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

NCT04208152 | Completed Phase 1 DMC

• 2 other identifiers: anle138b-P1-012019-004218-33
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Healthy Volunteers

Keywords

anle138b; alpha-Synuclein; Oligomer modulator; Parkinson Disease; Multiple System Atrophy; Neurodegenerative diseases; Alzheimer Disease; Tauopathies; Amyloid

Outcome Measures

Primary Outcomes (15)

• 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 Outcomes (22)

• Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state

  From dosing to 48 hours post dosing

• Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state

  From dosing to 48 hours post dosing

• Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state

  From dosing to 48 hours post dosing

• Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state

  From dosing to 48 hours post dosing

• Oral pharmacokinetics (PK) of single (Part 1) ascending doses of anle138b in the fasted state

  From dosing to 48 hours post dosing

Study Arms (2)

anle138b

ACTIVE COMPARATOR

Dosage: 50 mg and higher Dosage form: capsule Frequency: once daily Duration: One day for SAD and seven days for MAD

Drug: anle138b

placebo

PLACEBO COMPARATOR

Matching placebo Dosage form: capsule Frequency: once daily Duration: One day for SAD and seven days for MAD

Drug: Placebo

Interventions

anle138b DRUG

capsule containing excipient and anle138b

anle138b

Placebo DRUG

matching placebo capsule containing excipient

placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• MODAG GmbH: lead
• Quotient Sciences: collaborator
• Aptuit: collaborator

Study Sites (1)

Quotient Sciences

Nottingham, NG11 6JS, United Kingdom

Location

Related Publications (7)

• 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.

  PMID: 23604588 BACKGROUND

• 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.

  PMID: 24615514 BACKGROUND

• 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.

  PMID: 30452793 BACKGROUND

• 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.

  PMID: 31165254 BACKGROUND

• 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.

  PMID: 26439832 BACKGROUND

• 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.

  PMID: 29208638 BACKGROUND

• 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.

  PMID: 35500536 DERIVED

Related Links

• MODAG GmbH - Sponsor homepage

MeSH Terms

Conditions

Parkinson Disease 4, Autosomal Dominant Lewy Body; Parkinson Disease; Multiple System Atrophy; Neurodegenerative Diseases; Alzheimer Disease; Tauopathies

Interventions

3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Primary Dysautonomias; Autonomic Nervous System Diseases; Dementia; Neurocognitive Disorders; Mental Disorders

Study Officials

• Nand Singh, BSc, MD, DPM, MFPM

  Quotient Sciences Mere Way Ruddington Fields Ruddington Nottingham NG11 6JS, UK

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: This study is double-blind. Treatment assignment will not be known to the subjects, the sponsor or the staff who are involved in the clinical evaluation of the subjects and the analysis of data. The randomisation schedule and disclosure envelopes will be generated by an unblinded statistician at Quotient Sciences. The FES is an open label study which includes a randomized sequence of fasted and fed state.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 16, 2019
• First Posted: December 23, 2019
• Study Start: December 6, 2019
• Primary Completion: August 4, 2020
• Study Completion: August 4, 2020
• Last Updated: August 6, 2020

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)