A First-in-Human Study of Single and Multiple Doses of anle138b in Healthy Subjects

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety, tolerability and blood levels of orally administered anle138b in healthy subjects.

Detailed Description
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This is a single-centre, study of double-blind, randomised, placebo-controlled single ascending doses (SAD) and multiple ascending doses (MAD) of anle138b in healthy subjects in study Parts 1 and 2. In study Part 3 the effect of food (FES) on the safety and PK of anle138b in healthy subjects is examined. In the SAD cohorts, subjects will be randomly assigned to receive a single oral dose of active investigational medicinal product (IMP) or matching placebo in a sequential escalating manner with sufficient time planned between dose groups to allow interim review of the data. In the MAD cohorts, subjects will be randomly assigned to receive oral doses of active IMP or matching placebo once daily (QD) for 7 days, in a sequential escalating manner with sufficient time planned between dose groups to allow interim review of the data. In the FES, the effect of food on the safety and PK of anle138b is explored by administering a single dose of IMP after a high-fat breakfast. Subjects will be randomly assigned to one of 2 treatment sequence to receive anle138b in the fed or fasted state over 2 periods.

Official Title
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A First-in-Human Study to Assess the Safety, Tolerability and Pharmacokinetics of anle138b in Healthy Male and Female Subjects

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: anle138b
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males or women of no child bearing potential Age 18 to 55 years of age at the time of signing informed consent Body mass index (BMI) of 18.5 to 30.0 kg/m2 as measured at screening Must be willing and able to communicate and participate in the whole study Must provide written informed consent Must agree to adhere to the contraception requirements defined in Section 9.4 In the investigator's opinion, subject is able to understand the nature of the study and any risks involved in participation, and willing to cooperate and comply with the protocol restrictions and requirements. Exclusion Criteria: Subjects who have received any IMP in a clinical research study within the 90 days prior to Day 1. Subjects who are study site employees, or immediate family members of a study site or sponsor employee. Subjects who have previously been enrolled in this study. Subjects who have taken part in Part 1 are not permitted to take part in Part 2 or Part 3; subjects who have taken part in Part 2 are not permitted to take part in Part 3. History of any drug or alcohol abuse in the past 2 years. Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 units = 125 mL glass of wine, depending on type). A confirmed positive alcohol breath test at screening or admission. Current smokers and those who have smoked within the last 12 months. A confirmed breath carbon monoxide reading of greater than 10 ppm at screening or admission. Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months. Females of childbearing potential including those who are pregnant or lactating (all female subjects must have a negative urine pregnancy test at screening and serum pregnancy test on admission). A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy and bilateral oophorectomy) or is postmenopausal (had no menses for 12 months without an alternative medical cause and a serum follicle stimulating hormone concentration ≥40 IU/L). Subjects with pregnant or lactating partners. Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator or delegate at screening. Clinically significant abnormal clinical chemistry, haematology or urinalysis as judged by the investigator (laboratory parameters are listed in Appendix 1). Subjects with Gilbert's Syndrome are allowed. In addition the ALT and gamma glutamyl transferase (GGT) concentrations should not exceed the upper limit of normal (ULN) at screening and admission. Confirmed positive drugs of abuse test result (drugs of abuse tests are listed in Appendix 1) at screening or admission. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance of <70 mL/min using the Cockcroft-Gault equation. History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator. Serious adverse reaction or serious hypersensitivity to any drug or the IMP excipients. Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active. Donation or loss of greater than 400 mL of blood within the previous 3 months. Subjects who are taking, or have taken, any prescribed or over-the-counter drug or herbal remedies (other than 4 g of paracetamol per day or HRT) in the 14 days before IMP administration (See Section 11.4). Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as determined by the PI. Failure to satisfy the investigator of fitness to participate for any other reason. In Part 3, subjects must be able to eat 90% of the US Food and Drug Administration (FDA)-approved high-fat breakfast, including bacon. Subjects with a previous history of difficulty in swallowing tablets or capsules, or an anticipated problem with swallowing a large number of capsules. Blood pressure (supine) at Screening or admission outside the range: 90 to 140 mmHg for subjects <45 years or 90 to 160 mmHg for subjects >45 years for systolic BP or 40 to 90 mmHg for diastolic BP; and pulse rate outside the range of 40 to 100 bpm, unless deemed not clinically significant by the investigator and the sponsor's medical monitor. Subjects with a history of cholecystectomy or gall stones.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: anle138b<br>Dosage: 50 mg and higher Dosage form: capsule Frequency: once daily Duration: One day for SAD and seven days for MAD | Drug: anle138b<br>* capsule containing excipient and anle138b<br>|
| Placebo Comparator: placebo<br>Matching placebo Dosage form: capsule Frequency: once daily Duration: One day for SAD and seven days for MAD | Drug: Placebo<br>* matching placebo capsule containing excipient<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events in healthy volunteers with single ascending doses of anle138b (Part 1) | Adverse events (AEs) | Day 1 to day 30 post dose | 
| Incidence of treatment-emergent changes in clinical laboratory parameters in healthy volunteers with single ascending doses of anle138b (Part 1) | clinical laboratory tests including hematology and clinical chemistry including renal function tests, hepatic enzymes, electrolytes and creatine kinase | Day 1 to day 7 post dose | 
| Incidence of treatment-emergent changes in vital signs in healthy volunteers with single ascending doses of anle138b (Part 1) | Blood pressure, heart rate, oral temperature | Day 1 to day 7 post dose | 
| Incidence of treatment-emergent ECG changes in healthy volunteers with single ascending doses of anle138b (Part 1) | Electrocardiogram (ECG) parameters including QT interval corrected for heart rate using Fridericia's formula (QTcF) | Day 1 to day 7 post dose | 
| Incidence of treatment-emergent changes in physical examination in healthy volunteers with single ascending doses of anle138b (Part 1) | physical examination findings | Day 1 to day 7 post dose | 
| Incidence of treatment-emergent adverse events in healthy volunteers with multiple ascending doses of anle138b (Part 2) | Adverse events (AEs) | Day 1 to day 30 post dose | 
| Incidence of treatment-emergent changes in clinical laboratory parameters in healthy volunteers with multiple ascending doses of anle138b (Part 2) | clinical laboratory tests including hematology and clinical chemistry including renal function tests, hepatic enzymes, electrolytes and creatine kinase | Day 1 to day 7 post dose | 
| Incidence of treatment-emergent changes in vital signs in healthy volunteers with multiple ascending doses of anle138b (Part 2) | Blood pressure, heart rate, oral temperature | Day 1 to day 7 post dose | 
| Incidence of treatment-emergent ECG changes in healthy volunteers with multiple ascending doses of anle138b (Part 2) | Electrocardiogram (ECG) parameters including QT interval corrected for heart rate using Fridericia's formula (QTcF) | Day 1 to day 7 post dose | 
| Incidence of treatment-emergent changes in physical examination in healthy volunteers with multiple ascending doses of anle138b (Part 2) | physical examination findings | Day 1 to day 7 post dose | 
| Incidence of treatment-emergent adverse events in healthy volunteers with a single dose of anle138b both the fasted and fed state (Part 3) | Adverse events (AEs) | Day 1 to day 30 post dose. | 
| Incidence of treatment-emergent changes in clinical laboratory parameters in healthy volunteers with a single dose of anle138b both in the fasted and in the fed state (Part 3) | clinical laboratory tests including hematology and clinical chemistry including renal function tests, hepatic enzymes, electrolytes and creatine kinase | Day 1 to day 7 post dose | 
| Incidence of treatment-emergent changes in vital signs in healthy volunteers with a single dose of anle138b both in the fasted and in the fed state (Part 3) | Blood pressure, heart rate, oral temperature | Day 1 to day 7 post dose | 
| Incidence of treatment-emergent ECG changes in healthy volunteers with a single dose of anle138b both in the fasted and in the fed state (Part 3) | Electrocardiogram (ECG) parameters including QT interval corrected for heart rate using Fridericia's formula (QTcF) | Day 1 to day 7 post dose | 
| Incidence of treatment-emergent changes in physical examination in healthy volunteers with single ascending doses of anle138b both in the fasted and in the fed state (Part 3) | physical examination findings | Day 1 to day 7 post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state | Time prior to the first measurable concentration of anle138b. Time prior to the first measurable concentration of anle138b. | From dosing to 48 hours post dosing | 
| Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state | Time of maximum observed concentration of anle138b. | From dosing to 48 hours post dosing | 
| Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state | Maximum observed concentration of anle138b. | From dosing to 48 hours post dosing | 
| Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state | Area under the curve from 0 time to 24 h post-dose of anle138b. | From dosing to 48 hours post dosing | 
| Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state | Area under the curve from 0 time to the last measurable concentration of anle138b. | From dosing to 48 hours post dosing | 
| Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state | Area under the curve from 0 time extrapolated to infinity of anle138b levels. | From dosing to 48 hours post dosing | 
| Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state | Percentage of area under the curve (0-inf) extrapolated beyond the last measurable concentration of anle138b. | From dosing to 48 hours post dosing | 
| Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state | Slope of the apparent elimination phase of anle138b. | From dosing to 48 hours post dosing | 
| Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state | Apparent elimination half-life of anle138b. | From dosing to 48 hours post dosing | 
| Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state | Mean residence time from 0 time to the last measurable concentration after extravascular administration of anle138b. | From dosing to 48 hours post dosing | 
| Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state | Mean residence time extrapolated to infinity after extravascular administration of anle138b. | From dosing to 48 hours post dosing | 
| Oral pharmacokinetics (PK) of multiple (Part 2) ascending doses of anle138b in the fasted state | Time of maximum observed concentration of anle138b | Day 1 to day 9 | 
| Oral pharmacokinetics (PK) of multiple (Part 2) ascending doses of anle138b in the fasted state | Maximum observed concentration of anle138b | Day 1 to day 9 | 
| Oral pharmacokinetics (PK) of multiple (Part 2) ascending doses of anle138b in the fasted state | Area under the curve over the dosing interval from time 0 to tau of anle138b | Day 1 to day 9 | 
| Oral pharmacokinetics (PK) of multiple (Part 2) ascending doses of anle138b in the fasted state | Slope of the apparent elimination phase (last dose only) of anle138b | Day 7 to day 9 | 
| Oral pharmacokinetics (PK) of multiple (Part 2) ascending doses of anle138b in the fasted state | Apparent elimination half-life (last dose only) of anle138b | Day 1 to day 9 | 
| Oral pharmacokinetics (PK) of single (Part 1) and multiple (Part 2) ascending doses of anle138b in the fasted state | Accumulation Ratio based on Cmax repeated dose /Cmax single dose of anle138b | Day 1 to day 9 | 
| Oral pharmacokinetics (PK) of single (Part 1) and multiple (Part 2) ascending doses of anle138b in the fasted state | Accumulation Ratio based on area under the curve (0 tau) repeated dose/AUC(0 tau) single dose of anle138b | Day 1 to day 9 | 
| Oral pharmacokinetics (PK) (Part 3) for anle138b in the fed and fasted states. | Maximum observed concentration of anle138b. | From dosing to 48 hours post dosing | 
| Oral pharmacokinetics (PK) (Part 3) for anle138b in the fed and fasted states. | Area under the curve from 0 time to the last measurable concentration of anle138b. | From dosing to 48 hours post dosing | 
| Oral pharmacokinetics (PK) (Part 3) for anle138b in the fed and fasted states | Area under the curve from 0 time extrapolated to infinity of anle138b levels. | From dosing to 48 hours post dosing | 
| Oral pharmacokinetics (PK) (Part 3) for anle138b in the fed and fasted states | Percentage of area under the curve (0-inf) extrapolated beyond the last measurable concentration of anle138b. | From dosing to 48 hours post dosing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anle138b, alpha-Synuclein, Oligomer modulator, Parkinson Disease, Multiple System Atrophy, Neurodegenerative diseases, Alzheimer Disease, Tauopathies, Amyloid