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

NCT03186989 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: ISIS 814907-CS1NL60032.000.162016-002713-22
• Study Type: interventional
• Target: 46
• Locations: 6 countries
• Sites: 13

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.

Conditions

Mild Alzheimer's Disease

Keywords

Mild Alzheimer's Disease; ISIS 814907; Memory Loss; Alzheimers; MAPT; Tau

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (5)

• 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

Study Arms (11)

Part 1: Cohort A: ISIS 814907 10 mg

EXPERIMENTAL

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

Part 1: Cohort B: ISIS 814907 30 mg

EXPERIMENTAL

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

Part 1: Cohort C: ISIS 814907 60 mg

EXPERIMENTAL

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

Part 1: Cohort D: ISIS 814907 115 mg

EXPERIMENTAL

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

Part 1: Pooled Placebo

PLACEBO COMPARATOR

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

Interventions

IONIS MAPTRx DRUG

IONIS MAPTRx injections.

Also known as: ISIS 814907

Part 1: Cohort A: ISIS 814907 10 mg; Part 1: Cohort B: ISIS 814907 30 mg; Part 1: Cohort C: ISIS 814907 60 mg; Part 1: Cohort D: ISIS 814907 115 mg; Part 2: Early Start Cohort A + ISIS 814907 60 mg; Part 2: Early Start Cohort B + ISIS 814907 60 mg; Part 2: Early Start Cohort C + ISIS 814907 60 mg; Part 2: Early Start Cohort D + ISIS 814907 115 mg; Part 2: Late Start Cohort A + Cohort B + Cohort C + ISIS 814907 60 mg; Part 2: Late Start Cohort D + ISIS 814907 115 mg

Placebo OTHER

Artificial CSF injections.

Part 1: Pooled Placebo

Eligibility Criteria

• Age: 50 Years - 74 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Treatment with another Study Drug, biological agent, or device within one-month of Screening or 5 half-lives of investigational agent, whichever is longer
• Use of a disallowed CNS-active or antipsychotic medication within 4 weeks prior to Screening punctures
• Must have completed the Treatment Evaluation and Post-Treatment Periods in 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
• Use of a disallowed CNS-active or antipsychotic medication within 4 weeks prior to Screening punctures

Sponsors & Collaborators

• Ionis Pharmaceuticals, Inc.: lead

Study Sites (13)

Montreal Neurological Hospital

Montreal, Canada

Location

Clinical Research Services Turku CRST

Turku, Finland

Location

St Josef Hospital

Bochum, Germany

Location

Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)

Bonn, 53127, Germany

Location

MVZ Mittweida Gbr

Mittweida, Germany

Location

Universittsklinikum Ulm

Ulm, Germany

Location

VU University Medical Center

Amsterdam, 1081 HV, Netherlands

Location

QPS Netherlands BV

Groningen, 9713 AG, Netherlands

Location

Minnesmottagningen

Mölndal, Sweden

Location

Karolinska University Hospital Huddinge

Stockholm, Sweden

Location

Royal Liverpool University Hospital

Liverpool, United Kingdom

Location

University College London Hospitals NHS Foundation Trust

London, United Kingdom

Location

Sheffield Institute for Translational Neuroscience (SITraN)

Sheffield, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 38594621 DERIVED

• 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.

  PMID: 37902726 DERIVED

• 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.

  PMID: 37095250 DERIVED

MeSH Terms

Conditions

Memory Disorders; Pick Disease of the Brain

Condition Hierarchy (Ancestors)

Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Frontotemporal Dementia; Frontotemporal Lobar Degeneration; Dementia; Brain Diseases; Central Nervous System Diseases; Neurocognitive Disorders; Mental Disorders

Results Point of Contact

• Title: Ionis Pharmaceuticals, Inc.
• Organization: Ionis Pharmaceuticals, Inc.

globalregulatoryaffairs@ionis.com

760-603-2346

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 6, 2017
• First Posted: June 14, 2017
• Study Start: October 12, 2017
• Primary Completion: May 12, 2022
• Study Completion: May 12, 2022
• Last Updated: April 8, 2025
• Results First Posted: April 8, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

GB (3); FI (1); SE (2); DE (4); NL (2); CA (1)