ABSTRACT
MK‐8527 is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) in clinical development. Two Phase 1 trials evaluated single (trial A) and multiple (trial B) ascending doses of MK‐8527 in adults without HIV. In trial A, 34 participants were assigned to 1 of 4 panels and randomized to receive single oral doses of MK‐8527 (0.5–200 mg) or placebo after fasting, over 3 dosing periods; 25 mg was assessed after a high‐fat meal. In trial B, 32 participants were randomized to receive 3 once‐weekly (QW) oral doses of MK‐8527 (between 5 and 40 mg) or placebo. Safety and pharmacokinetics (PK) of MK‐8527 and MK‐8527‐triphosphate (TP) were assessed. MK‐8527 was generally well tolerated with no serious adverse events. Plasma exposure of MK‐8527 increased approximately dose‐proportionally, and intracellular exposure of MK‐8527‐TP was slightly less than dose‐proportional over administered doses between 5 and 200 mg. Participants who received MK‐8527 with a meal showed a 41% decrease in C max with no effect on AUC0–168, and a 20%, 22%, and 58% increase in intracellular MK‐8527‐TP C max, C 168, and AUC0–168, respectively. Across QW doses, plasma MK‐8527 median T max ranged from 0.5 to 1 h, and t 1/2 was 24–81 h; MK‐8527‐TP median T max ranged from 10 to 24 h on Day 15, and geometric mean apparent t 1/2 was 216–291 h. Accumulation of intracellular MK‐8527‐TP was modest (accumulation ratios [Day 15/Day 1] for C max and AUC0–168 ranged from 1.1 to 1.6; C 168 from 1.2 to 2.4). Single and multiple QW doses of MK‐8527 were generally well tolerated in adults without HIV. The safety and PK profiles of MK‐8527 support continued clinical development.
Trial Registration: EudraCT numbers: 2016‐004647‐36 (trial A); 2018‐000846‐20 (trial B)
Keywords: HIV, pharmacokinetics, Phase 1, safety
Study Highlights.
- What is the current knowledge on the topic?
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○To increase the uptake and adherence to pre‐exposure prophylaxis (PrEP) for prevention of HIV infection, more dosage and formulation options are needed for those at risk for HIV infection. Long‐acting oral agents have the potential to lessen the burden of daily medication requirements and improve adherence.
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- What question did this study address?
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○Two Phase 1 studies assessed the safety and pharmacokinetics of single ascending (0.5–200 mg) or multiple once‐weekly doses (5–40 mg) of MK‐8527, a novel nucleoside reverse transcriptase translocation inhibitor, in participants without HIV.
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- What does this study add to our knowledge?
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○MK‐8527 was generally well tolerated with no serious adverse events. MK‐8527 had rapid absorption in plasma and uptake into peripheral blood mononuclear cells. In its active phosphorylated form, MK‐8527‐TP in peripheral blood mononuclear cells had a long half‐life and modest accumulation with once‐weekly dosing. MK‐8527 can be taken with food.
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- How might this change clinical pharmacology or translational science?
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○These studies support the continued development of MK‐8527 for HIV PrEP with extended duration dosing.
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1. Introduction
Human immunodeficiency virus (HIV) remains a significant public health challenge, with an estimated global prevalence of 39.9 million individuals living with HIV and approximately 1.3 million new infections in 2023 [1]. In 2015, the World Health Organization (WHO) recommended that pre‐exposure prophylaxis (PrEP) with antiretroviral therapy (ART) should be offered as a preventative option to all people who could benefit from PrEP [2]. The biological properties of the reverse transcriptase inhibitors and first‐generation PrEP agents tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) demonstrate potent and early antiretroviral activity against all HIV subtypes, alongside daily dosing and favorable tolerability [3]. TDF/FTC is a recommended prophylactic option among populations with a greater likelihood of acquiring HIV, with alternatives including tenofovir alafenamide plus emtricitabine (TAF/FTC; excluding individuals who are at risk of HIV‐1 from receptive vaginal sex) or long‐acting injectable cabotegravir administered every 2 months, intramuscularly [4, 5]. Additionally, recent results from the PURPOSE 1 and PURPOSE 2 trials demonstrated that twice‐yearly lenacapavir administered subcutaneously was effective in preventing a diverse participant population from acquiring HIV [6, 7].
Increasing PrEP use in those with a greater likelihood of acquiring HIV, by improving adherence and persistence patterns, is a key component of HIV prevention [8]. There is an unmet need for a greater range of dosage forms and formulations, including long‐acting oral agents, to decrease barriers associated with PrEP uptake, adherence, and persistence [9]. Introduction of an increased number of long‐acting ART options has the potential to lessen the burden of daily pill‐taking and thus improve adherence [10].
MK‐8527 is a 7‐deaza‐deoxyadenosine analog that, in its intracellular pharmacologically active triphosphate (TP) form, is a potent inhibitor of HIV‐1 replication [11]. MK‐8527‐TP inhibits HIV‐1 replication via reverse transcriptase translocation inhibition and delayed chain termination [11]. Preclinical studies of MK‐8527 suggest a sub‐nanomolar potency, no off‐target activity, and suitable pharmacokinetics (PK) for once‐weekly (QW) or longer dosing intervals [11].
Here, we report the key findings from two Phase 1 trials evaluating the safety and PK of ascending single doses (trial A) and multiple QW doses (trial B) of MK‐8527 in adults without HIV.
2. Methods
2.1. Study Design
Trial A (protocol MK‐8527‐001; EudraCT number: 2016‐004647‐36) was a randomized, double‐blind, placebo‐controlled, single ascending‐dose study of MK‐8257 in adults without HIV (Figure 1a). Participants were assigned to 1 of 4 dosing panels, each consisting of eight participants. Within each panel, participants were randomly assigned in a 3:1 ratio to receive single oral doses of MK‐8527 (0.5–200 mg) or placebo across three treatment periods (Panels A–C, Periods 1–3) or 2 treatment periods (Panel D, Periods 1–2). For individual participants, the washout interval between periods was ≥ 27 days. Study drug was administered following an overnight fast of approximately 8 h (except for Panel C, Period 3). To assess the effect of food on the plasma MK‐8527 and peripheral blood mononuclear cells (PBMC) MK‐8527‐TP concentration profiles, participants in Panel C received a repeat 25‐mg dose of MK‐8527 following a standard high‐fat breakfast (total fat = 55.6 g, total carbohydrates = 55 g, total protein = 31.1 g; total calories = 500.4 in fat, 220 in carbohydrates, and 124.4 in protein) in treatment Period 3 (Figure 1a).
FIGURE 1.
Study design: trial A (a) and trial B (b). In trial A, participants were randomized in each period to receive single oral doses of MK‐8527 (n = 6) or placebo (n = 2). aTwo participants in trial A Panel B discontinued the study drug after Period 2 (1 due to personal reasons; 1 due to knee trauma unrelated to MK‐8527) and were replaced in Period 3. QW, once weekly.
Trial B (protocol MK‐8527‐003; EudraCT number: 2018‐000846‐20) was a randomized, double‐blind, placebo‐controlled, serial panel, ascending multiple‐dose study of MK‐8527 in adults without HIV. Participants enrolled in 1 of 4 dosing panels were randomly assigned in a 3:1 ratio to receive QW oral doses of MK‐8527 (5 mg, 10 mg, 20 mg, or 40 mg) or placebo on Days 1, 8, and 15 (Figure 1b). Study drug was administered following an overnight fast of approximately 8 h. A minimum 10‐day observation period was in place prior to initiating subsequent dose escalations.
Trial A was conducted at the SGS Clinical Pharmacology Unit in Antwerp, Belgium, and was approved by the Committee for Medical Ethics at Hospital Network Antwerp. Trial B was conducted at Ghent University Hospital in Ghent, Belgium, and was approved by the Medical Ethics Committee of Ghent University Hospital. Both trials were conducted in conformance with the Declaration of Helsinki and country and local requirements regarding ethical committee review, informed consent, and other statutes or regulations regarding the protection of the rights and welfare of humans participating in biomedical research.
2.2. Participants
In trial A, eligible participants were healthy adult males aged 18–55 years, while in trial B, healthy adult males or females aged 18–55 years were eligible for enrollment. Key exclusion criteria across both studies included creatinine clearance ≤ 90 mL/min, a history of clinically significant abnormalities or diseases, current or recent nicotine use, an inability to refrain from the use of any medication, and positivity for hepatitis B surface antigen, hepatitis C antibodies, or HIV. Males were required to be abstinent or use contraception, and females were required to be of non‐childbearing potential. A replacement participant could be enrolled if deemed appropriate by the investigator and Sponsor. Complete inclusion and exclusion criteria are included in the Supplement (trial A, Appendix S1; trial B, Appendix S2).
2.3. Assessments
2.3.1. Safety and Tolerability
Participants were monitored for safety during each study by review of adverse events (AEs), vital signs, physical examination findings, laboratory safety tests, and 12‐lead electrocardiograms (ECGs). Laboratory safety tests included a white blood cell count with differential, including analysis of the percentage of lymphocytes. Safety and PK data were reviewed on an ongoing basis; this informed escalation to the next dose level.
2.3.2. Pharmacokinetics
In trial A, blood samples were collected for plasma MK‐8527 PK analysis at pre‐dose and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, and 168 h post‐dose, and for PBMC MK‐8527‐TP PK analysis at pre‐dose and 6, 12, 24, 48, 96, 168, 336, 504, and 672 h post‐dose. In trial B, blood samples were collected for plasma MK‐8527 PK analysis at pre‐dose and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 16, 24, 48, 96, and 168 h post‐dose on Days 1 and 15, and for PBMC MK‐8527‐TP PK analysis at pre‐dose and 6, 10, 24, 48, 96, 144, and 168 h post‐dose on Days 1 and 15, with additional collections at 336, 504, and 672 h post‐dose on Day 15. PK variables for MK‐8527 and MK‐8527‐TP included concentration at 168 h post‐dose (C 168), area under the concentration time‐curve from time 0 to 168 h post‐dose (AUC0–168), area under the concentration time‐curve from 0 to infinity (AUC0–inf, trial A), maximum concentration (C max), time to maximum concentration (T max), and apparent terminal half‐life (t 1/2) following first dose in trial A and at Day 15 in trial B.
In both studies, urine samples were collected to assess MK‐8527 urine fraction excreted during the time intervals, including predose, 0–4, 4–8, 8–12, 12–24, and 24–48 h post‐dose, for participants who received a single 5‐mg or 100‐mg dose of MK‐8527 in trial A; and in all participants at Day 15 for trial B.
2.4. Statistical Analysis
Plasma MK‐8527 and PBMC MK‐8527‐TP values for AUC0–168, AUC0–inf, C max, and C 168 were natural log‐transformed and evaluated with a linear mixed effects model having a fixed effect for treatment and a random effect for participant. The 95% confidence intervals (CIs) for the geometric means (GMs) of MK‐8527 in plasma and MK‐8527‐TP in PBMC C 168 were constructed at each dose level and on Day 1 (both trials) and Day 15 (trial B). The primary hypothesis was evaluated by calculating, at each dose level, the posterior probability that the true mean PBMC MK‐8527‐TP C 168 was greater than 0.2 pmol/106 cells, a threshold based on preclinical assessments of antiviral activity, using the least squares estimates and total variance from the above model, assuming a noninformative prior and normality on the log scale. A 70% posterior probability or greater for at least 1 well‐tolerated dose level would support the primary hypothesis. Dose proportionality was assessed by creating a plot of PBMC MK‐8527‐TP AUC0–inf values versus dose across all single doses (0.5–200 mg) and fitting an overall estimated regression line with a 95% Scheffé confidence interval band.
In trial A, the same model was used to estimate the effect of food on the PK of MK‐8527‐TP. The geometric mean ratio (GMR) (fed/fasted) and 90% CI at the 25‐mg dose level were obtained for AUC0–inf, AUC0–168, C max, and C 168. The values of the plasma MK‐8527 PK parameters AUC0–∞, AUC0–168, and C max, as well as the effect of food on MK‐8527 plasma PK, were analyzed in a similar manner.
In trial B, the accumulation of MK‐8527 in plasma and MK‐8527‐TP in PBMCs was assessed through the construction of a GMR (Day 15/Day 1) and 90% CI for C 168, AUC0–168, and C max.
3. Results
3.1. Study Population
In trial A, 34 participants were randomized, and 32 (94.1%) completed the study between October 24, 2017, and August 24, 2018 (Figure S1A). All participants were male, with a median age of 48.5 years, and 97.1% were White (Table 1). Five participants discontinued treatment early, including 1 participant who completed a post‐study visit and was considered to have completed the study, and 2 participants who discontinued in Period 2 and were replaced in Period 3. Three participants discontinued due to AEs (knee trauma, elevated alanine transaminase, and heatstroke); 1 due to protocol violation; and 1 withdrew consent.
TABLE 1.
Participant demographics and baseline characteristics.
| Characteristic | Ascending single‐dose study (Trial A) | Ascending multiple‐dose study (Trial B) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Panel A | Panel B | Panel C | Panel D | Total | MK‐8527 5 mg | MK‐8527 10 mg | MK‐8527 20 mg | MK‐8527 40 mg | Placebo | Total | |
| n = 8 | n = 10 a | n = 8 | n = 8 | N = 34 | n = 6 | n = 6 | n = 6 | n = 6 | n = 8 | N = 32 | |
| Male, n (%) | 8 (100) | 10 (100) | 8 (100) | 8 (100) | 34 (100) | 5 (83.3) | 6 (100) | 5 (83.3) | 6 (100) | 8 (100) | 30 (93.8) |
| Age, median (range), years | 48.0 (32–55) | 43.5 (20–55) | 46.0 (38–55) | 49.5 (31–54) |
48.5 (20–55) |
42.5 (27–52) |
27.5 (20–39) |
34.0 (22–51) |
27.0 (20–35) |
40.0 (25–52) |
34.0 (20–52) |
| Race, White b , n (%) | 8 (100) | 9 (90) | 8 (100) | 8 (100) | 33 (97.1) | 6 (100) | 5 (83.3) | 6 (100) | 6 (100) | 8 (100) | 31 (96.9) |
| Not Hispanic or Latino, n (%) | 8 (100) | 9 (90) | 8 (100) | 8 (100) | 33 (97.1) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 8 (100) | 32 (100) |
| Discontinued, n (%) | 0 | 2 (20) | 2 (25) | 1 (12.5) | 5 (14.7) | 0 | 0 | 0 | 0 | 0 | 0 |
| Due to AE | 0 | 1 (10) | 1 (12.5) | 1 (12.5) | 3 (8.8) | 0 | 0 | 0 | 0 | 0 | 0 |
| Due to protocol violation | 0 | 0 | 1 (12.5) | 0 | 1 (2.9) | 0 | 0 | 0 | 0 | 0 | 0 |
| Due to withdrawal by participant | 0 | 1 (10) | 0 | 0 | 1 (2.9) | 0 | 0 | 0 | 0 | 0 | 0 |
Abbreviation: AE, adverse event.
Two participants discontinued the study drug after Period 2 (1 due to personal reasons; 1 due to knee trauma unrelated to MK‐8527) and were replaced in Period 3.
For trial A, the non‐White participant was Asian (n = 1); and for trial B, the non‐White participant was Black or African American (n = 1).
In trial B, 32 participants were randomly assigned, and all completed the study between October 3, 2018, and April 26, 2019 (Figure S1B). In total, 24 participants (Panels A–D) received QW oral doses of MK‐8527 for 3 weeks, and 8 participants received placebo. Most participants were male (30 [93.8%] of 32), with a median age of 34.0 years, and 96.9% were White (Table 1). No participants discontinued treatment in trial B.
3.2. Safety
In trial A, AEs were reported in 27 (79.4%) participants across all treatments in the trial (Table 2). The most common AEs (reported in > 2 participants) were headache and influenza‐like illness. Five participants (14.7%) had drug‐related AEs, all of which were mild and resolved by the end of the study. AEs of elevated liver enzymes (alanine aminotransferase, aspartate aminotransferase, and/or gamma‐glutamyltransferase, all > 2 times the upper limit of normal) were reported in 3 participants, 2 from the placebo group and 1 from the MK‐8527 150 mg group that was considered not to be drug‐related by the investigator. Elevated liver enzymes resolved in all participants by the end of the study.
TABLE 2.
Adverse event summary for participants receiving MK‐8527 in trial A a .
| n (%) | 0.5 mg fasted n = 6 | 1 mg fasted n = 6 | 2.5 mg fasted n = 6 | 5 mg fasted n = 6 | 10 mg fasted n = 6 | 25 mg fasted n = 5 | 25 mg fed n = 4 | 50 mg fasted n = 6 | 100 mg fasted n = 6 | 150 mg fasted n = 6 | 200 mg fasted n = 6 | Placebo n = 19 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≥ 1 AE | 3 (50) | 4 (66.7) | 3 (50) | 2 (33.3) | 4 (66.7) | 3 (60) | 0 | 1 (16.7) | 3 (50) | 3 (50) | 0 | 8 (42.1) |
| Drug‐related AE b | 0 | 0 | 0 | 2 (33.3) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 (15.8) |
| Serious AE | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Serious drug‐related AE | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Abbreviation: AE, adverse event.
The total number of AEs and drug‐related AEs was 27 (79.4%) and 5 (14.7%), respectively.
Determined by the investigator to be related to the study drug.
In trial B, AEs were reported in 29 (90.6%) participants across all treatments in the trial (Table 3); all were mild or moderate and resolved by the end of the study. The most common AEs (> 2 participants) were headache, oropharyngeal pain, cough, nausea, and abdominal pain. Eleven participants (34.4%) had drug‐related AEs.
TABLE 3.
Adverse event summary for participants in trial B.
| n (%) | MK‐8527 5 mg QW n = 6 | MK‐8527 10 mg QW n = 6 | MK‐8527 20 mg QW n = 6 | MK‐8527 40 mg QW n = 6 | Placebo n = 8 | Total n = 32 |
|---|---|---|---|---|---|---|
| ≥ 1 AE | 3 (50) | 6 (100) | 6 (100) | 6 (100) | 7 (87.5) | 29 (90.6) |
| Drug‐related AE a | 0 | 2 (33.3) | 1 (16.7) | 3 (50) | 5 (62.5) | 11 (34.4) |
| Serious AE | 0 | 0 | 0 | 0 | 0 | 0 |
| Serious drug‐related AE | 0 | 0 | 0 | 0 | 0 | 0 |
Note: Placebo is pooled across all panels. Total is obtained by counting participants only once with at least one event; if any event occurs in screening as well as in the treatment period for a participant, the participant will be counted only once for the total. In this table, there are four participants who had AEs in screening as well as in treatment periods.
Abbreviations: AE, adverse event; QW, once weekly.
Determined by the investigator to be related to the drug.
No serious AEs, no discontinuations due to drug‐related AEs, no events of clinical interest, and no deaths occurred. In addition, there were no dose‐related changes in vital signs, laboratory safety test results, or 12‐lead ECGs in either trial. A complete listing of AEs is provided in Table S2.
3.3. Pharmacokinetics
Following ascending single doses in trial A, MK‐8527 was rapidly absorbed with a median T max of 0.5 h (Table 4). Plasma concentrations decreased in a biphasic manner, with a GM apparent t 1/2 of 6–62 h (Table 4). The GM apparent t 1/2 for MK‐8527 and MK‐8527‐TP was determined in doses ≥ 2.5 mg in trial A. MK‐8527‐TP reached intracellular C max at a median T max of 12–48 h, and the concentrations in PBMCs declined with a GM apparent t 1/2 of 94–266 h (3.9–11.1 days) across doses. Plasma exposure of MK‐8527 was approximately dose‐proportional across the range of doses studied, and intracellular exposure of MK‐8527‐TP was less than dose‐proportional. An overall estimated regression line was fitted to MK‐8527‐TP AUC0–inf values versus dose (0.5–200 mg), producing an estimated slope (95% CI) of 0.84 (0.77, 0.91). At doses above 100 mg, MK‐8527‐TP C 168 showed no further increase in value (Figure 2a). The true GM C 168 (90% CI) values of MK‐8527‐TP for doses 5–200 mg were above the PK threshold for antiviral activity against wild‐type HIV‐1 based on preclinical translation (≥ 0.2 pmol/106 PBMCs) (Figure 2a).
TABLE 4.
PK of MK‐8527 and MK‐8527‐TP following administration of single oral doses of MK‐8527 (0.5–200 mg) in trial A.
| PK parameter, GM (95% CI) | 0.5 mg fasted n = 6 | 1 mg fasted n = 6 | 2.5 mg fasted n = 6 | 5 mg fasted n = 6 | 10 mg fasted n = 6 | 25 mg fasted n = 5 a | 25 mg fed n = 4 b | 50 mg fasted n = 6 | 100 mg fasted n = 6 | 150 mg fasted n = 6 | 200 mg fasted n = 6 | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| MK‐8527 | AUC0–168, c h•μmol/L | NR |
0.023 (0.020–0.027) |
0.099 (0.085–0.115) |
0.330 (0.285–0.382) |
0.973 (0.845–1.12) |
2.64 (2.25–3.09) |
2.58 (2.18–3.05) |
5.80 (5.02–6.72) |
12.1 (10.5–13.9) |
18.4 (15.9–21.3) |
24.6 (21.3–28.5) |
| AUC0–inf, c h•μmol/L | NR | 0.0295 (0.0254–0.0343) | 0.119 (0.102–0.139) | 0.368 (0.317–0.427) | 1.05 (0.913–1.22) | 2.72 (2.31–3.19) | 2.70 (2.28–3.19) | 6.12 (5.27–7.11) | 12.5 (10.8–14.4) | 20.1 (17.3–23.4) | 26.4 (22.7–30.7) | |
| C max, c μmol/L |
0.0059 (0.0045–0.0077) |
0.0128 (0.0098–0.0168) |
0.0345 (0.0260–0.0456) |
0.0726 (0.0552–0.0955) |
0.169 (0.129–0.222) |
0.557 (0.412–0.754) |
0.329 (0.237–0.456) |
0.974 (0.741–1.28) |
2.18 (1.66–2.86) |
3.30 (2.50–4.35) |
4.44 (3.36–5.87) |
|
| T max h d | 0.50 (0.50, 0.50) | 0.50 (0.50, 1.00) | 0.50 (0.50, 1.00) | 0.50 (0.50, 2.00) | 0.50 (0.50, 1.00) | 0.50 (0.25, 1.00) | 0.50 (0.50, 0.50) | 0.51 (0.50, 1.00) | 0.50 (0.50, 1.00) | 0.50 (0.50, 1.00) | 0.50 (0.50, 1.00) | |
| Apparent t 1/2, h e | NR | NR | 5.54 (30.76) | 14.60 (9.88) | 35.75 (43.45) | 38.05 (33.20) | 43.19 (25.72) | 43.50 (10.36) | 40.45 (5.16) | 61.53 (12.08) | 51.74 (19.22) | |
| MK‐8527‐TP | AUC0–168, c h•pmol/106 cells |
9.36 (6.47–13.5) |
20.7 (16.6–25.8) |
61.0 (48.9–76.1) |
127 (102–158) |
238 (191–296) |
483 (379–615) |
764 (585–997) |
1120 (899–1400) |
1860 (1490–2310) |
1930 (1550–2410) |
2380 (1900–2970) |
| C max, c pmol/106 cells |
0.14 (0.11–0.17) |
0.21 (0.17–0.26) |
0.69 (0.56–0.86) |
1.50 (1.21–1.85) |
2.69 (2.18–3.33) |
6.82 (5.42–8.60) |
8.20 (6.33–10.6) |
17.2 (13.9–21.2) |
22.0 (17.8–27.2) |
28.5 (23.1–35.2) |
33.5 (27.1–41.3) |
|
| C 168, c pmol/106 cells | 0.0424 (NR) | 0.0696 (0.0514–0.0942) | 0.157 (0.114–0.215) | 0.421 (0.308–0.575) | 0.786 (0.580–1.06) | 1.18 (0.844–1.66) | 1.44 (1.00–2.07) | 2.95 (2.16–4.03) | 5.65 (4.17–7.65) | 4.72 (3.45–6.45) | 4.61 (3.37–6.29) | |
| Apparent t 1/2, h e | NR | NR |
103.7 (53.8) |
104.9 (47.1) |
122.8 (29.8) |
173.2 (80.5) |
202.4 (116.4) |
140.9 (37.0) |
93.9 (36.8) |
266.4 (45.0) |
256.7 (29.9) |
|
| T max h d | 12.0 (12.0, 95.93) | 48.0 (48.0, 95.95) | 24.0 (6.0, 24.0) | 24.2 (12.0, 24.3) | 18.0 (12.0, 48.0) | 24.0 (12.0,2) | 47.9 (47.8, 48.0) | 12.0 (12.0, 12.0) | 12.0 (12.0, 24.2) | 24.0 (12.0, 24.1) | 12.0 (6.0, 24.0) |
Abbreviations: AUC0–168, area under the concentration time‐curve from time 0 to 168 h post‐dose; AUC0–inf, area under the concentration time‐curve from time 0 to infinity; C 168, area under the concentration time‐curve at 168 h; C max, maximum concentration; GM, geometric mean; NR, not recorded; PK, pharmacokinetics; t 1/2, apparent terminal half‐life; TP, triphosphate.
n = 5 due to participant discontinuation prior to dosing.
n = 4 due to participant discontinuations prior to dosing.
Back‐transformed least squares mean difference and 90% CI from mixed effects model performed on natural log‐transformed values.
Median (min, max).
Geometric mean (percent geometric coefficient of variation).
FIGURE 2.
Mean MK‐8527 and MK‐8527‐TP concentrations following ascending single doses of MK‐8527 in trial A (a). Mean MK‐8527‐TP concentrations after multiple ascending doses (QW for 3 weeks) of MK‐8527 on Day 1 and Day 15 in trial B (b). In trial A, PK sampling times were prespecified to extend to 96 or 168 h for plasma MK‐8527 and to 336 or 672 h for intracellular MK‐8527‐TP, which were deemed adequate to capture the PK profile based on previously estimated half‐life. The LLOQ for plasma was 0.00324 μM. PBMC concentration was calculated based on raw concentration within isolated PBMCs, with PBMC count and volume used for dilution. The LLOQ of the raw concentration was 0.00182 μM, but the LLOQ for the final reported PBMC concentration varied by sample due to differences in collected cell count and volume used for dilution. Samples with concentrations below the LLOQ were treated as “0.” LLOQ, lower limit of quantification; PBMC, peripheral blood mononuclear cell; PK, pharmacokinetic; QW, once weekly.
Following ascending multiple doses (QW for 3 weeks) in trial B, MK‐8527 was rapidly absorbed with a median T max of 0.5 to 1 h on Day 15 (Dose 3), with an apparent t 1/2 of 24–81 h (Table 5). Across all dose levels, the MK‐8527‐TP apparent t 1/2 ranged from 216 to 291 h (9.0–12.1 days) on Day 15 (Table 5). The true GM C 168 (90% CI) of MK‐8527‐TP was ≥ 0.2 pmol/106 PBMCs for all dose levels (Figure 2b). Accumulation of intracellular MK‐8527‐TP was modest (C max ratios ranged from 1.2 to 1.6; C 168 ratios ranged from 1.2 to 2.4; AUC0–168 ratios ranged from 1.1 to 1.6). After QW dosing for 3 weeks, accumulation of plasma MK‐8527 was minimal (C max and AUC0–168 ratios [Day 15/Day 1] ranged from 0.9 to 1.4).
TABLE 5.
PK of MK‐8527 and MK‐8527‐TP following administration of multiple oral doses of MK‐8527 (5–40 mg QW) in trial B.
| PK parameter, GM (95% CI) | 5 mg QW | 10 mg QW | 20 mg QW | 40 mg QW | |
|---|---|---|---|---|---|
| n = 6 | n = 6 | n = 6 | n = 6 | ||
| Day 1 | |||||
|
MK‐8527 |
AUC0–168, a h·μmol/L | 0.271 (0.228–0.322) | 0.650 (0.547–0.773) | 1.79 (1.50–2.12) | 3.92 (3.30–4.66) |
| C max, a μmol/L | 0.0653 (0.0495–0.0863) | 0.152 (0.115–0.200) | 0.274 (0.207–0.361) | 0.598 (0.453–0.790) | |
| C 168, a μmol/L | NR | NR | NR | 0.0051 (0.0039–0.0065) | |
| T max h b | 0.53 (0.53, 1.00) | 0.53 (0.53, 1.00) | 1.00 (0.55, 1.00) | 0.77 (0.53, 1.00) | |
|
MK‐8527‐TP |
AUC0–168, a h·pmol/106 cells | 144 (120–172) | 219 (183–262) | 429 (358–514) | 812 (679–973) |
| C max, a pmol/106 cells | 1.36 (1.08–1.70) | 2.37 (1.89–2.97) | 4.45 (3.55–5.58) | 9.96 (7.95–12.5) | |
| C 168, a pmol/106 cells | 0.460 (0.366–0.579) | 0.521 (0.414–0.656) | 1.14 (0.902–1.43) | 2.20 (1.75–2.77) | |
| T max h b | 24.00 (10.00, 47.78) | 10.00 (10.00, 24.00) | 10.00 (6.00, 47.75) | 17.00 (10.00, 24.00) | |
| Day 15 | |||||
| MK‐8527 | AUC0–168, a h·μmol/L | 0.376 (0.316–0.447) | 0.921 (0.775–1.10) | 2.44 (2.06–2.90) | 5.05 (4.25–6.00) |
| C max, a μmol/L | 0.0609 (0.0461–0.0804) | 0.132 (0.0997–0.174) | 0.270 (0.205–0.357) | 0.640 (0.485–0.846) | |
| C 168, a μmol/L | NR | NR | 0.0059 (0.0045–0.0078) | 0.0097 (0.0076–0.0126) | |
| T max h b | 1.00 (0.53, 1.00) | 0.53 (0.53, 1.00) | 0.54 (0.53, 1.00) | 1.00 (0.53, 1.00) | |
| Apparent t 1/2, h c | 23.97 (77.74) | 44.39 (33.81) | 79.16 (29.96) | 81.05 (12.71) | |
| MK‐8527‐TP | AUC0–168, a h·pmol/106 cells | 205 (171–245) | 259 (216–310) | 573 (478–686) | 928 (775–1110) |
| C max, a pmol/106 cells | 2.15 (1.72–2.70) | 2.82 (2.25–3.53) | 5.82 (4.64–7.30) | 12.4 (9.92–15.6) | |
| C 168, a pmol/106 cells | 0.670 (0.532–0.844) | 1.26 (0.999–1.58) | 2.27 (1.80–2.86) | 2.55 (2.03–3.21) | |
| T max h b | 17.00 (10.00, 24.00) | 24.00 (24.00, 24.00) | 24.00 (10.00, 24.27) | 10.00 (10.00, 24.00) | |
| Apparent t 1/2, h c | 215.72 (22.98) | 224.51 (36.08) | 223.68 (34.31) | 290.97 (30.15) | |
| Accumulation ratio: Day 15/Day 1 c (90% CI) | |||||
|
MK‐8527 |
AUC0–168 | 1.39 (1.27–1.52) | 1.42 (1.30–1.55) | 1.37 (1.25–1.49) | 1.29 (1.18–1.41) |
| C max | 0.93 (0.77–1.13) | 0.87 (0.72–1.05) | 0.99 (0.82–1.20) | 1.07 (0.88–1.30) | |
|
MK‐8527‐TP |
AUC0–168 | 1.42 (1.28–1.59) | 1.18 (1.06–1.32) | 1.33 (1.19–1.49) | 1.14 (1.02–1.28) |
| C max | 1.59 (1.32–1.90) | 1.19 (0.995–1.43) | 1.31 (1.09–1.57) | 1.25 (1.04–1.49) | |
| C 168 | 1.46 (1.25–1.70) | 2.42 (2.07–2.82) | 2.00 (1.71–2.33) | 1.16 (0.995–1.35) | |
Abbreviations: AUC0‐168, area under the concentration time‐curve from time 0 to 168 h post‐dose; C 168, area under the concentration time‐curve at 168 h; CI, confidence interval; C max, maximum concentration; GM, geometric mean; NR, not reported; QW, once weekly; t 1/2, apparent terminal half‐life; T max, time to maximum concentration.
Back‐transformed least squares mean difference and 90% CI from mixed effects model performed on natural log‐transformed values.
Median (min, max).
Geometric mean (percent geometric coefficient of variation).
Administration of MK‐8527 25 mg with a high‐fat meal in trial A resulted in no effect on MK‐8527 AUC0–168 and a 41% decrease in C max (Table S1). Intracellular MK‐8527‐TP exposures were increased following a high‐fat meal, as the observed GMRs (90% CI; fed/fasted) for MK‐8527‐TP AUC0–168, C 168, and C max were 1.58 (1.23–2.03), 1.22 (0.91–1.62), and 1.20 (0.92–1.58), respectively.
The GM of MK‐8527 fraction excreted in the urine up to 48 h post‐dose for participants who received MK‐8527 as a single 5‐mg or 100‐mg dose or as once‐weekly doses of 5–40 mg ranged from 27.6% to 37.6%.
4. Discussion
The findings from these two Phase 1 studies represent the first administration of MK‐8527 to human participants. Ascending single oral doses of MK‐8527 up to 200 mg and multiple ascending oral doses of MK‐8527 up to 40 mg dosed weekly for 3 weeks were generally well tolerated, with no serious AEs. The safety results from these studies support further clinical development of MK‐8527 with extended duration dosing.
The PK profile following single and multiple oral once‐weekly doses of MK‐8527 demonstrated rapid absorption in plasma and uptake into PBMCs. In its active phosphorylated form, MK‐8527‐TP has a long t 1/2 and a favorable PK profile, as shown in preclinical studies [11]. Preclinical studies in rats and rhesus monkeys demonstrated that MK‐8527 has high potency with a favorable in vitro off‐target profile and PK characteristics suitable for long‐acting oral dosing [11]. The totality of the data support the potential of a once‐monthly oral dosing regimen for MK‐8527.
The long t 1/2 and favorable PK profile of the active phosphorylated form, MK‐8527‐TP, is similar to that of the active phosphorylated form of islatravir, another investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) [12, 13, 14, 15]. MK‐8527 is the only NRTTI being developed for the prevention of HIV infection as PrEP. With the potential for once‐monthly oral dosing, MK‐8527 may provide a more discreet and less burdensome option for PrEP than currently approved PrEP medications.
MK‐8527‐TP in PBMCs achieved a PK threshold of C 168 > 0.2 pmol/106 cells for administered doses ≥ 5 mg. The PK threshold was derived from PK and pharmacodynamic (PD) modeling of preclinical data based on activity against wild‐type HIV‐1. Although a reduced plasma MK‐8527 C max was observed upon dosing with food, the effect on intracellular MK‐8527‐TP C max or C 168 was not considered to be clinically meaningful. We observed that plasma MK‐8527 C max was reduced upon dosing with food, while T max and AUC were not altered. This result could be due to variability and a smaller sample size in the food panel (n = 4), and it should be noted that the 95% CIs for C max dosing with food and fasted overlapped. Additionally, we observed that dosing with food did not alter the plasma MK‐8527 AUC0–168, whereas the intracellular MK‐8527‐TP AUC0–168 was higher with food. There is no known physiological reason for why food could impact the uptake and conversion of MK‐8527 in PBMCs, and this effect is likely due to variability in the analysis, specifically related to the cell counts used to determine the MK‐8527‐TP concentration in PBMCs and a small sample size (n = 4). These results support the conclusion that MK‐8527 can be administered regardless of food. Weekly oral doses of MK‐8527 resulted in minimal drug accumulation, consistent with the t 1/2 in plasma, while MK‐8527‐TP showed modest accumulation across all dose levels, consistent with the extended t 1/2 in PBMCs.
Based on preclinical data in rats and rhesus monkeys, the elimination of MK‐8527 is expected to occur predominantly through renal extraction and by metabolism via glucuronidation, with no significant involvement of cytochrome P450 enzymes [16]. In the current studies, urine samples were collected for PK assessment up to 48 h after single and multiple weekly doses of MK‐8527, and urine fraction excreted for MK‐8527 ranged from 27.6% to 37.6%, consistent with preclinical results.
These studies have limitations that should be considered. As first‐in‐human Phase 1 studies that explored a wide range of doses, the group sizes were small (n = 4–6). Furthermore, these studies were not diverse in sex or race, as most participants were male (96.9%) and White (96.9%). Potential reasons for this lack of diversity include that females had to be both of non‐childbearing potential and younger than 55 years old to be included in the study, that these studies were single‐site studies, and that the studies took place in Belgium.
In addition to the favorable safety and PK profile observed in these two Phase 1 studies, 2 proof‐of‐concept studies (NCT03615183 and NCT05494736) of MK‐8527 in ART‐naive participants living with HIV‐1 showed that participants receiving MK‐8527 achieved ≥ 1 log10 decrease in HIV‐1 RNA at Day 7 following the administration of single doses as low as 0.5 mg [17]. Further clinical investigations of MK‐8527 are ongoing, including a Phase 2 study (NCT06045507) assessing the safety, tolerability, and PK of oral MK‐8527 (3, 6, and 12 mg) administered once monthly in participants living without HIV‐1. A 3‐mg dose of MK‐8527 is not projected to be effective as PrEP; however, this dose was selected to further characterize PK and PK–PD relationships [18].
In conclusion, these Phase 1 data support further clinical development of MK‐8527 and will help to guide the selection of MK‐8527 doses and dosing regimens appropriate for upcoming studies.
Author Contributions
G.G., A.B., R.P.C., and M.I. wrote the manuscript; R.V., R.P.M., S.A.S., T.R., and M.I. designed the research; A.B., S.R., F.V., J.‐F.D., and T.R. performed the research; A.B., G.G., X.Z., R.V., Y.K., J.‐F.D., F.V., R.P.M., and M.I. analyzed the data.
Conflicts of Interest
G.G., R.P.C., X.Z., R.V., Y.K., A.B., J.‐F.D., T.R., R.P.M., S.A.S., and M.I. are current or former employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, NJ, USA, and may own stock or options of Merck & Co. Inc., Rahway, NJ, USA; S.R. received travel grants from Ipsen, Astellas, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, NJ, USA. S.R. has received honoraria from BMS, Ipsen, Pfizer, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, NJ, USA; S.R. has participated in advisory boards from Johnson & Johnson, Ipsen, BMS, and Astellas. All other authors declared no competing interests for this work.
Supporting information
Appendix S1: cts70331‐sup‐0001‐AppendixS1.docx.
Acknowledgments
The authors thank all the participants in these clinical studies. The contributions of the investigators and their staff are gratefully recognized. Finally, the authors acknowledge the contributions of Adedayo Adedoyin, PhD (former employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, NJ, USA), and Griet Van Lancker, MD (Drug Research Unit Ghent). Medical writing and/or editorial assistance was provided by Jared Cochran, PhD, Lorna Gcanga, PhD, and Claire Pouwels of ApotheCom (USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, NJ, USA.
Gillespie G., Carstens R. P., Zang X., et al., “Safety and Pharmacokinetics of MK‐8527 in Adults Without HIV ,” Clinical and Translational Science 18, no. 9 (2025): e70331, 10.1111/cts.70331.
Funding: Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, NJ, USA.
Previous Presentation: The results of these Phase 1 studies have been presented as an oral presentation at the Conference on Retroviruses and Opportunistic Infections (CROI), March 3–6, 2024 in Denver, Colorado. The results/data/figures in this manuscript have not been published or under consideration by another journal.
Data Availability Statement
The data sharing policy, including restrictions, of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, NJ, USA (MSD), is available at https://trialstransparency.msdclinicaltrials.com/policies‐perspectives.aspx. Requests for access to the clinical study data can be submitted via email to the Data Access mailbox (mailto: dataaccess@msd.com).
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Appendix S1: cts70331‐sup‐0001‐AppendixS1.docx.
Data Availability Statement
The data sharing policy, including restrictions, of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, NJ, USA (MSD), is available at https://trialstransparency.msdclinicaltrials.com/policies‐perspectives.aspx. Requests for access to the clinical study data can be submitted via email to the Data Access mailbox (mailto: dataaccess@msd.com).