A Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of anle138b in Parkinson's Disease

NCT04685265 | Completed Phase 1 DMC

• 2 other identifiers: anle138b-P1-022020-004869-38
• Study Type: interventional
• Target: 70
• 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 as well as the effect of food and early signs of efficacy in patients with mild to moderate Parkinson´s disease.

Conditions

Parkinson Disease

Keywords

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

Outcome Measures

Primary Outcomes (33)

• Incidence of treatment-emergent adverse events in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D).

  Adverse events

  Day 1 to day 14-16: cohorts A-C; day 1 to week 6 post dosing: cohort D

• Incidence of treatment-emergent adverse events in PD patients with multiple ascending doses of anle138b taken in the fed state (Cohorts A and B).

  Adverse events

  From fed dosing (day 9) to day 12-14

• Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D).

  Blood pressure

  Day 1 to week 1 post dosing: cohorts A-C; day 1 to week 6 post dosing: cohort D

• Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D).

  Heart rate

  Day 1 to week 1 post dosing: cohorts A-C; day 1 to week 6 post dosing: cohort D

• Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D).

  Oral temperature

  Day 1 to week 1 post dosing: cohorts A-C; day 1 to week 6 post dosing: cohort D

• Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken in the fed state (Cohorts A and B).

  Blood pressure

  From fed dosing to 1 week post dosing

• Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken in the fed state (Cohorts A and B).

  Heart rate

  From fed dosing to 1 week post dosing

• Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken in the fed state (Cohorts A and B).

  Oral temperature

  From fed dosing to 1 week post dosing

• Incidence of treatment-emergent ECG changes in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D).

  Electrocardiogram (ECG) parameters including QT interval corrected for heart rate using Fridericia's formula (QTcF)

  Day 1 to week 1 post dosing: cohorts A-C; day 1 to week 6 post dosing: cohort D

• Incidence of treatment-emergent ECG changes in PD patients with multiple ascending doses of anle138b taken in the fed state (Cohorts A and B).

  Electrocardiogram (ECG) parameters including QT interval corrected for heart rate using Fridericia's formula (QTcF)

  From fed dosing to 1 week post dosing

• Incidence of treatment-emergent changes in physical examination in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D).

  Physical examination findings

  Day 1 to week 1 post dosing: cohorts A-C; day 1 to week 6 post dosing: cohort D

• Incidence of treatment-emergent changes in physical examination in PD patients with multiple ascending doses of anle138b taken in fed state (Cohorts A and B).

  Physical examination findings

  From fed dosing to 1 week post dosing

• Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D).

  Clinical laboratory Tests: Hematology

  Day 1 to day 8

• Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D).

  Clinical chemistry: Renal function tests

  Day 1 to day 8

• Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D).

  Clinical chemistry: Hepatic enzymes

  Day 1 to day 8

• Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D).

  Clinical chemistry: Electrolytes

  Day 1 to day 8

• Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in the fasted state (cohorts A-C + D).

  Clinical chemistry: Creatine kinase

  Day 1 to day 8

• Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in fed state (Cohorts A and B).

  Clinical laboratory Tests: Hematology

  From fed dosing to 24 hours post dosing

• Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in fed state (Cohorts A and B).

  Clinical chemistry: Renal function tests

  From fed dosing to 24 hours post dosing

• Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in fed state (Cohorts A and B).

  Clinical chemistry: Hepatic enzymes

  From fed dosing to 24 hours post dosing

• Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in fed state (Cohorts A and B).

  Clinical chemistry: Electrolytes

  From fed dosing to 24 hours post dosing

• Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken in fed state (Cohorts A and B).

  Clinical chemistry: Creatine kinase

  From fed dosing to 24 hours post dosing

• Incidence of treatment-emergent adverse events in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E).

  Adverse events

  Day 1 to week 6 post dosing

• Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E).

  Blood pressure

  Day 1 to week 6 post dosing

• Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E).

  Heart rate

  Day 1 to week 6 post dosing

• Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E).

  Oral temperature

  Day 1 to week 6 post dosing

• Incidence of treatment-emergent changes in vital signs in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E).

  Electrocardiogram (ECG) parameters including QT interval corrected for heart rate using Fridericia's formula (QTcF)

  Day 1 to week 6 post dosing

• Incidence of treatment-emergent changes in physical examination in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E).

  Physical examination findings

  Day 1 to week 6 post dosing

• Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E).

  Clinical laboratory Tests: Hematology

  Day 1 to 24 hours post dosing

• Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E).

  Clinical chemistry: Renal function tests

  Day 1 to 24 hours post dosing

• Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E).

  Clinical chemistry: Hepatic enzymes

  Day 1 to 24 hours post dosing

• Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E).

  Clinical chemistry: Electrolytes

  Day 1 to 24 hours post dosing

• Incidence of treatment-emergent changes in clinical laboratory parameters in PD patients with multiple ascending doses of anle138b taken 28 days in the non-fasted state (cohort E).

  Clinical chemistry: Creatine kinase

  Day 1 to 24 hours post dosing

Secondary Outcomes (24)

• Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the fasted state (cohorts A-C + D).

  Day 1 to day 9

• Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the fasted state (cohorts A-C + D).

  Day 1 to day 9

• Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the fasted state (cohorts A-C + D).

  Day 1 to day 9

• Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the fasted state (cohort B).

  Day 1 to day 9

• Oral pharmacokinetics (PK) of multiple ascending doses of anle138b in PD patients taken in the fasted state (cohorts A-C + D).

  Day 1 to day 9

Study Arms (2)

anle138b

ACTIVE COMPARATOR

150 mg and higher dosage

Drug: anle138b

Placebo

PLACEBO COMPARATOR

Matching placebo dosage

Drug: Placebo

Interventions

anle138b DRUG

capsule containing excipient and anle138b

anle138b

Placebo DRUG

matching placebo capsule containing excipient

Placebo

Eligibility Criteria

• Age: 40 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males and females with a diagnosis of idiopathic PD as defined by the Movement Disorders Society criteria (either fulfilling criteria for "Clinically Established PD" or for "Clinically Probable PD").
• Body mass index (BMI) 18.5 to 35.0 kg/m2 or 18.5 to \<40.0 kg/m2 (Cohorts D and E) as measured at screening.
• Hoehn and Yahr stage I-III (able to walk unaided).
• Stable medication for PD for 1 month prior to screening at Quotient and anticipated over the study period.
• No history of dementia.
• 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 the study protocol.

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, or are immediate family members of, a study site or sponsor employee.
• Evidence of current SARS-CoV-2 infection.
• 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 (Cohorts A to C only).
• Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months (Cohorts A to C only).
• Females of childbearing potential including those who are pregnant or lactating (all female subjects must have a negative highly sensitive serum or urine pregnancy test). 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 \[FSH\] concentration ≥40 IU/L).
• Male 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 coagulation (Cohort E only), clinical chemistry, haematology or urinalysis as judged by the investigator.
• Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) antibody results.
• History of clinically significant cardiovascular, renal, hepatic, dermatological, chronic respiratory or gastrointestinal disease or psychiatric disorder, as judged by the investigator.
• Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients.

Sponsors & Collaborators

• MODAG GmbH: lead
• Aptuit: collaborator
• Quotient Sciences: collaborator
• Nottingham University Hospitals NHS Trust: collaborator

Study Sites (1)

Quotient Sciences

Nottingham, NG11 6JS, United Kingdom

Location

Related Publications (6)

• 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

Related Links

• Sponsor Homepage

MeSH Terms

Conditions

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

• Jonathan Evans, MD

  Nottingham University Hospitals NHS Trust

  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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 17, 2020
• First Posted: December 28, 2020
• Study Start: December 22, 2020
• Primary Completion: November 7, 2022
• Study Completion: December 22, 2022
• Last Updated: March 22, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)