A First in Human Phase 1 Study in Healthy Volunteers and in Participants With Frontotemporal Dementia (FTD) With Granulin Mutation
Latest Information Update: 04 Nov 2021
At a glance
- Drugs Latozinemab (Primary)
- Indications Dementia
- Focus Adverse reactions; First in man
- Acronyms INFRONT
- Sponsors Alector
- 31 Jul 2020 Results presented at the Alzheimer's Association International Conference 2020
- 27 Jul 2020 According to a Quanterix media release, new findings from this study will be presented at the Alzheimer's Association International Conference (AAIC) 2020.
- 23 Jul 2020 Status changed from active, no longer recruiting to completed.
Most Recent Events
Trial Overview
Purpose
This phase I/Ib, first in human trial is designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of intravenously administered AL001 in healthy volunteers and participants with frontotemporal dementia that carry the GRN mutation, known as FTD-GRN.
The study is designed to assess single and multiple doses of AL001 and measure the levels of progranulin, a disease specific biomarker, in plasma and in cerebrospinal fluid.
Primary Endpoints
Evaluation of safety and tolerability of AL001 measured by number of subjects with adverse events and Dose Limiting Adverse Event (DLAEs)
description: Incidence of adverse events and dose limiting Adverse Events during the DLAE observation period and/or study treatment periods.
time_frame: 85 days
Other Endpoints
Pharmacokinetics (PK) of AL001
description: Serum and cerebrospinal fluid (CSF) concentration of AL001 at specified time points
time_frame: 85 days
Maximum plasma concentration (Cmax) for AL001
description: Evaluate Cmax for serum and CSF concentration of AL001 at specified time points
time_frame: 85 days
Area under the curve concentration (AUC) for AL001
description: Evaluate AUC for serum and CSF concentration of AL001 at specified time points
time_frame: 85 days [1]
Diseases Treated
| Indication | Qualifiers | Patient Segments |
|---|---|---|
| Dementia | treatment | - |
Biomarker
| NCT Number | Biomarker Name | Biomarker Function |
|---|---|---|
| NCT03636204 | Granulin (GEP) | Brief Summary, Brief Title, Official Title |
Subjects
- Subject Type patients & volunteers
-
Number
Planned: 60
Actual: 64
- Sex male & female
- Age Group 18-80 years
Patient Inclusion Criteria
- BMI 18.0-35.0 kg/m2 - 45-120 kg, inclusive - At screening, females must be non-pregnant and non-lactating, or of nonchildbearing potential (either surgically sterilized or physiologically incapable of becoming pregnant, or at least 1-year postmenopausal (amenorrhoea duration of 12 consecutive months); nonpregnancy will be confirmed for all females by a pregnancy test conducted at screening, (each) admission, and at follow-up. - Female participants of child-bearing potential must agree to use adequate contraception from screening until 90 days after the follow-up visit. - In good physical health on the basis of no clinically significant findings from medical history, physical examination (PE), laboratory tests, 12 lead ECG, and vital signs, as judged by the Investigator. - Willingness and able to comply with the study protocol, in the investigator's judgement.
Patient Exclusion Criteria
- Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins. - Positive drug or alcohol at screening and prior to first dose - History of alcohol abuse or substance abuse
Trial Details
Identifiers
| Identifier | Owner |
|---|---|
| NCT03636204 | ClinicalTrials.gov: US National Institutes of Health |
| AL001-1 | - |
Organisations
- Sponsors Alector
- Affiliations Alector
Trial Dates
-
Initiation Dates
Planned : 15 Sep 2018
Actual : 14 Sep 2018
-
Primary Completion Dates
Planned : 31 Dec 2019
Actual : 31 Dec 2019
-
End Dates
Planned : 31 Dec 2019
Actual : 31 Dec 2019
Other Details
- Design double-blind; multicentre; open; parallel; prospective; randomised
- Phase of Trial Phase I
- Location Canada; England; USA
- Focus Adverse reactions; First in man
Interventions
| Drugs | Route | Formulation |
|---|---|---|
| LatozinemabPrimary Drug | Intravenous |
-
|
AL001
Up to six single ascending doses of AL001 Biological: AL001 (Active dose of AL001)
Saline Solution
Saline solution will be administered as a single infusion for each cohort in a ratio of 6 active and 2 placebo subjects Other: Placebo (Saline solution administered as a single infusion as palcebo.)
Results
Therapeutic efficacy
Results from the phase I INFRONT study showed that latozinemab was able to restore the level of progranulin in patients with frontotemporal dementia with a granulin mutation back to the normal range [2] .
Results from the single ascending dose part of the phase I trial of latozinemab, demonstrated dose dependent increase in PGRN levels in plasma and in cerebrospinal fluid in healthy volunteers and in patients with frontotemporal dementia [3] .
Adverse events
In a phase I trial, latozinemab was generally safe and well tolerated through the highest dose assessed, healthy volunteers and in patients with frontotemporal dementia [3] .
Results from phase I INFRONT study showed that latozinemab was well tolerated and was safe in patients with frontotemporal dementia with a granulin mutation [2] .
Pharmacodynamics
In a phase I/Ib trial, multiple ascending dose of latozinemab in frontotemporal dementia patients with a mutation in the progranulin (PGRN) gene showed a statistically significant normalisation in a number of disease-associated proteins, including inflammatory and lysosomal biomarkers (n=8; R=-0.36; P<0.0005). Five patients from symptomatic FTD-GRN cohort showed no significant increases in plasma neurofilament light chain (NfL) levels, after 12 weeks. Moreover, an initial trend showed a 14% reduction in plasma NfL levels compared to baseline levels (n=5; mean=14%; range=-4% to 41%). Compared to healthy volunteers, AL 001 treatment rescued cathepsin B (CTSB), a marker of lysosomal function, by 58%. Latozinemab treatment also partially normalized markers of inflammation and gliosis, osteopontin (SPP1) and chitotriosidase (CHIT1) by 52% and 22%, respectively. There was a 14% reduction in plasma neurofilament light chain (NfL), a marker of neuron injury and stress observed after 8 weeks after the last dose [4] .
Publications
-
Alector. Alector Announces Data from On-going Phase 1b Trial Demonstrating that AL001 Reverses Progranulin Deficiency in Frontotemporal Dementia Patients. Media-Rel 2019;.
Media Release -
Paul R, Ward M, Siddiqui O, Hagey M, Long H, King R, et al. A phase 1 study of AL001 in healthy volunteers and frontotemporal dementia patients carrying a granulin mutation. AAIC-2019 2019; abstr. 35586.
Available from: URL: https://eventpilotadmin.com/web/page.php?page=IntHtml&project=AAIC19&id=35586 -
Haynes BA, Rhinn H, Yeh FL, Long H, Ward M, Hagey M, et al. AL001 restores CSF PGRN levels and normalizes disease-associated biomarkers in individuals with frontotemporal dementia due to heterozygous mutations in the progranulin gene. AAIC-2020 2020; abstr. ODO3-06-03.
Available from: URL: https://alz.confex.com/alz/20amsterdam/meetingapp.cgi/Paper/46114 -
Alector. Alector Announces First Frontotemporal Dementia Patient Dosed in Phase 1b Study of AL001. Media-Rel 2017;.
Media Release
Trial Centres
Investigators
| Investigator | Centre Name | Trial Centre Country |
|---|---|---|
| George Stoica | Bioclinica Research |
-
|
|
Study Coordinator
+1-519-685-4292 cognitiveneurology@sjhc.london.on.ca
show details
|
Lawson Health Research Institute, St. Joseph's, Mayo Clinic, Sunnybrook Health Sciences Centre, UCSF, University College London, University of Alabama, University of Pennsylvania | Canada, United-Kingdom, USA |
|
Study Lead
4152315660 Ext: 328 info@alector.com
show details
|
Alector Inc. |
-
|
Centres
| Centre Name | Location | Trial Centre Country |
|---|---|---|
| Alector Inc. |
-
|
-
|
| Bioclinica Research |
-
|
-
|
| Lawson Health Research Institute, St. Joseph's | London, Ontario | Canada |
| Mayo Clinic | Rochester, Minnesota | USA |
| Study site | Orlando, Florida | USA |
| Sunnybrook Health Sciences Centre | Toronto | Canada |
| UCSF | San Francisco, California | USA |
| University College London | London | United-Kingdom |
| University of Alabama | Birmingham, Alabama | USA |
| University of Pennsylvania | Philadelphia, Pennsylvania | USA |
Trial History
| Event Date | Event Type | Comment |
|---|---|---|
| 31 Jul 2020 | Results | Results presented at the Alzheimer's Association International Conference 2020 Updated 28 Aug 2020 |
| 28 Jul 2020 | Other trial event | Last checked against ClinicalTrials.gov record. Updated 28 Jul 2020 |
| 27 Jul 2020 | Biomarker Update | Biomarkers information updated Updated 04 Nov 2021 |
| 27 Jul 2020 | Other trial event | According to a Quanterix media release, new findings from this study will be presented at the Alzheimer's Association International Conference (AAIC) 2020. Updated 29 Jul 2020 |
| 23 Jul 2020 | Status change - completed | Status changed from active, no longer recruiting to completed. Updated 28 Jul 2020 |
| 12 Aug 2019 | Status change - active, no longer recruiting | Status changed from recruiting to active, no longer recruiting (in Jul 2019), according to an Alector media release. Updated 09 Oct 2019 |
| 18 Jul 2019 | Results | Results from the single ascending dose (SAD) presented at the Alzheimer's Association International Conference 2019 Updated 23 Oct 2019 |
| 17 Jul 2019 | Interim results | According to an Alector media release, data from this study (n=50 healthy volunteers and n=4 patients with FTD-GRN) were presented today at the 2019 Alzheimer's Association International Conference (AAIC) by Robert Paul, M.D., Ph.D., (chief medical officer of Alector). Updated 10 Oct 2019 |
| 17 Jul 2019 | Interim results | Results from ongoing phase 1b portion of this trial (n=50 healthy volunteers and n=4 patients with FTD-GRN) presented in an Alector media release. Updated 10 Oct 2019 |
| 18 Apr 2019 | Completion date | Planned End Date changed from 30 Sep 2020 to 31 Dec 2019. Updated 22 Apr 2019 |
| 18 Apr 2019 | Other trial event | Planned primary completion date changed from 30 Mar 2020 to 31 Dec 2019. Updated 22 Apr 2019 |
| 17 Apr 2019 | Interim results | Results of phase I healthy volunteer portion of this study presented in an Alector media release. Updated 10 Oct 2019 |
| 17 Apr 2019 | Other trial event | According to an Alector media release, the first frontotemporal dementia (FTD) patient has been dosed in the Phase 1b portion of this trial after successful completion of the healthy volunteer single ascending dose escalation portion of the study. Updated 09 Oct 2019 |
| 19 Sep 2018 | Status change - recruiting | Status changed from not yet recruiting to recruiting, according to an Alector media release. Updated 09 Oct 2019 |
| 24 Aug 2018 | New trial record | New trial record Updated 24 Aug 2018 |
Table of Contents
References
-
ClinicalTrials.gov: US National Institutes of Health. Trial-Reg 2023;.
Available from: URL: http://clinicaltrials.gov -
Alector. Alector Announces Data from On-going Phase 1b Trial Demonstrating that AL001 Reverses Progranulin Deficiency in Frontotemporal Dementia Patients. Media-Rel 2019;.
Media Release -
Paul R, Ward M, Siddiqui O, Hagey M, Long H, King R, et al. A phase 1 study of AL001 in healthy volunteers and frontotemporal dementia patients carrying a granulin mutation. AAIC-2019 2019; abstr. 35586.
Available from: URL: https://eventpilotadmin.com/web/page.php?page=IntHtml&project=AAIC19&id=35586 -
Haynes BA, Rhinn H, Yeh FL, Long H, Ward M, Hagey M, et al. AL001 restores CSF PGRN levels and normalizes disease-associated biomarkers in individuals with frontotemporal dementia due to heterozygous mutations in the progranulin gene. AAIC-2020 2020; abstr. ODO3-06-03.
Available from: URL: https://alz.confex.com/alz/20amsterdam/meetingapp.cgi/Paper/46114 -
Quanterix. Quanterix to Participate in Alzheimers Association International Conference (AAIC) 2020. Media-Rel 2020;.
Media Release -
Alector. Alector Initiates Phase 1 Trial of AL001 for the Treatment of Frontotemporal Dementia. Media-Rel 2019;.
Media Release -
Alector. Alector Announces First Frontotemporal Dementia Patient Dosed in Phase 1b Study of AL001. Media-Rel 2017;.
Media Release -
Alector. Alector Reports Recent Business Highlights and Second Quarter 2019 Financial Results. Media-Rel 2019;.
Media Release
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