Healthy Volunteers
The baseline demographics of healthy volunteer subjects randomized across cohorts 1–3 were similar and are listed in Table 1 in the Electronic Supplementary Material (ESM). All subjects were male with a mean age of approximately 42 years and a body mass index (BMI) of approximately 26 kg/m2. Table 1 in the ESM also lists the number of subjects who were randomized in the study, completed, or withdrew from the study.
Table 1 Pharmacokinetic parameters for GSK2798745 in healthy volunteer subjects Cohort 1 planned to enroll eight subjects who received single GSK2798745 doses of 0.5, 1, 5, 12.5 mg and/or placebo (six active, two placebo) with adequate washout in a crossover design. One subject in cohort 1 was withdrawn from the second treatment period before dose administration because of an AE (vasovagal syncope after intravenous cannulation). This subject was replaced with a new subject for the remaining treatment periods in cohort 1. Thus, nine subjects were randomized in cohort 1. The emerging safety and PK data from cohort 1 were evaluated before progressing to cohorts 2 and 3 in healthy volunteers.
A 5-mg dose was evaluated in 12 subjects in cohort 2 to assess the relative bioavailability and effect of food on GSK279845 exposure. One subject in the fasted state in this cohort 2 (treated with GSK2798745 suspension) withdrew consent for personal reasons after completing the first treatment period. As per protocol, this subject was not replaced, leaving 11 subjects completing the remaining two treatment periods.
Cohort 3, which was conducted in parallel to cohort 2, also evaluated the 5-mg dose of GSK2798745 to characterize its PK with a once-daily repeat-dosing regimen. Eight subjects received 5 mg of GSK2798745 or placebo once daily (3:1 randomization ratio – six subjects on GSK2798745 and two subjects on placebo) for 14 days in this cohort 3. Four subjects (three active, one placebo) completed the 14-day period, but the second set of four subjects (three active, one placebo) were dosed for 8 days when dosing in that cohort was terminated based on the emerging data from a concurrent long-term preclinical safety study. It should be noted that, although a placebo subject in cohort 3 is included in Table 6 as having withdrawn consent, this was after completion of 8 days of dosing as the subject did not wish to complete the 72-h follow-up period.
Subjects with Heart Failure
Cohort 4 enrolled a total of 23 subjects with mild-moderate heart failure with ten subjects randomized to GSK2798745 and 13 subjects to placebo. Cohort 5 enrolled a total of eight subjects, six randomized to GSK2798745 and two randomized to matching placebo. All subjects in these cohorts completed the study as summarized in Table 2 in the ESM.
Table 2 Impact of formulation and food on the systemic exposure of GSK2798745 5 mg The baseline demographics of the subjects with heart failure were generally similar between the group receiving 2.4-mg repeat doses of GSK2798745 and the placebo group in cohorts 4 and 5 (Table 2 in the ESM). The subjects in both cohorts had a mean age of approximately 67 years and a BMI of approximately 29 kg/m2 (cohort 4) and 27 kg/m2 (cohort 5). All subjects in cohort 5 were male, and 7 of the 23 subjects in cohort 4 were female.
Pharmacokinetics in Healthy Subjects
The average concentration–time profiles for ascending GSK2798745 single doses are presented in Fig. 2. The summary PK parameters in healthy subjects in cohorts 1–3 are listed in Table 1. Dose escalation in cohort 1 demonstrated approximate dose-proportional PK for doses from 1 to 12.5 mg for Cmax and AUC. GSK2798745 was rapidly absorbed with Tmax between 1 and 4 h, with an approximate t½ of 13 h. TRPV4 channel blockade can be estimated corresponding to any systemic concentration and the potency (~ 2–4 nM) derived from preclinical experiments. The observed GSK2798745 peak systemic exposures at the single doses ≥ 5 mg were estimated to provide > 90% TRPV4 channel blockade based on its high potency. A once-daily dosing regimen in cohort 3 led to less than twofold drug accumulation as seen from the exposure data. Based on trough concentrations, steady state appeared to be attained in approximately 4–6 days with the once-daily dosing regimen.
The systemic exposure data from subjects in cohort 2 demonstrated a small increase in the Cmax (4%) and AUC (12%) when a 5-mg dose of GSK2798745 was administered as a capsule compared with the liquid formulation. Further administration of 5-mg GSK2798745 capsules with a standard FDA-recommended high-fat meal resulted in an increase of 9% in Cmax and 14% in AUC compared with administration in the fasted state. These changes are summarized in Table 2 and were not considered clinically relevant.
Pharmacokinetics in Subjects with Heart Failure
All available data from healthy subjects in the first 3 cohorts were used to develop a preliminary population PK model to simulate exposures in subjects with heart failure recruited in cohorts 4 and 5. In addition, preliminary data obtained from cohort 2 indicated small increases (~ 25%) in systemic exposure when GSK2798745 was administered with food as a capsule formulation. Subsequently, a 2.4-mg capsule formulation with food was determined as the highest dose predicted to provide exposures with the lowest likelihood of any subject exceeding exposure thresholds established based on data from preclinical safety studies. Thus, a 2.4-mg dose in capsules without meal restrictions was recommended to be administered to subjects in cohorts 4 and 5.
In cohort 4, six patients initially received a single dose of a 2.4-mg GSK2798745 capsule or placebo in period 1 followed by a 1-week washout before starting period 2 to evaluate the safety, tolerability, and PK of once-daily 7-day repeat dosing of GSK2798745. Based on preliminary safety data in the first six subjects, subsequent new patients enrolled in cohort 4 were directly randomized to receive once-daily 7-day repeat doses of 2.4 mg of GSK2798745 or placebo.
The PK results obtained from the patients with mild-moderate heart failure in these two cohorts are summarized in Table 3, and the day 1 profiles are presented in Fig. 2. The PK data in cohort 4 were obtained from few subjects and thus the PK parameters could not be adequately or reliably estimated in every subject. However, the limited data from period 1 indicated a systemic mean ± standard deviation (SD) for half-life of approximately 17 ± 4.5 h, with a Tmax ranging from 1 to 6 h (data on file). Systemic exposure of GSK2798745 in cohort 5 demonstrated less than twofold accumulation with the once-daily 7-day dosing regimen. The PK sampling scheme did not allow estimation of the t½ in this cohort. The Tmax ranged from 1 to 5 h and was comparable to that observed in cohort 4. Overall, the average exposures observed in subjects with heart failure were approximately 20% higher than those in healthy subjects. More data may be needed to reliably quantify such small differences. The peak exposures observed on days 1 and/or 7 in these cohorts were adequate to provide a predicted 80–90% TRPV4 channel blockade on average.
Table 3 Pharmacokinetic parameters from cohort 4 heart failure subjects (2.4-mg capsule once daily with food) Safety Results
Single and repeat doses of GSK2798745 between 0.25 and 12.5 mg were generally well tolerated in healthy volunteer subjects. A majority of subjects reported single AEs in cohorts 1–3, and all AEs were mild to moderate in intensity. One subject in cohort 1 was withdrawn from the second treatment period before dose administration due to an AE of vasovagal syncope after intravenous cannulation. This subject received 0.25 mg of GSK2798745 in the first treatment period. As per protocol, the withdrawn subject was replaced by a subject who received the remaining two doses of GSK2798745 in the sequence. Back pain and dyspnea were reported by two subjects each after treatment with the 5-mg liquid formulation of GSK2798745. No clinically significant safety concerns were observed with administration of GSK2798745 after single and repeat doses to healthy volunteers, and no serious AEs were reported in any of the subjects. AEs reported with single or repeat administration to healthy volunteers that were considered related to treatment with 5 mg of GSK2798745 included headache (two subjects), nasopharyngitis, dizziness, fatigue, nasal congestion, dyspepsia, and feeling abnormal (each in one subject). The detailed AE listings for cohorts 1, 2, and 3 are provided in Tables 3, 4, and 5 in the ESM.
Similarly, repeat doses of 2.4 mg of GSK2798745 for up to 7 days were also generally well-tolerated in patients with heart failure (Table 6 in the ESM). No clinically significant safety concerns were observed with administration of GSK2798745 to patients with heart failure. Furthermore, none of these patients were withdrawn from the study because of AEs. Within cohort 4, one subject who received 2.4 mg of GSK2798745 experienced an accelerated idioventricular rhythm that was considered drug related by the investigator. There were no reports of drug-related AEs in patients with heart failure in cohort 5. It should be noted that nonsustained ventricular tachycardia in these patients was frequently present at pre-dose.
Based on ECGs, telemetry (continuous to 24 h after single-dose administration in cohorts 1, 2, and 4 and up to 48 h after repeat dosing in patients with heart failure in cohorts 4 and 5), pulse oximetry, vital sign assessments, clinical laboratory assessments (including troponin), echocardiograms, weight measurements, appetite assessments, and suicidality questionnaires, no clinically significant safety concerns were noted. An oral glucose tolerance test administered in cohort 3 (four subjects who completed the scheduled 14-day repeat period) showed no indication of hyperglycemia.
The majority of subjects with heart failure in each treatment group in cohorts 4 and 5 did not report a change from baseline in audiometry. The proportion of subjects with heart failure with a change from baseline in audiometry was low and similar between the treatment groups. Other exploratory assessments were conducted in the repeat-dose cohorts 3–5 in healthy volunteers and subjects with heart failure, which will be reported separately.