Designing Clinical Trials for Frontotemporal Dementia

Tiffany Chow, MD

In a recent interview, Tiffany Chow, MD, a specialist in behavioral neurology and senior medical director at Alector, discusses the unique challenges of designing clinical trials for frontotemporal dementia (FTD), a type of dementia that typically affects individuals in mid-life and can have a severe impact on their financial security and quality of family life. Chow highlights the underdiagnosis of FTD, the need to raise public awareness of the disease, and the potential role of genetic testing and counseling in FTD diagnosis and treatment. She also emphasizes the importance of supporting patients and their families as clinical trials for FTD progress and expresses optimism for the future of FTD research.

Moe Alsumidaie: Can you talk to me about how FTD differs from Alzheimer’s, and can you discuss some of the challenges in designing trials for potential treatments that are effective for dementia patients?

Tiffany Chow: There are many causes of dementia, and Alzheimer's disease (AD) is highly prevalent around the world for people over the age of 65, with the average onset usually in the 70s. FTD, or frontotemporal dementia, on the other hand, usually has its onset when an individual is actively parenting, holding a job, and raising children. Additionally, there are genetic and nongenetic forms of FTD, the former typically being the cause of one of three types of gene mutations. In these ways, the impact of FTD on the patients’ financial security and quality of family life can be severe, not to mention the larger impact on the family.

When designing a trial for this population with marked changes in baseline personality, motivation and organizational skills, there are many important considerations. At Alector, we’re committed to understanding these unique challenges and have clinical trials in Phase II and Phase III for FTD. We have found that FTD is underdiagnosed out in the general population. It behooves us to make sure that our primary care physicians and general psychiatrists consider FTD before the much less common abrupt mid-life onset of bipolar affective disorder or attention deficit disorder. Alternatively, behavioral changes may fool families into thinking a 50–60-year-old is having a “midlife crisis” or a reaction to early retirement, which can delay seeking medical attention and an accurate FTD diagnosis by years. As awareness of FTD increases and when disease-modifying therapies become available, patients may be more likely to seek medical attention sooner. There might also be a boost in interest to pursue genetic testing, if therapies are specific to mutations that cause FTD.

As a specialist in behavioral neurology, I’ve had family members relieved to have an explanation for drastic changes in social skills and abilities at home and at work that haven’t fit typical depression or obsessive-compulsive disorder. It helps them to offset the tragedy of knowing they are facing a neurodegenerative disorder.

MA: You talked about FTD being so underdiagnosed. Because it is so underdiagnosed among patients, I would imagine education around FTD itself and how it differs from Alzheimer’s disease would be paramount in getting patients to participate in a clinical trial?

TC: Enhancing public awareness of FTD can help us combat that challenge of underdiagnosis, especially when you consider that FTD is not as common as AD. Because current clinical trials are focusing on specific genetic mutations causing the FTD syndrome, we need to cast a wide net, first to find as many FTD patients that exist and need appropriate medical support and to help patients understand which clinical trials they may enter. We need both the general public and primary care physicians to think of FTD in middle-aged persons who are having such 180-degree turnarounds in the way they conduct themselves professionally and socially. And we need to seek these patients out globally, not just in one country.

After a correct diagnosis is made, and the patient is informed whether there is a genetic mutation for which there is a therapy, the next hurdle may be the symptoms of their FTD. Difficulty with concentration and hyperactivity may make it hard for them and their families to participate in the activities that a clinical trial entails, such as regular travel for evaluations that may be more frequent than their routine doctor visits, being able to lie still for brain scans, being able to give blood and urine for labs, especially when the lack of insight about one’s own dementia makes it hard to understand why so many doctor visits are necessary. Family members may have to choose to save arguing for basic safety needs, such as keeping the patient from driving illegally. I have had to go down to the parking lot to evaluate a patient in the passenger seat of the family car, because she refused to come into the building.And as I started to mention, partners without FTD are working full-time themselves, perhaps as now the single income source for the household, and actively parenting young children or teenagers. In FTD, you have the difficulty of fitting it into a full and active life, but also there's the dire motivation to try something to stop this illness. Families are really doing the best that they can to manage this awful condition and there is no approved disease modifying therapy to stop the progression of FTD, which moves more quickly than AD.

MA: Tell me more about genetic testing, which sounds like it might potentially open the door for study participation among patients living with FTD?

TC: There may be several barriers to getting genetic testing. Patients and families may be wary of learning about a difficult future living with the risk of a dementia diagnosis that doesn’t have an approved therapy yet. Once there is a dementia diagnosis, we find that patients and families wanting to know more, including the genetics that may be contributing.

However, implications of positive genetic testing are daunting. For example, patient advocacy groups are working to preserve the confidentiality of genetic mutation status, but these are real concerns. Another barrier is the accessibility of getting genetic counseling and then testing. Historically, physicians will only suggest genetic testing if there is a strong family history of first-degree relatives (e.g., father, brother) who manifested the same illness. This works when the condition always presents the same way and can be readily diagnosed, but we found in our work in the 1990’s that for FTD, primary psychiatric diagnoses such as bipolar affective disorder must be included on the list of significant family history. We’re still learning whether the genetic mutations do cause a range of conditions outside of FTD or if those earlier generations were misdiagnosed! For this reason, asking for a family history as a criterion for going to genetic testing may not be adequate.

MA: Can you explain to me about the prospect of genetic counseling as a pre-cursor to genetic testing when it comes to FTD?

TC: I consider genetic counseling to be very important. Families need support in important decision-making, in terms of when genetic testing should be done, who will learn the results, and with whom the patient will want to share the results. Genetic counselors manage expectations and help to prevent undesired reporting outcomes for patients and family members who may be at risk for developing FTD later themselves.

MA: Talk to me a bit about what advancements in the treatment of other neurological diseases mean for the FTD treatment landscape and for the future of clinical trials in the space?

TC: One benefit of the progress that has been made in Alzheimer’s disease is the optimism and hope that has been offered, to stop Alzheimer's disease before it ruins our golden years. This is terrific, and it motivates people to get evaluated, whether they have early changes that count as mild cognitive impairment, or a later stage already diagnosed with dementia due to AD.

FTD affects fewer people, but it can cause much more collateral damage than AD in the workplace, in the home and in the community. As a society, we should also be thinking about how we can best support the patients and their families. They might need resources and support in getting the patient taken care of, keeping the family safe and healthy, and fostering the family’s growth and development. I think the more attention paid to how we can support the patients and families, the more we will meaningfully help everybody. This is an exciting time to watch for progress in clinical trials in FTD, and I must admit I wasn’t sure this would happen during my career, but I am proud to be part of Alector’s clinical program in FTD.

Moe Alsumidaie, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and regular contributor to Applied Clinical Trials.