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The rapidly advancing field of digital health technologies provides a great opportunity to radically transform the way clinical trials are conducted and to shift the clinical trial paradigm from a site‐centric to a patient‐centric model. Merck's (Kenilworth, NJ) digitally enabled clinical trial initiative is focused on introduction of digital technologies into the clinical trial paradigm to reduce patient burden, improve drug adherence, provide a means of more closely engaging with the patient, and enable higher quality, faster, and more frequent data collection. This paper will describe the following four key areas of focus from Merck's digitally enabled clinical trials initiative, along with corresponding enabling technologies: (i) use of technologies that can monitor and improve drug adherence (smart dosing), (ii) collection of pharmacokinetic (PK), pharmacodynamic (PD), and biomarker samples in an outpatient setting (patient‐centric sampling), (iii) use of digital devices to collect and measure physiological and behavioral data (digital biomarkers), and (iv) use of data platforms that integrate digital data streams, visualize data in real‐time, and provide a means of greater patient engagement during the trial (digital platform). Furthermore, this paper will discuss the synergistic power in implementation of these approaches jointly within a trial to enable better understanding of adherence, safety, efficacy, PK, PD, and corresponding exposure‐response relationships of investigational therapies as well as reduced patient burden for clinical trial participation. Obstacle and challenges to adoption and full realization of the vision of patient‐centric, digitally enabled trials will also be discussed. [ABSTRACT FROM AUTHOR]

Atogepant is a potent, selective, oral calcitonin gene–related peptide (CGRP) receptor antagonist in development for migraine prevention. The chemical structure of atogepant is distinct from previous CGRP receptor antagonists, which were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report the safety, tolerability, and pharmacokinetics (PKs) of a once‐daily supratherapeutic dose (170 mg) of atogepant for 28 days from a randomized, double‐blind, placebo‐controlled phase I trial in healthy participants. Overall safety, hepatic safety, and plasma PK parameters were evaluated. Thirty‐four participants aged 23–55 years enrolled; 28 (82.4%) completed the study in accordance with the protocol. Multiple doses of 170 mg atogepant for 28 consecutive days were generally well‐tolerated. All adverse events (AEs; reported in 87.0% of the atogepant group; 72.7%, placebo) were mild in severity except one serious AE of subarachnoid hemorrhage due to a bicycle accident and not considered related to treatment. There were two discontinuations due to AEs, both with atogepant, one considered possibly related to treatment. Over 28 days of treatment, no participant receiving atogepant had an ALT elevation above 1.5 × upper limit of normal. Change from baseline in serum ALT levels was not different between atogepant and placebo. Atogepant is rapidly absorbed (median time to maximum plasma concentration, ~ 2 hours) with an apparent terminal half‐life of ~ 11 hours, and no evidence of accumulation after once‐daily dosing. Overall, atogepant at a high oral dose is safe and well‐tolerated in healthy participants with no clinically meaningful elevations in ALT. [ABSTRACT FROM AUTHOR]

What is known and objective: Doravirine is a non‐nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus (HIV)‐1 infection. This phase 1 study in healthy adults investigated the pharmacokinetics, safety and tolerability of long‐acting parenteral (LAP) microsuspension formulations of doravirine administered as an intramuscular (IM) injection. Methods: After confirmation of tolerability and safety of oral doravirine, 36 participants were randomized 1:1:1 to receive IM doravirine 200 mg as Treatment A (1 × 1 mL, 20% [200 mg/mL] suspension), B (1 × 0.66 mL, 30% [300 mg/mL] suspension) or C (2 × 0.5 mL, 20% suspension). Blood samples were taken as venous plasma, venous dried blood spots (DBS) and fingerstick DBS. Results and discussion: Plasma concentration‐time profiles following IM treatments demonstrated rapid initial doravirine release, with initial peak ~4 days post‐injection, followed by decline over the next ~6 days; a second peak was reached at ~24‐36 days, corresponding to prolonged and sustained release, with measurable concentrations up to Day 183. Treatment C was associated with highest peak concentrations and shortest time to maximum concentration. Elimination half‐lives for all IM formulations were prolonged versus oral administration (~46‐58 days vs ~11‐15 hours). Oral doravirine and IM doravirine were generally well tolerated; injection‐site pain was the most common adverse event for IM doravirine. Doravirine concentrations from DBS samples showed strong correlations to venous plasma concentrations. What is new and conclusions: Novel doravirine LAP IM injection formulations investigated in this study demonstrated sustained plasma doravirine concentrations over a course of >20 weeks. [ABSTRACT FROM AUTHOR]

The incidence of migraine is higher among women than men and peaks during the reproductive years, when contraceptive medication use is common. Atogepant, a potent, selective antagonist of the calcitonin gene‒related peptide receptor—in development for migraine prevention—is thus likely to be used by women taking oral contraceptives. This phase 1, open‐label, single‐center, 2‐period, fixed‐sequence study examined the effect of multiple‐dose atogepant 60 mg once daily on the single‐dose pharmacokinetics of a combination oral contraceptive, ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg (EE/LNG), in healthy postmenopausal or oophorectomized women. For participants in period 1, a single dose of EE/LNG was followed by a 7‐day washout. In period 2, atogepant was given once daily on days 1‐17; an oral dose of EE/LNG was coadministered with atogepant on day 14. Plasma pharmacokinetic parameters for EE and LNG were assessed following administration with and without atogepant. Twenty‐six participants aged 45‐64 years enrolled; 22 completed the study in accordance with the protocol. The area under the concentration‐time curve extrapolated to infinity (AUC0‐∞) of LNG was increased by 19% when administered with atogepant. Coadministration of atogepant and a single dose of EE/LNG did not substantially alter the pharmacokinetics of EE; the ∼19% increase in plasma AUC0‐∞ of LNG is not anticipated to be clinically significant. Overall, atogepant alone and in combination with EE/LNG was generally well tolerated, with no new safety signals identified. [ABSTRACT FROM AUTHOR]

Ubrogepant is a novel, oral calcitonin gene‐related peptide (CGRP) receptor antagonist intended for the acute treatment of migraine attacks. Ubrogepant has a chemical structure distinct from previous small‐molecule CGRP receptor antagonists that were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report overall and hepatic safety data from two placebo‐controlled phase I trials of ubrogepant, spray‐dried oral compressed tablet (SD‐OCT) in healthy male volunteers. Trial A was a pharmacokinetic (PK) trial of single (100–400 mg) and multiple (40–400 mg) ascending doses. Trial B was a dedicated hepatic safety trial assessing daily use of ubrogepant 150 mg for 28 days. Serum ALT (as hepatotoxicity biomarker) and PK data are reported. Ubrogepant was well‐tolerated in both trials, with a low incidence of adverse events that did not differ greatly from placebo. Changes in mean ALT levels were minimal and similar to placebo. Over 28 days of treatment, the mean percentage change in ALT from baseline was < 5% at all time points. No participant in either trial demonstrated ALT ≥ 3× upper limit of normal at any time. Ubrogepant SD‐OCT demonstrated linear PK appropriate for acute treatment of migraine, with rapid uptake (time of maximum plasma concentration (tmax): 2–3 hours) and no accumulation with daily use. Overall, there was no evidence of ubrogepant‐associated hepatotoxicity with daily doses up to 400 mg for 10 days or with daily ubrogepant 150 mg for 28 days. Supratherapeutic dosing is a useful strategy for characterizing hepatic safety in early drug development. [ABSTRACT FROM AUTHOR]

β‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1) is required for the production of β‐amyloid peptides, which are implicated in the etiology of Alzheimer's disease. The safety and pharmacokinetics of the BACE1 inhibitor verubecestat have previously been studied in young adults aged 19–45 years. In this randomized, placebo‐controlled, phase I study (protocol MK‐8931‐006), we investigated the safety, tolerability, and pharmacokinetics of a single dose (100 mg) or multiple doses (30, 80, and 120 mg) once daily for 28 days of verubecestat in healthy elderly subjects. Safety end points were assessed at baseline and during the duration of the study period and indicated that verubecestat was generally well tolerated. Verubecestat pharmacokinetics were similar between healthy elderly male and female subjects and similar to those reported in healthy young males in previous studies. These data supported subsequent studies to assess the potential efficacy of verubecestat in subjects with Alzheimer's disease. [ABSTRACT FROM AUTHOR]

β‐site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of β‐amyloid (Aβ) peptides and is considered a potential treatment target for Alzheimer's disease (AD). To support Japan's participation in the global clinical development program, we characterized the safety, pharmacokinetics (PKs), and pharmacodynamics of the BACE1 inhibitor verubecestat (MK‐8931) in 24 healthy Japanese adults in a two‐part, single‐center, randomized, placebo‐controlled phase I trial (protocol MK‐8931‐007) and compared the results with historical data from non‐Japanese subjects. Both single (20, 100, and 450 mg) and multiple (80 and 150 mg once daily for 14 days) doses of verubecestat were well tolerated. Verubecestat's PK profile was similar in Japanese and non‐Japanese subjects. Verubecestat also reduced mean cerebrospinal fluid concentrations of the Aβ proteins Aβ40, Aβ42, and soluble β fragment of amyloid precursor protein; the level of reduction was comparable between Japanese and non‐Japanese subjects. These results support the continued global development of verubecestat as a potential disease‐modifying agent for Japanese and non‐Japanese subjects who are at risk for developing AD. [ABSTRACT FROM AUTHOR]

Merck & Co, Inc (Kenilworth, NJ) is investing in approaches to enrich clinical trial data and augment decision making through use of digital health technologies, outpatient sampling, and real‐time data access. As part of this strategy, a phase I study was conducted to explore a few technologies of interest. In this fixed‐sequence two‐period trial, 16 healthy subjects were administered 50‐mg once‐daily sitagliptin packaged in a bottle that electronically captured the date and time study medication was dispensed (period 1) and in a traditional pharmacy bottle (period 2). Dried blood spot samples were collected for sitagliptin concentration analysis on select study days, both in clinic and at home, with collection time recorded using an electronic diary in period 1 and by clinic staff in period 2. Study results demonstrated the feasibility and subject acceptance of collecting digital adherence data and outpatient dried blood spot samples in clinical trials and highlighted areas for future improvements. [ABSTRACT FROM AUTHOR]