Mild Alzheimer's Disease
Conditions
Keywords
Mild Alzheimer's Disease, ISIS 814907, Memory Loss, Alzheimers, MAPT, Tau
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.
Interventions
DRUGIONIS MAPTRx
IONIS MAPTRx injections.
OTHERPlacebo
Artificial CSF injections.
Sponsors
Ionis Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 74 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 |
| CSF Trough Concentration of ISIS 814907 | Pre dose on Day 85 in Part 1 and 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 |
| 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 |
| 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 |
Countries
Canada, Finland, Germany, Netherlands, Sweden, United Kingdom
Participant flow
Recruitment details
The study was conducted at 12 investigative sites in the Germany, United Kingdom, the Netherlands, Sweden, Canada, and Finland from 23 August 2017 to 12 May 2022.
Pre-assignment details
A total of 102 participants were screened and 46 participants with mild Alzheimer's disease were enrolled and randomized to receive ISIS 814907 or placebo in Part 1 (multiple ascending dose \[MAD\]). This study consists of two parts i.e., Part 1: MAD and Part 2: long-term extension (LTE). Out of 46 participants enrolled in Part 1, 33 participants who met the pre-specified eligibility criteria transitioned into Part 2.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Cohort A: ISIS 814907 10 mg Participants received 10 mg ISIS 814907 diluted in 20 mL artificial CSF, intrathecally, Q4W on Days 1, 29, 57, and 85 in Part 1 of the study. | 6 |
| 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. | 6 |
| 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. | 9 |
| Part 1: Cohort D: ISIS 814907 115 mg Participants received 115 mg ISIS 814907 diluted in 20 mL artificial CSF, intrathecally, Q12W on Days 1 and 85 in Part 1 of the study. | 13 |
| 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. | 12 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Part 1: MAD (Day 1 up to Week 36) | Voluntary Withdrawal | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part 2: LTE (Week 37 to Week 101) | Adverse Event or Serious Adverse Event (SAE) | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 0 | 0 |
| Part 2: LTE (Week 37 to Week 101) | Investigator Judgement | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Part 2: LTE (Week 37 to Week 101) | Voluntary Withdrawal | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | 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 1: Pooled Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 63.5 years STANDARD_DEVIATION 5.2 | 65.0 years STANDARD_DEVIATION 6.1 | 65.6 years STANDARD_DEVIATION 6.8 | 66.9 years STANDARD_DEVIATION 6.3 | 66.3 years STANDARD_DEVIATION 4.6 | 65.8 years STANDARD_DEVIATION 5.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 6 Participants | 9 Participants | 13 Participants | 11 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 6 Participants | 9 Participants | 13 Participants | 12 Participants | 46 Participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 5 Participants | 6 Participants | 6 Participants | 23 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 4 Participants | 7 Participants | 6 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 9 | 0 / 13 | 0 / 12 | 0 / 4 | 0 / 4 | 0 / 3 | 0 / 5 | 0 / 7 | 0 / 1 |
| other Total, other adverse events | 6 / 6 | 5 / 6 | 9 / 9 | 12 / 13 | 9 / 12 | 4 / 4 | 3 / 4 | 3 / 3 | 4 / 5 | 7 / 7 | 10 / 10 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 9 | 0 / 13 | 2 / 12 | 1 / 4 | 0 / 4 | 1 / 3 | 1 / 5 | 0 / 7 | 1 / 10 |
Outcome results
Primary
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.
Time frame: From first dose of study drug up to Week 37 in Part 1
Population: Safety population included all participants who were randomised and received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Cohort A: ISIS 814907 10 mg | Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Mild | 3 Participants |
| Part 1: Cohort A: ISIS 814907 10 mg | Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Severe | 0 Participants |
| Part 1: Cohort A: ISIS 814907 10 mg | Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Moderate | 0 Participants |
| Part 1: Cohort B: ISIS 814907 30 mg | Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Moderate | 1 Participants |
| Part 1: Cohort B: ISIS 814907 30 mg | Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Mild | 0 Participants |
| Part 1: Cohort B: ISIS 814907 30 mg | Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Severe | 0 Participants |
| Part 1: Cohort C: ISIS 814907 60 mg | Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Moderate | 1 Participants |
| Part 1: Cohort C: ISIS 814907 60 mg | Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Mild | 5 Participants |
| Part 1: Cohort C: ISIS 814907 60 mg | Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Severe | 0 Participants |
| Part 1: Cohort D: ISIS 814907 115 mg | Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Mild | 4 Participants |
| Part 1: Cohort D: ISIS 814907 115 mg | Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Severe | 0 Participants |
| Part 1: Cohort D: ISIS 814907 115 mg | Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Moderate | 1 Participants |
| Part 1: Pooled Placebo | Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Moderate | 0 Participants |
| Part 1: Pooled Placebo | Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Mild | 0 Participants |
| Part 1: Pooled Placebo | Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Severe | 0 Participants |
Primary
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.
Time frame: From first dose of study drug up to Week 64 in Part 2
Population: Safety population included all participants who were randomised and received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Cohort A: ISIS 814907 10 mg | Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Moderate | 0 Participants |
| Part 1: Cohort A: ISIS 814907 10 mg | Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Mild | 1 Participants |
| Part 1: Cohort A: ISIS 814907 10 mg | Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Severe | 0 Participants |
| Part 1: Cohort B: ISIS 814907 30 mg | Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Moderate | 2 Participants |
| Part 1: Cohort B: ISIS 814907 30 mg | Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Mild | 0 Participants |
| Part 1: Cohort B: ISIS 814907 30 mg | Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Severe | 0 Participants |
| Part 1: Cohort C: ISIS 814907 60 mg | Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Moderate | 1 Participants |
| Part 1: Cohort C: ISIS 814907 60 mg | Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Mild | 1 Participants |
| Part 1: Cohort C: ISIS 814907 60 mg | Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Severe | 0 Participants |
| Part 1: Cohort D: ISIS 814907 115 mg | Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Moderate | 1 Participants |
| Part 1: Cohort D: ISIS 814907 115 mg | Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Mild | 1 Participants |
| Part 1: Cohort D: ISIS 814907 115 mg | Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Severe | 0 Participants |
| Part 1: Pooled Placebo | Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Moderate | 1 Participants |
| Part 1: Pooled Placebo | Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Mild | 0 Participants |
| Part 1: Pooled Placebo | Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Severe | 0 Participants |
| Part 2: Early Start Cohort D + ISIS 814907 115 mg | Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Mild | 2 Participants |
| Part 2: Early Start Cohort D + ISIS 814907 115 mg | Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Severe | 1 Participants |
| Part 2: Early Start Cohort D + ISIS 814907 115 mg | Part 2: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907 | Moderate | 3 Participants |
Secondary
Areas Under the Plasma Concentration-time Curve From Zero Time (Predose) to 24 Hours After the IT Administration (AUC0-24h) of ISIS 814907
Time frame: 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
Population: PK population consisted of all participants who were randomized, received at least 1 dose of ISIS 814907, and had sufficient sampling (at least 1 evaluable post-Baseline PK sample) to permit PK evaluation. Overall number of participants analyzed is number of participants who received active treatment (ISIS 814907) in Part 1 or received active treatment in Part 2. As pre-specified in SAP, in case of very few participants in any active treatment groups, the analysis groups may have been pooled.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cohort A: ISIS 814907 10 mg | Areas Under the Plasma Concentration-time Curve From Zero Time (Predose) to 24 Hours After the IT Administration (AUC0-24h) of ISIS 814907 | 679 nanogram*hours per millilitre (ng*h/mL) | Geometric Coefficient of Variation 119 |
| Part 1: Cohort B: ISIS 814907 30 mg | Areas Under the Plasma Concentration-time Curve From Zero Time (Predose) to 24 Hours After the IT Administration (AUC0-24h) of ISIS 814907 | 3638 nanogram*hours per millilitre (ng*h/mL) | Geometric Coefficient of Variation 36 |
| Part 1: Cohort C: ISIS 814907 60 mg | Areas Under the Plasma Concentration-time Curve From Zero Time (Predose) to 24 Hours After the IT Administration (AUC0-24h) of ISIS 814907 | 6143 nanogram*hours per millilitre (ng*h/mL) | Geometric Coefficient of Variation 92.4 |
| Part 1: Cohort D: ISIS 814907 115 mg | Areas Under the Plasma Concentration-time Curve From Zero Time (Predose) to 24 Hours After the IT Administration (AUC0-24h) of ISIS 814907 | 7120 nanogram*hours per millilitre (ng*h/mL) | Geometric Coefficient of Variation 3066 |
| Part 1: Pooled Placebo | Areas Under the Plasma Concentration-time Curve From Zero Time (Predose) to 24 Hours After the IT Administration (AUC0-24h) of ISIS 814907 | 10523 nanogram*hours per millilitre (ng*h/mL) | — |
| Part 2: Early Start Cohort D + ISIS 814907 115 mg | Areas Under the Plasma Concentration-time Curve From Zero Time (Predose) to 24 Hours After the IT Administration (AUC0-24h) of ISIS 814907 | 5176 nanogram*hours per millilitre (ng*h/mL) | Geometric Coefficient of Variation 44.5 |
| Part 2: Cohort C + ISIS 814907 60 mg | Areas Under the Plasma Concentration-time Curve From Zero Time (Predose) to 24 Hours After the IT Administration (AUC0-24h) of ISIS 814907 | 6396 nanogram*hours per millilitre (ng*h/mL) | Geometric Coefficient of Variation 68.7 |
| Part 2: Cohort D + ISIS 814907 115 mg | Areas Under the Plasma Concentration-time Curve From Zero Time (Predose) to 24 Hours After the IT Administration (AUC0-24h) of ISIS 814907 | 12542 nanogram*hours per millilitre (ng*h/mL) | Geometric Coefficient of Variation 50.2 |
Secondary
CSF Trough Concentration of ISIS 814907
Time frame: Pre dose on Day 85 in Part 1 and Day 337 in Part 2
Population: PK population consisted of all participants who were randomized, received at least 1 dose of ISIS 814907, and had sufficient sampling (at least 1 evaluable post-Baseline PK sample) to permit PK evaluation. Overall number of participants analyzed is number of participants who received active treatment (ISIS 814907) in Part 1 or received active treatment in Part 2. As pre-specified in SAP, in case of very few participants in any active treatment groups, the analysis groups may have been pooled.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cohort A: ISIS 814907 10 mg | CSF Trough Concentration of ISIS 814907 | 5.56 nanogram per millilitre (ng/mL) | Standard Deviation 2.12 |
| Part 1: Cohort B: ISIS 814907 30 mg | CSF Trough Concentration of ISIS 814907 | 9.77 nanogram per millilitre (ng/mL) | Standard Deviation 3.46 |
| Part 1: Cohort C: ISIS 814907 60 mg | CSF Trough Concentration of ISIS 814907 | 9.79 nanogram per millilitre (ng/mL) | Standard Deviation 3.42 |
| Part 1: Cohort D: ISIS 814907 115 mg | CSF Trough Concentration of ISIS 814907 | 3.26 nanogram per millilitre (ng/mL) | Standard Deviation 1.24 |
| Part 1: Pooled Placebo | CSF Trough Concentration of ISIS 814907 | 5.96 nanogram per millilitre (ng/mL) | — |
| Part 2: Early Start Cohort D + ISIS 814907 115 mg | CSF Trough Concentration of ISIS 814907 | 8.22 nanogram per millilitre (ng/mL) | Standard Deviation 2.03 |
| Part 2: Cohort C + ISIS 814907 60 mg | CSF Trough Concentration of ISIS 814907 | 6.61 nanogram per millilitre (ng/mL) | Standard Deviation 2.89 |
| Part 2: Cohort D + ISIS 814907 115 mg | CSF Trough Concentration of ISIS 814907 | 7.82 nanogram per millilitre (ng/mL) | Standard Deviation 2.52 |
Secondary
Maximum Observed Drug Concentration (Cmax) of ISIS 814907 in Plasma
Time frame: 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
Population: PK population consisted of all participants who were randomized, received at least 1 dose of ISIS 814907, and had sufficient sampling (at least 1 evaluable post-Baseline PK sample) to permit PK evaluation. Overall number of participants analyzed is number of participants who received active treatment (ISIS 814907) in Part 1 or received active treatment in Part 2. As pre-specified in SAP, in case of very few participants in any active treatment groups, the analysis groups may have been pooled.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cohort A: ISIS 814907 10 mg | Maximum Observed Drug Concentration (Cmax) of ISIS 814907 in Plasma | 65.4 ng/mL | Geometric Coefficient of Variation 203 |
| Part 1: Cohort B: ISIS 814907 30 mg | Maximum Observed Drug Concentration (Cmax) of ISIS 814907 in Plasma | 285 ng/mL | Geometric Coefficient of Variation 50.5 |
| Part 1: Cohort C: ISIS 814907 60 mg | Maximum Observed Drug Concentration (Cmax) of ISIS 814907 in Plasma | 542 ng/mL | Geometric Coefficient of Variation 148 |
| Part 1: Cohort D: ISIS 814907 115 mg | Maximum Observed Drug Concentration (Cmax) of ISIS 814907 in Plasma | 830 ng/mL | Geometric Coefficient of Variation 879 |
| Part 1: Pooled Placebo | Maximum Observed Drug Concentration (Cmax) of ISIS 814907 in Plasma | 840 ng/mL | — |
| Part 2: Early Start Cohort D + ISIS 814907 115 mg | Maximum Observed Drug Concentration (Cmax) of ISIS 814907 in Plasma | 323 ng/mL | Geometric Coefficient of Variation 56.6 |
| Part 2: Cohort C + ISIS 814907 60 mg | Maximum Observed Drug Concentration (Cmax) of ISIS 814907 in Plasma | 524 ng/mL | Geometric Coefficient of Variation 90.2 |
| Part 2: Cohort D + ISIS 814907 115 mg | Maximum Observed Drug Concentration (Cmax) of ISIS 814907 in Plasma | 1011 ng/mL | Geometric Coefficient of Variation 130 |
Secondary
Terminal Elimination Half-life (t1/2λz) of ISIS 814907 in Plasma
Time frame: 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
Population: PK population consisted of all participants who were randomized, received at least 1 dose of ISIS 814907, and had sufficient sampling (at least 1 evaluable post-Baseline PK sample) to permit PK evaluation. Overall number of participants analyzed is number of participants who received active treatment (ISIS 814907) in Part 1 or received active treatment in Part 2. As pre-specified in SAP, in case of very few participants in any active treatment groups, the analysis groups may have been pooled.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cohort A: ISIS 814907 10 mg | Terminal Elimination Half-life (t1/2λz) of ISIS 814907 in Plasma | 19.4 days | Geometric Coefficient of Variation 62.7 |
| Part 1: Cohort B: ISIS 814907 30 mg | Terminal Elimination Half-life (t1/2λz) of ISIS 814907 in Plasma | 38.0 days | Geometric Coefficient of Variation 23.1 |
| Part 1: Cohort C: ISIS 814907 60 mg | Terminal Elimination Half-life (t1/2λz) of ISIS 814907 in Plasma | 34.8 days | Geometric Coefficient of Variation 22.6 |
| Part 1: Cohort D: ISIS 814907 115 mg | Terminal Elimination Half-life (t1/2λz) of ISIS 814907 in Plasma | 42.5 days | Geometric Coefficient of Variation 16.1 |
| Part 1: Pooled Placebo | Terminal Elimination Half-life (t1/2λz) of ISIS 814907 in Plasma | 10.7 days | — |
| Part 2: Early Start Cohort D + ISIS 814907 115 mg | Terminal Elimination Half-life (t1/2λz) of ISIS 814907 in Plasma | 10.3 days | Geometric Coefficient of Variation 8.99 |
| Part 2: Cohort C + ISIS 814907 60 mg | Terminal Elimination Half-life (t1/2λz) of ISIS 814907 in Plasma | 10.6 days | Geometric Coefficient of Variation 16.3 |
| Part 2: Cohort D + ISIS 814907 115 mg | Terminal Elimination Half-life (t1/2λz) of ISIS 814907 in Plasma | 13.8 days | Geometric Coefficient of Variation 54 |
Secondary
Time Taken to Reach Maximal Concentration (Tmax) of ISIS 814907 in Plasma
Time frame: 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
Population: PK population consisted of all participants who were randomized, received at least 1 dose of ISIS 814907, and had sufficient sampling (at least 1 evaluable post-Baseline PK sample) to permit PK evaluation. Overall number of participants analyzed is number of participants who received active treatment (ISIS 814907) in Part 1 or received active treatment in Part 2. As pre-specified in SAP, in case of very few participants in any active treatment groups, the analysis groups may have been pooled.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cohort A: ISIS 814907 10 mg | Time Taken to Reach Maximal Concentration (Tmax) of ISIS 814907 in Plasma | 3.13 hours |
| Part 1: Cohort B: ISIS 814907 30 mg | Time Taken to Reach Maximal Concentration (Tmax) of ISIS 814907 in Plasma | 4.00 hours |
| Part 1: Cohort C: ISIS 814907 60 mg | Time Taken to Reach Maximal Concentration (Tmax) of ISIS 814907 in Plasma | 4.02 hours |
| Part 1: Cohort D: ISIS 814907 115 mg | Time Taken to Reach Maximal Concentration (Tmax) of ISIS 814907 in Plasma | 3.38 hours |
| Part 1: Pooled Placebo | Time Taken to Reach Maximal Concentration (Tmax) of ISIS 814907 in Plasma | 2.05 hours |
| Part 2: Early Start Cohort D + ISIS 814907 115 mg | Time Taken to Reach Maximal Concentration (Tmax) of ISIS 814907 in Plasma | 4.02 hours |
| Part 2: Cohort C + ISIS 814907 60 mg | Time Taken to Reach Maximal Concentration (Tmax) of ISIS 814907 in Plasma | 4.15 hours |
| Part 2: Cohort D + ISIS 814907 115 mg | Time Taken to Reach Maximal Concentration (Tmax) of ISIS 814907 in Plasma | 4.03 hours |