Open-Label Study to Evaluate Safety of long-term AL001 dosing in FTD
Research type
Research Study
Full title
A Phase 2, Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AL001 in Heterozygous Carriers of Granulin or C9orf72 Mutations Causative of Frontotemporal Dementia
IRAS ID
264080
Contact name
Catherine Mummery
Contact email
Sponsor organisation
Alector Inc.
Eudract number
2019-000138-20
Duration of Study in the UK
1 years, 8 months, 8 days
Research summary
Summary of Research
This is a Phase 2 Open-Label study to see how safe and well-tolerated the experimental drug AL001 is when given intravenously to participants with a mutation in the gene for Granulin (GRN) or C9orf72, which causes frontotemporal dementia (FTD). This study will enrol symptomatic and asymptomatic participants with a GRN mutation who completed the AL001-1 study, as well as symptomatic patients with a GRN or C9orf72 mutation who have not had AL001 before.
FTD is the second most common early-onset form of dementia after Alzheimer’s Disease and leads to cognitive dysfunction, e.g. issues with attention and memory, behavioural and personality changes, as well as language problems. Patients with FTD decline rapidly, and may die within 3-5 years. No effective treatment has been approved for the treatment of FTD, and only symptomatic care can be provided.
Mutations such as GRN and C9orf72 cause accumulation of a protein called TDP-43 in the brain, leading to disruption of brain activity, and neurodegeneration. Al001 prevents the breakdown of another protein, Progranulin, which has been found to reduce TDP-43 in non-clinical studies. Therapeutics targeted at reducing TDP-43 may slow the progression of disease in FTD. This is the second clinical study using AL001; however, non-clinical studies have not identified any potential risks that would prevent the initiation of this study.
Approximately 32 participants will be enrolled during the trial to receive up to 13 doses of AL001 over a 48 week period. Study procedures will include blood sampling, adverse event monitoring, ECG, blood pressure, physical and neurological examinations, lumbar puncture, questionnaires, and MRI. The effects of AL001 on the body, and how the body processes AL001 will be measured, and the study will also look at whether AL001 affects markers of disease progression, or if there is any effect on cognitive function in participants with a GRN mutation.
Summary of Results
SAFETY AND TOLERABILITY OF LATOZINEMAB IN PARTICIPANTS WITH A GENETIC MUTATION ASSOCIATED WITH FRONTOTEMPORAL DEMENTIA
What was this study about?
Frontotemporal dementia (FTD) is a rare, early-onset form of dementia caused by damage to nerve cells in certain parts of the brain (specifically the frontal and temporal lobes). This affects the person’s decision-making, behavior, emotions, and language abilities. FTD can be related to genetic mutations that some people have. Currently, no approved treatment can stop or slow the progression of FTD.
Latozinemab is an antibody, a type of molecule that can bind to other molecules. It binds to a receptor called sortilin and is designed to block the destruction of a protein called progranulin.
This helps increase progranulin levels. Genetic mutations that lead to a lower amount of progranulin in the brain can cause FTD in some people. Therefore, increasing the amount of progranulin might help people with FTD. Latozinemab is being developed by Alector, Inc. for the treatment of FTD caused by a mutation in the granulin (GRN) gene and the C9orf72 gene to increase levels of progranulin.What was the goal of the study?
Latozinemab was studied previously in healthy participants and participants with FTD (Phase 1 study) to test its safety and determine the best dose. This Phase 2 study examined the safety and tolerability (ie, possible side effects) of latozinemab in participants with FTD.
How was the study done?
Alector developed and helped guide the study with the assistance of PPD, a company that helps run clinical trials. GlaxoSmithKline helped fund the study. The study took place at 15 locations across the United States, Canada, the European Union, and the UK. The study started on
27 September 2019 and ended on 05 June 2024.
This was an “open-label” study, meaning the participants and researchers knew that all participants were receiving latozinemab in the study. There was no comparison group receiving a placebo (a dummy treatment with no active medicine). The participants joined the study voluntarily after being informed of all the important information. Participants received latozinemab every 4 weeks at the clinic by slow infusion into a vein. The study included adult men and women. The amount of time that participants were in the study varied, but the entire study lasted about 4 years.The study included 3 groups:
• participants with a GRN mutation and symptoms of FTD (12 participants), • participants with a C9orf72 mutation and symptoms of FTD (16 participants), • and participants with a GRN mutation but no symptoms of FTD (5 participants).To determine if latozinemab was safe, researchers recorded all adverse events that participants experienced during the study. An adverse event is any medical event occurring while a participant was receiving latozinemab, even if not related to the treatment (having COVID-19, for example). The study doctors also used medical questionnaires, did checkups at certain times, took blood samples, checked the heart’s rhythm, and took detailed pictures of the brain.
What were the results of this study?
A total of 33 participants took part in the study (19 men and 14 women). The average age of participants was 60 years. The results showed that latozinemab was generally well-tolerated over a long period, even by participants who had other long-term health problems and were taking additional medications.
Most participants (31 out of 33, or 94%) experienced at least 1 adverse event, but most of the events were judged by the study doctors as not due to latozinemab. Twelve participants experienced adverse events that were judged possibly due to latozinemab. The most common were nausea, headache, and a rise in a digestive enzyme called lipase (each reported by 2 participants).
Two participants stopped the study due to health problems not related to latozinemab. One participant died due to the worsening of another medical condition.
Due to the small number of participants in the study and lack of a control group (placebo), it was not possible to say if latozinemab helped to treat FTD. To do so, a Phase 3 study including a control group and more participants is underway. This study will help researchers evaluate if latozinemab works to treat FTD.Where can I learn more about this study?
For more details, visit:
https://gbr01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrialsregister.eu%2Fctr-search&data=05%7C02%7Clondoncentral.rec%40hra.nhs.uk%7C8dd60bf27def4c55355108ddaa637af7%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638854066428845183%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=z%2F8fRRNQxSY719FBxqcokV0qIrf1xNkVxogE6rwSBP0%3D&reserved=0, EudraCT number: 2019-000138-20.
https://gbr01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrials.gov%2F&data=05%7C02%7Clondoncentral.rec%40hra.nhs.uk%7C8dd60bf27def4c55355108ddaa637af7%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638854066428860952%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=1UWj17OpLQ3Mq56d6y9O23hRMicSjZD80e3m6k9Fv6s%3D&reserved=0, NCT number: NCT03987295.
The full title of the study is: A Phase 2, Multicenter, Open-Label Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AL001 in Heterozygous Carriers of Granulin or C9orf72 Mutation Causative of Frontotemporal Dementia.
The sponsor was Alector, Inc.: 131 Oyster Point Boulevard, Suite 600, South San Francisco, CA 94080, US.
We thank everyone who took part in this study and their relatives. Your commitment helped researchers learn more about latozinemab and how it can help patients with FTD.REC name
London - Central Research Ethics Committee
REC reference
19/LO/1134
Date of REC Opinion
18 Nov 2019
REC opinion
Further Information Favourable Opinion