Clinical trial NCT04208152: A First-in-Human Study of Single and Multiple Doses of anle138b in Healthy Subjects
Official title: A First-in-Human Study to Assess the Safety, Tolerability and Pharmacokinetics of anle138b in Healthy Male and Female Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: anle138b
alpha-Synuclein
Oligomer modulator
Parkinson Disease
Multiple System Atrophy
Neurodegenerative diseases
Alzheimer Disease
Tauopathies
Amyloid
Lead sponsor: MODAG GmbH
Sponsor class: INDUSTRY
Collaborators: name: Quotient Sciences
name: Aptuit
First posted: 2019-12-23
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Healthy males or women of no child bearing potential
2. Age 18 to 55 years of age at the time of signing informed consent
3. Body mass index (BMI) of 18.5 to 30.0 kg/m2 as measured at screening
4. Must be willing and able to communicate and participate in the whole study
5. Must provide written informed consent
6. Must agree to adhere to the contraception requirements defined in Section 9.4
7. 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:

1. Subjects who have received any IMP in a clinical research study within the 90 days prior to Day 1.
2. Subjects who are study site employees, or immediate family members of a study site or sponsor employee.
3. 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.
4. History of any drug or alcohol abuse in the past 2 years.
5. 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).
6. A confirmed positive alcohol breath test at screening or admission.
7. 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.
8. Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months.
9. 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).
10. Subjects with pregnant or lactating partners.
11. Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator or delegate at screening.
12. 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.
13. Confirmed positive drugs of abuse test result (drugs of abuse tests are listed in Appendix 1) at screening or admission.
14. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results
15. Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance of \<70 mL/min using the Cockcroft-Gault equation.
16. History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator.
17. Serious adverse reaction or serious hypersensitivity to any drug or the IMP excipients.
18. Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active.
19. Donation or loss of greater than 400 mL of blood within the previous 3 months.
20. 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.
21. Failure to satisfy the investigator of fitness to participate for any other reason.
22. In Part 3, subjects must be able to eat 90% of the US Food and Drug Administration (FDA)-approved high-fat breakfast, including bacon.
23. Subjects with a previous history of difficulty in swallowing tablets or capsules, or an anticipated problem with swallowing a large number of capsules.
24. 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.
25. Subjects with a history of cholecystectomy or gall stones.

Primary outcomes:
measure: Incidence of treatment-emergent adverse events in healthy volunteers with single ascending doses of anle138b (Part 1)
timeFrame: Day 1 to day 30 post dose
measure: Incidence of treatment-emergent changes in clinical laboratory parameters in healthy volunteers with single ascending doses of anle138b (Part 1)
timeFrame: Day 1 to day 7 post dose
measure: Incidence of treatment-emergent changes in vital signs in healthy volunteers with single ascending doses of anle138b (Part 1)
timeFrame: Day 1 to day 7 post dose
measure: Incidence of treatment-emergent ECG changes in healthy volunteers with single ascending doses of anle138b (Part 1)
timeFrame: Day 1 to day 7 post dose
measure: Incidence of treatment-emergent changes in physical examination in healthy volunteers with single ascending doses of anle138b (Part 1)
timeFrame: Day 1 to day 7 post dose
measure: Incidence of treatment-emergent adverse events in healthy volunteers with multiple ascending doses of anle138b (Part 2)
timeFrame: Day 1 to day 30 post dose
measure: Incidence of treatment-emergent changes in clinical laboratory parameters in healthy volunteers with multiple ascending doses of anle138b (Part 2)
timeFrame: Day 1 to day 7 post dose
measure: Incidence of treatment-emergent changes in vital signs in healthy volunteers with multiple ascending doses of anle138b (Part 2)
timeFrame: Day 1 to day 7 post dose
measure: Incidence of treatment-emergent ECG changes in healthy volunteers with multiple ascending doses of anle138b (Part 2)
timeFrame: Day 1 to day 7 post dose
measure: Incidence of treatment-emergent changes in physical examination in healthy volunteers with multiple ascending doses of anle138b (Part 2)
timeFrame: Day 1 to day 7 post dose
measure: Incidence of treatment-emergent adverse events in healthy volunteers with a single dose of anle138b both the fasted and fed state (Part 3)
timeFrame: Day 1 to day 30 post dose.
measure: 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)
timeFrame: Day 1 to day 7 post dose
measure: 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)
timeFrame: Day 1 to day 7 post dose
measure: 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)
timeFrame: Day 1 to day 7 post dose
measure: 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)
timeFrame: Day 1 to day 7 post dose
Secondary outcomes:
measure: Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state
timeFrame: From dosing to 48 hours post dosing
measure: Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state
timeFrame: From dosing to 48 hours post dosing
measure: Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state
timeFrame: From dosing to 48 hours post dosing
measure: Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state
timeFrame: From dosing to 48 hours post dosing
measure: Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state
timeFrame: From dosing to 48 hours post dosing
measure: Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state
timeFrame: From dosing to 48 hours post dosing
measure: Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state
timeFrame: From dosing to 48 hours post dosing
measure: Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state
timeFrame: From dosing to 48 hours post dosing
measure: Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state
timeFrame: From dosing to 48 hours post dosing
measure: Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state
timeFrame: From dosing to 48 hours post dosing
measure: Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state
timeFrame: From dosing to 48 hours post dosing
measure: Oral pharmacokinetics (PK) of multiple (Part 2) ascending doses of anle138b in the fasted state
timeFrame: Day 1 to day 9
measure: Oral pharmacokinetics (PK) of multiple (Part 2) ascending doses of anle138b in the fasted state
timeFrame: Day 1 to day 9
measure: Oral pharmacokinetics (PK) of multiple (Part 2) ascending doses of anle138b in the fasted state
timeFrame: Day 1 to day 9
measure: Oral pharmacokinetics (PK) of multiple (Part 2) ascending doses of anle138b in the fasted state
timeFrame: Day 7 to day 9
measure: Oral pharmacokinetics (PK) of multiple (Part 2) ascending doses of anle138b in the fasted state
timeFrame: Day 1 to day 9
measure: Oral pharmacokinetics (PK) of single (Part 1) and multiple (Part 2) ascending doses of anle138b in the fasted state
timeFrame: Day 1 to day 9
measure: Oral pharmacokinetics (PK) of single (Part 1) and multiple (Part 2) ascending doses of anle138b in the fasted state
timeFrame: Day 1 to day 9
measure: Oral pharmacokinetics (PK) (Part 3) for anle138b in the fed and fasted states.
timeFrame: From dosing to 48 hours post dosing
measure: Oral pharmacokinetics (PK) (Part 3) for anle138b in the fed and fasted states.
timeFrame: From dosing to 48 hours post dosing
measure: Oral pharmacokinetics (PK) (Part 3) for anle138b in the fed and fasted states
timeFrame: From dosing to 48 hours post dosing
measure: Oral pharmacokinetics (PK) (Part 3) for anle138b in the fed and fasted states
timeFrame: From dosing to 48 hours post dosing
Other outcomes:
Locations:
city: Nottingham
country: United Kingdom
facility: Quotient Sciences
Study officials:
affiliation: Quotient Sciences Mere Way Ruddington Fields Ruddington Nottingham NG11 6JS, UK
name: Nand Singh, BSc, MD, DPM, MFPM
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wagner J, Ryazanov S, Leonov A, Levin J, Shi S, Schmidt F, Prix C, Pan-Montojo F, Bertsch U, Mitteregger-Kretzschmar G, Geissen M, Eiden M, Leidel F, Hirschberger T, Deeg AA, Krauth JJ, Zinth W, Tavan P, Pilger J, Zweckstetter M, Frank T, Bahr M, Weishaupt JH, Uhr M, Urlaub H, Teichmann U, Samwer M, Botzel K, Groschup M, Kretzschmar H, Griesinger C, Giese A. Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease. Acta Neuropathol. 2013 Jun;125(6):795-813. doi: 10.1007/s00401-013-1114-9. Epub 2013 Apr 19.
citation: Levin J, Schmidt F, Boehm C, Prix C, Botzel K, Ryazanov S, Leonov A, Griesinger C, Giese A. The oligomer modulator anle138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset. Acta Neuropathol. 2014 May;127(5):779-80. doi: 10.1007/s00401-014-1265-3. Epub 2014 Mar 11. No abstract available.
citation: Heras-Garvin A, Weckbecker D, Ryazanov S, Leonov A, Griesinger C, Giese A, Wenning GK, Stefanova N. Anle138b modulates alpha-synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy. Mov Disord. 2019 Feb;34(2):255-263. doi: 10.1002/mds.27562. Epub 2018 Nov 19.
citation: Wegrzynowicz M, Bar-On D, Calo' L, Anichtchik O, Iovino M, Xia J, Ryazanov S, Leonov A, Giese A, Dalley JW, Griesinger C, Ashery U, Spillantini MG. Depopulation of dense alpha-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson's disease model. Acta Neuropathol. 2019 Oct;138(4):575-595. doi: 10.1007/s00401-019-02023-x. Epub 2019 May 31.
citation: Wagner J, Krauss S, Shi S, Ryazanov S, Steffen J, Miklitz C, Leonov A, Kleinknecht A, Goricke B, Weishaupt JH, Weckbecker D, Reiner AM, Zinth W, Levin J, Ehninger D, Remy S, Kretzschmar HA, Griesinger C, Giese A, Fuhrmann M. Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies. Acta Neuropathol. 2015 Nov;130(5):619-31. doi: 10.1007/s00401-015-1483-3. Epub 2015 Oct 6.
citation: Martinez Hernandez A, Urbanke H, Gillman AL, Lee J, Ryazanov S, Agbemenyah HY, Benito E, Jain G, Kaurani L, Grigorian G, Leonov A, Rezaei-Ghaleh N, Wilken P, Arce FT, Wagner J, Fuhrmann M, Caruana M, Camilleri A, Vassallo N, Zweckstetter M, Benz R, Giese A, Schneider A, Korte M, Lal R, Griesinger C, Eichele G, Fischer A. The diphenylpyrazole compound anle138b blocks Abeta channels and rescues disease phenotypes in a mouse model for amyloid pathology. EMBO Mol Med. 2018 Jan;10(1):32-47. doi: 10.15252/emmm.201707825.
citation: Levin J, Sing N, Melbourne S, Morgan A, Mariner C, Spillantini MG, Wegrzynowicz M, Dalley JW, Langer S, Ryazanov S, Leonov A, Griesinger C, Schmidt F, Weckbecker D, Prager K, Matthias T, Giese A. Safety, tolerability and pharmacokinetics of the oligomer modulator anle138b with exposure levels sufficient for therapeutic efficacy in a murine Parkinson model: A randomised, double-blind, placebo-controlled phase 1a trial. EBioMedicine. 2022 Jun;80:104021. doi: 10.1016/j.ebiom.2022.104021. Epub 2022 Apr 29.