Efficacy, Safety, Tolerability, and Pharmacokinetics of MMV390048 in Acute Uncomplicated Malaria

ABSTRACT. An open label, phase IIa study conducted in Ethiopia evaluated the efficacy, safety, tolerability, and pharmacokinetics of a single 120-mg dose of the phosphatidylinositol 4-kinase inhibitor MMV390048 in Plasmodium vivax malaria. The study was not completed for operational reasons and emerging teratotoxicity data. For the eight adult male patients enrolled, adequate clinical and parasitological response at day 14 (primary endpoint) was 100% (8/8). Asexual parasites and gametocytes were cleared in all patients by 66 and 78 hours postdose, respectively. There were two recurrent P. vivax infections (days 20 and 28) and a new Plasmodium falciparum infection (day 22). MMV390048 exposure in P. vivax patients was lower than previously observed for healthy volunteers. Mild adverse events, mainly headache and gastrointestinal symptoms, were reported by eight patients. Single-dose MMV390048 (120 mg) rapidly cleared asexual parasites and gametocytes in patients with P. vivax malaria and was well tolerated.

Malaria remains major threat to global health. 1 The need for new measures to support malaria elimination and the emergence of drug-resistant Plasmodium strains requires the discovery and development of new antimalarial drugs. 2 MMV390048 is a phosphatidylinositol 4-kinase inhibitor with in vitro activity against all Plasmodium life cycle stages, excepting late-stage hypnozoites in the liver. [3][4][5] MMV390048 lacks cross-resistance with current antimalarial drugs, 6 and in vivo studies showed both transmission blocking and chemoprotective activity. 6 In phase I clinical studies, MMV390048 was well tolerated at doses up to 120 mg. 7,8 Pharmacokinetic/pharmacodynamic modeling predicted that an adequate clinical and parasitological response (ACPR) . 80% would be achieved at day 14 posttreatment with a single 120-mg dose of MMV390048 with 92% certainty. 8 Thus, MMV390048 has potential as a single-dose therapy for the treatment and control of malaria, [6][7][8] although this would require combination with a suitable partner drug with antimalarial activity.
This open label, adaptive, phase IIa study was designed to evaluate the efficacy, safety, tolerability, and pharmacokinetics of a single 120-mg dose of MMV390048 in adult patients with uncomplicated malaria. The study was conducted between October 6, 2017 and January 5, 2018 at two hospitals in Ethiopia (in Gondar and Jimma). Recruitment was suspended on December 4, 2017 to allow assessment of a teratogenicity signal in a concurrent investigation in rodents. 9 Although approval to restart the study was obtained in August 2019, the study was terminated on October 21, 2020 for operational reasons related to the coronavirus 2019 pandemic and because of the teratogenic findings. Herein, we briefly describe the study design and report the abbreviated dataset on the eight enrolled patients.
The study protocol was approved by the independent Ethics Committees of the College of Public Health and Medical Sciences, Jimma University (now the Institute of Health Institutional Review Board), the Institutional Review Board of the University of Gondar, Ethiopia, and the Ethiopian National Research Ethics Review Committee and Ethiopian Food and Drug Administration, Addis Ababa, and was registered with ClinicalTrials.gov (NCT02880241). Study conduct conformed to the national regulatory requirements of Ethiopia and the Declaration of Helsinki.
Planned enrollment was for three P. vivax and three P. falciparum cohorts of 17 patients each (102 patients in total). MMV390048 was supplied as 20-mg tablets (Medicines for Malaria Venture, Geneva, Switzerland). The first P. vivax and P. falciparum cohorts were to receive a single 120-mg oral dose of MMV390048 in the fasted state, with de-escalating dosing of subsequent cohorts determined by the results obtained. Four patients were to be enrolled into the P. vivax arm and followed until day 14 before enrolment into the P. falciparum arm was to begin, dependent on an acceptable review by the safety review team.
Eligible patients were adults aged 18-55 years, weighing 40-90 kg with microscopically confirmed P. vivax or P. falciparum monoinfection (1,000-40,000 asexual parasites per microliter of blood), fever or history of fever within the previous 48 hours for P. vivax and 24 hours for P. falciparum, and no signs or symptoms of severe or complicated malaria. Patients were admitted and received a single oral dose of 120-mg MMV390048 on day 0 and remained as inpatients until day 3 and two consecutive negative parasite assessments. Outpatient follow-up visits were made on days 7, 10/11, 14, 17/18, 21, 24/25, and 28. Rescue therapy for P. vivax was chloroquine. At the time of the study start, primaquine was not the standard of care in Ethiopia for patients living in malaria endemic regions. However, primaquine radical cure was administered to six of eight patients at the investigator's discretion after a negative glucose-6-phosphate dehydrogenase test.
Giemsa-stained thick and thin blood films for parasite identification and enumeration were prepared using standard methods. 10 Species-specific Pf_ and Pv_18S rRNA quantitative polymerase chain reaction (qPCR) was consistent with published protocols. 11 MMV390048 plasma concentrations were determined using a validated assay and analyzed using non-compartmental methods. 7,8 Adverse events were coded according to MedDRA version 23.0.
The primary outcome for P. vivax malaria was unadjusted ACPR at day 14, defined as complete clearance of microscopically detected parasitemia without previous treatment failure. This enabled a rapid readout of clinical efficacy (i.e., early treatment failure) and safety for dose adjustment of subsequent cohorts and progression to enrolment of the P. falciparum arm. Secondary efficacy outcomes for P. vivax were ACPR and recurrence rate at day 28. Safety outcomes included the frequency of adverse events up to day 35, and signs and symptoms of malaria up to day 28. Parasite clearance kinetics and MMV390048 pharmacokinetics were also planned analyses. Summary statistics were prepared for efficacy and safety data; no inferential statistical analysis was performed for this abbreviated dataset.
The eight enrolled patients were males, self-defined as black, mean age 24.5 years (range 20-50 years), with a mean (SD) body mass index of 18.1 (1.2) kg/m 2 . All were infected with P. vivax malaria with a mean (SD) pre-dose asexual parasite count of 6,406 (6767) parasites/mL.
The primary endpoint of ACPR at day 14 was 100% (8/8). Asexual parasites were cleared by 24 hours postdose in four patients, by 48 hours in two patients, and by 66 hours in the remaining two patients (Figure 1). All patients remained parasite free until day 14. Recurrent P. vivax infection was reported in two patients (days 20 and day 28), both of whom received primaquine. A new P. falciparum infection was detected on day 22 in one patient (no primaquine). Thus, ACPR at day 28 was 62.8% (5/8) in the modified intention-to-treat analysis, and 71.4% (5/7) when the patient with the new P. falciparum infection was excluded.
Gametocytes were detected in all patients at baseline and were cleared by 24 hours postdose in four patients, by 30 hours in two patients, and by 78 hours in two patients ( Figure  1). Gametocytes were detectable in the two patients with P. vivax recurrence on days 20 and 28.
Using qPCR, parasite clearance was achieved between 20 and 161 hours (Figure 1), with three recurrences detected  (days 17, 20, and 22). Overall, MMV390048 rapidly cleared both asexual parasites and gametocytes, although recurrent infections before day 28 suggest that greater drug exposure is needed to maintain efficacy, particularly in patients with high baseline parasitemia (Figure 1).
MMV390048 pharmacokinetic parameters are shown in Table 1. Although C max (peak plasma concentration) was comparable with studies in healthy volunteers, t 1/2 (estimated elimination phase half-life) and AUC inf (area under the concentration-time curve from 0 hour to infinity) were lower than previously reported (Table 1). 7,8 The reasons for these differences are currently unknown, but drug exposures between patients were highly variable, most likely because of variable bioavailability and the small number of patients available for comparison across the studies. Less likely, but observed for some other antimalarials, are the possible effects on drug metabolism of inflammation caused by P. vivax infection 12-14 and pharmacogenetic differences. 15,16 There were no deaths, serious adverse events, or adverse events leading to study discontinuation. A total of 27 adverse events were reported during the study across all eight patients ( Table 2). All adverse events were grade 1 (mild); headache and abdominal discomfort were most commonly reported ( Table 2). Seven drug-related adverse events were reported in four patients: abdominal discomfort, abdominal pain, constipation, dyspepsia, headache, neutropenia, and decreased hemoglobin.
There were three adverse events of special interest occurring in two patients. One patient had neutropenia, considered possibly drug related. This event started on day 2 (baseline neutrophil count 3.39 3 10 9 /L; 0.97 3 10 9 /L on day 2) and spontaneously resolved by day 6 and was concurrent with an upper respiratory tract infection that started on day 3. One patient had sinus tachycardia on day 1 that resolved the same day and was considered related to malaria infection. This patient also had decreased hemoglobin on day 2 (baseline 13.9 g/dL; 11.8 g/dL on day 2) that had resolved by day 6 and was considered related to drug treatment and malaria infection.
Clinical laboratory tests showed no drug-related trends. Baseline low platelet and hemoglobin levels, consistent with malaria infection, tended to improve throughout the study. There were no other safety concerns.
In summary, a single oral dose of 120-mg MMV390048 rapidly cleared asexual parasites and gametocytes in eight male patients with P. vivax malaria. ACPR was 100% at day 14, but with recurrent P. vivax infection in two patients (days 20 and 28). MMV390048 drug exposures were lower than expected based on previous findings in healthy volunteers. There were no safety or tolerability concerns with MMV390048 administration. Tesfa Delelegn. The contributions of Helen Demarest, Susan Podmore, and Charles Stoyanov for additional support in study management are acknowledged. We thank the Swiss Tropical Public Health Institute and Harald Noedl for their contributions to laboratory training during the study and Martina Wibberg of DATAMAP GmbH for statistical support. Naomi Richardson of Magenta Communications, funded by Medicines for Malaria Venture, wrote the first draft of this article and provided editorial and graphic services. The authors confirm that all ongoing and related trials for this drug/intervention are registered (#NCT02880241).This trial is registered at ClinicalTrials.gov (#NCT02880241, https://clinicaltrials.gov/ct2/show/NCT02880241).
Financial support: The study was funded, designed, conducted, and analyzed by Medicines for Malaria Venture. Medicines for Malaria Values are geometric mean (coefficient of variation), except for T max , which is median (range). AUC inf 5 area under the concentration-time curve from 0 hour to infinity; AUC last 5 area under the concentration-time curve from 0 hour to the last measured time point; C max 5 peak plasma concentration; t 1/2 5 estimated elimination phase half-life; T max 5 time point at which peak plasma concentration is reached.
* The reported t 1/2 in this study was median (range).