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

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.

• IONIS MAPTRx (Drug), also known as ISIS 814907: IONIS MAPTRx injections.
• Placebo (Other): Artificial CSF injections.

Primary outcomes

• Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 [From first dose of study drug up to Week 37 in Part 1]: 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.
• Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 [From first dose of study drug up to Week 64 in Part 2]: 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.

Secondary outcomes

• 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]

Sex: All, ages: 50 Years to 74 Years

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

Participant flow

Outcome results

• Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 (Primary), Count of participants, Participants: Part 1: Cohort A: ISIS 814907 10 mg 3; Part 1: Cohort B: ISIS 814907 30 mg 0; Part 1: Cohort C: ISIS 814907 60 mg 5; Part 1: Cohort D: ISIS 814907 115 mg 4; Part 1: Pooled Placebo 0
• Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 (Primary), Count of participants, Participants: Part 2: Late Start Cohort A + Cohort B + Cohort C + ISIS 814907 60 mg 1; Part 2: Late Start Cohort D + ISIS 814907 115 mg 0; Part 2: Early Start Cohort A + ISIS 814907 60 mg 1; Part 2: Early Start Cohort B + ISIS 814907 60 mg 1; Part 2: Early Start Cohort C + ISIS 814907 60 mg 0; Part 2: Early Start Cohort D + ISIS 814907 115 mg 2
• CSF Trough Concentration of ISIS 814907 (Secondary), Mean, nanogram per millilitre (ng/mL): Part 1: Cohort A: ISIS 814907 10 mg 5.56 +/- 2.12; Part 1: Cohort B: ISIS 814907 30 mg 9.77 +/- 3.46; Part 1: Cohort C: ISIS 814907 60 mg 9.79 +/- 3.42; Part 1: Cohort D: ISIS 814907 115 mg 3.26 +/- 1.24; Part 2: Cohort A + ISIS 814907 60 mg 5.96 +/- NA; Part 2: Cohort B + ISIS 814907 60 mg 8.22 +/- 2.03; Part 2: Cohort C + ISIS 814907 60 mg 6.61 +/- 2.89; Part 2: Cohort D + ISIS 814907 115 mg 7.82 +/- 2.52
• Maximum Observed Drug Concentration (Cmax) of ISIS 814907 in Plasma (Secondary), Geometric mean, ng/mL: Part 1: Cohort A: ISIS 814907 10 mg 65.4 +/- 203; Part 1: Cohort B: ISIS 814907 30 mg 285 +/- 50.5; Part 1: Cohort C: ISIS 814907 60 mg 542 +/- 148; Part 1: Cohort D: ISIS 814907 115 mg 830 +/- 879; Part 2: Cohort A + ISIS 814907 60 mg 840 +/- NA; Part 2: Cohort B + ISIS 814907 60 mg 323 +/- 56.6; Part 2: Cohort C + ISIS 814907 60 mg 524 +/- 90.2; Part 2: Cohort D + ISIS 814907 115 mg 1011 +/- 130
• Time Taken to Reach Maximal Concentration (Tmax) of ISIS 814907 in Plasma (Secondary), Median, hours: Part 1: Cohort A: ISIS 814907 10 mg 3.13 (1.02 to 24.7); Part 1: Cohort B: ISIS 814907 30 mg 4.00 (3.02 to 5.00); Part 1: Cohort C: ISIS 814907 60 mg 4.02 (2.00 to 24.2); Part 1: Cohort D: ISIS 814907 115 mg 3.38 (1.02 to 338); Part 2: Cohort A + ISIS 814907 60 mg 2.05 (1.02 to 3.08); Part 2: Cohort B + ISIS 814907 60 mg 4.02 (3.02 to 5.07); Part 2: Cohort C + ISIS 814907 60 mg 4.15 (2.02 to 24.3); Part 2: Cohort D + ISIS 814907 115 mg 4.03 (0.500 to 23.5)
• Terminal Elimination Half-life (t1/2λz) of ISIS 814907 in Plasma (Secondary), Geometric mean, days: Part 1: Cohort A: ISIS 814907 10 mg 19.4 +/- 62.7; Part 1: Cohort B: ISIS 814907 30 mg 38.0 +/- 23.1; Part 1: Cohort C: ISIS 814907 60 mg 34.8 +/- 22.6; Part 1: Cohort D: ISIS 814907 115 mg 42.5 +/- 16.1; Part 2: Cohort A + ISIS 814907 60 mg 10.7 +/- NA; Part 2: Cohort B + ISIS 814907 60 mg 10.3 +/- 8.99; Part 2: Cohort C + ISIS 814907 60 mg 10.6 +/- 16.3; Part 2: Cohort D + ISIS 814907 115 mg 13.8 +/- 54.0
• Areas Under the Plasma Concentration-time Curve From Zero Time (Predose) to 24 Hours After the IT Administration (AUC0-24h) of ISIS 814907 (Secondary), Geometric mean, nanogram*hours per millilitre (ng*h/mL): Part 1: Cohort A: ISIS 814907 10 mg 679 +/- 119; Part 1: Cohort B: ISIS 814907 30 mg 3638 +/- 36.0; Part 1: Cohort C: ISIS 814907 60 mg 6143 +/- 92.4; Part 1: Cohort D: ISIS 814907 115 mg 7120 +/- 3066; Part 2: Cohort A + ISIS 814907 60 mg 10523 +/- NA; Part 2: Cohort B + ISIS 814907 60 mg 5176 +/- 44.5; Part 2: Cohort C + ISIS 814907 60 mg 6396 +/- 68.7; Part 2: Cohort D + ISIS 814907 115 mg 12542 +/- 50.2

Adverse events

Time frame: From first dose of study drug up to Week 37 in Part 1 and up to Week 64 in Part 2

Serious adverse events by term

Other adverse events by term

81 more terms not shown.

• Results publication: Shulman M, Wu S, Ziogas N, Edwards A, Collins J, Lin L, Tien I, Curiale G, Li Y, Mummery C, Lane R, Junge C, Beaver J, Tian Y, Landen J, Bullain S, Gallagher D. Exploratory analyses of clinical outcomes from the BIIB080 phase 1b study in mild Alzheimer's disease. Nat Aging. 2026 Feb;6(2):445-453. doi: 10.1038/s43587-025-01031-9. Epub 2026 Feb 11. PMID 41673497
• Results publication: 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
• Results publication: 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
• Results publication: 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

• Study Protocol and Statistical Analysis Plan (PDF, 2022-04-27)

NIH grants: 2016