Abstract
Background
Dengue is a growing global health threat with no specific antiviral drugs available for treatment or prophylaxis. This first-in-human, double-blind, randomized, placebo-controlled study aimed to examine the safety, tolerability, and pharmacokinetics of increasing single and multiple oral doses of JNJ-1802, a pan-serotype dengue antiviral small molecule.
Methods
Eligible healthy participants (18–55 years of age) were randomized to receive oral JNJ-1802 in fasted conditions as (1) single doses (50–1200 mg; n = 29) or placebo (n = 10); or (2) once-daily doses (50–560 mg for 10 consecutive days or 400 mg for 31 days; n = 38) or placebo (n = 9). Safety and tolerability were evaluated throughout the study. Plasma and urine samples were collected at predetermined time points to characterize pharmacokinetics.
Results
JNJ-1802 was generally safe and well-tolerated. One grade 3 adverse event (depression) was reported but not considered drug-related by the investigator. Two grade 2 events of rash occurred (multiple-dose part) that were considered very likely related to JNJ-1802 by the investigator and resolved. No clinically relevant changes were observed in laboratory tests, electrocardiograms, or vital signs.
JNJ-1802 exposure after single or multiple doses increased dose-proportionally from 50 to 150 mg and less than dose-proportionally for higher doses. The terminal elimination half-life was 6.3–9.2 days and the accumulation factor was 4.3–7.3 after 10 days and 14.6 after 31 days with low amounts of unchanged drug in urine (<0.001% of the 400 mg dose).
Conclusions
Pharmacokinetics and safety results of JNJ-1802 support further clinical development for the treatment and prevention of dengue infection.
Keywords: dengue, antiviral small molecule, pan-serotype, first-in-human, dose-escalation
This first-in-human, double-blind, randomized, placebo-controlled study demonstrates that increasing single and multiple oral doses of JNJ-1802, a pan-serotype dengue antiviral small molecule, are generally safe and well-tolerated. Pharmacokinetics and safety results support further clinical development for treatment/prevention of dengue infection.
Dengue can be caused by any of the 4 antigenically distinct dengue virus (DENV) serotypes (DENV1–4) when transmitted through the bite of an infected female mosquito of the genus Aedes. The spread of the vector is anticipated to intensify due to urbanization and climate change, exposing an estimated 60% of the world's population to the risk of dengue in 2080 [1]. About 400 million DENV infections occur globally each year, of which 100 million manifest clinically [2]. Most dengue infections are asymptomatic and numbers of dengue cases are underreported [3]. Each year about 500 000 dengue cases require hospitalization due to severe and life-threatening disease and up to 25 000 patients die due to dengue [4]. Once bitten by a DENV-infected and viremic mosquito, clinical symptoms appear within 3–7 days followed by defervescence and resolution of infection within 3–7 days [5]. A proportion of patients with symptomatic dengue develop severe dengue with outcomes such as intravascular volume depletion, end organ damage, and the potential for coagulation disruption and hemorrhage contributing to shock [5]. Treatment is generally supportive as no dengue-specific therapy exists. Efforts to develop antivirals specific for the treatment or prevention of dengue have been challenging, as exemplified by the discontinuation of various drug discovery programs [6–8]. We recently published data about JNJ-1802 demonstrating that the molecule has picomolar to nanomolar pan-serotype in vitro potency against a representative DENV genotype panel and showed in vivo efficacy in mouse and nonhuman primate (NHP) models [9]. JNJ-1802 blocks formation of the viral replication by inhibiting complex formation between 2 viral proteins, nonstructural protein 3 (NS3) and NS4B, thus preventing formation of new viral RNA [9].
Primary objectives of this first-in-human study included investigating the safety and tolerability of JNJ-1802 in healthy participants after single or multiple oral doses in fasted conditions. Secondary study objectives were to investigate the pharmacokinetics (PK) of JNJ-1802 in healthy participants after single and multiple oral doses in fasted conditions.
METHODS
Study Design and Participants
This double-blind, randomized, placebo-controlled phase 1 first-in-human study was conducted between October 2018 and June 2019 in 1 center in Belgium and included healthy participants 18–55 years of age.
In the single-dose phase (part 1), 39 eligible healthy participants were randomized 3:1 (planned 6 active, 2 placebo per cohort) to receive oral JNJ-1802 single doses (50–1200 mg; n = 29) or placebo (polyethylene glycol 400 [PEG400]; n = 10) in fasted conditions (Supplementary Figure 1). The JNJ-1802 dose started at 50 mg (cohort 1) and was escalated to doses of 150 mg (cohort 2), 400 mg (cohort 3) and 1200 mg (cohort 4), based on the totality of the safety, tolerability, and PK data collected prior to starting a new study cohort/dose. To further characterize the dose proportionality, an intermediate dose of 240 mg (cohort 5) was included (Supplementary Figure 1).
In the multiple-dose part (part 2), 47 eligible healthy participants were randomized 4:1 (planned 8 active, 2 placebo per cohort) to receive JNJ-1802 once daily (50–560 mg for 10 consecutive days or 400 mg for 31 days; n = 38), or placebo (n = 9) in fasted conditions. The JNJ-1802 dose was escalated with once-daily (QD) doses of 50 mg (cohort 7), 150 mg (cohort 8), 400 mg (cohort 9), and 560 mg (cohort 10). In cohort 11, 7 participants received 400 mg QD JNJ-1802 and 2 participants received placebo for 31 days (Supplementary Figure 1). Dose selection in the different cohorts was based on the totality of the safety, tolerability, and PK data collected prior to starting a new study cohort/dose escalation.
The study consisted of a screening phase, study drug administration phase, and safety follow-up period until 30–35 days (due to observed long half-life of JNJ-1802) after last study drug intake. More details about randomization, blinding, and the full inclusion and exclusion criteria are listed in the Supplementary Text.
The study was conducted in accordance with Good Clinical Practice guidelines and applicable regulatory requirements outlined in the Declaration of Helsinki. Written informed consent was obtained from each participant prior to any study-related activities. The study protocol and informed consent form were reviewed and approved by an independent ethics committee.
Study Drug Composition
JNJ-1802 was provided as a 250 mg/vial and a 4000 mg/vial containing white to off-white powder. JNJ-1802 was reconstituted for oral use with a diluent (PEG400) to obtain 25 mL of a 10 or 160 mg/mL oral solution. PEG400 also served as placebo for parts 1 and 2 of the study.
Safety Analysis
All individuals who were enrolled and received at least 1 dose of the study drug were included in the safety and tolerability analysis. Adverse events (AEs), serious AEs (SAEs), treatment-emergent adverse events (TEAEs, defined as AEs occurring during the treatment phase), clinical laboratory tests, electrocardiographic monitoring, vital signs, and physical examinations were evaluated throughout the study period or until the participant had been deemed lost to follow-up. All AEs were followed by the investigator until satisfactory resolution or a clinically stable endpoint. Blood samples for biochemistry, blood coagulation, and hematology were collected at predefined time points. Laboratory abnormalities were determined according to the criteria specified in the World Health Organization Toxicity Grading Scale and in accordance with the normal ranges of the clinical laboratory if no gradings were available.
Pharmacokinetic Evaluation
Venous blood samples were collected for measurement of plasma concentrations of JNJ-1802, and full PK profiles were determined in part 1 of the study within 2 hours predose and 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, 72, 96, and 120 hours after study drug intake and at 10–14 days and 30–35 days after study drug intake. In part 2 of the study, blood was taken on day 1 within 2 hours before study drug intake and 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, 72, 96, and 120 hours after study drug intake and at 10–14 days and 30–35 days after study drug intake. Plasma concentrations of JNJ-1802 were determined using a validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) method. For the assessment of the urinary excretion of JNJ-1802, urine samples were collected in part 1 within 3 hours predose and during intervals 0–6, 6–12, 12–24, 24–36, 36–48, 48–72, 72–96, and 96–120 hours after study drug intake. In part 2 of the study, urinalysis samples were collected at screening, on day –1, on day 1 (4 hours [morning] postdose), predose (in the morning) on day 3, on day 10 (predose and 4 hours postdose), on day 11 (24 hours postdose), on day 15 (120 hours postdose), and at follow-up. Predose samples were taken within 3 hours before study drug intake. Urine JNJ-1802 concentrations were determined using a qualified research LC-MS/MS method.
Pharmacokinetic Analysis
All participants who received at least 1 dose of JNJ-1802 and who had at least 1 PK parameter value were included in the PK analysis. All participants who received at least 1 dose of study drug and had at least 1 plasma concentration data value after administration were included in the descriptive statistics. PK (noncompartmental analysis; model type: plasma [200–202], dose type: extravascular) and statistical analyses were done using the validated computer program Phoenix WinNonlin (version 6.2.1, Tripos LP). Furthermore, SAS software (version 9.3, SAS Institute, Cary, North Carolina) was used predominantly for the creation of PK tables and figures in addition to calculation of treatment ratios and dose-normalized PK parameters. Descriptive statistics (sample size [number], mean and standard deviation, median and range) were calculated for continuous variables where appropriate.
Statistical Analysis
As this was a first-in-human study and no clinical data were available for JNJ-1802, no formal sample size determination and power calculations were performed at setup of the study.
RESULTS
Characteristics of the Study Participants
In the single-dose phase (part 1), all 39 randomized participants completed the treatment regimen and the study. In the multiple-dose phase (part 2), all 47 randomized participants completed the study treatment, and 45 (95.7%) participants completed the study including the follow-up period. The 2 participants in part 2 who discontinued the study withdrew consent during the follow-up period.
Most participants were White (part 1, 39 [100%]; part 2, 44 [93.6%]) and male (part 1, 33 [84.6%]; part 2, 45 [95.7%]) with a median age of 49 years in part 1 and 44 years in part 2, and a median body mass index of approximately 25.0 kg/m2 across both study parts. Demographic data were comparable across all treatment groups in each study part (Table 1). All participants were included in the safety analysis and 1 participant from part 1 was excluded from the PK analysis due to the AE “vomiting,” which occurred approximately 3 hours after study drug intake and thus within 2 times the median time to reach the maximum plasma concentration (tmax).
Table 1.
Demographic Characteristics of Study Participants (Safety Analysis Set)
| Characteristic | JNJ-1802a | ||||||
|---|---|---|---|---|---|---|---|
| Part 1 (Single Dose) | Placebo (n = 10) |
50 mg (n = 6) |
150 mg (n = 5) |
240 mg (n = 6) |
400 mg (n = 6) |
1200 mg (n = 6) |
Total (N = 39) |
| Age, y, median (range) | 49.5 (24–55) | 42.5 (28–50) | 51.0 (23–55) | 52.5 (37–55) | 46.5 (32–55) | 48.5 (25–52) | 49.0 (23–55) |
| Male sex, No. (%) | 7 (70.0) | 5 (83.3) | 4 (80.0) | 5 (83.3) | 6 (100.0) | 6 (100.0) | 33 (84.6) |
| BMI at baseline, kg/m², median (range) | 24.8 (20.2– 27.6) | 26.1 (22.7– 29.6) | 23.3 (20.0– 28.7) | 26.5 (22.8– 29.3) | 24.7 (23.4– 26.9) | 27.6 (19.4– 29.0) | 25.1 (19.4– 29.6) |
| Weight at baseline, kg, median (range) | 73.0 (56.3– 98.2) | 84.1 (70.8– 98.0) | 67.8 (61.3– 81.5) | 82.2 (72.7– 91.0) | 77.9 (72.8– 86.0) | 79.5 (59.0– 99.9) | 79.0 (56.3–99.9) |
| White race, No. (%) | 10 (100.0) | 6 (100.0) | 5 (100.0) | 6 (100.0) | 6 (100.0) | 6 (100.0) | 39 (100.0) |
| Part 2 (Multiple Dose) | 10 d | 31 d | |||||
|---|---|---|---|---|---|---|---|
| Placebo (n = 9) |
50 mg (n = 8) |
150 mg (n = 7) |
400 mg (n = 8) |
560 mg (n = 8) |
400 mg (n = 7) |
Total (N = 47) |
|
| Age, y, median (range) | 34.0 (27–55) | 39.5 (21–55) | 49.0 (35–52) | 46.5 (42–54) | 50.5 (31–54) | 46.0 (24–55) | 44.0 (21–55) |
| Male sex, No. (%) | 9 (100.0) | 8 (100.0) | 7 (100.0) | 7 (87.5) | 8 (100.0) | 6 (85.7) | 45 (95.7) |
| BMI at baseline, kg/m², median (range) | 25.4 (20.0–28.6) | 25.1 (19.6–28.3) | 24.9 (18.7–29.5) | 26.7 (21.3–29.2) | 25.3 (21.4–27.3) | 24.6 (22.5–27.1) | 25.0 (18.7–29.5) |
| Weight at baseline, kg, median (range) | 80.4 (60.0–95.4) | 81.4 (67.3–91.5) | 79.9 (62.4–94.2) | 80.9 (63.4–97.4) | 79.4 (70.2–87.8) | 79.2 (60.1–89.1) | 79.9 (60.0–97.4) |
| Race/ethnicity, No. (%) | |||||||
| American Indian/Alaska Native | 0 | 1 (12.5) | 0 | 0 | 0 | 0 | 1 (2.1) |
| Asian | 0 | 0 | 0 | 0 | 2 (25.0) | 0 | 2 (4.3) |
| White | 9 (100.0) | 7 (87.5) | 7 (100.0) | 8 (100.0) | 6 (75.0) | 7 (100.0) | 44 (93.6) |
Data are presented as No. (%) of participants unless otherwise indicated. The n values indicate the number of participants with available data.
Abbreviation: BMI, body mass index.
All indicated doses refer to JNJ-1802.
Safety Results
In the single-dose part, no deaths, SAEs, AEs leading to study drug discontinuation, or AEs with severity grade of at least 3 were reported (Table 2). No AEs were considered at least possibly related to the study drug by the investigator in participants who received active treatment. In the multiple-dose part, no deaths, SAEs, or AEs leading to study drug discontinuation were reported (Table 2). All TEAEs were of severity grade 1 or 2, except for 1 grade 3 AE (depression) reported for a participant who received 400 mg of JNJ-1802 for 31 days. This grade 3 AE started 5 days after the participant had received the last dose (ie, 36 days after start of treatment) and was considered not related to the study drug by the investigator. All AEs considered at least possibly related to the study drug by the investigator were reported for at most 1 participant on active treatment except for diarrhea (reported in 5 of 7 [71.4%] participants in the 10-day 150 mg JNJ-1802 group, 1 of 8 [12.5%] participants in the 10-day 400 mg JNJ-1802 group, and 2 of 9 [22.2%] participants who received placebo) and rash (drug eruption; reported in 1 of 8 [12.5%] participants in the 10-day 560 mg JNJ-1802 group [starting at day 10 after treatment initiation], 1 of 7 [14.3%] participants in the 31-day 400 mg JNJ-1802 group [starting at day 13 after treatment initiation], and 0 of 9 [0%] participants on placebo). All diarrhea events were mild and resolved within 2–12 days. The rashes resolved 35–47 days or 29‒35 days after multiple-dose treatment stopped. None of the differences in AE incidences between cohorts were considered clinically relevant across both study parts. In both study parts, AEs resolved. None of the observed treatment-emergent laboratory abnormalities were considered clinically significant by the investigator, and none were reported as AEs. No electrocardiogram- or vital signs–related AEs were reported.
Table 2.
Safety Outcomes (Safety Analysis Set)a
| Characteristic | JNJ-1802b | ||||||
| Part 1 (Single Dose) | Placebo (n = 10) |
50 mg (n = 6) |
150 mg (n = 5) |
240 mg (n = 6) |
400 mg (n = 6) |
1200 mg (n = 6) |
All Doses (N = 29) |
|---|---|---|---|---|---|---|---|
| At least 1 AE | 5 (50.0) | 1 (16.7) | 2 (40.0) | 3 (50.0) | 1 (16.7) | 1 (16.7) | 8 (27.6) |
| At least 1 AE leading to temporarily discontinuation of the study drug | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| At least 1 AE leading to permanent discontinuation of the study drug | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| At least 1 AE with grade 1 as worst grade | 5 (50.0) | 1 (16.7) | 1 (20.0) | 2 (33.3) | 1 (16.7) | 1 (16.7) | 6 (20.7) |
| At least 1 AE with grade 2 as worst grade | 0 | 0 | 1 (20.0) | 1 (16.7) | 0 | 0 | 2 (6.9) |
| At least 1 AE with grade 3 as worst grade | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| At least 1 AE thought to be possibly, probably, or very likely related to the study drug | 2 (20.0) | 0 | 0 | 0 | 0 | 0 | 0 |
| Most common AEs | |||||||
| Nervous system disorders | 3 (30.0) | 0 | 0 | 2 (33.3) | 0 | 1 (16.7) | 3 (10.3) |
| Headache | 3 (30.0) | 0 | 0 | 2 (33.3) | 0 | 0 | 2 (6.9) |
| Part 2 (Multiple Dose) | 10 d | 31 d | |||||
|---|---|---|---|---|---|---|---|
| Placebo (n = 9) |
50 mg (n = 8) |
150 mg (n = 7) |
400 mg (n = 8) |
560 mg (n = 8) |
400 mg (n = 7) |
All Doses (N = 38) |
|
| At least 1 AE | 6 (66.7) | 2 (25.0) | 6 (85.7) | 4 (50.0) | 3 (37.5) | 3 (42.9) | 18 (47.4) |
| At least 1 AE leading to temporarily discontinuation of the study drug | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| At least 1 AE leading to permanent discontinuation of the study drug | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| At least 1 AE with grade 1 as worst grade | 5 (55.6) | 1 (12.5) | 5 (71.4) | 2 (25.0) | 2 (25.0) | 1 (14.3) | 11 (28.9) |
| At least 1 AE with grade 2 as worst grade | 1 (11.1) | 1 (12.5) | 1 (14.3) | 2 (25.0) | 1 (12.5) | 1 (14.3) | 6 (15.8) |
| At least 1 AE with grade 3 as worst grade | 0 | 0 | 0 | 0 | 0 | 1 (14.3) | 1 (2.6) |
| At least 1 AE thought to be possibly, probably, or very likely related to the study drug | 4 (44.4) | 0 | 6 (85.7) | 1 (12.5) | 1 (12.5) | 2 (28.6) | 10 (26.3) |
| Most common AEs | |||||||
| Gastrointestinal disorders | 5 (55.6) | 1 (12.5) | 6 (85.7) | 2 (25.0) | 0 | 0 | 9 (23.7) |
| Diarrhea | 3 (33.3) | 0 | 5 (71.4) | 1 (12.5) | 0 | 0 | 6 (15.8) |
Data are presented as No. (%) of participants. The n values indicate the number of participants with available data. Participants are only counted once for any given event, regardless of the number of times they experienced the event. AEs are coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 21.1.
Abbreviation: AE, adverse event.
Summary table of AEs reported during the treatment phase defined as the period between first study drug intake and first follow-up visit (scheduled 10–14 days after last drug intake).
All indicated doses refer to JNJ-1802.
Pharmacokinetic Results
Following single-dose administration with JNJ-1802 (50–1200 mg), formulated as oral solution in fasted conditions, the exposure increased dose-proportionally from 50 to 150 mg and less than dose-proportionally at higher doses up to 1200 mg, based on area under the curve from time 0 to 24 hours postdose (AUC24h) and maximum observed plasma concentration (Cmax) (Table 3 and Figure 1). The median tmax ranged from 7–10 hours. The plasma concentrations followed a biphasic decline with a terminal elimination half-life (t1/2term) ranging from 6.3 to 8.0 days (Table 3 and Figure 1). Overall, mean plasma concentrations, mean Cmax, AUC24h, and AUC from time 0 to infinity (AUC∞) of JNJ-1802 increased with increasing dose, except for the 240 mg dose in cohort 5, which resulted in lower mean values for these parameters than for the 150 mg dose in cohort 2 at all sampling points (Table 3).
Table 3.
Pharmacokinetic Results of JNJ-1802 in the Single-Dose Part (Part 1, Pharmacokinetic Data Analysis Set)
| Pharmacokinetics | JNJ-1802a | ||||
|---|---|---|---|---|---|
| 50 mg (n = 6b) |
150 mg (n = 5) |
240 mg (n = 5) |
400 mg (n = 6) |
1200 mg (n = 6) |
|
| Cmax, ng/mL | 161 (39.6) | 494 (133) | 361 (204) | 702 (213) | 759 (305) |
| tmax, h, median (range) | 8.0 (5.0–8.0) | 7.0 (7.0–12.0) | 10.0 (7.0–12.0) | 9.0 (5.0–12.0) | 8.0 (8.0–10.0) |
| C24h, ng/mL | 76.1 (9.9) | 284 (25.5) | 191 (82.5) | 418 (116) | 518 (212) |
| AUC24h, ng*h/mL | 2509 (481) | 8439 (1524) | 5858 (3022) | 11 891 (3681) | 13 650 (5593) |
| AUC∞, ng*h/mL | 16 190 (3259) | 55 393 (18 257) | 45 723 (24 529) | 74 346 (31 718) | 139 556 (62 275) |
| t1/2term, h | 187.1 (47.6) | 151.9 (59.8) | 192.6 (62.7) | 190.4 (70.9) | 168.4 (35.1) |
| CL/F, L/h | 3.2 (0.6) | 2.9 (0.9) | 7.8 (6.5) | 6.2 (2.5) | 10.3 (4.7) |
| Vdz/F, L | 893 (156) | 584 (43.0) | 1846 (1059) | 1549 (460) | 2500 (1181) |
Data are presented as mean (standard deviation) unless otherwise indicated. The n values indicate the number of participants with available data.
Abbreviations: AUC24h, area under the curve from time 0 to 24 hours postdose, calculated by linear-linear trapezoidal summation; AUC∞, AUC from time 0 to infinity, calculated as AUClast + Clast/λz, where Clast is the last observed measurable (non-below-quantification-limit) concentration; extrapolations of >20.00% of the total AUC are reported as approximations and λz, is the apparent terminal elimination rate constant, estimated by linear regression using the terminal log-linear phase of the log-transformed plasma analyte concentration versus time curve; C24h, observed plasma analyte concentration at 24 hours postdose; Cmax, maximum observed plasma analyte concentration; CL/F, total apparent oral clearance, calculated as dose/AUC∞ after single dose, or as dose/AUCτ at steady-state; t1/2term, apparent terminal elimination half-life, calculated as 0.693/λz; tmax, the actual sampling time to reach the maximum observed plasma analyte concentration; Vdz/F, apparent volume of distribution, calculated as dose/(λz*AUC∞).
All indicated doses refer to JNJ-1802.
n = 5 for AUC∞, CL/F, and Vdz/F.
Figure 1.
Mean plasma JNJ-1802 concentration-time profile of the single ascending oral dose part on a semi-logarithmic scale (part 1, pharmacokinetics data analysis set). JNJ-1802 was administered as a single oral dose at 50 mg (cohort 1), 150 mg (cohort 2), 400 mg (cohort 3), 1200 mg (cohort 4), and 240 mg (cohort 5) under fasted conditions.
Following 10 days of QD administration with JNJ-1802 (50–560 mg), formulated as oral solution in fasted conditions, a (close to) dose-proportional increase in exposure was observed between 50 and 150 mg JNJ-1802, and a less than dose-proportional increase was noted following higher doses up to 560 mg, based on Cmax and AUC from 0 to τ hours (AUCτ; τ = dosing interval, 24 hours) on day 10 (Table 4 and Figure 2). The mean accumulation per cohort ranged from 4.3- to 7.3-fold, based on the individual geometric mean ratio (GMR) of AUCτ on day 10 compared with day 1. Following 31 days of QD administration with 400 mg JNJ-1802, formulated as oral solution, steady-state was reached between 24 and 27 days with a mean accumulation of 14.6-fold, based on the individual GMR of AUCτ on day 31 compared with day 1 (Table 4 and Figure 2). Median tmax was achieved within 9 to 10 hours on day 10 and within 10 hours on day 31. Plasma concentrations showed a biphasic decline with t1/2term ranging from 7.7 to 9.2 days (Table 4). Interparticipant variability was 8.6%–58.1% following single- and multiple-dose administration.
Table 4.
Pharmacokinetic Parameters of JNJ-1802 Following Multiple Doses (Part 2, Pharmacokinetic Data Analysis Set)
| Parameter | JNJ-1802a | ||||
|---|---|---|---|---|---|
| 50 mg, 10 d QD (n = 8) |
150 mg, 10 d QD (n = 7) | 400 mg, 10 d QD (n = 8) | 560 mg, 10 d QD (n = 8) | 400 mg, 31 d QD (n = 7) |
|
| Day 1 | Day 1 | Day 1 | Day 1 | Day 1 | |
| Cmax, ng/mL | 173 (31.8) | 426 (35.5) | 572 (228) | 711 (230) | 580 (144) |
| tmax, h, median (range) | 8.0 (7.0–8.0) | 8.0 (8.0–10.0) | 7.0 (5.0–10.0) | 8.0 (7.0–8.0) | 10.0 (5.0–23.9) |
| Cτ, ng/mL | 92.2 (13.4) | 248 (50.9) | 340 (104) | 434 (121) | 403 (150) |
| AUCτ, ng*h/mL | 2835 (443) | 7193 (672) | 9409 (3330) | 11 945 (3668) | 9492 (2219) |
| Cmax,dn, ng/mL/mg | 3.5 (0.6) | 2.8 (0.2) | 1.4 (0.6) | 1.3 (0.4) | 1.5 (0.4) |
| Cτ,dn, ng/mL/mg | 1.8 (0.3) | 1.7 (0.3) | 0.8 (0.3) | 0.8 (0.2) | 1.0 (0.4) |
| AUCτ,dn, ng*h/mL/mg | 56.7 (8.7) | 48.0 (4.5) | 23.5 (8.3) | 21.3 (6.6) | 23.7 (5.6) |
| Day 10 | Day 10 | Day 10 | Day 10 | Day 31 | |
| Ctrough, ng/mL | 423 (43.0) | 1163 (449) | 2305 (1081) | 3029 (721) | 6009 (2383) |
| Cmin, ng/mL | 407 (47.7) | 1064 (411) | 2158 (1054) | 2693 (568) | 5387 (2264) |
| Cmax, ng/mL | 642 (60.9) | 1671 (739) | 3510 (1655) | 4070 (960) | 6813 (2735) |
| tmax, h, median (range) | 9.0 (8.0–12.0) | 10.0 (7.0–24.0) | 10.0 (6.0–12.0) | 10.0 (7.0–12.0) | 10.0 (8.0–12.0) |
| Cτ, ng/mL | 465 (56.4) | 1406 (817) | 2504 (1088) | 3224 (595) | 5906 (2644) |
| AUCτ, ng*h/mL | 12 586 (1087) | 32 853 (13 391) | 67 141 (29 115) | 82 722 (16 824) | 144 899 (59 267) |
| Cavg,ss, ng/mL | 524 (45.3) | 1369 (559) | 2794 (1210) | 3436 (696) | 6038 (2468) |
| FI, % | 44.9 (9.6) | 43.4 (8.4) | 47.7 (7.3) | 39.8 (9.9) | 24.4 (4.1) |
| CL/F, L/h | 4.0 (0.3) | 5.2 (2.0) | 6.9 (2.7) | 7.0 (1.3) | 3.2 (1.2) |
| λz, L/h | 0.00406 (0.00195) | 0.00441 (0.00196) | 0.00391 (0.00111) | 0.00330 (0.000816) | 0.00415 (0.00154) |
| t1/2term, h | 203.7 (85.5) | 185.1 (73.4) | 189.4 (50.4) | 221.6 (54.4) | 188.1 (69.3) |
| Cmax,dn, ng/mL/mg | 12.8 (1.2) | 11.1 (4.9) | 8.8 (4.1) | 7.3 (1.7) | 17.0 (6.8) |
| Cτ,dn, ng/mL/mg | 9.3 (1.1) | 9.4 (5.5) | 6.3 (2.7) | 5.8 (1.1) | 14.8 (6.6) |
| AUC.τ.,dn, ng*h/mL/mg | 252 (21.7) | 219 (89.3) | 168 (72.8) | 148 (30.0) | 362 (148) |
| Fold change Cmax, Day x/Day 1b | 3.8 (0.7) | 3.9 (1.4) | 6.7 (3.1) | 6.8 (4.5) | 11.7 (3.2) |
| Fold change Cτ, Day x/Day 1b | 5.1 (0.6) | 5.4 (1.9) | 7.6 (2.6) | 8.2 (3.7) | 15.3 (6.4) |
| Fold change AUCτ, Day x/Day 1b | 4.5 (0.6) | 4.5 (1.4) | 7.5 (2.9) | 8.1 (5.1) | 15.2 (4.6) |
Data are presented as mean (standard deviation) unless otherwise indicated. The n values indicate the number of participants.
Abbreviations: AUCτ, area under the plasma concentration-time curve from 0 to τ hours (τ = dosing interval, 24 hours); Cavg, ss, average plasma concentration at steady-state over the dosing interval; CL/F, total apparent oral clearance; Cmax, maximum observed plasma analyte concentration; Cmin, minimum plasma concentration; Cτ, observed plasma concentration at τ hours (τ = dosing interval, 24 hours); Ctrough, observed plasma analyte concentration just prior to the beginning of a dosing interval; dn, dose-normalized; FI, percentage fluctuation; λz, apparent terminal elimination rate constant; QD, once daily; t1/2term, apparent terminal elimination half-life; tmax, time to reach the maximum plasma concentration.
All indicated doses refer to JNJ-1802.
Day x is day 10 for JNJ-1802 50 mg, 150 mg, 400 mg, or 560 mg administered once daily for 10 days and day 31 for JNJ-1802 400 mg administered once daily for 31 days.
Figure 2.
Plasma JNJ-1802 concentration-time profiles of the multiple-dose part on semi-logarithmic scale (part 2, pharmacokinetics data analysis set). JNJ-1802 was administered at 50 mg (cohort 7), 150 mg (cohort 8), 400 mg (cohort 9), and 560 mg (cohort 10) once daily for 10 days, under fasted conditions (A) or 400 mg once daily for 31 days (cohort 11) (B).
After single- and multiple-dose administration in healthy participants, the mean total amount of unchanged JNJ-1802 excreted in urine was low (<0.001% of the dose).
DISCUSSION
JNJ-1802 was generally safe and well-tolerated. Following single-dose and multiple-dose administration orally in fasted conditions, formulated as a solution, the exposure of JNJ-1802 increased dose-proportionally from 50 to 150 mg and less than dose-proportionally for the higher doses (up to 1200 mg for single-dose and 560 mg for multiple-dose administration), based on AUC24h and Cmax. Although a lower mean exposure for the 240 mg dose (n = 5) was observed, compared to the 150 mg dose (n = 5), individual exposures largely overlapped between the 2 groups, making it difficult to draw conclusions why on average we observed a lower exposure. Higher interparticipant variability (coefficient of variation 49.7%‒56.4%) in this cohort, compared to other cohorts, may potentially be attributed to increased variability in absorption close to saturation. The long terminal elimination half-life of JNJ-1802 (t1/2term was 6.3–9.2 days) minimizes the risk of a drop in exposure in case of a missed dose and suggests that exposure persists long after stopping of dosing.
It has been shown in 2 NHP infection models that JNJ-1802 is highly efficacious against DENV-1 and DENV-2 infections in a prophylactic setting. In addition, in vitro and mice experiments have shown that this compound has potent activity against all 4 serotypes, which are genetically diverse [9]. The results from this FIH study together with the preclinical results [9] were used to guide dose selection for future clinical trials with JNJ-1802.
The limited renal clearance points toward an elimination via metabolic clearance of JNJ-1802, potentially governed by CYP3A4 and UGT1A9 as primary enzymes (based on in vitro data; unpublished data). Nonetheless, JNJ-1802 was the predominant circulating entity in human plasma at >97% of total drug-related material at steady-state.
As mentioned above, JNJ-1802 was generally safe and well-tolerated. In the multiple-dose phase, the incidence of diarrhea was highest in the 10-day 150 mg JNJ-1802 cohort but was also observed in the placebo arm and was considered very likely related to study drug. Participants in this cohort received the highest volume of PEG400 diluent (5, 15, 2.2, and 3.1 mL of PEG400 was administered in the 50, 150, 400, and 560 mg JNJ-1802 cohorts, respectively), which is known for its laxative effects. Diarrhea episodes stopped once dosing concluded or soon thereafter, suggesting that the incidence of diarrhea may likely be attributed to the PEG400 diluent. Polyethylene glycol is a commonly used co-solvent, especially for early clinical studies. Alternative formulations without PEG400 are developed and will be carried forward for future clinical development of JNJ-1802.
The rash events reported in the study all resolved after 35–47 days or 29‒35 days after multiple-dose treatment stopped. Rash is one of the signs and symptoms of dengue disease and will be assessed during clinical development of the dengue compound in placebo-controlled human challenge trials as well as in phase 2 and phase 3 trials. The risk/benefit equation will include all data generated during clinical development studies. To aid this evaluation, a rash assessment tool has been developed and is implemented in phase 1 drug–drug interaction studies as well as in the phase 2 human challenge studies and future clinical trials.
Prophylaxis and treatment with a dengue antiviral drug may complement vaccine and vector-control measures (which are lacking sustainable outcomes) to reduce the dengue disease burden [10]. Attempts to control mosquito populations include, among others, source reduction through elimination of oviposition sites, ovitraps, or chemical interventions to kill mosquito larvae or adult mosquitoes [11]. The integration of prophylaxis in the efforts of tackling dengue has gained recent interest [8], as travelers (eg, aid workers, missionaries, military, and tourists) to dengue-epidemic regions or at-risk individuals living in an endemic region might benefit from prophylaxis, like the successful use of prophylactic drugs for malaria [12]. A prophylactic agent would be present in the body before peak viremia has been reached or before infection and could thus mitigate or even prevent dengue-associated morbidity and mortality [13]. A successful candidate would need to have a good safety profile and a low dosing frequency and pill burden to facilitate long-term compliance. In addition, preclinical studies of our compound suggest a high barrier to resistance [9], which has been seen as a high risk for direct antivirals against dengue and other flaviviruses [14, 15].
A strength of the study is the broad exposure range investigated and the extensive multiple-dose assessment, including the 31-day cohort, which allowed for characterizing the accumulation of JNJ-1802. As a limitation, like a lot of phase 1 studies, the current study only included healthy volunteers. PK and safety results should be confirmed in dengue patients. While the current study population was mainly White and male, future studies evaluating the activity of JNJ-1802 plan to include a more diverse population (eg, females, broad age/weight ranges, and a wider geographical distribution) allowing the investigation of intrinsic and extrinsic factors affecting the PK of JNJ-1802.
In summary, the promising PK and safety/tolerability profile of JNJ-1802 in this first-in-human study encourages further investigation of its efficacy and safety for prophylaxis or treatment of dengue.
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.
Supplementary Material
Contributor Information
Oliver Ackaert, Janssen Clinical Pharmacology and Pharmacometrics, Janssen Pharmaceutica NV, Beerse, Belgium.
Frédéric Vanhoutte, SGS Clinical Pharmacology Unit, Antwerp, Belgium.
Nathalie Verpoorten, Global Public Health R&D, Janssen Pharmaceutica NV, Beerse, Belgium.
Annemie Buelens, Statistics & Decisions Sciences, Janssen Pharmaceutica NV, Beerse, Belgium.
Sophie Lachau-Durand, Preclinical Sciences and Translational Safety, Janssen Pharmaceutica NV, Beerse, Belgium.
Lieve Lammens, Preclinical Sciences and Translational Safety, Janssen Pharmaceutica NV, Beerse, Belgium.
Richard Hoetelmans, Janssen Clinical Pharmacology and Pharmacometrics, Janssen Pharmaceutica NV, Beerse, Belgium.
Marnix Van Loock, Global Public Health R&D, Janssen Pharmaceutica NV, Beerse, Belgium.
Guillermo Herrera-Taracena, Global Public Health, Janssen Research and Development, Horsham, PA, USA.
Notes
Acknowledgments. The authors thank the study participants, investigators, study coordinators, study teams, study nurses, and other staff members for their contribution to this study. The authors thank Anne-Theres Henze (Akkodis Belgium, on behalf of Janssen Pharmaceutica NV), who provided writing support and coordinated the manuscript development.
Financial support . This work was supported by Janssen Research and Development, including all costs associated with the development and publishing of the manuscript.
References
- 1. Messina JP, Brady OJ, Golding N, et al. The current and future global distribution and population at risk of dengue. Nat Microbiol 2019; 4:1508–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Bhatt S, Gething PW, Brady OJ, et al. The global distribution and burden of dengue. Nature 2013; 496:504–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. World Health Organization . Global strategy for dengue prevention and control, 2012–2020. 2012. Available at: http://apps.who.int/iris/bitstream/10665/75303/1/9789241504034_eng.pdf?ua=1. Accessed 27 November 2020.
- 4. World mosquito program . Dengue fact sheet. 2020. Available at: https://www.worldmosquitoprogram.org/sites/default/files/2020-11/WMP%20dengue_0.pdf. Accessed 27 April 2021.
- 5. Simmons CP, Farrar JJ, Nguyen VV, Wills B. Dengue. N Engl J Med 2012; 366:1423–32. [DOI] [PubMed] [Google Scholar]
- 6. Low JG, Sung C, Wijaya L, et al. Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial. Lancet Infect Dis 2014; 14:706–15. [DOI] [PubMed] [Google Scholar]
- 7. Low JG, Gatsinga R, Vasudevan SG, Sampath A. Dengue antiviral development: a continuing journey. Adv Exp Med Biol 2018; 1062:319–32. [DOI] [PubMed] [Google Scholar]
- 8. Whitehorn J, Yacoub S, Anders KL, et al. Dengue therapeutics, chemoprophylaxis, and allied tools: state of the art and future directions. PLoS Negl Trop Dis 2014; 8:e3025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Goethals O, Kaptein SJF, Kesteleyn B, et al. Blocking NS3–NS4B interaction inhibits dengue virus in non-human primates. Nature 2023; 615:678–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Low JG, Ooi EE, Vasudevan SG. Current status of dengue therapeutics research and development. J Infect Dis 2017; 215:S96–102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. World Health Organization . Dengue guidelines for diagnosis, treatment, prevention and control. 2009. Available at: https://apps.who.int/iris/bitstream/handle/10665/44188/9789241547871_eng.pdf?sequence=1&isAllowed=y. Accessed 7 November 2021.
- 12. Nakato H, Vivancos R, Hunter PR. A systematic review and meta-analysis of the effectiveness and safety of atovaquone proguanil (Malarone) for chemoprophylaxis against malaria. J Antimicrob Chemother 2007; 60:929–36. [DOI] [PubMed] [Google Scholar]
- 13. Hernandez-Morales I, Van Loock M. An industry perspective on dengue drug discovery and development. Adv Exp Med Biol 2018; 1062:333–53. [DOI] [PubMed] [Google Scholar]
- 14. Boldescu V, Behnam MAM, Vasilakis N, Klein CD. Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond. Nat Rev Drug Discov 2017; 16:565–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Troost B, Smit JM. Recent advances in antiviral drug development towards dengue virus. Curr Opin Virol 2020; 43:9–21. [DOI] [PubMed] [Google Scholar]
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