Safety, Tolerability and PK of Multiple-ascending Doses of Emodepside

A Phase 1, Single-Blind, Randomized, Placebo Controlled, Parallel-Group, Multiple-Dose-Escalation Study to Investigate Safety, Tolerability, and Pharmacokinetics of Emodepside (BAY 44-4400) After Oral Dosing in Healthy Male Subjects

The study evaluates safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of emodepside, after administration as a Liquid Service Formulation (LSF), over 10 days, in healthy male caucasian subjects.

There is an urgent need for a macrofilaricidal drug, killing or sterilizing permanently O. volvulus adult worms, which could be used in individual case management and, after appropriate testing, as an alternative drug to ivermectin in Mass Drug Administration (MDA) programs. Emodepside is a promising candidate to kill the adult and sexually mature O. volvulus as explained below. Emodepside was shown to be macrofilaricidal against a variety of filarial nematodes and is a registered drug for animal health, commercialized by Bayer AG under the name of Profender® (in combination with praziquantel) or Procox® (in combination with toltrazuril).

A first-in-human (FIH) double-blind, placebo-controlled study of single ascending doses of emodepside in healthy Caucasian men has been conducted and the preliminary results are favourable, supporting continuation of the Phase I development program. In the present repeat dose study, PK as well as safety and tolerability of the liquid service formulation of emodepside, given over 10 days, will be tested.

Inclusion Criteria:

1. Male, Caucasian volunteers, deemed healthy based on a clinical history, physical examination, ECG, vital signs, and laboratory tests of blood and urine.
2. 18 to 45 years of age.
3. Normal body weight (BMI; Quetelet index) in the range 18 to 30.1 kg/m2 at screening.
4. Blood pressure and heart rate in the supine position prior to randomisation must be within the ranges 90-140 mm Hg systolic, 60-90 mm Hg diastolic; heart rate 45-100 beats/min.
5. Sufficient intelligence to understand the nature of the trial and any hazards of participating in it. Ability to communicate satisfactorily with the Investigator and to participate in, and comply with the requirements of, the entire trial.
6. Willingness to give written consent to participate, after reading the information and consent form, and after having the opportunity to discuss the trial with the Investigator or his delegate.
7. Willingness to give written consent to have data entered into the Overvolunteering Prevention System.
8. Willingness to agree to the contraceptive requirements of the study from the first dose until 120 days after the last dose of study medication.

Exclusion Criteria:

1. Administration of a licensed or unlicensed medicinal product as part of another clinical trial within the 3 months before, or within 5 half-lives of, their first dose of study medication, whichever is longer, or is currently in the follow-up period for any clinical trial.
2. Clinically relevant abnormal medical history, concurrent medical condition, acute or chronic illness or history of chronic illness (such as diabetes mellitus or other abnormalities of glucose homeostasis) sufficient to invalidate the subject's participation in the trial or make it unnecessarily hazardous.
3. Past surgery (e.g., stomach bypass) or medical condition that might affect absorption of study drug taken orally.
4. Presence of abnormal physical findings, ECG, or laboratory values at the pre-trial screening assessment that could interfere with the objectives of the trial or the safety of the subject.
5. Loss of more than 400 mL of blood within 3 months before admission.
6. Clinically relevant history of vital organ disease or other disease of an organ or the central nervous system.
7. Current or previous medical or psychiatric disorder, condition or history of such (e.g., seizures) that, in the opinion of the Investigator or the Sponsor, would increase the risk associated with study participation, or impair the subject's ability to participate or complete this study.
8. Positive test for hepatitis B, hepatitis C or HIV.
9. Febrile illness within 1 week before the first dose of study medication.
10. History of severe allergy, non-allergic drug reactions, severe adverse reaction to any drug, or multiple drug allergies.
11. Subjects with hypersensitivity to any ingredient of the study medication, including the active ingredient, emodepside.
12. Presence or history of drug or alcohol abuse in the last 10 years, or intake of more than 21 units of alcohol weekly.
13. Regular daily consumption of more than one liter of xanthine-containing beverages.
14. Regular daily consumption of more than 5 cigarettes daily, or use more than 3 grams (1/8 ounce) of tobacco.
15. Use of a prescription medicine during the 28 days before the first dose of study medication or use of an over-the-counter medicine (with exception of acetaminophen [paracetamol]), during the 7 days before the first dose of study medication.
16. Use of dietary supplements or herbal remedies (such as St John's Wort) that are known to be inducers or inhibitors of CYP3A4, or other co-medications known to be relevant substrates of CYP3A4, during the 28 days before the first dose of study medication (see list in the Study Procedures Manual).
17. Use of dietary supplements or herbal remedies (such as St John's Wort) that are known to be strong inhibitors of P-gp, or other co-medications known to be relevant substrates of P-gp, during the 28 days before the first dose of study medication (see list in the Study Procedures Manual).
18. Relevant pathological abnormalities in the ECG at screening, such as a second or third-degree atrioventricular (AV) block or prolongation of the QRS complex over 120 msec or QTc-interval over 450 msec (corrected using Bazett's [QTcB] or Fridericia's [QTcF] formulae).
19. Evidence of drug abuse (via urine testing) at the screening assessment or admission to the ward.
20. Use of excluded therapies that may impact on the interpretation of study results in the opinion of the Investigator or Sponsor.
21. Objection by General Practitioner (GP) to subject entering trial.
22. History of residing for 6 or more continuous months, within the last 3 years, in regions with endemic parasitic infections as determined by the Investigator.
23. Possibility that subject will not cooperate with the requirements of the protocol.
24. No contact lenses wear within 1 month before dosing. Wearing contact lenses is not permitted during the study.
25. Any ocular disorder for which topical ocular therapy is currently or chronically prescribed, including inflammatory eye disease (dry eye allergic conjunctivitis [seasonal allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis], uveitis and glaucoma).
26. Past history of ocular disease requiring ongoing treatment.
27. Past ocular surgery including laser or other refractive corneal surgery.
28. Evidence of eye irritation, visual difficulties, corneal opacity, ocular surface (corneal or conjunctival damage, with or without ocular symptoms).
29. Evidence of narrow anterior chamber angles causing increased risk of acute glaucoma.
30. Evidence of ocular media opacity including lens opacity/vitreous opacities.
31. Evidence of retinal or optic nerve pathology.
32. Evidence of pronounced colour blindness, as indicated by an Ishihara score of 9/13 or below.