4. Discussion
De novo discovery and development of new therapeutics is an extremely costly and time-consuming process that is rarely conducted for neglected tropical diseases, including onchocerciasis, where drug discovery is notoriously under-funded. Since emodepside is a registered product in animal health, the present studies confirm the usefulness of drug repurposing as a strategy for identifying and developing new therapeutic agents. Its safety and efficacy profiles are well established after nearly 15 years of use in the veterinary setting. As expected, the early development results in healthy male subjects from the three Phase I studies reported here show promising safety profiles.
Across all three Phase I clinical studies, emodepside was found to be rapidly absorbed under fasting conditions. Dose-proportional increases in plasma emodepside concentrations were observed with increasing doses from 1 mg to 40 mg after oral administration of the LSF. Conventional IR tablets containing 5 mg or 20 mg crystalline emodepside were somewhat more slowly and poorly absorbed as compared to the LSF.
The half-life during the first 24 hours after dosing, i.e. during the distribution-elimination phase, was short at around 11 hours, and was followed by a very long terminal elimination half-life, estimated at > 500 hours. Owing to the long terminal elimination half-life, steady state was not reached after repeated dosing with emodepside for 10 days in the MAD study. In all three studies, plasma concentration-time profiles for emodepside showed a distinct biphasic pattern in the descending part of the curve, which is postulated to reflect initial rapid distribution of the compound followed by very slow terminal elimination. This finding is particularly promising since rapid distribution of emodepside in the tissues suggests that exposure of the parasites may be high, given that microfilariae reside mainly in the skin and adult worms in subcutaneous tissue. This hypothesis is backed up by preclinical findings with radio-labelled emodepside, showing that radioactivity levels were higher in most tissues than in the blood, the highest concentrations being detected in the fat at all time-points. In addition, the long terminal half-life is expected to be advantageous in maintaining patient exposure to pharmacodynamically active drug levels. The long half-life is not expected to raise any safety issues, based on the available toxicological data and the safety profile of emodepside across the three studies.
In both studies comparing dosage forms, the LSF showed consistently higher bioavailability than the tablet formulations. Indeed, in the SAD study, the conventional IR tablet containing crystalline emodepside had insufficient bioavailability compared to the LSF and was considered unsuitable for further study. This is due to the biopharmaceutical properties of emodepside, and optimisation of the dosage form was required to improve the dissolution kinetics. New ASD tablets containing 5 mg emodepside in amorphous form were developed and showed markedly better bioavailability. The gastrosoluble ASD tablet was more bioavailable than the gastroresistant ASD tablet. With both ASD tablets, intake under fed conditions slowed the rate of absorption of emodepside and reduced its bioavailability. Based on data from the RBA study, a 15 mg dose with the gastrosoluble ASD tablet is predicted to provide equivalent exposure to 10 mg LSF.
From the outset it was known that, for logistical reasons, the liquid formulation would not be practical for use in the field in Phase II and III studies in countries where onchocerciasis is endemic. Nevertheless, as these Phase I studies showed, the LSF leads to higher exposure as compared to the tablet formulations, making it useful in assessing the safety profile. Overall, TEAEs were more frequent with the LSF, particularly at higher doses.
No important safety risks, either potential or identified, have been identified with emodepside to date. Safety data accrued in the three Phase I studies indicate that potential effects on the central nervous system and vision will require close monitoring in future studies.
Lastly, in the MAD study, the increase in plasma emodepside concentration after the final dose of the LSF on Day 9 was lower after 10 mg BID than after 10 mg OD, with Cmax/Ctrough ratios of 1.9 and 3.0, respectively (data on file). Although the total daily dose in the 10 mg BID dosing group was twice as high as that in the 10 mg OD dosing group on Days 0–8, geometric mean Cmax on Day 9 was only 1.2-fold higher in the 10 mg BID dosing group compared to the 10 mg OD group. This suggested that twice-daily dosing might be beneficial in mitigating any adverse effects related to Cmax, thereby improving tolerability.
Thus, the three Phase I studies provided invaluable information on the safety, PK profile and relative bioavailability of emodepside in healthy humans. The LSF is not suitable for easy and accurate clinical use under the conditions expected for patients treated for onchocerciasis, and the Phase I data enabled us to select a field-adapted tablet formulation compatible with the biopharmaceutical properties of emodepside. We also identified a dose and dosing regimen that will achieve the target effective concentration in humans, i.e. 100 ng/mL (10-7 M) of emodepside, and open the way for Phase II and III studies in individuals infected with O. volvulus .