RESULTS
Subject demographics. A total of 40 subjects (17 subjects in Part 1 and 23 subjects in Part 2) were randomized to the study. All subjects were male Caucasians. One subject in Part 1 discontinued after 5 mg and was replaced for the subsequent dose levels, and one subject in Part 2 withdrew consent before randomization and was not replaced. Subject disposition is shown in Table 1. Subject demographics are shown in Table 2-3. The treatment groups within each study part were comparable with respect to demographic parameters as well as concomitant medication and medical history.
Safety and tolerability. All 40 subjects were included in the safety analysis. There were no SAEs in the study and no AEs led to withdrawal.
The first subject administered a single dose at the highest pre-defined dose level, 160 mg, experienced adverse central nervous system (CNS) symptoms of antidopaminergic character such as disturbance in attention, dizziness, tremor, restlessness, nervousness and cold sweat. The main symptoms disappeared within seven hours post dose and the subject was fully recovered after one day. Due to these AEs the dose was reduced to 120 mg for the remaining subjects.
All AEs were coded according to MedDRA version 19.0. A detailed account of AEs occurring after first administration of IMP (Treatment Emergent AEs, TEAEs) is presented by SAD cohort (Part 1) in Table 4 and by MAD dose group (Part 2) in Table 5. During single dose escalation (part 1), the AEs most frequently represented were Infections and infestations (nasopharyngitis) andNervous system disorders (headache being the most frequently reported event). Increased frequency or intensity of events by dose or by treatment (mesdopetam/placebo) was not seen in any of the AEs represented up to 120 mg mesdopetam. At the 160 mg dose level the only subject treated experienced disturbance in attention, dizziness, tremor, restlessness, nervousness and cold sweat. Disturbance in attention and restlessness was also experienced by one (20.0%) of the subjects given 120 mg mesdopetam.
In the part 2 (MAD) of the study the AEs most frequently represented were Infections and infestations (nasopharyngitis), Nervous system disorders (somnolence, disturbance in attention, headache and tremor), and Respiratory, thoracic and mediastinal disorders(nasal congestion, epistaxis and oropharyngeal pain). All 17 events reported within Nervous system disorders occurred after administration of 80 mg mesdopetam. Two subjects (25.0%) reported a total of eight events of somnolence whereof seven were assessed as probably related to the IMP and one as not related. One subject (12.5%) reported seven events of disturbance of attention, all assessed as probably related to IMP.
Any TEAE was experienced at all dose levels in part 1 of the study, including placebo. Of the TEAEs reported, 20/35 (57.1%) were assessed as not related to study treatment and 27/35 (77.1%) were of mild intensity. The one subject exposed to 160 mg mesdopetam experienced AEs of moderate intensity and one mild event, all assessed as probably related to the IMP.
In part 2 of the study, any TEAE was experienced in all dose groups, including placebo. The proportion of subjects experiencing any TEAE at doses 40 mg, 80 mg and placebo was 55.6%, 50.0%, and 16.7%, respectively. The average number of TEAEs reported by subject (m/n) was 1.2 and 5.8 at doses 40 mg, 80 mg and 1.0 for subjects given placebo. Following administration of 80 mg mesdopetam 16/23 events reported (69.6%) were assessed as possibly (2) or probably (14) related to the IMP whereas all events occurred following administration of 40 mg mesdopetam or placebo were assessed as not related. Of the totally 30 TEAEs reported 66.7% were of mild intensity.
There were no remarkable mean changes over time or individual clinically significant abnormal findings with regards to any of the vital signs parameters and no abnormal findings upon physical examination were reported at any of the time-points assessed in the SAD or the MAD part of the study.
Electrocardiogram (Single 12-lead ECG in both part 1 and 2 and ambulatory ECG telemetry in part 1 only) showed no remarkable mean changes over time or individual clinically significant abnormal values with regards to any of the ECG parameters measured.
Safety laboratory parameters showed no remarkable changes in mean values over time for any of the parameters analysed.
Dopamine released from tuberoinfundibular dopamine neurons inhibits prolactin secretion from the anterior pituitary (8). As a biomarker for target engagement plasma prolactin was measured at regular intervals in both Part 1 and Part 2 of the study. Following single dosing, mesdopetam produced a dose-dependent increase in plasma levels of prolactin indicating target engagement. Also, in the MAD part of the study modest, dose dependent elevations of plasma prolactin were seen. Table 6 -7 shows the median plasma prolactin levels by dose and time after administration for the SAD and MAD parts of the study.