7 ± 26.8 (54.0%)	36.8 ± 26.6 (72.2%)b	…
CL/F, L/hour	20.9 ± 4.6 (22.1%)	20.3 ± 5.2 (25.4%)	22.4 ± 5.7 (25.6%)	36.2 ± 7.0 (19.3%)a	…	…
Vz/F, L	1660 ± 425 (25.6%)	1530 ± 385 (25.2%)	2230 ± 628 (28.2%)	2180 ± 461 (21.1%)a	…	…

All plus–minus PK values are means ± SD (CV%), except for T_max, which is presented as median (range). Some parameters are missing because they could not be reliably estimated with the available data.

Abbreviations: AUC, Area Under the Curve; AUC_inf, area under the plasma concentration-time curve from time zero to infinity; AUC_last, area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration; AUC_0–24, area under the plasma concentration-time curve from time zero to 24 hours after administration; CHMI, controlled human malaria infection; CL/F, apparent systemic clearance of KAF156 from plasma; C_max, maximum plasma drug concentration after administration; n, number of subjects who provided reliable estimate of the parameter; PK, pharmacokinetics; T_max, time to reach maximum plasma concentration after administration; T_1/2, terminal elimination half-life; Vz/F, apparent volume of distribution during terminal elimination phase.

^aThe noted parameters are n = 11.

^bThe noted parameter is n = 4 because these could not be estimated reliably in other subjects.

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.

DISCUSSION

New malaria chemoprophylaxis drugs are needed. Important attributes for such drugs include weekly or monthly dosing; causal and suppressive prophylactic activities to suppress liver-, blood-, and gametocyte-stage parasites; a safety profile acceptable to all ages, including women of childbearing potential and pregnant women; ease of manufacturing; and affordability.

Here, we report our investigation of KAF156, a novel imidazolopiperazine antimalarial, for causal prophylaxis and demonstrate high levels of pre- and post-CHMI PE. The modeled predicted PE of the combined 800-, 300-, and 100-mg doses was 98.9% or higher. The part 2 dose de-escalation design allowed for the precise determination of effective drug exposure, and post-CHMI dosing confirmed intrahepatic KAF156 activity observed in preclinical studies [14–16]. In addition to its known suppressive prophylactic activity against blood stages [17], our findings confirm preclinical studies that KAF156 has causal prophylactic activity (Supplementary Table 7). The PK characteristics and the projected effective exposure indicate that KAF156 has the potential to achieve the required PE with weekly dosing. The PK properties of KAF156 were similar to those in prior human studies [6, 18]. Since KAF156 activity provides both causal and suppressive prophylaxis, the drug requires fewer doses after a potential exposure. At lower than effective KAF156 exposures, we observed delayed blood-stage infection (qRT-PCR–defined infection threshold), indicating that, at lower exposures, KAF156 has static effects on liver-stage parasites. However, the KAF156 mechanism of action is unknown, so such effects cannot be ascertained.

Adverse events were measured for 42 days post-CHMI (42–43 days post-KAF156/placebo dosing) in the study, and KAF156 was generally safe and well tolerated. Two observed SAEs were not treatment related, and additional grade 3 and 4 AEs that were not considered to be SAEs occurred in the 20-mg and placebo groups, respectively. Although statistically significant changes in QTcF were seen inconsistently, the clinical relevance of this observation could not be established as the study was controlled for this measurement. Comparable QTcF increases were also reported in a KAF156/piperiquine drug interaction study but was not previously seen for KAF156 alone [13]. This finding will continue to be investigated in future studies, although PE at lower doses may mitigate this potential concern. The safety profile of KAF156 given in multiple daily doses to treat malaria [6] suggests that weekly dosing would not result in drug concentrations associated with more severe AEs, but this will need to be tested. With its CHMI design, our study was limited to healthy adults aged 18–40 years and, due to the early phase of KAF156 clinical development and unknown reproductive effects, all enrolled participants but 1 were male. Additional testing of the drug is required to confirm these trends and expand our understanding of KAF156 to other populations and dosing/exposure scenarios.

This trial was one of the first CHMI studies submitted under an FDA Investigational New Drug (IND) to rely on a molecular biomarker. Our testing approach has since obtained Biomarker Qualification through the FDA Center for Drug Evaluation and Research’s Drug Development Tool program [10, 19]. With earlier infection detection, the study design eliminated the domiciled “hotel” phase typically used in TBS-based CHMI studies. Results confirmed accelerated infection detection using a molecular endpoint compared with TBS-based endpoints, consistent with observations in other studies [20, 21]. Accelerated infection detection by qRT-PCR leads to earlier treatment, reduces symptoms, and provides a further safety advantage. This trial also was the first CHMI study to utilize a dose de-escalation strategy with interim analyses and design adaptations, which identified a protective drug concentration through PK/PD modeling. This approach may prove useful for bridging preclinical and clinical studies as KAF156 combination therapies and other antimalarial drugs are evaluated.

Our findings demonstrate that KAF156 has great promise and may one day contribute to public health gains in malaria-endemic regions. The need for improved prophylaxis among travelers, militaries, and vulnerable populations such as pregnant women and children begs for better prevention tools including effective and durable causal prophylactic drugs. Beyond the above uses, strategic use of malaria prophylaxis can have population effectiveness through mass drug administration and intermittent chemoprevention during pregnancy [22, 23]. Our findings highlight the need to further investigate the safety, efficacy, and utility for KAF156 for reducing malaria morbidity and mortality.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Acknowledgments. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication. The authors thank Dr Mindy Miner for technical editing assistance.

Financial support. Novartis was the sponsor of the study and participated in study design (including dose selection) and in data collection, analysis, and interpretation.

Potential conflicts of interest. E. D. reports a research grant for cytomegalovirus studies from Merck and Co, Inc, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.