3.3 Safety
Safety monitoring across all three studies did not identify any major concerns. Only one SAE occurred in the MAD study, an abscess requiring hospitalisation for surgery, but was not considered treatment-related. Mild to moderate non-serious treatment-related treatment-emergent adverse events (TEAEs) were reported in all three studies.
In the SAD, the onset of TEAEs involving visual disorders occurred at approximately tmax, but with no clear evidence that they were directly related to plasma emodepside concentrations, since the duration ranged from 1 hour to 1 day. Drug-related visual disorder TEAEs were reported after doses of 10, 20 and 40 mg LSF in the fasting state (Table 8) but were all mild and resolved spontaneously within 24 hours. Onset ranged from 20 minutes to 4 hours post-dose, most often 1 to 2.5 hours post-dose. The occurrence of drug-related visual disorder TEAEs increased with emodepside dose.
Cases involving transient, mild visual disturbances, considered drug-related, also occurred in the MAD study, frequently associated with mild euphoria (Table 9). One subject treated with the lower dose also reported blurred vision of moderate intensity. Unlike in the SAD study, there was no clear relationship between the frequency of visual AEs and the dose of emodepside up to 10 mg BID, however, the duration of visual AEs was longer after 10 mg emodepside BID, with intermittent symptoms recurring up to 21 days. Based on these observations, 10 mg emodepside BID was considered to be the maximum tolerated dose as the LSF in the MAD study.
Across both parts of the RBA study and consistent with findings from the SAD study, the most frequent drug-related TEAEs involved visual disorders (2 subjects) (Table 10), with onset around tmax, 1.5–2 hours after dosing with the gastrosoluble ASD tablet at 5 or 10 mg in the fasting state. In both cases, another drug-related TEAE, i.e. dizziness and feeling of relaxation, respectively, coincided with visual disturbances. Notably, subjects who received the gastrosoluble tablet at 10 mg in the fasting state (in which 1 subject reported 2 concomitant treatment-related TEAEs: visual disturbances and feeling of relaxation) had the highest geometric mean Cmax and AUC0−7d. However, no drug-related TEAEs were reported in either the 5 mg LSF or 10 mg gastroresistant ASD tablet groups in the fasting state, both of which had higher mean Cmax and AUC0–7d than the 5 mg gastrosoluble ASD tablet fasting group in which three treatment-related TEAEs occurred: visual disturbances and dizziness, concomitantly in one subject. Thus, the results in the RBA study indicated that the gastrosoluble ASD tablet provided overall exposure closer to that of the LSF, but with a better safety profile.