Newly Initiated ASPIRE-FTD Trial Opens Door for Gene Therapy to Treat Frontotemporal Dementia

David Cooper, MD

Frontotemporal dementia (FTD), a neurodegenerative disorder, is the result of damage to neurons in the frontal and temporal lobes of the brain. Many possible symptoms can result, including unusual behaviors, emotional problems, trouble communicating, difficulty with work, or difficulty with walking. To date, there have been no effective treatments that have shown an ability to slow down or prevent FTD. Typically, the disorder has been managed through a team of specialists—doctors, nurses, and speech, physical, and occupational therapists—in conjunction with medications that might reduce agitation, irritability, and/or depression.

Earlier this month, AviadoBio announced that its phase 1/2 ASPIRE-FTD trial, which evaluates the safety and efficacy of AVB-101, an investigational gene therapy for FTD, is now open and recruiting patients. AVB-101, delivered as a one-time-only treatment, will be tested in those with FTD with progranulin (GRN) gene mutations. The study is also recruiting in Europe with study sites in the Netherlands, Poland, and Spain, with additional sites expected to open in multiple countries.

In the study, patients will receive a single administration of AVB-101 delivered as a one-time infusion into the thalamus via a stereotactic neurosurgical procedure at expert neurosurgical centers throughout Europe and the United States. Following the study’s initiation, David Cooper, MD, chief medical officer at AviadoBio, gave thoughts on some of the details of the study, and why the company believes AVB-101 can be a successful treatment candidate. He spoke on the drug’s mechanism of action, the types of patients that will be involved, and what needs to be shown for it to be deemed a “successful” study. Furthermore, he gave comment on some of the ongoing challenges associated with gene therapies in FTD, and how the company will overcome these.

NeurologyLive: What are some of the main details of this study that clinicians should be aware of?

David Cooper, MD: ASPIRE-FTD is a Phase 1/2 open-label, multicenter study to evaluate the safety and preliminary efficacy of AVB-101 an investigational gene therapy for people with frontotemporal dementia with progranulin mutations (FTD-GRN). The goal of the study is to restore levels of progranulin in the brain, potentially slowing or stopping the progression of FTD-GRN. AVB-101 is delivered as a one-time treatment administered directly to the thalamus in an MRI-guided neurosurgical procedure.¹

This Phase 1/2 study is open to early symptomatic patients with FTD and a GRN mutation ages 30-75 who will each be followed over five years with clinical assessments, MRI imaging, and assessment of biofluid biomarkers. This is a dose-escalation study with two planned doses to be evaluated. Visits will be more frequent in the first year, while follow-up visits will be every six months in the following four years.

Why do we believe AVB-101 can be effective in treating FTD-GRN? Discuss its mechanism of action.

We believe AVB-101 can be effective in potentially treating FTD-GRN as it is designed to be delivered directly to the thalamus. This innovative approach avoids both the blood-brain barrier and the pial membrane surrounding the brain, delivering the therapy directly to the brain to restore progranulin (GRN) levels in the frontal and temporal cortex while reducing the dose required and potential systemic exposure.

From extensive pre-clinical animal studies (including rodents, sheep, and non-human primates), we have demonstrated that AVB-101 can restore levels of PGRN to the brain cortex.^2,3 The safety of intrathalamic administration and cortical biodistribution of AVB-101 has been confirmed in animal studies and has demonstrated that elevations in cerebrospinal fluid(CSF) PGRN are directly correlated with restoration of normal PGRN levels in brain cortex itself.^2,3 The doses proven effective in these studies have been significantly lower than those used in intrathecal and intravenous gene therapy approaches.^4,5,6

What needs to happen for this study to be considered positive? Talk about the major goals you’re looking to achieve.

For ASPIRE-FTD to be considered positive, we hope to achieve the following goals:

• Demonstrate the safety of a one-time treatment with AVB-101 for patients with FTD-GRN
• Identify a dose of AVB-101 that should restore PGRN levels
• Explore the potential impact of AVB-101 on disease progression over the 5-year follow-up period

What are some of the main questions surrounding gene therapy in FTD? Considering this is a relatively new approach.

Tackling FTD has proven to be enormously challenging, which is why the unmet need remains so high. At AviadoBio, we are trying to do what was previously considered impossible. We are confident that targeted delivery of gene therapy will be a game-changer that overcomes the challenges of both crossing the blood-brain barrier and the unwanted systemic exposure that comes with administration into the cerebrospinal fluid (CSF).

Delivering gene therapies either directly into the brain itself or to the CSF that surrounds it puts the gene therapy on the brain side of the blood-brain barrier.^4,5,6 Putting the gene therapy directly into the brain has the advantage of the therapy staying in the brain. This has advantages over therapies administered to the CSF, which tend to mostly end up in the bloodstream and go to the rest of the body.

Gene therapies offer the potential for transformative impact or even potential cure. The difference in patients’ lives could be huge as we’ve seen recent gene therapy approvals that are changing treatment paradigms. By replacing or modifying gene function, disease progression can be halted or potentially even prevented. This may potentially be the start of a revolution in healthcare that would bring tremendous hope for people living with genetic neurodegenerative diseases.

Any notable inclusion/exclusions for this study?

• Patients may be eligible to participate if they meet the following criteria1:
• 30-75 years old
• Carrier of a pathogenic GRN mutation
• Clinical presentation of behavioral variant FTD (bvFTD) or primary progressive aphasia (PPA)
• No other causes of dementia or structural findings on brain MRI
• Able to undergo a neurosurgical administration procedure under anesthesia
• Able to provide informed consent
• Have a caregiver who is able to provide support (including attending study visits) for the duration of the study (5 years and 3 months)

Further details about this study can be found at clinicaltrials.gov

REFERENCES
1. NCT06064890_A Study to Evaluate the Safety and Effect of AVB-101, a Gene Therapy Product, in Subjects With a Genetic Sub-type of Frontotemporal Dementia (FTD-GRN) (ASPIRE-FTD) [Last accessed 11 July 2024: https://clinicaltrials.gov/study/NCT06064890?cond=Frontotemporal%20Dementia&term=aspire&rank=1]
2. Lee YB et al. Oral presentation at ESGCT Annual Congress 2022
3. Miranda CJ et al. Poster presented at ESGCT Annual Congress 2023
4. Kimura S and Harashima H. Pharmaceutics 2020;12.
5. Lonser RR et al. J Neurosurg 2020;134:1751–63.
6. Perera A et al. Acta Neurochir (Wien) 2024;166136.