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Ongoing Clinical Trials Provide Hope for the Most Common Early-Onset form of Dementia

Unlike Alzheimer’s disease, which is characterized primarily by memory difficulties, but generally not major changes to personality or language, Frontotemporal dementia strikes at the core of what makes us who we are. Fortunately, there are several ongoing clinical trials addressing this disease.

By Lawrence Carter on December 16, 2022

Frontotemporal dementia (FTD) or frontotemporal lobar degeneration (FTLD) is a rare, rapidly progressing neurodegenerative disease that is the most common form of dementia for people under the age of 60. FTD affects the frontal and temporal lobes of the brain – areas generally associated with personality, behavior, and language. Thus, people with FTD frequently develop symptoms such as behavioral changes, lapses in judgment, and severely diminished language skills when they are in their 40s and 50s. Unlike Alzheimer’s disease, which is characterized primarily by memory difficulties, but generally not major changes to personality or language, FTD strikes at the core of what makes us who we are.

Given that FTD is a rare condition, estimated to affect <0.02% of the population in the United States and European Union, it is easy for individuals who present with symptoms of FTD to be misdiagnosed as having a psychiatric disorder or another more common type of dementia such as Alzheimer’s disease. In addition, some of the cognitive, behavioral, and language difficulties in FTD can either go unrecognized or can be stigmatizing and embarrassing for individuals and their families to discuss. As a result, the path to getting an accurate diagnosis is often long and complicated for FTD patients and their families. To make matters worse, once a diagnosis of FTD is received, there are currently no approved treatment options available for any form of FTD.

The good news is that there are now multiple interventional clinical trials that are evaluating potential investigational therapies for the treatment of different types of FTD. A subset of FTD cases are genetic or hereditary in nature, meaning a parent can pass a genetic variant associated with FTD to their child. The 3 most common genes that have been associated with the development of FTD are GRN (progranulin gene), C9orf72, and MAPT. In the past, genetic testing for variants of these genes was less common; however, now that potential therapies are being developed to target the underlying problems associated with each of these different gene variants, genetic testing is becoming more common and is more important than ever to help carriers of these variants know which type of investigational therapy is best suited for them. There are several options available for individuals to receive genetic counseling and genetic testing at no cost. The Association for Frontotemporal Dementia (AFTD) is a great resource for individuals who are interested in genetic testing.

Ongoing clinical trials in FTD

Once an individual is aware of their genetic status, they might be eligible to participate in a clinical trial of an investigational therapy that is designed to slow or halt the progression of the disease in that specific genetic subtype of FTD. There are several ongoing interventional trials that are listed by genetic subtype below.

FTD-GRN:

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    • We at Alector, are conducting a Phase 3, double-blind, placebo-controlled study evaluating the efficacy and safety of a monoclonal antibody (AL001) administered intravenously in participants who are either at risk for, or who have been diagnosed, with FTD due to having a mutation in the progranulin gene
    • Prevail Therapeutics is conducting a Phase 1/2, open-label, ascending dose, first-in-human study that will evaluate the safety and effect of intra-cisternal administration of an investigational gene therapy (PR006) on progranulin levels in patients with FTD with a mutation in the progranulin gene
    • Passage Bio is conducting a Phase 1/2 open-label, single-arm, dose-escalation study of the safety, tolerability, and efficacy of intra-cisternal administration of an investigational gene therapy (PBFT02) on progranulin levels in patients with FTD with a mutation in the progranulin gene
    • Denali Therapeutics is conducting a Phase 1/2, randomized, placebo-controlled, double-blind study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of DNL593 in healthy volunteers and patients with FTD with a mutation in the progranulin gene

FTD-C9orf72:

      • Transposon Therapeutics is conducting a Phase 2a randomized, double-blind, placebo-controlled study to assess the safety and tolerability of a LINE-1 reverse transcriptase inhibitor (TPN-101) in patients with Amyotrophic Lateral Sclerosis (ALS) and/or FTD Associated with Hexanucleotide Repeat Expansion in the C9orf72 gene (C9ORF72 ALS/FTD)
      • Wave Life Sciences is conducting a Phase 1b/2a randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, PK, and PD of intrathecal administration of an antisense oligonucleotide (WVE-004) in adult patients with C9orf72-associated ALS or FTD

There is tremendous unmet medical need to develop effective therapies for FTD, and this is an exciting time with multiple studies of new potential treatments underway. Participation in interventional clinical trials is critical to bringing new therapies to market. Anyone who has been diagnosed with FTD or who has a potential family history of FTD and is interested in genetic testing and clinical trial opportunities can learn more at the links above.

Photo: Andreus, Getty Images

Lawrence Carter

Lawrence (Larry) Carter, PhD is Vice President, Clinical Development at Alector, where he is working to develop new therapies for FTD and ALS. Throughout his career, Larry has worked across academic, industry, and government settings, including as VP of R&D at Alexza Pharmaceuticals where he led drug-device combination development programs in rare diseases, and as an Executive Director, Clinical Development at Jazz Pharmaceuticals where he led the global development program for Sunosi®, resulting in approvals for multiple indications in the US, EU, and Canada. Larry has served as a Special Government Employee to FDA and serves as an Adjunct Assistant Professor of Pharmacology and Toxicology at the University of Arkansas for Medical Sciences. His training includes a PhD in Pharmacology from the University of Texas Health Sciences Center at San Antonio and a postdoctoral clinical research fellowship in the Department of Psychiatry at Johns Hopkins University School of Medicine.