Scoping Review of Antimalarial Drug Candidates in Phase I and II Drug Development

ABSTRACT The emergence and spread of parasite resistance to currently available antimalarials has highlighted the importance of developing novel antimalarials. This scoping review provides an overview of antimalarial drug candidates undergoing phase I and II studies between 1 January 2016 and 28 April 2021. PubMed, Web of Science, Embase, clinical trial registries, and reference lists were searched for relevant studies. Information regarding antimalarial compound details, clinical trial characteristics, study population, and drug pharmacokinetics and pharmacodynamics (PK-PD) were extracted. A total of 50 studies were included, of which 24 had published their results and 26 were unpublished. New antimalarial compounds were evaluated as monotherapy (28 studies, 14 drug candidates) and combination therapy (9 studies, 10 candidates). Fourteen active compounds were identified in the current antimalarial drug development pipeline together with 11 compounds that are inactive, 6 due to insufficient efficacy. PK-PD data were available from 24 studies published as open-access articles. Four unpublished studies have made their results publicly available on clinical trial registries. The terminal elimination half-life of new antimalarial compounds ranged from 14.7 to 483 h. The log10 parasite reduction ratio over 48 h and parasite clearance half-life for Plasmodium falciparum following a single-dose monotherapy were 1.55 to 4.1 and 3.4 to 9.4 h, respectively. The antimalarial drug development landscape has seen a number of novel compounds, with promising PK-PD properties, evaluated in phase I and II studies over the past 5 years. Timely public disclosure of PK-PD data is crucial for informative decision-making and drug development strategy.

of published studies were then retrieved by one author (A.N.A.-R.) and reviewed for inclusion. Studies that did not satisfy the eligibility criteria were excluded and classified according to reason for exclusion.
Data charting process. One author (A.N.A.-R.) extracted the relevant information from eligible studies using a standardized form. The design of this extraction form was initially piloted by three authors (A.N.A.-R., R.J.C., and S.Z.) for six compounds and refined with input from all coauthors.
Data items. The data on antimalarial compound details (compound name, dose, route of administration), clinical trial characteristics (registration number, phase, status, country), study population, sample size, PK, and parasite clearance information were extracted for each study by a single author (A.N.A.-R.). Extracted values were recorded in standard units.
Synthesis of results. Data were explored using narrative analysis. Studies were organized and described by type of therapy (monotherapy or combination therapy), status of antimalarial compounds in drug development pipeline, and data availability. A narrative synthesis of PK-PD parameter estimates of new antimalarial compounds was also performed.
Search results. Approximately 652 studies were returned from the database and clinical trial registry search (Fig. 1). After removing duplicates (n = 182), 470 studies were screened by titles and abstracts. Following the screening process, 406 studies were excluded for reasons detailed in Fig. 1. Studies that did not meet eligibility criteria were excluded after full-text review (n = 22). An additional eight studies were identified by cross-referencing. As a result, 50 studies were included in this review.
Characteristics of included studies. There were 27 phase I, 20 phase II, and 3 combined phase I and II studies for 31 antimalarial drug candidates. Of the included studies, 24 had published their results, while the remaining 26 were not published. For the unpublished studies, 12 had completed the recruitment, 6 were in the process of recruiting, 3 were terminated, 2 were withdrawn, 2 had not started recruitment, and the status of 1 study was unknown (Table 1). Key information of published studies is presented in Table 2. The phase I studies enrolled between 6 and 72 participants, and the phase II studies recruited 8 to 437 participants.
A total of 14 new antimalarial compounds were identified, 9 of which are in phase II ( Table 3). The majority of these compounds have activity against asexual blood stages of Plasmodium (target candidate profile 1 [TCP-1], 13 compounds). Some of the compounds concomitantly have activity against parasite gametocytes (TCP-5, 9 compounds), hepatic schizonts (TCP-4, 5 compounds), and hypnozoites (TCP-3, 1 compound). Ten compounds exert their antimalarial activity via seven different mechanisms of action, while the mode of action of another four compounds is not well understood. Compounds that inhibit P. falciparum P-type ATPase (PfATP4), such as cipargamin, GSK3191607, and (1)-SJ000557733, were the most frequently studied (n = 7).
Combination therapy studies of antimalarial drug candidates. Antimalarial drug candidates as combination therapies were evaluated in nine published and completed, unpublished studies (30)(31)(32)(33)(34)(35). Almost half of these studies were conducted in Australia (n = 4). Of these studies, four involved healthy volunteers (34,35), two were undertaken in IBSM subjects (32), and the remaining three recruited malaria patients (31,33). P. falciparum was the only parasite species investigated in IBSM subjects and malaria patients. Of studies involving malaria patients, two were carried out in both adults and children (31) and one in adults (33).
Ten different combination therapies were identified (Table 3). Of these, combinations of two compounds were evaluated in six studies (31)(32)(33)(34). The remaining three studies investigated triple antimalarial combination therapies (30,35). Most of the studies (n = 8) examined the combination of one new antimalarial drug candidate with an on-market compound(s). Only two studies examined a combination of new antimalarial drug candidates. Five nonartemisinin-based combination therapies (non-ACT) were tested in five studies. Artefenomel was frequently investigated as a non-ACT, in combination with DSM265 (32), piperaquine (31), and ferroquine (unpublished). ACTs were examined in four studies, four of which were triple antimalarial combination therapies (30,35).
Status of antimalarial drug candidates in the phase I and II drug development pipeline. The status of antimalarial drug candidates in the phase I and II drug development pipeline is summarized in Table 3. As of 28 April 2021, the antimalarial drug development landscape includes 25 antimalarial drug candidates, of which 14 are active and the remaining 11 are inactive for reasons given in Table 3. Of the 14 confirmed active projects, 8 have been evaluated as monotherapies and another 6 as combination therapies. Although the status of ACT-451840 is active, there has been no progress reported for the last 2 years. The reasons for an inactive status included insufficient      Antimalarial compounds listed are from published and unpublished, completed studies as well as studies that were in the process of recruiting subjects between 1 January 2016 and 28 April 2021. b Asexual blood stages, TCP-1; relapse prevention, TCP-3; transmission reduction, TCP-5 and TCP-6; causal prophylaxis, TCP-4.
d As solid dispersion formulation. e PfATP4, P. falciparum P-type ATPase; PfDHODH, P. falciparum dihydro-orotate dehydrogenase; PfeEF2, P. falciparum translational elongation factor 2; PfPI4K, P. falciparum phosphatidylinositol-4-kinase; PfGR, P. falciparum glutathione reductase; JAK, Janus-associated kinases; DHA, dihydroartemisinin; PK-PD, pharmacokinetics-pharmacodynamics. efficacy level (n = 6), formulation challenge (n = 3), short half-life for development of an oral single-dose cure (n = 1), and concern about the rise of resistance (n = 1). Data availability. Detailed summaries of PK-PD data were available from 24 openaccess published manuscripts for 17 antimalarial drug candidates, with 1 study also providing deidentified individual participant data (IPD) (23). In addition to summaries of PK-PD data, deidentified IPD can be requested through the Clinical Study Data Request repository (n = 1) (25) or by contacting the corresponding authors (n = 2) (28,29). Of 12 completed, unpublished studies, deidentified IPD sharing was available for three studies through the Clinical Study Data Request repository or stated by the investigators as available upon reasonable request. Results were also posted on clinical trial registries for four completed, unpublished studies.
This scoping review presents a systematic overview of antimalarial drug candidates that have undergone phase I and II studies in the past 5 years. In this review, we have identified 50 studies, and evidence regarding studies investigating antimalarial drug candidates used as monotherapy and combination therapy, status of antimalarial drug candidates in the drug development pipeline, and data availability were synthesized from 37 published and completed, unpublished studies. It reveals that 14 antimalarial compounds were tested as monotherapy, and 10 different antimalarial combinations were investigated. It highlights that 14 antimalarial candidates are currently active in the drug development pipeline, with detailed summaries of the PK and PD data available for 24 studies.
While almost all published and completed, unpublished studies investigated antimalarial drug candidates for clearance of asexual blood stages (TCP-1), only nine and three studies evaluated compounds with concomitant hepatic schizonticide (TCP-3) and both hepatic schizonticide and hypnozoiticide (TCP-3 and TCP-4) activities, respectively. Although the blood-stage infection is responsible for clinical symptoms, targeting liverstage parasites presents a promising strategy for malaria eradication, as this stage is a crucial checkpoint in the parasite life cycle. The lack of efficient high-throughput screening assays contributes to the limited development of antimalarial drug candidates against liver schizonts and hypnozoites (38,39). Beyond liver stages, targeting parasite transmission is another critical step toward malaria eradication. Transmission blocking is achieved either by targeting the mosquito vector (TCP-5) or sexual blood stages (TCP-6). Although concomitant endectocidal activity was not tested in the studies examining compounds, concomitant gametocytocidal or transmission-blocking activity had been characterized in 25 studies testing compounds (40).
Ideally, a combination of at least two antimalarial compounds administered as a single dose should clear asexual blood stages, block transmission, and eliminate hepatic schizonts, including hypnozoites (single-exposure radical cure and prophylaxis [SERCaP]). Achieving cure with a single-dose cure would decrease the cost of treatment and allow directly observed administration, thus ensuring compliance. However, none of the new compounds given as monotherapy were predicted to lead to complete clearance of all asexual and sexual stage parasites with a single dose (10), requiring repeated administration for a complete cure. Therefore, this ambitious target product profile may require multiple exposures of two compounds or a single exposure of three or more antimalarial combinations (10). We found two-thirds of the published and completed, unpublished studies investigated administration of the drug as a monotherapy. Initially characterizing the PK-PD relationship from monotherapy studies is important for guiding dose optimization before being deployed as a combination therapy. Information on contribution of individual drugs and their interactions (i.e., on drug concentration, parasite growth and killing, or both) derived from monotherapy and combination studies is a prerequisite for defining rational dosing regimens of antimalarial combinations (41)(42)(43)(44).
Our findings suggest that the current antimalarial drug development pipeline mirrors those of infectious diseases in general. Of 25 projects, 14 were active over the last 5 years. This number is comparable to the success rate of phase I and II for anti-infective medicines (38.4 to 70.1%) (45,46) and antimalarial compounds in the Medicines for Malaria Venture (MMV) discovery portfolio (60 to 70%) (10). The percentage of antimalarial drug candidates that progress from phase I and II studies to successful product registration ranged from 16% to 30% (10), consistent with the likelihood of approval from phase I and II for infectious diseases (13.2 to 22.8%) (46). Half of the inactive compounds in this review have been associated with poor efficacy where the cure rate at day 28 ranged from 59 to 91% with a single dose (24,29,31). These cure rates did not achieve the target efficacy of .95% (10). A similar percentage (48%) was observed for phase II clinical trial failure attributable to efficacy issues between 2013 and 2015 (47).
Given the importance of PK-PD characterization for dose optimization, we have included information on data availability and provided the estimated PK and PD parameters. We identified 25 open-access published manuscripts that provided detailed summaries of PK-PD data. In addition, the findings of four studies have been posted on clinical trial registries. The World Health Organization has outlined the timeline for submission of main findings to be published in a peer-reviewed, open-access journal within 12 to 24 months after completing the trial (https://www.who.int/clinical-trials-registry-platform/ reporting-on-findings). Additionally, it is also required to report the key outcomes on the clinical trial registry within 12 months after completion of the trial (https://www.who.int/ clinical-trials-registry-platform/reporting-on-findings). Open-access availability of data in the public domain maximizes the benefit of these data to the scientific community. In addition, many government and philanthropic funders require, as a condition of support, that raw data be made available to the scientific community. To the best of our knowledge, there is no repository of PK-PD data of antimalarial drug candidates under investigation in phase I and II studies. We took the initiative to collate this information to help generate insights on how these antimalarial compounds compare against TCP criteria and current therapies.
All of the new antimalarial compounds in these published studies have a long duration of action, with an elimination t1 =2 ranging from 14.7 to 483.9 h. This is a significant improvement over the short elimination t1 =2 of artemisinin derivatives ( [50]). This is to be expected, as compounds in development have been selected based on their ability to maintain therapeutic concentrations for at least 4 days (10). These values are consistent with the elimination t1 =2 of amodiaquine (12.4  There are several limitations of our review that warrant care in the interpretation of the findings. Although we made every effort to collate PK-PD data for antimalarial drug candidates undergoing phase I and II investigation, our findings may be impacted by data unavailability due to the delay between study completion and publication. This was mitigated by extracting study results posted on clinical trial registries. Database and clinical trial registry searching was limited to the last 5 years on the basis of the average duration spent by anti-infectives in phase I and II (46). Hence, PK-PD data before this period were not included in this review; such historical data may be valuable in providing additional knowledge of the compounds. Clinical trial registry information such as recruitment status are not updated regularly, which may affect our findings. In one study, it was reported that 31% of clinical trials either had incorrect listed recruitment status or had a delay of recruitment status update of over 1 year (59). We addressed this by checking the date of last update on trial registries and providing a statement if the study status has not been updated for more than 2 years. Study status was not updated for more than 2 years in three studies; these constituted only a small percentage of the included studies (6%). It must be noted that sample sizes of the included studies were small, and the majority of the PK parameter estimates were derived from noncompartmental analysis. Because antimalarial drugs are often reported to have multiple-compartment kinetics, the compound concentration may have declined rapidly to a value below the concentration at half of the maximum effect (EC 50 ) before the elimination phase, making it difficult to assess the drug's potential effect. This was investigated by comparing the compound concentration at the start of the elimination phase and its EC 50 (reported by the authors or from in vitro studies). We found that the compound concentration reached the EC 50 in 68% of the studies before being eliminated, and we were unable to infer for 29% of the studies due to insufficient information. Another limitation is related to the use of PCt1 =2 as a PD measure. In addition to the effect of the drug, host-acquired immunity is an important factor that influences parasite clearance. However, the contribution of immunity on parasite clearance is relatively small, with a maximum shortening of PCt1 =2 values ,40 min (60). Moreover, 71% of the included studies that reported PCt1 =2 were conducted in volunteer-infected studies where acquired immunity plays little or no role. Cytoadherence could also influence the interpretation of the parasite clearance curve following treatment with antimalarial drugs which do not kill ring-form parasites (44). Most of the compounds that reported parasite clearance information in this scoping review have a broad-spectrum activity against blood-stage parasites. Additionally, other measures such as PRR were also used to capture the PD response of antimalarial drugs. PRR cancels out the effect of cytoadherence, as the parasite populations were assessed at the same stages of development separated by one cycle (44).
Conclusions. The need for antimalarial compounds with novel modes of action has become a high priority in drug development due to the emergence of multidrug-resistant malaria. The last 5 years have seen a number of antimalarial drug candidates being investigated as monotherapy and in combination with other antimalarial therapies. Some of these compounds have demonstrated promising PK-PD properties, with 14 compounds currently active in the antimalarial drug development landscape. Given that PK-PD data from phase I and II studies are informative for streamlining the progress of antimalarial compounds to the next phase, timely public disclosure of these data is paramount.

SUPPLEMENTAL MATERIAL
Supplemental material is available online only. We declare no conflict of interests.