This is a phase 1 randomized double blind, first in human (FIH) study with the novel oral Alzheimer drug candidate REM0046127, which consists of two main parts, a single ascending dose (SAD) study with 7 cohorts followed by a multiple ascending dose (MAD) study with 2 cohorts.
SAD As a baseline, 5 cohorts of 8 young healthy males are foreseen, with a repeat to assess food impact and an additional elderly cohort. Depending on the early FIH findings, the number of cohorts could be more or less. FIH studies include initially only males due to the incomplete nature of preclinical reproductive toxicology studies * Treatment duration: single day * Each cohort: * 2 volunteers on placebos, of which 1 sentinel * 6 volunteers on study drug, of which 1 sentinel * Timing for each cohort will be about 21 days * Subjects will be screened for selection from day -21 to day -1 before starting the experimental phase of each cohort * First the 2 sentinels will be dosed * Following the review of sentinel safety and tolerability data through the Data Safety Monitoring Board (DSMB) after one day or 2 half-life times following the sentinel dosing, the remaining 1+5 subjects will be randomized and dosed approximately 7 days after the sentinels MAD * First cohort of 10 healthy young male subjects. This cohort can be initiated after the food interaction has been assessed in the last safe SAD cohort, and does not need to wait for the elderly cohort. * Second cohort of 12 healthy elderly subjects: * The 1st cohort of healthy young male at about 75% of the Maximum Tolerated Dose (MTD) of the SAD * The 2nd cohort of healthy older male and female (not of child-bearing potential) at about 50 or 100% of the highest tolerable dose of the SAD, depending on the observations in the 1st MAD cohort to assess potential impact of age on Pharmacokinetics (PK) * Treatment duration: 7 days * Timing for each cohort will be about 35 days * Subjects will be screened for selection from day -21 to day -1 before starting the experimental phase each cohort * First the sentinels will be dosed * Following the review of sentinel safety and tolerability data through the DSMB, the remaining subjects will be randomized and dosed approximately 14 days later * According to plan the sentinels of the 2nd cohort will be dosed about 35 days after the sentinels of the 1st cohort.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
77
Oral solution: 100 mg/mL REM0046127
Oral solution with 0 mg/mL REM0046127
Medical University Vienna, Department of Clinical Pharmacology
Vienna, Austria
Adverse Events
Number of Adverse Events either related or not related to treatment in the verum group in comparison to the placebo group
Time frame: SAD: from dosing to 72 hours after dosing. MAD: from the first dosing until 48 hours after the last dosing on day 7.
SAD: Plasma Concentration including Peak Plasma Concentration (Cmax)
The plasma concentration during 48 hours after the dosing.
Time frame: Plasma samples will be taken during SAD at baseline and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose.
SAD: Plasma Concentration including Half-Life(t1/2)
The plasma concentration during 48 hours after the dosing.
Time frame: Plasma samples will be taken during SAD at baseline and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose.
SAD: Area under the Curve (AUC)
The AUC between baseline and 48 hour safter dosing.
Time frame: Plasma samples will be taken during SAD at baseline and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose.
MAD: Half-Life(t1/2) between Baseline and 48 hours after the last dosing.
Half-Life(t1/2) between Baseline and 48 hours after the last dosing.
Time frame: Plasma samples will be taken pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24 hours post-dose, pre-dose on Day 5 and on Day 7: 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24 hours (Day 8) and 48 hours (Day 9).
MAD: Plasma Concentration
Peak Plasma Concentration (Cmax) between Baseline and 48 hours after the last dosing.
Time frame: Plasma samples will be taken pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24 hours post-dose, pre-dose on Day 5 and on Day 7: 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24 hours (Day 8) and 48 hours (Day 9).
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MAD: Area under the Curve (AUC)
The AUC and steady-state volume of distribution(Vss) during the time interval from the first dose and 48 hour safterlast dose
Time frame: Plasma samples will be taken pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24 hours post-dose, pre-dose on Day 5 and on Day 7: 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24 hours (Day 8) and 48 hours (Day 9).
Cerebrospinal Fluid (CSF) PK (MAD)
In CSF the unbound brain/plasma partition coefficient (Kp,u) will be determined.
Time frame: CSF samples will be collected on the last day of dosing (Day 7) at approximately Tmax determined during SAD