A Drug-Drug Interaction Study to Assess the CYP1A2 and CYP3A4 Interaction Potential of TEV-56286 (anle138b)

An Open-Label, One-Sequence, Two-Part Drug-Drug Interaction Study in Healthy Volunteers to Assess the CYP1A2 and CYP3A4 Perpetrator Interaction Potential and CYP1A2 Victim Potential of TEV-56286 (anle138b)

The purpose of this healthy volunteers drug-drug interaction study is to assess the CYP1A2 and CYP3A4 perpetrator interaction potential and CYP1A2 victim potential of TEV-56286 (anle138b).

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: anle138b (TEV-56286); Drug: Fluvoxamine 100 mg QD for 5 days

Detailed Description

This a 2-part DDI study that will assess the CYP1A2 and CYP3A4 perpetrator interaction potential of TEV-56286 single dose and multiple dose, using caffeine and midazolam as substrates and CYP1A2 victim potential of TEV-56286 (anle138b) at steady state induction using fluvoxamine as inhibitor [1,2].The estimated time from screening until the follow-up visit is approximately up to 8 weeks for each subjects.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Nottingham, United Kingdom, NG11 6JS
    • Quotient Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy males or healthy females of non-childbearing potential
• Must provide written informed consent for participation in the study and must be able to understand the study requirements
• Body mass index (BMI) 18.5 to 32.0 kg/m2.
• Must agree to adhere to the contraception requirements defined in the study protocol.

Exclusion Criteria:

• Serious adverse reaction or serious hypersensitivity to any drug or formulation excipients e.g. fluvoxamine, caffeine, midazolam or benzodiazepines or any of its excipients, or a known drug hypersensitivity idiosyncratic reaction to TEV-56286, or one of its excipients
• History of clinically significant cardiovascular, renal, hepatic, dermatological, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, metabolic diseases or a history of any illness that, in the opinion of the investigator, might pose additional risk to the subject by participation in the study or confound the results of the study
• Acute infection and/or antibiotic treatment within 28 days of Day 1
• Major trauma or surgery in the 2 months before screening or at any time between screening and Day 1, or surgery scheduled during the study or follow up period
• History of malignancy or treatment of malignancy in the last 5 years
• History of suicidal ideation with an intent and/or plan and behaviour based upon either clinical history or source documents
• Personal or family history of arrhythmia, sudden unexplained death at a young age (before 40 years) in a first-degree relative, or long QT syndrome, or a personal history of syncope or previous treatment for high blood pressure (BP). Abnormality of 12-lead ECG that may, in the opinion of the investigator, interfere with study participation
• Any procedure or disorder that may interfere with drug absorption, distribution, metabolism, or excretion
• Clinically significant abnormal clinical chemistry, haematology or urinalysis as judged by the investigator.
• Subjects who have received any IMP in a clinical research study within the 90 days prior to Day 1, or less than 5 elimination half-lives prior to Day 1, whichever is longer
• Subjects who are taking, or have taken, any prescribed or over-the-counter drug or herbal remedies in the 14 days before study medication administration or within 5 half-lives whichever is longer.
• Subjects who are taking, or have taken hormonal contraceptives (e.g., oral, patch, injectable or intrauterine device) hormone replacement therapy (HRT) or a long-acting injectable hormonal within 4 weeks prior to first dose of IMP
• Subjects who are taking, or have taken any inducer of CYP 1A2, CYP3A4 within 28 days prior to Day -2
• History of any drug or alcohol abuse in the past 2 years
• Current smokers and those who have smoked within the last 12 months or has a positive urine cotinine test
• Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months
• Subjects with a previous history of difficulty in swallowing tablets or capsules, or an anticipated problem with swallowing a large number of capsules
• Subjects who have consumed grapefruit, grapefruit juice, Seville oranges, pomelo-containing products, vegetables from the mustard green family (e.g., kale, broccoli, watercress, collard greens, kohlrabi, brussel sprouts, and mustard) and charbroiled meats within the 14 days prior to Day -2
• Subjects who are unwilling to comply with the restricted use of caffeinated beverages (e.g. coffee, tea, cola) during the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: anle138b (TEV-56286) as perpetrator (part I); Drug: TEV-56286 300 mg QD (single dose and multiple dose for 14 days) Victim drugs: Caffeine 200 mg Midazolam 2 mg	Drug: anle138b (TEV-56286); Anle138b (TEV-56286) as perpetrator; Other Names: Midazolam; Caffeine; Fluvoxamine
Experimental: anle138b (TEV-56286) as victim (part II); Drug: fluvoxamine 100 mg QD for 5 days Victim drug: TEV-56286 150 mg QD for 14 days + 5 days of co-administation with fluvoxamine	Drug: Fluvoxamine 100 mg QD for 5 days; Anle138b (TEV-56286) as victim; Other Names: TEV-56286 150 mg QD for 14 days + 5 days of co-administation with fluvoxamine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oral pharmacokinetics (PK) of caffeine administered without TEV-56286 in healthy volunteers in the fasted state (Part I).	PK parameter: Cmax for caffeine.	Day 1
Oral pharmacokinetics (PK) of caffeine administered without TEV-56286 in healthy volunteers in the fasted state (Part I).	PK parameter: AUC(0-inf) for caffeine.	Day 1
Oral pharmacokinetics (PK) of caffeine administered without TEV-56286 in healthy volunteers in the fasted state (Part I).	PK parameter: AUC (0-last) for caffeine.	Day 1
Oral pharmacokinetics (PK) of midazolam administered without TEV-56286 in healthy volunteers in the fasted state (Part I).	PK parameter: Cmax for midazolam.	Day 1
Oral pharmacokinetics (PK) of midazolam administered without TEV-56286 in healthy volunteers in the fasted state (Part I).	PK parameter: AUC(0-inf) for midazolam.	Day 1
Oral pharmacokinetics (PK) of midazolam administered without TEV-56286 in healthy volunteers in the fasted state (Part I).	PK parameter: AUC (0-last) for midazolam.	Day 1
Oral pharmacokinetics (PK) of caffeine after single co-administration with TEV-56286 in healthy volunteers in the fasted state (Part I).	Cmax for caffeine.	Day 3
Oral pharmacokinetics (PK) of caffeine after single co-administration with TEV-56286 in healthy volunteers in the fasted state (Part I).	PK parameter: AUC(0-inf) for caffeine.	Day 3
Oral pharmacokinetics (PK) of caffeine after single co-administration with TEV-56286 in healthy volunteers in the fasted state (Part I).	PK parameter: AUC (0-last) for caffeine.	Day 3
Oral pharmacokinetics (PK) of midazolam after single co-administration with TEV-56286 in healthy volunteers in the fasted state (Part I).	Cmax for midazolam	Day 3
Oral pharmacokinetics (PK) of midazolam after single co-administration with TEV-56286 in healthy volunteers in the fasted state (Part I).	PK parameter: AUC(0-inf) for midazolam.	Day 3
Oral pharmacokinetics (PK) of midazolam after single co-administration with TEV-56286 in healthy volunteers in the fasted state (Part I).	PK parameter: AUC (0-last) for midazolam.	Day 3
Oral pharmacokinetics (PK) of caffeine after repeated administration of TEV-56286 in healthy volunteers in the fasted state (Part I).	PK parameter: Cmax for caffeine.	Day 18
Oral pharmacokinetics (PK) of caffeine after repeated administration of TEV-56286 in healthy volunteers in the fasted state (Part I).	AUC(0-inf) for caffeine.	Day 18
Oral pharmacokinetics (PK) of caffeine after repeated administration of TEV-56286 in healthy volunteers in the fasted state (Part I).	PK parameter: AUC (0-last) for caffeine.	Day 18
Oral pharmacokinetics (PK) of midazolam after repeated administration of TEV-56286 in healthy volunteers in the fasted state (Part I).	PK parameter: Cmax for midazolam.	Day 18
Oral pharmacokinetics (PK) of midazolam after repeated administration of TEV-56286 in healthy volunteers in the fasted state (Part I).	PK parameter: AUC(0-inf) for midazolam.	Day 18
Oral pharmacokinetics (PK) of midazolam after repeated administration of TEV-56286 in healthy volunteers in the fasted state (Part I).	PK parameter: AUC (0-last) for midazolam.	Day 18
Oral pharmacokinetics (PK) of TEV-56286 without fluvoxamine in healthy volunteers after repeated administration in the fasted state (Part II).	PK parameter: Cmax for TEV-56286.	Day 14
Oral pharmacokinetics (PK) of TEV-56286 without fluvoxamine in healthy volunteers after repeated administration in the fasted state (Part II).	PK parameter: AUC(0-tau) for TEV-56286.	Day 14
Oral pharmacokinetics (PK) of TEV-56286 in healthy volunteers after repeated co-administration with fluvoxamine in the fasted state.	PK parameter: Cmax for TEV-56286 (Part II).	Day 19
Oral pharmacokinetics (PK) of TEV-56286 in healthy volunteers after repeated co-administration with fluvoxamine in the fasted state.	PK parameter: AUC(0-tau) for TEV-56286 (Part II).	Day 19

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oral pharmacokinetics (PK) of substrates caffeine and midazolam	PK parameter: Tmax	Day 1, Day 3, Day 18
Oral pharmacokinetics (PK) of substrates caffeine and midazolam	PK parameter: Tlag	Day 1, Day 3, Day 18
Oral pharmacokinetics (PK) of substrates caffeine and midazolam	PK parameter: lambda-z	Day 1, Day 3, Day 18
Oral pharmacokinetics (PK) of substrates caffeine and midazolam	PK parameter: T1/2	Day 1, Day 3, Day 18
Oral pharmacokinetics (PK) of substrates caffeine and midazolam	PK parameter: CL/F	Day 1, Day 3, Day 18
Oral pharmacokinetics (PK) of substrates caffeine and midazolam	PK parameter: Vz/F	Day 1, Day 3, Day 18
Oral pharmacokinetics (PK) of TEV-56286 after repeated co-administration with fluvoxamine	PK parameter: Tmax	Day 19
Oral pharmacokinetics (PK) of TEV-56286 after repeated co-administration with fluvoxamine	PK parameter: lambda-z	Day 19
Oral pharmacokinetics (PK) of TEV-56286 after repeated co-administration with fluvoxamine	PK parameter: T1/2	Day 19
Oral pharmacokinetics (PK) of TEV-56286 after repeated co-administration with fluvoxamine	PK parameter: CL/F	Day 19
Oral pharmacokinetics (PK) of TEV-56286 after repeated co-administration with fluvoxamine	PK parameter: Vz/F	Day 19
Oral pharmacokinetics (PK) of TEV-56286 as perpetrator drug after co-administration with caffeine and midazolam	PK parameter: Tmax	Day 3
Oral pharmacokinetics (PK) of TEV-56286 as perpetrator drug after co-administration with caffeine and midazolam	PK parameter: Cmax	Day 3
Oral pharmacokinetics (PK) of TEV-56286 as perpetrator drug after co-administration with caffeine and midazolam	PK parameter: AUC (0-last)	Day 3
Oral pharmacokinetics (PK) of TEV-56286	PK parameter: Trough concentration for TEV-56286	Day 3-18
Oral pharmacokinetics (PK) of TEV-56286 after single co-administration with caffeine and midazolam	PK parameter: Tmax	Day 18
Oral pharmacokinetics (PK) of TEV-56286 after single co-administration with caffeine and midazolam	PK parameter: Cmax	Day 18
Oral pharmacokinetics (PK) of TEV-56286 after single co-administration with caffeine and midazolam	PK parameter: Cmin	Day 18
Oral pharmacokinetics (PK) of TEV-56286 after single co-administration with caffeine and midazolam	PK parameter: Cavg	Day 18
Oral pharmacokinetics (PK) of TEV-56286 after single co-administration with caffeine and midazolam	PK parameter: AUC (0-tau)	Day 18
Oral pharmacokinetics (PK) of TEV-56286 after single co-administration with caffeine and midazolam	PK parameter: AUC (0-last)	Day 18
Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286	PK parameter: Tmax	Day 19
Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286	PK parameter: Cmax	Day 19
Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286	PK parameter: Cmin	Day 19
Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286	PK parameter: Cavg	Day 19
Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286	PK parameter: AUC (0-tau)	Day 19
Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286	PK parameter: AUC (0-last)	Day 19
Oral pharmacokinetics (PK) of fluvoxamine after repeated co-administration with TEV-56286	PK parameter: Trough concentration for fluvoxamine	Day 15-19
Oral pharmacokinetics (PK) of TEV-56286 after first dose administered as part of repeated administration	PK parameter: Tlag for TEV-56286	Day 1
Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose	PK parameter: Tmax	Day 1, Day 14
Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose	PK parameter: Cmax	Day 1, Day 14
Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose	PK parameter: AUC (0-tau)	Day 1, Day 14
Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose	PK parameter: lambda-z	Day 1, Day 14
Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose	PK parameter: T1/2	Day 1, Day 14
Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose	PK parameter: CL/F	Day 1, Day 14
Oral pharmacokinetics (PK) of TEV-56286 following single dose and multiple dose	PK parameter: Vz/F	Day 1, Day 14
Oral pharmacokinetics (PK) of TEV-56286 following multiple dose	PK parameter: AUC (0-last)	Day 14
Oral pharmacokinetics (PK) of TEV-56286 following multiple dose	PK parameter: Cmin	Day 14
Oral pharmacokinetics (PK) of TEV-56286 following multiple dose	PK parameter: Cavg	Day 14
Oral pharmacokinetics (PK) of TEV-56286 following multiple dose	PK parameter: Accumulation ratio	Day 14
Oral pharmacokinetics (PK) of metabolites paraxanthine and 1-hydroxy midazolam after single administration of caffeine and midazolam	PK parameter: Tmax	Day 1, Day 3, Day 18
Oral pharmacokinetics (PK) of metabolites paraxanthine and 1-hydroxy midazolam after single administration of caffeine and midazolam	PK parameter: Cmax	Day 1, Day 3, Day 18
Oral pharmacokinetics (PK) of metabolites paraxanthine and 1-hydroxy midazolam after single administration of caffeine and midazolam	PK parameter: AUC (0-last)	Day 1, Day 3, Day 18
Oral pharmacokinetics (PK) of metabolites paraxanthine and 1-hydroxy midazolam after single administration of caffeine and midazolam	PK parameter: AUC (0-inf)	Day 1, Day 3, Day 18
Oral pharmacokinetics (PK) of metabolites paraxanthine and 1-hydroxy midazolam after single administration of caffeine and midazolam	PK parameter: lambda-z	Day 1, Day 3, Day 18
Oral pharmacokinetics (PK) of metabolites paraxanthine and 1-hydroxy midazolam after single administration of caffeine and midazolam	PK parameter: T1/2	Day 1, Day 3, Day 18
Oral pharmacokinetics (PK) of metabolites paraxanthine and 1-hydroxy midazolam after single administration of caffeine and midazolam	PK parameter: parent: metabolite ratio	Day 1, Day 3, Day 18
Incidence of treatment-emergent adverse events including clinically significant changes in vital signs, ECGs and safety labs	adverse events and clinically significant changes in vital signs, ECGs and safety labs	Day 1 up to follow up visit (5-11 days post last TEV-56286 dose)
Number of participants reporting use of concomitant medications	Number of participants reporting use of concomitant medications	Day 1 up to follow up visit (5-11 days post last TEV-56286 dose)
Columbia-Suicide Severity Rating Scale (C-SSRS) total score	Columbia-Suicide Severity Rating Scale (C-SSRS) total score	Day 3 to day 21

Collaborators and Investigators

• Sponsor: MODAG GmbH
• Collaborators: Teva Pharmaceutical Industries, Ltd.; Quotient Sciences; Aptuit
• Investigators: Principal Investigator: Nand Singh, MD, Quotient Sciences Mere Way Ruddington Fields Ruddington Nottingham NG11 6JS, UK

Publications and helpful links

General Publications

• 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.
• 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.
• Drug Interaction Studies M12. ICH Harmonised Guideline. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Draft version endorsed on 24 May 2022.
• Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry. US Food and Drug Administration. 07 Jul 2020. Available online: https://www.fda.gov/regulatoryinformation/search-fda-guidance-documents/clinical-drug-interaction-studiescytochrome-p450-enzyme-and-transporter-mediated-drug-interactions (accessed 23 Jun 2022).

Helpful Links

• Description Sponsor Homepage

Study record dates

Study Major Dates

• Study Start (Actual): September 12, 2022
• Primary Completion (Actual): January 28, 2023
• Study Completion (Actual): February 10, 2023

Study Registration Dates

• First Submitted: September 4, 2022
• First Submitted That Met QC Criteria: September 4, 2022
• First Posted (Actual): September 8, 2022

Study Record Updates

• Last Update Posted (Actual): March 23, 2023
• Last Update Submitted That Met QC Criteria: March 21, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Neurodegenerative diseases; Alzheimer Disease; Parkinson Disease; Multiple System Atrophy; Drug-drug interaction; Amyloid; Tauopathies; alpha-Synuclein; Oligomer modulator; anle138b (TEV-56286)
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Purinergic Antagonists; Purinergic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Midazolam; Caffeine; Fluvoxamine
• Other Study ID Numbers: anle138b-P1-03; 2022-002467-30 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No