Earlier this year, the biopharmaceutical company Alector announced that the U.S. Food and Drug Administration (FDA) had granted a “breakthrough therapy designation” to latozinemab, the company’s investigational drug designed to address FTD caused by a variant in the GRN gene. The special designation enables expedited regulatory review of therapies intended to treat serious conditions. A Phase 3 clinical trial evaluating latozinemab, developed by Alector in partnership with GSK, is currently underway.

AFTD recently spoke with Alector Vice President of Clinical Development, Lawrence (Larry) Carter, PhD, about progress being made in developing therapeutic options to treat FTD. The conversation has been edited for length and clarity.

More information about the FDA’s definition on breakthrough therapies can be found here.

What approach is your company using to treat FTD?

Our approach to treating FTD at Alector is to start by studying genetic forms of FTD because those are areas where underlying causes are better understood than sporadic forms of the disease. For example, FTD-GRN is believed to be caused by a loss of function variant, or mutation, in one of the two copies of an individual’s granulin gene that codes for the progranulin protein. If one of those genes does not produce normal levels of progranulin, then that person can have approximately half of the progranulin levels they should have, which results in the development of FTD in almost all cases.

Alector has developed a monoclonal antibody – latozinemab – which is designed to bind to a receptor called sortilin and block the interaction between progranulin and sortilin, preventing the degradation of progranulin. By preventing the interaction between the two proteins (sortilin and progranulin), latozinemab has been shown to increase the endogenous levels of progranulin in blood and cerebrospinal fluid by approximately two- to three-fold in our Phase 2 study. We like this approach because it involves raising the body’s own progranulin, and only raising it to levels of what is seen in healthy volunteers without a loss of function variant, versus raising levels much higher.

We will learn from clinical trials about the efficacy and safety profile of this and other therapies that raise progranulin levels to different extents. Progranulin can serve as a growth factor and have several other functions. It is going to be important to comprehensively characterize the efficacy and safety profile of these investigational interventions, including any side effects people may experience, and changes in laboratory values and vital signs.

AFTD Note: A monoclonal antibody (mAb) is a synthesized protein designed to act like an antibody, helping to stimulate a person’s innate immune system by binding to receptors and modifying cellular processes.

Please visit AFTD’s page on FTD & Genetics for more information about genetic forms of the disease.

What do you think is the most urgent need to be addressed for people facing FTD and their families?

I really think this question is best answered by those with lived experience. One of the things we hear all the time is about the tremendous impact an FTD diagnosis has on the entire family in terms of economic hardship – It has been estimated to be almost twice that of an Alzheimer’s diagnosis – and trying to manage behavior symptoms, to name just a couple. I think AFTD is a great resource for connecting families with resources, support groups, clinicians, and research opportunities – through these interactions we can learn about the most urgent needs directly from those with lived experience.

How do you think we can empower the global FTD community to reach our shared goals?

AFTD and Alector have very similar goals with regard to empowering the community and reaching a future without this disease. The stated mission at Alector is to create a world in which neurodegenerative diseases are a thing of the past. So we also envision a future that is free of FTD. Right now, we’re very focused on our late-stage Phase 3 trial in FTD-GRN, which could support an approval for the first disease-modifying therapy specifically for FTD. In conducting our trial, we’ve tried to raise awareness of FTD, provide no-cost genetic testing options, and help people find FTD centers of excellence because we know that we are asking a lot from patients and families who are already dealing with a lot following an FTD diagnosis.

I also think that helping to make people’s voices heard – either by raising awareness within their communities or by working with regulators such as the FDA or European Medicines Agency – is necessary to help everyone better understand the condition and the unmet needs people have. Also, advocating with elected officials can really go a long way to effect change and empower the broader community. People want to hear from those with lived experience.

AFTD’s FTD Research Roundtable is another great example of how we can empower each other for shared goals. Bringing together advocacy organizations, industry, academia, and regulatory stakeholders – who all play important and complementary roles to develop therapies and improve healthcare and quality of life – for these types of meetings and conversations is extremely important. I think by working closely with one another, being transparent about our goals and our limitations, building trust with one another, and being aligned about what we’re trying to achieve is one way we can empower each other to reach shared goals.

What do you find to be the most encouraging about today’s research landscape?

This is a really exciting time with regard to all the research and clinical trials being done in FTD and other neurodegenerative conditions. There is a lot of work being done these days, building on the work done by organizations such as the FTD Disorders Registry, ALLFTD, and GENFI, which has led in part to today’s ongoing interventional clinical trials that could lead to the first approved therapy targeting FTD – that itself is very exciting.

If we are successful in treating FTD-GRN, then we will have a potential foothold and momentum that could carry over into treating other forms of FTD. Folks are starting to recognize there are common underlying pathologies to these conditions – they may manifest in different ways, but we can focus on treating the underlying causes that lead to the signs and symptoms we can observe.

A good analogy that we were just discussing over lunch at the AFTD Research Roundtable Meeting is stroke: a stroke can cause different symptoms based on where it occurs, but the underlying pathophysiology is the same, and that is what we should treat. With FTD, we can move toward thinking about characterizing the disease based on the pathology – such as TDP-43 or tau pathology – instead of trying to categorize it on the basis of behavior, language, or motor symptoms. This shift in how we think about FTD and how to treat it could enable larger clinical trials and faster development pathways for what we now consider to be different FTD phenotypes.

AFTD Note: Though many trials right now are focusing on FTD caused by variants in the GRN gene, their potential success may help treat other forms of FTD, as the disease is caused by an excessive aggregation of proteins in the brain: often TDP-43 (associated with variants in the C9orf72 or GRN genes) or tau (associated with the MAPT gene). If a drug targeting a specific genetic cause leads to reduced protein aggregation, researchers may better understand how to prevent TDP-43 or tau protein accumulations found in other genetic forms of FTD, and in people without an identifiable genetic cause.

What are the challenges you see and your hopes for how stakeholders can overcome these together?

I know that referring to FTD or FTD-GRN as a “rare disease” carries different connotations for different people, but there are real challenges when conducting clinical trials or drug development in small populations. We need to work together to do the required clinical trials and convince stakeholders, including health authorities and payers, that the benefits we hope to see in studies are clinically meaningful to patients and their families.

AFTD has been a great partner in helping raise awareness about available studies and building trust within the FTD community. Once there is an effective therapy, there will still be a need to educate families and clinicians that there is now hope – there is a treatment option where there was not one before. It will be a change to the historic narrative and that is the day I really look forward to seeing.

AFTD Note: While the Alector trial on latozinemab has completed enrollment, several other clinical trials are actively seeking people affected by FTD-GRN to test other promising treatments. Visit the Studies Seeking Participants page to learn more about trials that are actively recruiting. Signing up for the FTD Disorders Registry is another way that persons diagnosed, care partners, and family can participate in research.

AFTD is sincerely grateful for Alector’s ongoing dedication to our mission and the people we serve. If you are interested in learning more about their work, please visit their website.