Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS-MAPTRx in Patients With Mild Alzheimer's Disease

NCT ID: NCT03186989

Last Updated: 2025-04-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 46 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-10-12
• Study Completion Date: 2022-05-12

Brief Summary

The purpose of this study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of IONIS-MAPTRx in patients with Mild Alzheimer's Disease.

Detailed Description

This was a randomized, double-blind, placebo-controlled study in 46 participants, followed by an Open-Label Extension. This study consisted of two parts:

Part 1: a randomized, double-blind, placebo-controlled multiple ascending dose period in participants with Mild Alzheimer's Disease, followed by Part 2: the open-label, long-term extension period.

Conditions

Mild Alzheimer's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: DOUBLE

Study Groups

Part 1: Cohort A: ISIS 814907 10 mg

Participants received 10 milligrams (mg) ISIS 814907 diluted in 20 milliliters (mL) artificial cerebrospinal fluid (CSF), intrathecally, every four weeks (Q4W) on Days 1, 29, 57, and 85 in Part 1 of the study.

Group Type: EXPERIMENTAL

IONIS MAPTRx

Intervention Type: DRUG

IONIS MAPTRx injections.

Part 1: Cohort B: ISIS 814907 30 mg

Participants received 30 mg ISIS 814907 diluted in 20 mL in artificial CSF, intrathecally, Q4W on Days 1, 29, 57, and 85 in Part 1 of the study.

Group Type: EXPERIMENTAL

IONIS MAPTRx

Intervention Type: DRUG

IONIS MAPTRx injections.

Part 1: Cohort C: ISIS 814907 60 mg

Participants received 60 mg ISIS 814907 diluted in 20 mL artificial CSF, intrathecally, Q4W on Days 1, 29, 57, and 85 in Part 1 of the study.

Group Type: EXPERIMENTAL

IONIS MAPTRx

Intervention Type: DRUG

IONIS MAPTRx injections.

Part 1: Cohort D: ISIS 814907 115 mg

Participants received 115 mg ISIS 814907 diluted in 20 mL artificial CSF, intrathecally, every 12 weeks (Q12W) on Days 1 and 85 in Part 1 of the study.

Group Type: EXPERIMENTAL

IONIS MAPTRx

Intervention Type: DRUG

IONIS MAPTRx injections.

Part 1: Pooled Placebo

Participants received 20 mL artificial CSF, intrathecally, as placebo on Days 1, 29, 57, and 85 for the 4-dose regimens, or on Days 1 and 85 for the 2-dose regimens in Part 1 of the study.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Artificial CSF injections.

Part 2: Late Start Cohort A + Cohort B + Cohort C + ISIS 814907 60 mg

Participants from MAD Cohorts A, B, C that were placebo-treated, received 60 mg ISIS 814907 diluted in 20 mL artificial CSF, intrathecally, Q12W on Days 1, 85, 169, 253, and 337 in Part 2 of the study.

Group Type: EXPERIMENTAL

IONIS MAPTRx

Intervention Type: DRUG

IONIS MAPTRx injections.

Part 2: Late Start Cohort D + ISIS 814907 115 mg

Participants from MAD Cohort D that were placebo-treated, received 115 mg ISIS 814907 diluted up in 20 mL artificial CSF, intrathecally, Q12W on Days 1, 85, 169, 253, and 337 in Part 2 of the study.

Group Type: EXPERIMENTAL

IONIS MAPTRx

Intervention Type: DRUG

IONIS MAPTRx injections.

Part 2: Early Start Cohort A + ISIS 814907 60 mg

Participants from MAD Cohort A that were ISIS 814907 10 mg -treated, received 60 mg ISIS 814907 diluted in 20 mL artificial CSF, intrathecally, Q12W on Days 1, 85, 169, 253, and 337 in Part 2 of the study.

Group Type: EXPERIMENTAL

IONIS MAPTRx

Intervention Type: DRUG

IONIS MAPTRx injections.

Part 2: Early Start Cohort B + ISIS 814907 60 mg

Participants from MAD Cohort B that were ISIS 814907 30 mg-treated, received 60 mg ISIS 814907 diluted in 20 mL artificial CSF, intrathecally, Q12W on Days 1, 85, 169, 253, and 337 in Part 2 of the study.

Group Type: EXPERIMENTAL

IONIS MAPTRx

Intervention Type: DRUG

IONIS MAPTRx injections.

Part 2: Early Start Cohort C + ISIS 814907 60 mg

Participants from MAD Cohort C that were ISIS 814907 60 mg-treated, received 60 mg ISIS 814907 diluted in 20 mL artificial CSF, intrathecally, Q12W on Days 1, 85, 169, 253, and 337 in Part 2 of the study.

Group Type: EXPERIMENTAL

IONIS MAPTRx

Intervention Type: DRUG

IONIS MAPTRx injections.

Part 2: Early Start Cohort D + ISIS 814907 115 mg

Participants from MAD Cohort D that were ISIS 814907 115 mg-treated, received 115 mg ISIS 814907 diluted in 20 mL artificial CSF, intrathecally, Q12W on Days 1, 85, 169, 253, and 337 in Part 2 of the study.

Group Type: EXPERIMENTAL

IONIS MAPTRx

Intervention Type: DRUG

IONIS MAPTRx injections.

Interventions

IONIS MAPTRx

IONIS MAPTRx injections.

Intervention Type: DRUG

Placebo

Artificial CSF injections.

Intervention Type: OTHER

Other Intervention Names

ISIS 814907

Eligibility Criteria

Inclusion Criteria

• Males or females aged 50-74 years, inclusive, at the time of informed consent
• Diagnosed with mild Alzheimers disease, including CSF biomarkers consistent with this diagnosis
• Body Mass Index BMI ≥ 18 and ≤ 35 kg/m2 and total body weight > 50 kg (110 lbs)
• Able and willing to meet all study requirements, including toleration for MRI scans, blood draws and lumbar punctures, travel to Study Center and participation in all procedures and measurements at study visits
• Have a trial partner who is reliable, competent and at least 18 years of age, is willing to accompany the patient to select trial visits and to be available to the Study Center by phone if needed
• Reside within 4 hours travel of the Study Center

• Must have completed the Treatment Evaluation and Post-Treatment Periods in Part 1

Exclusion Criteria

• Treatment with another Study Drug, biological agent, or device within one-month of Screening or 5 half-lives of investigational agent, whichever is longer
• Clinically significant medical condition which would make the patient unsuitable for inclusion or could interfere with the patient participating in or completing the study
• Use of a disallowed CNS-active or antipsychotic medication within 4 weeks prior to Screening punctures

• Treatment with another Study Drug, biological agent, or device within one-month of Screening or 5 half-lives of investigational agent, whichever is longer
• Clinically significant medical condition which would make the patient unsuitable for inclusion or could interfere with the patient participating in or completing the study
• Use of a disallowed CNS-active or antipsychotic medication within 4 weeks prior to Screening punctures

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 74 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ionis Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Montreal Neurological Hospital

Montreal, , Canada

Clinical Research Services Turku CRST

Turku, , Finland

St Josef Hospital

Bochum, , Germany

Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)

Bonn, , Germany

MVZ Mittweida Gbr

Mittweida, , Germany

Universittsklinikum Ulm

Ulm, , Germany

VU University Medical Center

Amsterdam, , Netherlands

QPS Netherlands BV

Groningen, , Netherlands

Minnesmottagningen

Mölndal, , Sweden

Karolinska University Hospital Huddinge

Stockholm, , Sweden

Royal Liverpool University Hospital

Liverpool, , United Kingdom

University College London Hospitals NHS Foundation Trust

London, , United Kingdom

Sheffield Institute for Translational Neuroscience (SITraN)

Sheffield, , United Kingdom

Countries

Canada; Finland; Germany; Netherlands; Sweden; United Kingdom

References

Lane RM, Darreh-Shori T, Junge C, Li D, Yang Q, Edwards AL, Graham DL, Moore K, Mummery CJ. Onset of Alzheimer disease in apolipoprotein varepsilon4 carriers is earlier in butyrylcholinesterase K variant carriers. BMC Neurol. 2024 Apr 9;24(1):116. doi: 10.1186/s12883-024-03611-5.

Reference Type: DERIVED

PMID: 38594621 (View on PubMed)

Edwards AL, Collins JA, Junge C, Kordasiewicz H, Mignon L, Wu S, Li Y, Lin L, DuBois J, Hutchison RM, Ziogas N, Shulman M, Martarello L, Graham D, Lane R, Budd Haeberlein S, Beaver J. Exploratory Tau Biomarker Results From a Multiple Ascending-Dose Study of BIIB080 in Alzheimer Disease: A Randomized Clinical Trial. JAMA Neurol. 2023 Dec 1;80(12):1344-1352. doi: 10.1001/jamaneurol.2023.3861.

Reference Type: DERIVED

PMID: 37902726 (View on PubMed)

Mummery CJ, Borjesson-Hanson A, Blackburn DJ, Vijverberg EGB, De Deyn PP, Ducharme S, Jonsson M, Schneider A, Rinne JO, Ludolph AC, Bodenschatz R, Kordasiewicz H, Swayze EE, Fitzsimmons B, Mignon L, Moore KM, Yun C, Baumann T, Li D, Norris DA, Crean R, Graham DL, Huang E, Ratti E, Bennett CF, Junge C, Lane RM. Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer's disease: a phase 1b, randomized, placebo-controlled trial. Nat Med. 2023 Jun;29(6):1437-1447. doi: 10.1038/s41591-023-02326-3. Epub 2023 Apr 24.

Reference Type: DERIVED

PMID: 37095250 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NL60032.000.16

Identifier Type: OTHER

Identifier Source: secondary_id

2016-002713-22

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ISIS 814907-CS1

Identifier Type: -

Identifier Source: org_study_id