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ALS and FTD Drug Development Perspectives

As a unique group in the ALS and FTD community, we represent individuals impacted by these diseases by virtue of our family history and genetic makeup. This means that we are stakeholders in the efforts to eradicate these diseases and want to add our voice to the dialogue on what “patients” need from manifest ALS and FTD Clinical Trials. For this we are setting aside our eagerness for earlier trials in the disease in genetic carriers who may appear unaffected and solely looking at how drug development is being carried out for manifest disease.

Who is ALS and FTD Drug Development For?

We believe that rather than discussions of “patient-friendly trials” when contemplating a trial design’s impact on those in the trial, we should use the phrase “participant-friendly trials.” This is needed as a very small share of people currently living with ALS or FTD are ever in a clinical trial, and what may feel like a benefit to a participant actually is not beneficial to the goal of finding cures or treatments for patients now and into the future. Ensuring all current and future patients are considered when designing trials transforms our care and concern for trial design from a few hundred people for a few months to thousands upon thousands for all time.

The most patient-friendly trial is one that truly answers the questions of an agent’s efficacy. Results that are not clear or even questionable do not guide the field for further drug development and can result in the approval of agents that produce very little, if any, benefit to those taking it and may introduce undue burdens to those taking it in the form of costs or side effects.

Pivotal Trial Length

In determining the efficacy of a pharmacologic agent to slow down the disease, we need to be assured that the drug effect accounts for differences between the treatment and placebo arms especially when the outcome is functionally based. This is best accomplished by increasing the duration of the trials. It has been well-established that motor neurons are damaged extensively prior to any manifestation of ALS symptoms. Further, the progression of disability throughout the course of ALS within an individual is not regular and transverses differing motor neurons at different times. This means at the time of trial enrollment, the clinically involved regions do not clearly reflect incumbent nerve damage in regions where there is no clinical loss of function nor do we know the full extent of damage in involved areas. Therfore, two patients looking exactly the same clinically at the start of the trial may be dramatically different in terms of nerve pathology. Consider motor domains that are unaffected at the start of the trial. One participant may have full clinical function and little or no neuronal loss in that domain while another may have full clinical function but 30% of the neurons damaged in the domain in question. In a short clinical trial, despite continued neuronal loss, the latter patient might demonstrate clinical progression while the former may remain clinically strong and therefore would not be considered as progressing nor would their ALS FRS subscore change. Thus, any clinical outcome measure might inaccurately reflect the progression in these two individuals in a short trial while a longer trial duration would allow for better control over time for these differences.

What Is The Goal for ALS and FTD Drug Development?

At this point, we have had 3 drugs approved in the USA for slowing disease progression for all types of ALS. In each case, individuals are not able to perceive the proven benefit alone or in combination as the potential benefits of these drugs are small in the scope of the disease. One of these has been proven not to work and has since ceased to be marketed. With the push from many stakeholders for access to any medications, it has become accepted by some that these types of drugs are the best patients could hope for, and we should keep adding to the pile with more approved drugs with limited or unclear benefits. The resulting burden to patients and families is tangible. There are insurance battles, copays, confusion about drug benefits as clinicians have mixed views on efficacy, and willingness to accept potential side effects all because a drug is approved. All of these burdens occur as patients continue to progress and face the physical, mental, and financial challenges of ALS. Additionally as these drugs are approved, they may impact the outcomes of other ongoing trials in which they are allowed as standard of care without a clear understanding of their risks or benefits. In this scenario, pharmaceutical companies are paid handsomely without having a meaningful impact on a patient's disease. Approving drugs with negligible benefit should not be the goal of ALS drug development. We need large effect drugs. We need to make a huge change in disease trajectories. It’s true if a mild benefit is definitively proven in a well-controlled trial of adequate length, we should accept that addition to the arsenal against the disease. However, this does not mean that questionable proof of mild benefit is enough, and it certainly should not be the goal.

International Society for Frontotemporal Dementia 2024 Symposium Report Back 3 of 3:
Concerns We Walked Away With

We attended the largest research meeting of the year for Frontotemporal Dementia research as representatives and advocates for the genetic ALS and FTD community. We offer these concerns from our unique perspectives and welcome dialogue. Email us at info@endthelegacy.org to continue the conversation!

Concern 1: The absence of reflection that the ALS Pipeline is relevant to at minimum C9orf72 and all TDP-43 FTD.

It was momentous to see all the discussion regarding ongoing in human trials focused on Progranulin at ISFTD and there was a panel discussion on clinical trials on the first day of the meeting. The ALS pipeline was not mentioned despite approaches targeting TDP-43 that are in human trials in ALS and c9orf72 targeted trials in ALS. If TDP-43 is the basis of disease, these approaches hold great promise for half of FTD cases. If an approach is theorized to work to treat c9orf72 ALS, it stands to reason it would impact c9orf72 FTD and any disease stages outlined prior to manifest ALS or FTD. We heard about Alzheimer’s drugs and PSP trials, so it would have been very appropriate to consider ALS trials as well. It should be noted a key-note from basic researcher Dr Michael Ward even referenced some ALS trials as being important tests for theories of TDP-43 in ALS and FTD, but still it did not come up in the big picture clinical trial conversation.

Concern 2: Responding to the assertion that there exists a phenotype of cognitive disability in adult C9orf72 Carriers who do not have ALS or FTD

Our families are full of stellar examples of success in educational achievement, personal fulfillment and professional success. This holds true among those later diagnosed with FTD or ALS. Narratives that demean families with c9orf72 or other genetic variants linked to late-onset neurodegenerative diseases are unacceptable. We have come under the microscope of research due to our risk of ALS and FTD, which appear manifest on average at age 58. We did not come to the attention of research for any aspect of cognitive disability prior to those conditions. We must be vigilant that narratives that could worsen prospects for our descendants across their whole lifespan are not allowed to take hold.

A few examples that present concerns for Genetic families.

A GENFI poster from ISFTD asserted, “…presymptomatic C9orf72 mutation carriers exhibit significant cognitive impairment…” (Foster P, et al) Questions we have about this assertion: Is IQ being controlled for amongst groups? What were the effect sizes? Was a sensitivity analysis on age conducted to test whether prodromal symptoms in even a small number of participants could drive the overall effect? Were there any differences in the context or setting in which the different groups completed the tasks? It also appears that the significance referenced in this quote is based on statistical significance but is being used as of clinical or actual significance.

A GENFI poster from ISFTD discussed the need for studying children in c9orf72 families for the purpose of “development and testing of potential interventions for FTD, from target selection and clinical trial design including optimal timing of treatments, to non-pharmacologic interventions and supports for youths at-risk.” (Coleman K, et al) Questions we have about this effort: Where is the evidence there is a phenotype our families seek to solve for in our children or in our healthy and productive adult years? Where is the evidence children in our families need services related to development that are different than those offered to all children? Establishing biological knowledge and setting up the best effort to prevent or forestall manifest FTD or ALS is welcome but the balance is fraught to not pathologize fully functional years of our lives.

If it is established that there exists a lifelong cognitive disability for c9orf72 carriers where we have not asked for one, our families may no longer want to be participants in research knowing through their data they or their children will be stigmatized. Communities define for themselves what matters to them, and there is no evidence our genetic community has asked for help with lifelong cognition. It is true gathering information across the lifespan may be interesting in developing theories of disease pathogenesis and possibly to allow for intervening prior to the development of disabling symptoms. However, the cure should never be worse than the disease, and we must protect the dignity and assumption of competence of all healthy members of our families.

Concern 3

Assertions that prodromal or purely biological states of disease prior to fully manifest ALS or FTD are not protected in the United States the way most illnesses or disabilities are.

In discussion of presymptomatic disease and ultimately solving these diseases at that stage, it was asserted that there are no legal protections for individuals told they have a prodromal or purely biological disease, in contrast to legal protections for those with well-established diseases or disabilities. If this is accepted as fact it could chill the interest in our community to address these diseases early and may impart fear to participate in research based on those stages. The Americans with Disabilities Act is a broad law that provides protections for Americans impacted by a wide variety of issues. Broadly, any neurological medical issue is statutorily covered.

First, how would a medical diagnosis that is not yet impacting function in a severe way reveal itself to an employer? As the prodromal or only biological state would be invisible to observers the only way for an employer or other person in a patient’s life would learn of this state, would be for the patient to tell them directly or share it publicly.

Returning to the assertion that these are not protected states, the main way this is being justified is that prodromal or biological diagnosis of early disease are not yet medical diagnoses. Despite research conducted by medical experts having allowed for the categorization of these states, it may be asserted that academically the existence of these states as medical conditions is not firm until broad consensus across the field over time is achieved. However, the EEOC (the federal agency in charge of enforcing the ADA) or civic judges do not neatly follow the culture of academia and could accept that a state with published confirmation of being related to ALS and FTD would be enough to confirm its medical relevance and coverage as a medical condition.

The second way is a bit harder to discern – as the ADA actually does not require anyone to have an actual medical diagnosis, but merely for an employer or other actor to think one has. So if we accept that being diagnosed with biological ALS in advance of manifest ALS is not a medical condition, but an employer learned this and fired you as they did not want to employ someone who was impacted by ALS it is clear they fired you as they thought you had ALS. In fact, if the information was not related to these manifest diseases, why would anyone discriminate based on it? One concern I heard from a party to the unprotected view is that this would be hard to prove. This is true, but all discrimination is very hard to prove. Much of the value of non-discrimination protections is in chilling any efforts to formalize discriminatory policies and to dis-incentivize discriminatory speech. Protections exist and are effective even if enforcement is difficult.

International Society for Frontotemporal Dementia 2024 Symposium Report Back 2 of 3:
Our Presence at the Meeting

As World FTD Awareness Week comes to a close, we are sharing our second of 3 report backs from the largest FTD research meeting of the year, ISFTD. Today’s report concerns whether it made sense for our small organization to go across the world to attend. While this was primarily a scientific meeting, a value End the Legacy holds dear is that patient advocates must interplay with the science about them, summed up in the phrase “Nothing about us, without us.”

Formal Contribution to the Gathering:

End the Legacy members Jean, Daniel, and Jary presented a poster identifying for the first time the rationale that using informants in at-risk genetic FTD research in a purportedly healthy couple, is a credible risk to the people in the relationship and to the relationship itself. We reviewed informed consent documents from 4 studies, and none of them mentioned this. See the poster here. We shared some of the questions that are asked of the informants in these healthy dyads who may be in their 20s or 30s, including “Do you feel you have lost control of your life due to your relative’s illness?” For next steps we called for, among other things, informing people of this risk, clarifying the risk in more detail, and using scales made for presumably healthy people rather than scales that presume the person being informed on is cognitively impaired.

End the Legacy member Wanda Smith presented a poster on her network of GRN families and what those family members desire to see in research.

End the Legacy member Betsy Hall, through her NGO For Their Thoughts®, presented a poster on the plenary stage in a “poster blitz” session on “The Empathy Effect: Improving fTD Support, Medical Practices and Societal Awareness with an Immersive Approach.” This highlighted her organization's use of an interactive session to foster empathy for dementia patients. Additionally, her team led 40+ attendees through the session over the course of the weekend. Go to their website to learn more!

All of us participated in a non-profit organization gathering hosted by the AFTD where good connections and issues of mutual concern were discussed.

Contributions to Open Dialogue

In an overview of the GENFI and the FTD Prevention Initiative, we pointed out a phrase that was offensive to the genetic community, and the studies quickly moved to amend their website.

Ensuring any current theories on disease pathogenesis are openly debated is a priority for us. In a discussion on tdp-43 in ALS and FTD, we asked a scientist presenting on nuclear mislocalization to provide thoughts on nuclear tdp-43 aggregation published by a few labs recently.

In a review of the need for C9orf72 Prevention studies, we added that these efforts would not only be beneficial to c9orf72 but could also provide answers for earlier use of interventions in sporadic cases and better able to discern if any ALS drug is viable.

An ETL member who was attending in his role as a Board member for the AFTD provided context that trouble enrolling genetic drug studies is not just related to the families impacted but also the history of exchange with the medical system where clear feedback that there was no hope for people in these positions means getting through to people now is even harder.

Informal dialogue and Networking

Productive conversations and connections with many prominent FTD researchers, including on topics of c9orf72 penetrance in the Netherlands, tissue donations of those at risk, a potential collaboration of als and ftd at risk studies, and avoided stigmatizing language. We connected the global FTD group with the global ALS MND Alliance. In-person connections can be valuable for all.

In full consideration, it is a must that advocates dedicated to genetic ALS, and FTD families are enmeshed in any discussion of our communities, and End the Legacy has executed that role fully here. To support our work, get involved or donate here.

International Society for Frontotemporal Dementia 2024 Symposium Report Back 1 of 3:
Exciting Things We Observed

We celebrate World FTD Awareness week this week and we are proud to share some simple observations of the most important FTD research meeting of the year. End the Legacy was proud to be able to send our Executive Director Jean Swidler to the meeting in Amsterdam, where she was accompanied by other ETL volunteers who attended with other organizations. As fitting for a celebratory week of progress in the disease, we are starting with exciting things we observed.

Frames of analysis that were centered at the meeting and we cheer !

Genetics was front and center at the meeting, despite being a minority of cases. The fact genetics are more tractable for natural history analysis and drug development did not seem to be contentious as it sometimes is in diseases like ALS.
A clear charge to hold concepts of cultural and linguistic differences around the world in the analysis of findings in the disease and in the development of research studies.
A large complement of ALS insights including a key note from Dr Benatar and many promises to break down silos between the diseases. There was even a touching note of wanting prominent people suffering from FTD to be like Lou Gherig was for ALS from their caregiver.

Scientific Progress We Heard :

The charge to solve Progranulin FTD continues in full swing. So many companies with approaches in humans, or soon to be so, were present and sharing initial data in some cases. Especially thrilling was a call to action from a senior researcher to start bringing these trials to presymptomatic GRN carriers, one of which is in active development!
A thrilling new platform trial in PSP, a tau related neurodegenerative cognitive and movement disorder , was detailed with further envisioning from Dr Adam Boxer of UCSF to a potential MAPT platform trial. These are complicated and labor intensive endeavors to plan and we cheer the commitment leading to these updates.
The ever finer classification of disease onset biological changes with many avenues being chased down – especially interesting were proteomic investigations led by researchers from UCSF ,well detailed imaging and NFL categorization which grows ever finer with time, and network approaches that view complicated in-vivo processes and their relation to disease progression.

An Amazing Thing We Witnessed And Experienced:

Exciting teamwork from many organizations and institutions including World FTD United, the AFTD, For Their Thoughts, Cure MAPT FTD, The Bluefield Project, ALLFTD, GENFI, and many dedicated scientists and patient advocates.

New Development + New Momentum = New Initiatives

The position of those at genetic risk of ALS and FTD is rapidly shifting. Our organization Genetic ALS & FTD: End the Legacy is rising to the occasion we helped bring about. We must ensure the changes here now and coming soon result in actual improvements in our families outcomes.

New Developments

With the publication of the Miami Framework, we now know there is support for the capability of serial observation to allow for earlier diagnosis and initiation of treatments in the genetic ALS community. We previously analyzed this development and we cheer it.

The prolific and dedicated Dr. Benatar also has another work in a review that we participated in. The September 2023 workshop chaired by Dr. Benatar and our mentor, Dr. Terry Heiman-Patterson, for the first time, contemplated what the guidance should be for those at genetic risk. As our families have all experienced, the accepted advice was that there was no advice. Sure, research participation may have been discussed, and many of us cheered for it. However, research studies are not care, and the investigators who conduct the studies do not work for the benefit of the participant. We have to sign forms acknowledging that reality.

The workshop was a great discussion with open dialogue from the at-risk community and many dedicated researchers, genetic counselors, and others. The resulting preliminary guidance is currently under review.

So we will likely have a new reality consisting of two pillars - an acceptance of a new way of diagnosing genetic ALS earlier if serial monitoring was in place, and a framework for monitoring outside of research.

New Momentum

There is so much changing in the Genetic ALS & FTD landscape that shows so much wind is at the sails of progress for our community. These forces are coming from drug development, patient advocacy, and new research initiatives.

We have genetically targeted drugs approved or close to submission ( Tofersen, Latozinemab ) . Tofersen alone has driven huge learnings about Neurofilament Lightchain providing the first surrogate marker candidate in ALS. And drug targets relevant to our community are either newly in clinic or close to it numbering in the dozens.

We have an organization and network dedicated to our interests that does not let our community be forgotten in any venue, with the logic of “intervening earlier will work better” forced to be reckoned with. This community coalesced for its first in-person meeting, where over 40 carriers and loved ones gathered in Chicago. The united power of our determination was palpable. What can’t we accomplish when we operate as a team? Other advocates and groups are now paying attention to our community as a unique interest group as well, and we say, “Welcome Aboard!”

The research community is keeping apace with new enthusiasm for many of the things we cheer. The ALL ALS study will soon be the largest reaching genetically at risk study in existence. The Foundations For the National Institutes of Health is qualifying NFL as a biomarker with the FDA for GRN FTD. Today, Jean is meeting with many prominent researchers, advocacy groups, and the FDA in a formal discussion to plan for C9orf72 interventional prevention trials. We will share more about that in a future post—cheers to the hosts the ALS Association and AFTD, and the chairs Drs Benatar and Boxer.

New Initiatives

With these new developments and this new momentum, we are proud to announce and embark on two important initiatives that will allow our community to capitalize on the above.

First, our attempt to overcome a hurdle related to the formulation of the first-ever guidance for those at risk. Our families have had the fact that there is no advice and there is “nothing” to do in relation to their risk provided to them for generations. There is the chance of getting new info when one more family member becomes diagnosed, but with the spread in symptom onset in many genes close to 30 years from parent to child, this clinic connection is a rare event. Their primary care practitioners will never hear of such niche news. So how can the tens of thousands of at-risk community members who need to hear this guidance actually learn of it beyond traditional broad-based communication approaches such as webinars? The Genetic ALS & FTD Peer Navigator Program.

End the Legacy will train willing community members on the substance of this guidance, so that they may responsibly communicate this new information to their impacted family members. Importantly this is completely separate from traditional family information letters our families may have sent or received that did not have the benefit of this new guidance. Importantly this will also create a network of communication that can be utilized when developments in this guidance, which we expect, debut in the future. If you would like to know more about this program please email us at info@endthelegaacy.org

Our proudest effort, and one that is long overdue, is all about embracing the concept of proactive healthcare provision for the at risk genetic community. We are people and not just research subjects, and if our risk of cancer which is unlikely for most can be looked after, why cannot our risk of diseases that have haunted our families for generations be part of our care? The rationale of the Miami Framework, the forthcoming at risk guidance, and the strong imperative of prompt initiation of drugs proven to modify the disease process make this a must.
To speed the adoption of this care paradigm by practitioners, we will be certifying End the Legacy At Risk Genetic ALS & FTD Center of Compassion. Through both financial support and resource sharing we will spur the creation of centers across the United States. These centers would fulfill a few simple requirements:

Providing Cultural Competency for our population by both acknowledging our risks and our likely many years of perfectly functional health and evolving knowledge of penetrance.
Time dedicated to providing this care. While some of us have been seen in related to this risk before, it has always been ad-hoc. We deserve time dedicated to this task. Especially at first, monthly or quarterly days for this would be very reasonable.
Commitment to staying on top of developments related to this care, as shared by End the Legacy and others. And working in partnership with the person at risk to settle on monitoring strategies that work for them.
Commitment to sharing of support and educational resources, such as those provided by End the legacy.

We are so proud to announce the first recognition under this program has been awarded to the clinic of Dr Terry-Heiman Patterson at Temple University. They have announced a clinic dedicated to meeting our criteria and beyond which will be starting this summer. May many more soon follow! If you are a provider and would like to learn more, please email us at info@endthelegacy.org.

We are so proud to offer these programs, to bring our mobilize our community together in person, to do all of the work on education, support and advocacy we have focused on from the start. We hope you can support this mission if it speaks to you by getting involved or donating to keep it moving.

A Momentus Development, Long Overdue

The newly published "Miami Framework" brings some relief to the inherited ALS community

The story is the same across many genetic ALS families. Despite clear knowledge of risk, carriers and others at risk are met with disbelief and suspicions of malingering as the functional use of their body recedes with weakness spreading from one hand to another, as well as their feet and speech. Only after this high burden of symptoms appears have our family members commonly been allowed to partake in disease-modifying therapies and adaptive supports. The cruelty of this delay may be hard to accept, but it is the reality that so many have faced, and we must no longer shy away from it.

Diagnostic Standards Through Time

With the ever-finer classification of ALS by committed researchers, a few key hallmarks of the disease became paramount - Upper and Lower Motor Neuron signs and progressive symptoms. Our families have been especially confounded by the need to document progressive decline. While in theory, a verbal confirmation of history from the patient or referring practitioner or documentation in a medical record could suffice to show this progression, in practice, reliance on specialists bearing witness to the progression in appointments stretched over time enabled much of the delay to diagnoses that our families have suffered with the specialist only being engaged after substantial symptoms have appeared.

Complicating this discussion is that the formal diagnostic standards of ALS have changed little over time, while the definitions for "research" are in constant debate and most likely inform general understanding. A long time standard for research was called the "El Escorial Criteria". Following the discovery of C9orf72 a revision of this criteria was established in 2015, which included a lower bar of a single upper or lower motor neuron sign to confirm ALS in a genetic carrier. However, this lower bar was done away with in subsequent research criteria, most recently in the Gold Coast Criteria of 2020. The lack of a firm voice advocating for our community prior to our founding surely played into this dynamic.

The Miami Framework

With great excitement, we heard Dr Michael Benatar detail a brand new concept of ALS diagnosis for genetic carriers at the 2023 ALS MND Symposium in Basel ( see our report on the event below). However, he requested sharing this wait for the publication that became "The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology" by Benatar et al., published in Nature Reviews Neurology. With it's debut last week we were able to digest it in full. Of note they confirm the lower bar in this passage:

"For the diagnosis of ALS, we recommend the use of either the revised El Escorial criteria (especially if categorization based on the number of body regions with both UMN and LMN signs, such as in definite ALS, is of interest) or the Gold Coast criteria but with the caveat that people with a known pathogenic variant, as described in the revised El Escorial criteria, require progressive weakness in only LMN or UMN for the diagnosis of ALS. This special consideration for pathogenic variant carriers is necessary for the consistency in how ALS is diagnosed among prospectively followed pre-symptomatic individuals who phenoconvert and those first seen in the clinic with already clinically manifest disease."

Implications for our community

With the importance of serial observation stressed we know the concept of a specialist witnessing progression has not been fully removed. But it is acknowledged in writing for the first time that new emergence of symptoms when the patient was previously confirmed to be healthy confirm progression. We celebrate this! We do acknowledge its long delay, as evidenced by the clinical trials for recent genetically targeted ASOs with unknown safety profiles using pure weakness inclusion criteria rather than a normal diagnostic standard.

As serial observation is needed for this benefit, we are proud we supported and participated in the first workshop to establish care guidelines for those at genetic risk. With the publication of those guidelines in process, our community is on the precipice of a major adjustment in how our family's health needs are addressed. In our Community Summit coming next week, we will build our capacity to make good on both these new diagnostic standards and the forthcoming new care guidelines to ensure no one must endure what our families have in the past in order to receive care and treatment.

Miami Framework

End The Legacy's Genetic ALS & FTD Community Summit

Save the Date Conference in Chicago (1) (1).jpg

We are so excited that our first-ever in-person meeting, this June 7th-9th in Chicago, is coming close to reality. With a committed team of activists who have been meeting weekly for four years, joined by those new to the movement and others who are curious, it has the potential to be a life-changing experience.

With an initial recruitment from our existing team, we have dozens of commitments; soon, a general registration will open for anyone impacted by Genetic ALS & FTD.

Attendees will have precious time to network and connect with others who understand and have been in their shoes. They will receive the Clinical Research Learning Institute training from NEALS experts like Dr. Terry Heiman-Patterson. They will learn skills needed for our movement to be a success through panels focused on lessons from other patient advocacy movements with pre-symptomatic phases, how to communicate with your relatives about shared risk and research opportunities, and how to share your Genetic ALS & FTD story with differing audiences.

We are so grateful to our partner, the ALS Hope Foundation, and our local host for the event, the Les Turner ALS Foundation.

Please stay tuned for our general registration link. If you are interested in sponsoring the event or have any other questions, reach out to info@endthelegacy.org

One year Out

We have recently celebrated one year as an organized not-for-profit organization. Here's our self report.

We are all familiar with the devastation that ALS and/or FTD brings. As the scientific and medical fields developed studying these diseases, the terrible plight of the many suffering with the manifest symptoms of the complete phenotype of the diseases rightly took prominence. The interests of the individuals at significant genetic risk were easy to miss, considering the forgoing. If a person went searching for resources to see their situation reflected in others, very little could be found. If information relating to a person’s genetic risk debuted, an individual at risk may not learn about it at all. If our government, through its legislators, regulators, and government-directed science institutes, considered the stakeholders of these diseases, they would not easily consider the genetically at-risk community as being especially relevant.

All of this and more led Daniel Barvin, myself, and many others to come together a few years ago to get organized. In 2023, it compelled us to debut as a new non-profit Genetic ALS & FTD: End the Legacy. With our founding and our efforts, we have:

Spurred intense discussion and debate coinciding with shifts in thinking in the scientific field on the issues important to us - notably ever more consideration for earlier disease trials and the first-ever presymptomatic care conference recently concluded in Pennsylvania.

Through the regular work of our team ( weekly meetings for 4 years) and special support-focused meetings, we have documented improved senses of well-being and positivity in relation to our collective risk and provided an avenue for engagement and connection for those searching like we were before our founding.

Through our meetings, website, and webinars, we bring the latest scientific news to our community promptly, for example, the first public airing of the recent new analysis of the penetrance of the C9orf72 expansion. And the first patient-facing guide to the c9orf72 expansion.

When it was clear the scientific field was not leading on questions vital to us, we decided to answer some ourselves through a survey of our community on our desires and considerations for presymptomatic treatment and simple but novel estimations of the size of our community.

When the NIH announced a desire to plan for its ALS work, they explained the stakeholders for the work were “patients and caregivers.” We pointed out immediately that they were missing the largest group of people in whom scientific advances in ALS could be practically implemented - the at-risk genetic community. Within a day, and ever since the NIH has been clear that they now see the genetically at-risk community as part of the stakeholders they serve.

When scientists maligned the hundreds of thousands of us in families impacted by C9orf72, we were there to bear witness and spread the news that this prejudice existed so it may be contained before the downstream impacts of such bias will be felt in our daily lives.

We need to continue pushing on these initiatives and develop them more. We need your support. To join or dialogue with us, email info@endthelegacy.org. To support our growing organization, donate here. As part of the ALS Hope Foundation, donations are tax deductible.

Anchor 2

Reflections on the ALS MND Symposium 3 of 3: A Few Concerns for our Community

We will provide three blog posts reflecting on the ALS MND Symposium and its lead-in meetings. You can read exciting things we heard and an account of our presence at the symposium on our website. The final post concerns itself with things we observed that warrant concern for the genetic ALS and FTD community.

These notes are our subjective interpretation; we welcome others to share their evaluation of these concerns or the facts as we present them. Drop us a line at info@endthelegacy.org

We are offering some critiques here as educated advocates. Still, we must first again celebrate the work, effort, and dedication from the scientific field that has led to so much progress in these diseases, including identifying many of the genes responsible and the forward push into treating and hopefully one day curing these genetic diseases from the root. With that significant caveat, we have just 2 points we would like to focus on. And both could be well addressed simply with more communication between our community and the field.

1) The forward push into trials for prevention without our community at the table.

We are confident that our passionate advocacy over the last few years has helped lead to the unmistakable thundering demand for c9orf72 and other prevention trials. Those involved in designing and implementing these trials must include the impacted community in the decision-making process. Without our voice at the table, these trials risk not only not filling. They may not ask the correct research questions without the community’s input, risking the trial’s ability to have a relevant outcome.

2)Why are we debating the worth of a whole class of people for their whole lives when the area of interest is a progressive, not fully penetrant, age-dependent set of diseases?

As an organization of impacted people, we are concerned about statements that were made that classify an entire group of people and their lived human experience as less than others based solely on genes they inherited or families they live in. Labeling people as deficient and their families as “fractured” is not just hurtful but inaccurate as we know the lives of achievement and fulfillment with which many of us and our ancestors have lived.

Like all humans, those at risk of genetic ALS and/or FTD have a rich tapestry of human existence. Like all humans, there are successes and failures intertwined with love and heartbreak. How can a gene or family history be but a single thread of this tapestry when our entire exposome is composed of innumerable factors? The fact that physical brain differences from controls exist in some fashion in presymptomatic C9orf72 is clear and well documented. It seems rational that whatever theory of disease needs proving can be done with these physical readings. Searching for cognitive issues in healthy people included in this analysis based solely on their possession of rare immutable characteristics seems likely to lead to unintended outcomes.

In Basel, the issue first emerged in the Encals satellite meeting:

Trinity College researchers reported a study of 149 relatives of ALS patients, of which 91 were in Familial ALS families, further narrowed to 41 in familial ALS families with C9 (the study did not report on the presence of C9 in the sporadic family members or the control group). The results were presented as everyone in a C9 family is “not normal.” Unsaid was the clause in the paper that related these deficiencies were subtle and sub-clinical. The presented theory was that the C9 mutation alone was not to blame for the issues, but perhaps many causative genes were shared in the families.

Following this came a talk on the recent C9 penetrance analysis, with the senior author from UMC Utrecht stating definitively that in the absence of knowledge of family history, no personalized risk assessment should be offered. Then, the author of the C9 penetrance paper and the author of the paper showing family member deficiencies began agreeing at the front of the room about the deficiencies present in c9 people and how we have “fractured” families due to this supposed deficit. We express our gratitude to the prominent UK MND researcher from Oxford who spoke out on behalf of the genetic community in that session to warn against unfairly stigmatizing these families. We did not comment at that moment. However, we are grateful we were present for this discussion. If these are the comments made publicly, we can’t help but wonder what is said behind closed doors. And if the desire is to categorize us in this way, surely representatives of us should be in the room for it.

Later at the Symposium proper, in the session on surrogate markers, a Foundation Doctor, also from Oxford, candidly shared that while his research showed no cognitive impairment in C9 carriers, it was due to there not being a “quantifiable measure of craziness” available to him. In context, he implied these asymptomatic C9orf72 carriers were indeed crazy, but he could not record it with the validated measures at his disposal. He went on to say it is accepted among the scientific community that asymptomatic C9 carriers are different and overly gregarious in this context, proving in his eye they have cognitive impairment of some kind despite his study not finding it.

How can a difference be accepted by the scientific community without any evidence? Is any inquiry into cognition in healthy members of a genetic minority okay when the supposed deficits they seek to establish are not contrary to successful and happy lives? What would the consent to participate in that kind of research look like, and is it being used now?

In a footnote to this, on behalf of the C9 genetic community, a young patient fellow with C9 ALS felt compelled to share his successful career and his happy family life to rebuke the picture painted of C9orf72 carriers by the Foundation Doctor. Why should anyone have to assert their dignity in a meeting supposedly about helping this same person? Our concerns are related to progressive paralysis and progressive dementia, not interrogations and invalidation of our lives and families.

In Closing

In closing, we are determined to ensure the research into our community is centered on the devastating issues that occur with progressive paralysis and dementia. We desire to bring together those studying us for a conversation on how we may untangle some of these knotty issues with the patient and research communities on equal footing. Please contact us at info@endthelegacy.org to start dialoguing with us if you have not already.

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Reflections on the ALS MND Symposium 2 of 3 : Was there value in having End the Legacy attend?

End the Legacy was so pleased and honored to be able to send both our Executive Director, Jean Swidler, and one of our volunteer Board Members, Cassandra Haddad, to the Basel meetings this year. This was only possible due to our donors and sponsors, and we thank them profusely. A special shout to the Patient Fellows Program and their sponsors for selecting Cassandra for some support in the run-up to the meeting.

We will provide three blog posts reflecting on the ALS MND Symposium and its lead-in meetings. The first blog covered exciting things we heard. This second post concerns itself with our self-evaluation on having 2 ETL patient advocates attend - was it worth it for our movement and our community?

These notes are our subjective interpretation, we welcome others to share their evaluation of our presence. Pursuing progress can be messy, and we don’t mind being challenged! Drop us a line at info@endthelegacy.org

Talks Presented

We gave one talk during the ALS MND Alliance meeting. The topic was informing the gathered group of ALS Associations from around the world about End the Legacy’s support efforts. It was well received, and we had many positive conversations following it. The take home is that people in our position of being at genetic risk need support options, and the support ETL has provided has been beneficial. The slides can be viewed here.

Posters Presented

We presented one poster at the ALS MND Symposium. The title was “Estimating the Size of the Asymptomatic Genetic ALS & FTD Community in the United States,” and it can be viewed here. We had excellent interactions with many, including esteemed clinicians and researchers. The take-home is that there are a lot of people in the US with these genes. A short social media clip is below.

Questions and Concerns Raised in formal Q&A

In discussions of C9orf72 prevention trials, the 2022 ALLFTD/ GENFI paper that simulated trial designs for prevention was relied on to discuss the feasibility of such a thing. This paper really is a blockbuster, and we have spent the past two years trying to get the ALS field to grapple with it. Why would ALS researchers bother with an FTD paper? Well, the paper's findings were drawn from pooling the data of hundreds of genetic FTD carriers, mostly presymptomatically. This means the largest group of people in the study were presymptomatic C9orf72 carriers, and no one can tell if they will develop ALS or FTD or neither.

Despite the data in the study coming from longitudinal studies with lots of natural history data, when simulating the trials, the paper does not assume any natural history data would be available. We knew only those who had looked at that paper very closely would know that (it took us reading it a few times to really grasp it). So, in the Q & A, we limited ourselves to querying that if there were patient natural history data leading into the trial, would it would lower the number of people needed? Dr Boxer confirmed this. This is imperative for the field to grapple with, as the practicalities of such approaches require using the smallest ( and least expensive) number of participants.

One tangent on this, especially for NFL: presymptomatically NFL is only of value over time. One-time point results can be noisy and thus would require big groups in a trial if you are basing trial inclusion on that one-time look. NFL that is measured in an individual with a clear trendline over years would show much more concretely where a presymptomatic person is with the disease and what the value of any reduction in NFL that is sustained is. Nothing stops us from gathering NFL in preparation for trials from c9orf72 and other carriers in the many longitudinal studies or even in clinical care.

In a talk on clinical care for ALS, prominent Swedish ALS researcher Dr. Caroline Ingre of the Karolinska Institute in Sweden made firm points on the need for genetic testing and the need to diagnose as early as possible. In the Q&A, I paired the two issues together and asked her perspective on the monitoring of at-risk relatives - she enthusiastically agreed and spoke in detail of her vision for that.

A great set of presentations about TDP-43 at the cellular level was a little high level for our non-scientist patient advocate representatives, but it did have a fantastic update to the talk Prof. Jenna Gregory gave for us ( and repeated callouts from her to focus on treating the disease early), some exciting work from Prof. Alicia Coyne of Johns Hopkins in IPSC derived neurons, and a fascinating talk from Prof. Magdalini Polymenidou on her findings also in IPSCs. Professor Polymenidou shared a lot about a protein called NPTX2, which she showed was a driver of TDP-43 pathology. For our patient advocates, NPTX2 rang a bell - just in November, a GENFI paper revealed that NPTX2 was a significant difference in plasma between symptomatic genetic FTD carriers and controls. Interestingly and mysteriously, NPTX2 was higher in the carriers' plasma but lower in the CSF. As the Professor did not mention this, I asked about it in the q and A. The professor shared that she was familiar with the paper, but it did not fit with her findings, and it was still unclear if what they measured was the same as what she was looking at.

Networking and relationship-building

Our team was running the entire time, deepening connections with those we already knew and forging new ones. Many thanks to all who were so kind with their time to share it with us.

In Summary

The information we gathered at the meetings we are using as patient advocates to inform our community and clarify our asks on the field and of funders. The networking we did as individuals and as an organization was beneficial. The perspectives we shared helped ensure the discussions considered our community.
We think for ourselves, our community, our organization, and for the best chance of cracking these diseases, having genetic ALS and FTD patient advocates generally, and End the Legacy in particular, involved in these meetings is a clear win.

Reflections on the ALS MND Symposium 1 of 3 : Exciting Things we Heard

We will provide three blog posts reflecting on the ALS MND Symposium and its lead-in meetings. The first blog sharing exciting things we heard is below.

These notes are our subjective interpretation of the presentations and posters we were able to see and certainly not reflective of all of the fantastic information presented at the Symposium. Therefore, we welcome others to share their points of excitement or even to question our interpretations. Pursuing progress can be messy, and we don’t mind being challenged! Drop us a line at info@endthelegacy.org to keep the conversation going.

Exciting Developments for the Genetic ALS & FTD Community

The promise of C9orf72 Repeat Length and Instability as avenues for discerning C9orf72 pathogenesis.

This is an area ripe for more exploration. End the Legacy will be following up with those who study our community (especially longitudinally) to ensure this avenue is not being overlooked. Information from presentations and posters from Dr. Hasse and Evan Udine, as noted below, as well as conversations with researchers, including Phillip McGolddirk, were particularly enlightening.

Dr. George Haase from France presented–, Mechanisms of C9orf72 Repeat Instability in Blood and Brain–at the ENCALS Satellite meeting
Evan Udine from Mayo presented a poster, “Targeted long-read sequencing of C9orf72 in multiple human tissues”
Dr. Phillip McGolddirk presented a poster on C9orf72. We were also able to discuss his 2018 paper with a documented case of C9orf72 Mosaicism in an asymptomatic carrier who died without developing disease.

New Abilities to See TDP-43 Aggregation in more areas of body.

More information on Gregory Lab’s ability to see TDP-43 issues in the nucleus of the cell and in more areas of the body than just the brain.
With the compelling theory that the cascade starts outside the brain, this area of research could allow for possible early detection and treatment of disease.
Professor Gregory gave a talk for us with earlier data a few months ago, so we were excited to see more information in this evolving area.

The highlighting of the ALS and FTD Overlap with a special Track

We celebrate the research community’s embracing the closeness of these two diseases (which has become boilerplate background for any journal article on the disease) with shared presentations from experts in both fields.
A particularly noteworthy item was the drilling down on the use of models in some FTD field papers portraying a gradual rise in neurofilament in presymptomatic C9orf72 carriers. The sharing of charts showing individual marks that tracked the model hopefully tempers some of the criticisms going forward.

Ever finer detailing of various biomarker methods beyond NFL, including Lipid panels and neuroimaging.

We appreciate the many efforts going on all over the world on this!

Further defining the prodromal stages of ALS / FTD.

The more formal definition of prodromal ALS/FTD from Dr. Benatar, with an acceptance it will be a composite of many domains. There were some especially thrilling simple statements as part of this for a firm threshold for full ALS conversion that would revolutionize care for those at risk. I will not name those bright lines here, but trust they will make their way to public discourse soon.

The highlighting of the importance of Genetic Testing and New Resources

The importance of genetics to forward progress in ALS was clear.
We were happy to see not only the hard work of many being rightly celebrated and shared but also to witness the acknowledgment of not only our participation but also that of generations of our families in studies, including the ultimate sacrifice of brain donations.
Other significant developments shared in Basel included the new Genetic Testing Guidelines, services from the Les Turner ALS Foundation, and the new Light the Way project through Sano Genetics.

The Closing Plenary in its entirety

The importance of genetics and biomarkers to the field was fully displayed with the acknowledgment of the development of the FUS ASO therapy and the herculean effort to bring Neurofilaments to the bedside by many across the field. We share in thanks and wonder at the work of these teams.
As advocates, we must constantly stress areas for improvement, and in FUS, it is clear with the knowledge that those with a strong family history of FUS ALS are not getting diagnosed in time to make it into the FUS trial more could be done to support those families.
The talk from Dr Harms on the further application of genetics in treatment and from Dr. Westeneng on ever-finer prediction models were excellent reminders of all that is possible now.

We are Thankful for Wanda Smith, a Finalist For the 2023 RareVoice Awards

Wanda Smith is a fierce advocate for the Genetic FTD and ALS community. We are filled with gratitude to have her on the team! She has been pushing for better for decades, working with many groups and, when needed, independently. She is a fantastic storyteller and organizer. We are glad the Everylife Foundation for Rare Diseases agreed, placing her in a select group of nominees for the 2023 State Advocacy Award. Read more and see all the nominees here.

This week, she was also recently profiled in her hometown paper in a great story to introduce more people to Genetic FTD.

Just this month, she traveled to Washington, meeting with the NIH, Congress, and the Milken Institute all in one trip!

And we can't celebrate Wanda without remembering her powerful testimony to the FDA in our January Patient Listening Session.

Cheers to you, Wanda!