Frontotemporal Dementia
Conditions
Brief summary
A Phase 2 open label study evaluating the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AL001 in participants with a Granulin mutation or C9orf72 mutation causative of frontotemporal dementia.
Detailed description
This is a Phase 2, multicenter, open label study evaluating the safety, tolerability, PK and PD of AL001 administered intravenously in participants with a Granulin mutation or C9orf72 mutation causative of frontotemporal dementia.
Interventions
DRUGAL001
60 mg/kg of AL001 every 4 weeks
Sponsors
GlaxoSmithKline
Alector Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* At screening, female participants must be nonpregnant and nonlactating * In good physical health on the basis of no clinically significant findings from medical history, physical examinations (PEs), laboratory tests, ECGs, and vital signs. * Participant is a carrier of a loss of function progranulin gene (GRN) mutation or carrier of a hexanucleotide repeat expansion C9orf72 mutation
Exclusion criteria
* Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins. * History of alcohol abuse or substance abuse * Participant resides in a skilled nursing facility, convalescent home, or long term care facility
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Severity of TEAEs | 197 weeks | Number of TEAEs categorized by severity |
| Severity of Treatment-Related TEAEs | 197 weeks | Number of treatment-related TEAEs categorized by severity |
| Any TEAE Leading to Study Drug Discontinuation | 197 weeks | Number of TEAEs leading to study drug discontinuation |
| Immunogenicity Antidrug Antibodies (ADA) Titer | 97 weeks | Titer values of antidrug antibodies (ADAs) in participants receiving latozinemab at week 97/Part 1 end of study |
| Confirmatory Immunogenicity Antidrug Antibodies (ADA) Responses | 97 weeks | Presence of confirmatory antidrug antibodies (ADAs) in participants who test positive for ADA at week 97 (Part 1 End of Study). |
| Change From Baseline in Sheehan Suicidality Tracking Scale | 197 weeks | The Sheehan Suicidality Tracking Scale (S-STS) is a structured assessment tool used to evaluate the presence, severity, and frequency of suicidal ideation and behavior. It includes items that address passive thoughts of death, active suicidal ideation, intent, planning, suicide attempts, and non-suicidal self-injury. The S-STS total score ranges from 0 to 64, based on 16 items each rated from 0 (not at all) to 4 (extremely), with higher scores indicating greater severity of suicidal ideation, intent, or behavior. The total score provides a quantitative measure of suicidality severity and is sensitive to change over time, making it suitable for clinical monitoring and research use. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Longitudinal Percent Change From Baseline of CSF PGRN | 97 weeks | The percent change from baseline to specified timepoints of PGRN in CSF. The baseline visit is labeled as week 1 and therefore the 96th week is labeled as week 97. |
| Longitudinal Percent Change From Baseline in Plasma PGRN | 97 weeks | The percent change from baseline to specified timepoints for PGRN in plasma. The baseline visit is labeled as week 1 and therefore the 96th week is labeled as week 97. |
| Longitudinal Levels of Sortilin in WBCs | 97 weeks | The overall change from baseline in Sortilin in WBCs. |
| Latozinemab Concentration in Serum | 97 weeks | Serum concentration of Latozinemab at week 97. |
| Cmax of Latozinemab at Specified Timepoints | 97 weeks | Maximum observed concentration of Latozinemab at week 96 of treatment. |
| Ctrough of Latozinemab at Specified Timepoints | 97 weeks | Trough concentration of Latozinemab at week 96 of treatment |
| ARCmax of Latozinemab | 61 weeks | Ratio of latozinemab Cmax at week 61 to the Cmax at week 1 |
Countries
Canada, Germany, Italy, Netherlands, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| aFTD-GRN aFTD-GRN - asymptomatic frontotemporal dementia with heterozygous progranulin gene mutation
Part 1 - Latozinemab administered intravenously (60 mg/kg, every 4 weeks \[q4w\]), for a total of 25 doses (96-week dosing period); Part 2 - Latozinemab administered intravenously (60 mg/kg, every 4 weeks \[q4w\]), for a total of 25 doses (96-week dosing period). | 5 |
| FTD-GRN FTD-GRN - symptomatic carriers of GRN mutation causative of FTD
Part 1 - Latozinemab administered intravenously (60 mg/kg, every 4 weeks \[q4w\]), for a total of 25 doses (96-week dosing period); Part 2 - Latozinemab administered intravenously (60 mg/kg, every 4 weeks \[q4w\]), for a total of 25 doses (96-week dosing period). | 12 |
| FTD-C9orf72 FTD-C9orf72 - symptomatic carriers of C9orf72 hexanucleotide repeat expansion mutation causative of FTD
Part 1 - Latozinemab administered intravenously (60 mg/kg, every 4 weeks \[q4w\]), for a total of 25 doses (96-week dosing period); Part 2 - Latozinemab administered intravenously (60 mg/kg, every 4 weeks \[q4w\]), for a total of 25 doses (96-week dosing period). | 16 |
| Total | 33 |
Baseline characteristics
| Characteristic | FTD-C9orf72 | Total | aFTD-GRN | FTD-GRN |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 10 Participants | 0 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 23 Participants | 5 Participants | 7 Participants |
| Age, Continuous | 60.0 years | 59.0 years | 59.0 years | 59.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 31 Participants | 5 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 16 Participants | 31 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Female | 9 Participants | 14 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 7 Participants | 19 Participants | 4 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 12 | 1 / 16 |
| other Total, other adverse events | 4 / 5 | 9 / 12 | 13 / 16 |
| serious Total, serious adverse events | 1 / 5 | 3 / 12 | 2 / 16 |
Outcome results
Primary
Any TEAE Leading to Study Drug Discontinuation
Number of TEAEs leading to study drug discontinuation
Time frame: 197 weeks
Population: There is no statistical analysis for this primary end point.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| aFTD-GRN | Any TEAE Leading to Study Drug Discontinuation | 0 TEAE leading to discontinuation |
| FTD-GRN | Any TEAE Leading to Study Drug Discontinuation | 1 TEAE leading to discontinuation |
| FTD-C9orf72 | Any TEAE Leading to Study Drug Discontinuation | 1 TEAE leading to discontinuation |
Primary
Change From Baseline in Sheehan Suicidality Tracking Scale
The Sheehan Suicidality Tracking Scale (S-STS) is a structured assessment tool used to evaluate the presence, severity, and frequency of suicidal ideation and behavior. It includes items that address passive thoughts of death, active suicidal ideation, intent, planning, suicide attempts, and non-suicidal self-injury. The S-STS total score ranges from 0 to 64, based on 16 items each rated from 0 (not at all) to 4 (extremely), with higher scores indicating greater severity of suicidal ideation, intent, or behavior. The total score provides a quantitative measure of suicidality severity and is sensitive to change over time, making it suitable for clinical monitoring and research use.
Time frame: 197 weeks
Population: There is no statistical analysis for this primary endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| aFTD-GRN | Change From Baseline in Sheehan Suicidality Tracking Scale | 0 Scores | Standard Deviation 0 |
| FTD-GRN | Change From Baseline in Sheehan Suicidality Tracking Scale | 0 Scores | — |
| FTD-C9orf72 | Change From Baseline in Sheehan Suicidality Tracking Scale | 0 Scores | Standard Deviation 0 |
Primary
Confirmatory Immunogenicity Antidrug Antibodies (ADA) Responses
Presence of confirmatory antidrug antibodies (ADAs) in participants who test positive for ADA at week 97 (Part 1 End of Study).
Time frame: 97 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| aFTD-GRN | Confirmatory Immunogenicity Antidrug Antibodies (ADA) Responses | ADA Positive | 1 Participants |
| aFTD-GRN | Confirmatory Immunogenicity Antidrug Antibodies (ADA) Responses | ADA Negative | 4 Participants |
| FTD-GRN | Confirmatory Immunogenicity Antidrug Antibodies (ADA) Responses | ADA Positive | 0 Participants |
| FTD-GRN | Confirmatory Immunogenicity Antidrug Antibodies (ADA) Responses | ADA Negative | 5 Participants |
| FTD-C9orf72 | Confirmatory Immunogenicity Antidrug Antibodies (ADA) Responses | ADA Positive | 2 Participants |
| FTD-C9orf72 | Confirmatory Immunogenicity Antidrug Antibodies (ADA) Responses | ADA Negative | 7 Participants |
Primary
Immunogenicity Antidrug Antibodies (ADA) Titer
Titer values of antidrug antibodies (ADAs) in participants receiving latozinemab at week 97/Part 1 end of study
Time frame: 97 weeks
Population: There is no statistical analysis for this primary end point.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| aFTD-GRN | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 37 - ADA Titer | 0 Titers | — |
| aFTD-GRN | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 97 - ADA Titer | 20.0 Titers | — |
| aFTD-GRN | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 61 - ADA Titer | 0 Titers | — |
| aFTD-GRN | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 49 - ADA Titer | 0 Titers | — |
| aFTD-GRN | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 2 - ADA Titer | 320.0 Titers | — |
| aFTD-GRN | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 85 - ADA Titer | 0 Titers | — |
| aFTD-GRN | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 25 - ADA Titer | 320.0 Titers | — |
| aFTD-GRN | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 13 - ADA Titer | 160.0 Titers | — |
| aFTD-GRN | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 73 - ADA Titer | 0 Titers | — |
| FTD-GRN | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 49 - ADA Titer | 320.0 Titers | — |
| FTD-GRN | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 2 - ADA Titer | 20.0 Titers | — |
| FTD-GRN | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 13 - ADA Titer | 160.0 Titers | — |
| FTD-GRN | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 25 - ADA Titer | 330.0 Titers | — |
| FTD-GRN | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 37 - ADA Titer | 80.0 Titers | — |
| FTD-GRN | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 61 - ADA Titer | 0 Titers | — |
| FTD-GRN | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 73 - ADA Titer | 160.0 Titers | — |
| FTD-GRN | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 85 - ADA Titer | 160.0 Titers | — |
| FTD-GRN | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 97 - ADA Titer | 0 Titers | — |
| FTD-C9orf72 | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 25 - ADA Titer | 80.0 Titers | — |
| FTD-C9orf72 | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 2 - ADA Titer | 40.0 Titers | Full Range 0 |
| FTD-C9orf72 | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 73 - ADA Titer | 0 Titers | — |
| FTD-C9orf72 | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 13 - ADA Titer | 120.0 Titers | — |
| FTD-C9orf72 | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 97 - ADA Titer | 160.0 Titers | — |
| FTD-C9orf72 | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 49 - ADA Titer | 20.0 Titers | — |
| FTD-C9orf72 | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 37 - ADA Titer | 90.0 Titers | — |
| FTD-C9orf72 | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 85 - ADA Titer | 20.0 Titers | — |
| FTD-C9orf72 | Immunogenicity Antidrug Antibodies (ADA) Titer | Week 61 - ADA Titer | 160.0 Titers | — |
Primary
Severity of TEAEs
Number of TEAEs categorized by severity
Time frame: 197 weeks
Population: There is no statistical analysis for this primary end point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| aFTD-GRN | Severity of TEAEs | Mild | 43 TEAEs (all) |
| aFTD-GRN | Severity of TEAEs | Life Threatening | 0 TEAEs (all) |
| aFTD-GRN | Severity of TEAEs | Severe | 3 TEAEs (all) |
| aFTD-GRN | Severity of TEAEs | Death | 0 TEAEs (all) |
| aFTD-GRN | Severity of TEAEs | Moderate | 4 TEAEs (all) |
| FTD-GRN | Severity of TEAEs | Severe | 1 TEAEs (all) |
| FTD-GRN | Severity of TEAEs | Mild | 58 TEAEs (all) |
| FTD-GRN | Severity of TEAEs | Moderate | 9 TEAEs (all) |
| FTD-GRN | Severity of TEAEs | Life Threatening | 0 TEAEs (all) |
| FTD-GRN | Severity of TEAEs | Death | 0 TEAEs (all) |
| FTD-C9orf72 | Severity of TEAEs | Death | 1 TEAEs (all) |
| FTD-C9orf72 | Severity of TEAEs | Life Threatening | 0 TEAEs (all) |
| FTD-C9orf72 | Severity of TEAEs | Mild | 84 TEAEs (all) |
| FTD-C9orf72 | Severity of TEAEs | Severe | 4 TEAEs (all) |
| FTD-C9orf72 | Severity of TEAEs | Moderate | 24 TEAEs (all) |
Primary
Severity of Treatment-Related TEAEs
Number of treatment-related TEAEs categorized by severity
Time frame: 197 weeks
Population: There is no statistical analysis for this primary end point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| aFTD-GRN | Severity of Treatment-Related TEAEs | Mild | 5 TEAEs (treatment-related) |
| aFTD-GRN | Severity of Treatment-Related TEAEs | Life Threatening | 0 TEAEs (treatment-related) |
| aFTD-GRN | Severity of Treatment-Related TEAEs | Severe | 0 TEAEs (treatment-related) |
| aFTD-GRN | Severity of Treatment-Related TEAEs | Death | 0 TEAEs (treatment-related) |
| aFTD-GRN | Severity of Treatment-Related TEAEs | Moderate | 1 TEAEs (treatment-related) |
| FTD-GRN | Severity of Treatment-Related TEAEs | Severe | 0 TEAEs (treatment-related) |
| FTD-GRN | Severity of Treatment-Related TEAEs | Mild | 1 TEAEs (treatment-related) |
| FTD-GRN | Severity of Treatment-Related TEAEs | Moderate | 1 TEAEs (treatment-related) |
| FTD-GRN | Severity of Treatment-Related TEAEs | Life Threatening | 0 TEAEs (treatment-related) |
| FTD-GRN | Severity of Treatment-Related TEAEs | Death | 0 TEAEs (treatment-related) |
| FTD-C9orf72 | Severity of Treatment-Related TEAEs | Death | 0 TEAEs (treatment-related) |
| FTD-C9orf72 | Severity of Treatment-Related TEAEs | Life Threatening | 0 TEAEs (treatment-related) |
| FTD-C9orf72 | Severity of Treatment-Related TEAEs | Mild | 12 TEAEs (treatment-related) |
| FTD-C9orf72 | Severity of Treatment-Related TEAEs | Severe | 0 TEAEs (treatment-related) |
| FTD-C9orf72 | Severity of Treatment-Related TEAEs | Moderate | 5 TEAEs (treatment-related) |
Secondary
ARCmax of Latozinemab
Ratio of latozinemab Cmax at week 61 to the Cmax at week 1
Time frame: 61 weeks
Population: There is no statistical analysis for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| aFTD-GRN | ARCmax of Latozinemab | 1.22 Ratio | Standard Deviation 0.192 |
| FTD-GRN | ARCmax of Latozinemab | 1.23 Ratio | Standard Deviation 0.236 |
| FTD-C9orf72 | ARCmax of Latozinemab | 1.39 Ratio | Standard Deviation 0.712 |
Secondary
Cmax of Latozinemab at Specified Timepoints
Maximum observed concentration of Latozinemab at week 96 of treatment.
Time frame: 97 weeks
Population: There is no statistical analysis for this secondary end point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| aFTD-GRN | Cmax of Latozinemab at Specified Timepoints | 1810 ug/mL | Standard Deviation 352 |
| FTD-GRN | Cmax of Latozinemab at Specified Timepoints | 1320 ug/mL | Standard Deviation 255 |
| FTD-C9orf72 | Cmax of Latozinemab at Specified Timepoints | 1510 ug/mL | Standard Deviation 145 |
Secondary
Ctrough of Latozinemab at Specified Timepoints
Trough concentration of Latozinemab at week 96 of treatment
Time frame: 97 weeks
Population: There is no statistical analysis for this secondary endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| aFTD-GRN | Ctrough of Latozinemab at Specified Timepoints | 236 ug/mL | Standard Deviation 69.1 |
| FTD-GRN | Ctrough of Latozinemab at Specified Timepoints | 250 ug/mL | Standard Deviation 24.7 |
| FTD-C9orf72 | Ctrough of Latozinemab at Specified Timepoints | 252 ug/mL | Standard Deviation 66.7 |
Secondary
Latozinemab Concentration in Serum
Serum concentration of Latozinemab at week 97.
Time frame: 97 weeks
Population: There is no statistical analysis for this secondary end point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| aFTD-GRN | Latozinemab Concentration in Serum | 236000 ng/mL | Standard Deviation 69100 |
| FTD-GRN | Latozinemab Concentration in Serum | 250000 ng/mL | Standard Deviation 24700 |
| FTD-C9orf72 | Latozinemab Concentration in Serum | 265000 ng/mL | Standard Deviation 77000 |
Secondary
Longitudinal Levels of Sortilin in WBCs
The overall change from baseline in Sortilin in WBCs.
Time frame: 97 weeks
Population: WBC samples for analysis for Sortilin expression were collected to serve as a pharmacodynamic biomarker of target engagement. Development of this assay found that stability of these samples was not reliable for accurate measurement. Hence, we did not measure Sortilin in this study.
Secondary
Longitudinal Percent Change From Baseline in Plasma PGRN
The percent change from baseline to specified timepoints for PGRN in plasma. The baseline visit is labeled as week 1 and therefore the 96th week is labeled as week 97.
Time frame: 97 weeks
Population: There is no statistical analysis for this secondary end point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| aFTD-GRN | Longitudinal Percent Change From Baseline in Plasma PGRN | Week 97 | 185.37 percent change in ug/L | Standard Deviation 43.763 |
| aFTD-GRN | Longitudinal Percent Change From Baseline in Plasma PGRN | Week 49 | 177.39 percent change in ug/L | Standard Deviation 51.352 |
| FTD-GRN | Longitudinal Percent Change From Baseline in Plasma PGRN | Week 49 | 151.32 percent change in ug/L | Standard Deviation 59.321 |
| FTD-GRN | Longitudinal Percent Change From Baseline in Plasma PGRN | Week 97 | 188.12 percent change in ug/L | Standard Deviation 47.847 |
| FTD-C9orf72 | Longitudinal Percent Change From Baseline in Plasma PGRN | Week 49 | 178.82 percent change in ug/L | Standard Deviation 58.406 |
| FTD-C9orf72 | Longitudinal Percent Change From Baseline in Plasma PGRN | Week 97 | 157.93 percent change in ug/L | Standard Deviation 92.695 |
Secondary
Longitudinal Percent Change From Baseline of CSF PGRN
The percent change from baseline to specified timepoints of PGRN in CSF. The baseline visit is labeled as week 1 and therefore the 96th week is labeled as week 97.
Time frame: 97 weeks
Population: There is no statistical analysis for this secondary end point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| aFTD-GRN | Longitudinal Percent Change From Baseline of CSF PGRN | Week 49 | 198.16 percent change of ug/L | Standard Deviation 110.255 |
| aFTD-GRN | Longitudinal Percent Change From Baseline of CSF PGRN | Week 97 | 189.46 percent change of ug/L | Standard Deviation 113.802 |
| FTD-GRN | Longitudinal Percent Change From Baseline of CSF PGRN | Week 49 | 104.05 percent change of ug/L | Standard Deviation 103.349 |
| FTD-GRN | Longitudinal Percent Change From Baseline of CSF PGRN | Week 97 | 59.73 percent change of ug/L | Standard Deviation 24.034 |
| FTD-C9orf72 | Longitudinal Percent Change From Baseline of CSF PGRN | Week 49 | 101.61 percent change of ug/L | Standard Deviation 38.492 |
| FTD-C9orf72 | Longitudinal Percent Change From Baseline of CSF PGRN | Week 97 | 144.73 percent change of ug/L | Standard Deviation 54.994 |