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

A Randomized, Double-Blind, Placebo-Controlled Study, Followed by an Open-Label Extension, to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of Intrathecally Administered ISIS 814907 in Patients With Mild Alzheimer's Disease

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

Study Overview

• Status: Completed
• Conditions: Mild Alzheimer's Disease
• Intervention / Treatment: Drug: IONIS MAPTRx; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Montréal, Canada
    • Montreal Neurological Hospital
• Finland
  • Turku, Finland
    • Clinical Research Services Turku CRST
• Germany
  • Bochum, Germany
    • St Josef Hospital
  • Bonn, Germany, 53127
    • Deutsches Zentrum fur Neurodegenerative Erkrankungen (DZNE)
  • Mittweida, Germany
    • MVZ Mittweida Gbr
  • Ulm, Germany
    • Universittsklinikum Ulm
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VU University Medical Center
  • Groningen, Netherlands, 9713 AG
    • QPS Netherlands BV
• Sweden
  • Mölndal, Sweden
    • Minnesmottagningen
  • Stockholm, Sweden
    • Karolinska University Hospital Huddinge
• United Kingdom
  • Liverpool, United Kingdom
    • Royal Liverpool University Hospital
  • London, United Kingdom
    • University College London Hospitals NHS Foundation Trust
  • Sheffield, United Kingdom
    • Sheffield Institute for Translational Neuroscience (SITraN)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria for Part 1:

• 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

Exclusion Criteria for Part 1:

• 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

Inclusion Criteria for Part 2:

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

Exclusion Criteria for Part 2 (only applicable to participants in Cohorts A and B, as participants from Cohorts C and D will seamlessly transition to Part 2):

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: IONIS MAPTRx; IONIS MAPTRx injections.; Other Names: ISIS 814907
Experimental: 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.	Drug: IONIS MAPTRx; IONIS MAPTRx injections.; Other Names: ISIS 814907
Experimental: 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.	Drug: IONIS MAPTRx; IONIS MAPTRx injections.; Other Names: ISIS 814907
Experimental: 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.	Drug: IONIS MAPTRx; IONIS MAPTRx injections.; Other Names: ISIS 814907
Placebo Comparator: 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.	Other: Placebo; Artificial CSF injections.
Experimental: 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.	Drug: IONIS MAPTRx; IONIS MAPTRx injections.; Other Names: ISIS 814907
Experimental: 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.	Drug: IONIS MAPTRx; IONIS MAPTRx injections.; Other Names: ISIS 814907
Experimental: 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.	Drug: IONIS MAPTRx; IONIS MAPTRx injections.; Other Names: ISIS 814907
Experimental: 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.	Drug: IONIS MAPTRx; IONIS MAPTRx injections.; Other Names: ISIS 814907
Experimental: 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.	Drug: IONIS MAPTRx; IONIS MAPTRx injections.; Other Names: ISIS 814907
Experimental: 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.	Drug: IONIS MAPTRx; IONIS MAPTRx injections.; Other Names: ISIS 814907

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907	An adverse event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of medicinal (investigational) product, whether or not the AE was considered related to the medicinal (investigational) product. A TEAE was defined as any AE that starts or worsens on or after the date of first dose of study treatment. TEAEs were categorised as mild, moderate, and severe to aid in severity assessment.	From first dose of study drug up to Week 37 in Part 1
Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907	An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of medicinal (investigational) product, whether or not the AE was considered related to the medicinal (investigational) product. A TEAE was defined as any AE that starts or worsens on or after the date of first dose of study treatment. TEAEs were categorised as mild, moderate, and severe to aid in severity assessment.	From first dose of study drug up to Week 64 in Part 2

Secondary Outcome Measures

Outcome Measure	Time Frame
CSF Trough Concentration of ISIS 814907	Pre dose on Day 85 in Part 1 and Day 337 in Part 2
Maximum Observed Drug Concentration (Cmax) of ISIS 814907 in Plasma	Pre-dose, 0.5, 1, 2, 3, 4, and 5 hours post-intrathecal (IT) bolus injection on Day 85 in Part 1 and on Day 337 in Part 2
Time Taken to Reach Maximal Concentration (Tmax) of ISIS 814907 in Plasma	Pre-dose, 0.5, 1, 2, 3, 4, and 5 hours post-IT bolus injection on Day 85 in Part 1 and on Day 337 in Part 2
Terminal Elimination Half-life (t1/2λz) of ISIS 814907 in Plasma	Pre-dose, 0.5, 1, 2, 3, 4, and 5 hours post-IT bolus injection on Day 85 in Part 1 and on Day 337 in Part 2
Areas Under the Plasma Concentration-time Curve From Zero Time (Predose) to 24 Hours After the IT Administration (AUC0-24h) of ISIS 814907	Pre-dose, 0.5, 1, 2, 3, 4, and 5 hours post-IT bolus injection on Day 85 in Part 1 and on Day 337 in Part 2

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): October 12, 2017
• Primary Completion (Actual): May 12, 2022
• Study Completion (Actual): May 12, 2022

Study Registration Dates

• First Submitted: June 6, 2017
• First Submitted That Met QC Criteria: June 13, 2017
• First Posted (Actual): June 14, 2017

Study Record Updates

• Last Update Posted (Actual): April 8, 2025
• Last Update Submitted That Met QC Criteria: March 20, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Tau; Alzheimers; Memory Loss; Mild Alzheimer's Disease; ISIS 814907; MAPT
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease
• Other Study ID Numbers: ISIS 814907-CS1; NL60032.000.16 (Other Identifier: CCMO); 2016-002713-22 (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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes