NTSAD GM2 Voice of the Patient Report

GM2 Gangliosidosis (Tay-Sachs and Sandhoff)

GM2 Gangliosidosis (Tay-Sachs and Sandhoff)

VoiceofthePatientReport VoiceofthePatientReport

Externally-led Patient-Focused Drug Development Meeting

Externally-led Patient-Focused Drug Development Meeting

Public Meeting:

Report Submitted:

Hosted by:

February 15, 2024

July 30, 2024

National Tay-Sachs & Allied Diseases Association

This report is dedicated to the courageous patients and families impacted by Tay-Sachs or Sandhoff disease.

Together, we will make a difference.

My child has been given a death sentence. I have to slowly watch him fade away until the day comes when GM2 finally wins the battle over his body.

Mother to a three-year-old child with infantile Tay-Sachs

VOICE OF THE PATIENT:

GM2 GANGLIOSIDOSIS (TAY-SACHS AND SANDHOFF DISEASES)

AUTHORS:

This report was submitted and prepared on behalf of the National Tay-Sachs & Allied Diseases Association (NTSAD) with input from Kathleen Flynn, CEO, and Diana Jussila, Director of Family Services. Consultant Trista Dawson Rutledge was contracted for assistance in writing this report.

CONSULTING

ADVISORS:

Larry Bauer, RN, MA, and James Valentine, JD, MHS, offered indispensable assistance and support for the meeting. Hyman, Phelps & McNamara, P.C. is a law firm that represents sponsors who are developing drugs for rare diseases and patient advocacy organizations. We also extend our thanks to the team at Dudley Digital for providing seamless technical support.

ACKNOWLEDGMENT:

We are grateful beyond words to all caregivers and patients who participated, whether actively caring for someone with GM2, living with GM2 or mourning the loss of a loved one.

Thank you to Florian Eichler, MD, (Massachusetts General Hospital) and Cynthia Tifft, MD, PhD, (National Institutes of Health) for providing insightful medical overviews of GM2.

We deeply appreciate the participation of Jacqueline Karp, MD, (FDA) for discussing the importance of integrating the patient/caregiver perspective into drug development and evaluation.

NTSAD also acknowledges the collaboration and invaluable support of fellow patient advocacy community partners: Blu Genes Foundation, Cure Tay-Sachs Foundation, The CATS Foundation, Mathew Forbes Romer Foundation, and members of the Global GM1 & GM2 Alliance.

DISCLOSURES:

This meeting was organized by NTSAD with financial support by Sanofi, Cure Tay-Sachs Foundation, Mathew Forbes Romer Foundation, New York Area Fund at NTSAD, Azafaros, and JCR Pharmaceuticals. No pharmaceutical company was involved in the planning and coordination of the meeting.

PUBLIC MEETING:

PUBLICATION DATE: SUBMITTED TO:

February 15, 2024

July 30, 2024

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

U.S. Food and Drug Administration (FDA)

VERSIONS AND MODIFICATIONS:

This document has not been revised and/or modified in any way after the report date. The submitters have all necessary permissions to submit this external resource to the FDA and linking to this resource from the FDA website does not violate the proprietary rights of others.

POINTS OF CONTACT:

Kathleen Flynn, CEO (kflynn@ntsad.org), Diana Jussila, Director of Family Services (diana@ntsad.org)

Thank you to our generous sponsors who made this meeting possible.

New York Area Fund

Every single task I do in my life is planned around Tay-Sachs. It’s 24/7 on my mind. It’s a constant struggle every day.

A young woman living with late onset Tay-Sachs

Executive Summary

GM2 gangliosidosis (Tay-Sachs and Sandhoff diseases) is a rare condition that steadily destroys nerve cells in the brain and spinal cord. Patients with GM2 lose fundamental abilities such as mobility, speech and swallowing. GM2 imposes an incalculable burden on the patient and the family as it requires constant vigilance and upends every aspect of their lives, while inflicting severe physical, emotional and mental tolls. The childhood forms of GM2 are fatal, while the late-onset form in adults has progressively debilitating physical and mental health impacts.

There are no FDA-approved treatments that target the underlying cause of GM2. While a cure is the ultimate goal, the GM2 community would welcome any treatment that could help preserve even the most fundamental functions, such as the ability for a child to smile or hold their parent’s hand, or for an adult to walk without a constant fear of falling. To achieve that, parents of young children with GM2 and adults living with late onset GM2 are willing to take greater risks in drug development in the hopes of improving their daily functioning, as quality of life was deemed much more important than merely extending survival.

On February 15, 2024, the National Tay-Sachs & Allied Diseases Association (NTSAD) convened an Externally-led Patient-Focused Drug Development (EL-PFDD) meeting on GM2. The goal of this meeting was to enable the FDA and other important drug development stakeholders to hear firsthand from patients and caregivers about their journey with Tay-Sachs and Sandhoff diseases and what would be the most meaningful for patients in terms of future treatments.

The expert presentations, patient and caregiver video stories, panelist discussions, caller remarks, meeting polling data and comments submitted online during and after the meeting provided the content for this “Voice of the Patient” report.

Key Meeting Themes

Testimonials throughout the meeting painted a clear picture of the devastation caused by GM2. While the different onsets of GM2 (infantile, juvenile and adult) vary in their symptoms, impact and outcomes, several common themes emerged as noted below and explored throughout the report.

GM2 gangliosidosis, known as Tay-Sachs and Sandhoff diseases, is a rare neurodegenerative condition that is fatal in children (infantile/juvenile form) and progressively disabling in adults (late-onset form).

Children with the infantile onset form of GM2 don’t typically live past five years of age, while those with juvenile onset can survive into adolescence.

Adults living with the late onset form of GM2 may experience worsening physical limitations and potential impacts to their mental health, ranging from anxiety/depression to psychosis, all of which compromises their ability to live independently.

Patients with GM2 endure a heartbreaking journey marked by relentless disease progression that strips away abilities they once had, including their capacity to walk, talk and eat.

Parents watch in agony as their children who appear at first to be healthy and thriving, regress as they lose basic abilities and miss developmental milestones.

Adults living with late onset GM2 confront a continuous and frustrating decline in their capabilities, with a constant dread of the next fall, further loss of function or mental decline.

GM2 is all-consuming for the patient, caregiver and family as a whole, with patients often entirely dependent on others for every aspect of daily life.

Parents of young children described the intense nature of GM2, which requires constant vigilance and upends every aspect of their lives.

Adults living with the late onset form of GM2 fear further decline and what that means for their ability to care for themselves or others.

There are no FDA-approved treatments that can alter the cruel course of GM2, which is fatal in children and life-altering in adults.

Parents are powerless to help their children who face a “death sentence.”

Every day that passes without a disease-modifying treatment, patients lose more and more of their abilities, robbing them of precious moments with loved ones and chipping away at their quality of life.

Although the hope is for a cure, parents and patients would be grateful for a treatment that slows or halts disease progression to preserve basic abilities, such as communicating clearly, holding the hand of a loved one, walking with minimal assistance or eating independently.

Parents of young children and adults living with GM2 are willing to take on greater risks to improve their daily functioning, noting that quality of life matters more than merely extending survival.

A treatment that offers small gains or marginal improvements would be a lifeline for the GM2 community, providing hope in the face of overwhelming daily challenges.

Introduction

The Externally-led Patient-Focused Drug Development (EL-PFDD) meeting on GM2 gangliosidosis (Tay-Sachs and Sandhoff diseases) was held on February 15, 2024.

The EL-PFDD initiative by the U.S. Food and Drug Administration (FDA) emerged from the realization that the firsthand experiences of patients, caregivers and families provide vital insights that can inform the development and evaluation of new therapies.

The information gathered at the meeting and summarized in this report may guide therapeutic development and inform the FDA’s evaluation of potential therapies that address GM2. Involving patients and families in the drug development process can help bring to light what matters most for those affected with rare diseases such as GM2. The hope is that this information will help fuel the development of new treatments, accelerate their approvals, and ultimately improve the lives of those impacted by these diseases which cause untold heartbreak and devastation.

The EL-PFDD meeting was organized by National Tay-Sachs & Allied Diseases Association (NTSAD), one of the oldest advocacy organizations in the U.S. for rare genetic diseases, founded nearly 70 years ago. NTSAD puts family support at the cornerstone of their mission, while also nurturing community, cultivating collaborations and advancing research.

In Memoriam:

Soon after the EL-PFDD meeting on February 15, 2024, two families that participated in the meeting experienced a devastating loss that we see all too often in the GM2 community. The legacies of Cayden and Phillip will live on in our hearts and in this report.

GM2 Gangliosidosis (GM2): Tay-Sachs and Sandhoff Diseases

GM2 is a rare, life-limiting lysosomal storage disorder. Lysosomes house specific enzymes responsible for breaking down and recycling molecules within the body. GM2 is caused by a mutation in either the HEXA gene (associated with Tay-Sachs) or the HEXAB gene (linked to Sandhoff disease), impairing the β-hexosaminidase enzyme from breaking down and recycling gangliosides within the body's cells. As a result, toxic gangliosides accumulate in the cells and tissues resulting in progressive damage primarily affecting nerve cells in the brain and spinal cord and leading to eventual death of the cells. Tay-Sachs and Sandhoff diseases are inherited in an autosomal recessive pattern, meaning that an affected child has received one altered copy of the gene from each of their parents.

There are no FDA-approved treatments that address the underlying disease.

Treatments

for

symptoms include anticonvulsants (for seizures), muscle relaxers (for spasticity), gastric tube placement (for aspirations and nutrition when a child can no longer eat by mouth safely), antibiotics (for infections) and others.

GM2 is ultra-rare, affecting fewer than an estimated 1,000 people in the U.S. (based on NTSADrecorded cases), with the infantile form the most common. Although originally believed to exclusively affect individuals of Jewish descent, Tay-Sachs and Sandhoff diseases are now acknowledged as conditions that transcend ethnic boundaries. Tay-Sachs is more common than Sandhoff disease.

INFANTILE | ONSET 3-6 MONTHS

Elevated noise sensitivity, exaggerated startle, hypotonia (decreased muscle tone), developmental arrest, reduced vocalization, spasticity (stiff or rigid muscles), seizures, cherry-red maculae, diminished eyesight as well as loss of the ability to sit, move the head side-to-side and reach for an object

Only half of infantile patients gain the ability to sit independently and all that gain the ability lose it within an average of one year

Only half of patients survive to three to four years of age

JUVENILE | ONSET 2-5 YEARS

Gait problems, speech difficulties, incoordination, intellectual deficits and delays, muscle weakness and wasting, feet deformities, incontinence, behavioral/psychiatric issues, feeding problems, seizures, visual problems and more

Clinical features are more heterogeneous compared to infantile GM2

LATE ONSET | ONSET ADOLESCENCE AND INTO ADULTHOOD

Muscle weakness particularly in anti-gravity muscles, increased falls, inability to rise from the floor, unstable walking, dysarthria (slurred speech) and sensory neuropathy

Patients with late onset GM2 have more variability in the age of onset and rate of disease progression than patients with infantile or juvenile onset

Roughly 30-50% of adults with Tay-Sachs experience psychiatric symptoms throughout the course of the disease Most severe

Meeting Overview

This meeting was designed to highlight the patient and caregiver perspectives of GM2 across both childhood and adult forms, notably the impact of disease symptoms on their daily lives, as well as their hopes for future treatments. Because of the vast differences between childhood disease (infantile and juvenile) and adult (late onset), the meeting was divided up accordingly with separate medical overviews, testimonials and discussions (see agenda in Appendix 1).

The meeting began with opening remarks by co-moderator Kathleen Flynn, CEO of NTSAD. She highlighted the severe impact that GM2 has on quality of life, affecting children and adults in ways that can be difficult for those outside of the GM2 community to fully understand. With no FDA-approved treatments, the hope is that this meeting will inform the development and approval of treatments that are urgently needed.

Jacqueline Karp, MD, Division of Rare Diseases and Medical Genetics, Center for Drug Evaluation and Research (CBER), FDA, highlighted the importance of EL-PFDD meetings to integrate patients’ perspectives, needs and priorities into drug development and evaluation. She reinforced the importance of identifying and measuring outcomes in clinical trials that matter most to patients and caregivers.

James Valentine, JD, MHS, who helped launch the PFDD program at the FDA, served as co-moderator, outlining the meeting format/guidelines and conducting demographic polling.

The morning session explored the impact of GM2 on daily life, featuring in-depth medical presentations on both the childhood and late onset forms. These insights were provided by Florian Eichler, MD, Director of the Center for Rare Neurological Diseases at Massachusetts General Hospital, and Cynthia Tifft, MD, PhD, Deputy Clinical Director and Senior Clinician at the National Human Genome Research Institute of the National Institutes of Health, respectively. The afternoon session on current and future treatment approaches, as well as the morning session, included pre-recorded patient/caregiver panels, audience polling (by phone, computer or tablet) and moderated discussions.

The meeting concluded with a summary provided by Larry Bauer, RN, MA, a former member of the FDA Rare Diseases Program, and closing remarks from Kathleen Flynn and James Valentine.

Members of the GM2 community were invited to submit written comments both during the meeting and in the 30 days following, which were incorporated into this report as possible.

A recording of this EL-PFDD meeting in its entirety may be found here: https://ntsad.org/gm2pfdd

Report Overview

This “Voice of the Patient” report intends to support the FDA’s and other key stakeholders’ understanding of patients’ experiences, perspectives, and needs living with GM2, including the impact on daily living along with patient and caregiver desires for future treatments. The hope is that these firsthand insights may help inform drug development and evaluation, including identifying meaningful endpoints and outcomes used in clinical trials.

This report aims to summarize the input graciously provided by patients and caregivers during the EL-PFDD meeting and is not meant to represent in any way the views and experiences of any specific group of individuals or entities. There may be symptoms, perspectives or other aspects of GM2 that are not included in the report.

Meeting Participants by the Numbers

Parents or caregivers of a child currently living with GM2 or those whose child has passed away from the disease

Adults living with late onset GM2 (Tay-Sachs and Sandhoff)

80% of participants represented Tay-Sachs, with the most common being the infantile form; ~20% Sandhoff disease

~50% were diagnosed at the age three years or older and patients represented were diagnosed at age two years or less,

People joined and took part in the EL-PFDD from around the world:

Europe

New Zealand

United Kingdom

United States

Infantile/Juvenile GM2: Symptoms and Impact on Daily Life

Parents shared heart-wrenching experiences of caring for children with infantile or juvenile GM2, the most severe forms of disease. Although children with Tay-Sachs or Sandhoff disease may initially meet typical milestones, they can suffer developmental arrest and regression. Families grapple with a range of debilitating symptoms, numerous hospitalizations and various surgeries. Constant demands of GM2 include administering daily medications to control seizures, performing suctioning to manage secretions and facilitating movement to prevent muscle contractions. Disability and death are prominent features of infantile and juvenile Tay-Sachs and Sandhoff diseases.

Children lose basic abilities as the disease progresses

Many children with GM2 are born seemingly healthy, reaching developmental milestones and thriving. However, this picture drastically changes when symptoms of Tay-Sachs or Sandhoff disease appear and children start to miss milestones or lose abilities they once had. Parents described the anguish of witnessing their children decline.

Rick wrote about his daughter Krystie who died from Tay-Sachs at age nine, saying that “she was perfect” when she was born but that “the dark clouds of GM2” set in when Krystie started falling behind in her development around nine months of age.

Wendy wrote about her three-year-old son Victor who has infantile Tay-Sachs: “Victor's diagnosis was devastating for us, but seeing the progress of his illness little by little is even more so, how he smiled less and less every day, how he stopped moving little by little, how we realized that his eyesight is getting worse and worse. How this damn disease is stealing our beautiful son from us little by little is really hard, the hardest and most painful thing in life.”

Mandy, mother of young daughters Mollie and Madelyn who both have juvenile Sandhoff disease, said that although their disease journeys were different, “what they had in common was that they went from walking to school to needing wheelchairs. They went from eating their favorite treats by mouth to needing feeding tubes. They went from talking full sentences to just making sounds and occasional laughter. And instead of continuing to go to soccer practice and dance class, they go to therapies.”

Parents mourn the life that could have been

Parents express the heartbreak seeing their child deprived of a typical childhood along with having their own dreams of raising a healthy child crushed by GM2. They describe their pain around losing out on everyday moments and milestones.

“My two-year-old never played at a park. He never had the chance to be a kid. Tay-Sachs took that opportunity away from him. It also took away my motherhood experience that I had envisioned for my life,” said Kim, who lost her young Greyson to Tay-Sachs just before his third birthday.

“This is a systematically progressive disorder and unfortunately, we do not have newborn screening in place to diagnose children before the onset of symptoms,” said Florian Eichler, MD, Director of the Center for Rare Neurological Diseases at Massachusetts General Hospital

“Because of Sandhoff disease, I am being robbed of many of his ‘firsts’ but instead, I will only witness his ‘lasts,’” shared Crystal, whose four-year-old son Cayden died from Sandhoff disease.

Rennie wrote about her six-year-old daughter with juvenile Tay-Sachs: “We have mourned for who Chloe would have been in the future, but we continue to mourn our Chloe now, who she was just a few months ago, weeks ago, and even days ago, as we slowly see her skills and abilities deteriorate.”

Childhood

GM2 can present with a

wide range of severe symptoms

Participants described an array of symptoms their children endure, including weakness, motor deficits, difficulty swallowing, cognitive delays and developmental delays/loss of milestones (Chart 1). Other common symptoms include hypotonia, decreased responsiveness, exaggerated startle response, seizures and more. Symptoms can also evolve over time, with one mother remarking that every new or worsening symptom significantly affected her son’s quality of life and emotionally taxed the entire family unit as they adapted to changes. A meeting poll revealed that the daily life activities most impacted by GM2 were the ability to move/walk, eat and talk (Chart 2).

Chart 1

Participants ranked the most troublesome GM2-related health concerns that their loved one has ever had (they were asked to select up to three topics)

Difficulty swallowing: A constant fear of choking, infections and more

Participants highlighted secretion management as a formidable challenge, with patients losing the natural ability to clear mucus from their airways and swallow on their own. This can result in liquid being aspirated into the airway, presenting serious respiratory risks such as infections, chronic coughing and breathing difficulties. Parents also highlighted the substantial burden caused by continuous care required to manage secretions.

Crystal, mother to four-year-old Cayden who passed away from infantile Sandhoff disease, said: “Secretion management is our biggest struggle…. Suddenly, one day the suction machine started coming with us everywhere we go. It had gotten so bad to a point where we couldn't even leave the house because suctioning had to be constant or worse, when you're driving in the car, everything is fine at the beginning until you're constantly having to pull over to suction and eventually turn around to go home.”

Abby, mother to three-year-old son Levi with infantile Tay-Sachs, noted that “issues with swallowing, secretion management, shallow breathing, need to be addressed repeatedly throughout the day.”

Unable to eat: A major setback for children and a complex issue for parents

Parents discussed the challenge of maintaining their children’s independent eating while ensuring adequate nutrition. They shared the grief of transitioning to an assistive feeding device for children who were once “great eaters,” a decision that can be devastating for parents.

Yasmina, mother to 11-year-old Lily with juvenile Tay-Sachs, shared that her daughter greatly enjoyed food, including pizza, candy and chocolate, but “it was getting harder and harder for her to swallow, and she would spit out her food, and she started choking and aspirating. It just gets stuck in the wrong spot and the coughing, and it's harder for her to cough as the symptoms, as the disease takes over.”

Jennifer said that her 12-year-old daughter Madelyn who has juvenile Sandhoff disease also loves food: “I want her to be able to still experience that, the flavors, holding onto food with her hand and getting it to her mouth, even if she can no longer use utensils. But when we go to her doctor appointments and they say, ‘Well, she hasn't gained weight’…. you start questioning….you want her to be happy and enjoy everything in life that normal children get to enjoy, but you also want her to have a healthy body.”

Ongoing seizures: A constant concern for many children with GM2

Seizures are a common symptom in childhood GM2, particularly in the infantile form. They are often difficult to manage and can significantly impact the quality of life of patients and their families.

“The level of her seizure activity was cumbersome… even with multiple medications over the span of her entire life, we were never truly able to really get that in line. Positioning, noise, movement, even things like wind or rain, all of that could affect her seizures,” said Becky, whose young daughter Elliott died from infantile Tay-Sachs.

Abby wrote about her son Levi with infantile Tay-Sachs that “seizures have been the most difficult symptom to control and have had the most disruptive effect on his quality of life.” Kaitlyn shared a similar sentiment, whose young son Phillip passed away from infantile Sandhoff disease and suffered from “multiple seizures a day, making it difficult to do simple activities.”

Chart 2

Participants selected the daily life activities that are important to their loved one that they are not able to do or struggle with due to GM2 (they were asked to select up to three topics)

Mobility decline: Children become unable to sit, stand or walk without assistance

While other children, and in many cases siblings, are outside playing, running and jumping, children with GM2 are often physically disabled, with many confined to a wheelchair and unable to take part in normal childhood activities. Although some babies with the infantile form may never have learned to walk, children with the juvenile form may have enjoyed years of being active before GM2 gradually stripped away their ability to move, step by step.

“Lily used to be the fastest little child. She could run like no other. She could jump and play, and she did ballet for a couple of years and gymnastics, and she loved to do somersaults. And then all of a sudden, we noticed it was harder for her to run. Then it slowly began harder for her to walk…slowly all the things that were just so natural to her became unnatural to her,” recalled Yasmina, mother to 11-yearold Lily with juvenile Tay-Sachs.

“Madelyn has gone from being able to walk independently to needing a walker to requiring the use of a wheelchair daily. She can no longer walk or stand unassisted,” said Jennifer, about her 12-year-old daughter with juvenile Sandhoff disease.

Communication challenges: Frustrated children and concerned parents

The inability to communicate effectively results in a child being frustrated that they can’t express their needs and wants, while parents worry that they aren’t correctly assessing their pain or comfort levels. Providing care becomes particularly challenging once their child becomes (or remains) non-verbal. This necessitates an acute awareness of subtle clues to understand their needs, something that is often borne solely by the primary caregiver, as others may not as easily recognize these nuances.

“His regressed speech made the biggest impact. It started getting harder for him to get his words out,” said Kelly, whose eight-year-old son lives with juvenile Tay-Sachs. “Kipley mostly talks with one-word phrases, which is so sad because I have videos of him speaking clear and with sentences at a much younger age.”

“I think one of our things that we always worried about was her being able to communicate that pain level or the pain and what was going on,” said Nate, whose young daughter Olly Belle died from infantile Tay-Sachs. “I can't tell you the number of times that the nurses would come in, especially early in her first hospital stay and ask, "Does she look like she's in pain? What do you think? How do you think she feels right now?”

Vision loss and blindness: Challenges in early detection

Several parents shared the challenges in recognizing vision loss in infants or non-verbal children affected by GM2. These children might have appeared aloof, disinterested in visual tasks or in discomfort due to other symptoms, leading their parents to initially overlook the possibility of vision impairment. Only upon careful reflection did these parents come to grasp the reality of their child's vision loss.

Aaron, who lost his daughter Annabella to juvenile Tay-Sachs just after her fifth birthday, recalled: “I remember when she was very young, she had good eyesight and she liked to watch people. We didn't find out she lost her eyesight until the last five months…She was just kind of staring off into space and we'd have her watch her favorite shows, but then I noticed she wasn't really looking at the TV anymore.” Nate shared similar challenges in assessing vision loss with his daughter Olly Belle who also died from infantile Tay-Sachs.

Respiratory issues: Challenges and complications

Respiratory issues present significant challenges and complications, impacting daily life and requiring constant vigilance and intervention. Families talked about coping with demands of respiratory therapies and hospitalization, as well as facing hurdles in travel and managing necessary equipment to ensure their loved ones' well-being.

Kevin, whose son Mathew died from infantile Tay-Sachs at seven years old, said that one of the hardest parts was “the number of times that our son had to be hospitalized” due to respiratory infections. He went on to share that “two to three times a year, we were in intensive care with our child for two weeks at a time and our world just stopped.”

Cognitive and behavioral issues: Children stall or regress in their abilities

Children affected by GM2 may experience developmental delays, intellectual disability, behavioral challenges and regression in skills they've already acquired.

“It has greatly impacted his learning abilities. In his last evaluation, he was functioning at three months old at the age of three years old,” said Kate about her three-year-old son Felix with Tay-Sachs.

Kelly, whose eight-year-old son Kipley lives with juvenile Tay-Sachs, noted that he has been most affected by cognitive decline, particularly struggling in public settings where he “displays inappropriate behaviors,” often running and yelling with no regard to his surroundings or safety in addition to having “extreme emotional swings.”

Caregiving is all-consuming and upends every aspect of daily life

Caregivers expressed the multitude of challenges when caring for a child with GM2. Managing fundamental necessities like eating, dressing and toileting, as well as navigating numerous medical appointments and therapy sessions is just the beginning. They face ever-evolving symptoms and care needs for their child, particularly challenging when children are non-verbal and are unable to ambulate independently.

“It really did truly affect our daily functioning and daily life for all of us … she needed 24-hour, very specialized care,” said Becky, whose daughter Elliott passed away from infantile Tay-Sachs. “Just navigating very small tasks that one may not think about otherwise were quite the challenge for us in many, many ways when caring for our daughter.”

Lorelei, mother to 13-year-old son Isaac with infantile Tay-Sachs, who had a stem cell transplant at 10 months old, said: “He doesn't communicate verbally or directly with any communication device. We have to read him, we have to know with those little smiles or those little frowns or those little sounds if he's happy or uncomfortable.”

“We have to face that she is going to die. She was given a death sentence,” said Yasmina whose 11-year-old daughter Lily has juvenile Tay-Sachs.

Parents fear for the future and brace themselves for the inevitable loss

Without any treatments to slow the relentless progression of GM2, parents feel powerless as they witness their children's decline. A meeting poll showed that the number one concern about the future is that their children’s symptoms will get worse (see Appendix 2). They grapple with worry over worsening symptoms or new manifestations, all while facing the inevitable outcome of the disease.

“I'm most afraid of what will happen next, the move to a feeding tube, the fact that she may become non-verbal or have seizures. Can you imagine knowing that your child will never say the words ‘I love you’ ever again, that instead they'll be trapped inside of their body, a slave to this horrible disease?” said Jennifer, mother of 12-year-old Madelyn with juvenile Sandhoff disease.

“I can vividly remember tucking him in at night and saying, when you're done, you go. When your body is done, you let go. Mommy and Daddy will survive, but you have to go when it's your time. I should be reading him a bedtime story rather than having that conversation with him,” said Kim, mother to Greyson who died from infantileTay-Sachs just before his third birthday.

Late Onset GM2: Symptoms and Impact on Daily Life

Individuals with late onset GM2 shared their experience with this progressively debilitating condition that is marked by a spectrum of symptoms, including extensive physical limitations. In addition, medical literature suggests that up to 50% of late-onset adults (more often late onset Tay Sachs) may develop severe psychiatric symptoms. The addition of the mental impact can result in isolation and further mental decline.

Unique to having GM2 over many decades, participants recounted experiences of symptom dismissal much earlier in their lives and enduring many years of misdiagnoses. Reflecting on the past, a patient shared that he felt bad about himself, saying “I always felt that I was just out of shape and lazy, not knowing that it was Tay-Sachs, it was the problem.” Others echoed the similar sentiments.

Living with late onset GM2: Navigating daily challenges with careful planning

Many patients detailed the meticulous planning required to manage daily activities, reduce the risk of falls, and ensure that outings are equipped with accessible accommodations. Adults with late onset GM2 shared their experiences navigating a world where every task, from visiting a friend's house to completing daily activities like showering or getting out of bed, requires careful planning and consideration due to the physical limitations imposed by their condition.

Zoë, 36 years old, living with late onset Tay-Sachs said: “It's just sort of a constant battle of figuring out what's going to be the next issue, and where I go whether it will be accessible or not, or if I can get in the parking lot, or can I use the bathroom there? Will that be accessible?”

Ken, 57 years old, living with late onset Tay-Sachs: “I need to plan everywhere I go in advance. If I'm invited to a friend's house, I need to evaluate if I have easy access or if the door accessible. How many stairs are there? Can I use the toilet? You realize as things get more difficult, you must plan everything you do in your life, and you must analyze everywhere you want to go.”

Chart 3

Participants were asked to select what daily life activities that are important to them or their loved one that they are not able to do or struggle with due to GM2

Adults face a range of physically limiting symptoms and devastating mental health issues

Adults living with late onset GM2 ranked muscle weakness, motor deficits and anxiety/depression as the most troublesome GM2 health-related concerns (see Chart 4). The interplay between the physical symptoms and the psychological stress appears to exacerbate the disease's impact, making navigating late onset Tay-Sachs and Sandhoff diseases particularly complex and multifaceted.

Chart 4

“Late onset patients have a high incidence of psychosis and this can be the first symptom of disease. Psychiatric symptoms like psychosis can lead to significant disability for patients and for their caregivers,” said Cynthia Tifft, MD, PhD, Deputy Clinical Director and Senior Clinician at the National Human Genome Research Institute of the National Institutes of Health

Participants ranked the most troublesome GM2-related health concerns that they or their loved one has ever had

Mobility decline: Coping with muscle weakness and lack of mobility

Adults living with late onset disease discussed the profound impact of mobility limitations on their daily lives. From struggles walking up stairs and getting up from chairs to relying on mobility aids like walkers and wheelchairs, their accounts shed light on the significant challenges faced with respect to ambulation and muscle weakness. Despite their efforts to stay active through exercises and adaptive strategies, the progressive nature of the disease presents ongoing obstacles to mobility and physical function.

Alan, a 50-year-old living with late onset Tay-Sachs disease, shared the same sentiment, noting that his reduced mobility, along with stiff straight legs, balance and energy levels have the most significant impact on his life.

Michael, a 54-year-old with late onset Sandhoff disease, talked about the impact on work, saying that “clients tend to meet me in their car parks or somewhere accessible as I cannot navigate stairs.”

Caregivers and individuals affected by late onset GM2 provided compelling insights into the pervasive fear of falls and the efforts required to mitigate potential risks. Their accounts detailed a constant vigilance needed to navigate everyday tasks safely along with the realities of dealing with frequent falls.

“I fell down a flight of stairs at home at night breaking my big toe. I couldn't understand why or how I fell. There was no warning prior to the fall, and I walked down the same stairs in the dark many times before without a problem,” said Michael, 54 years old living with late onset Sandhoff disease.

“When I was pregnant, I was leaving the supermarket. I had just finished unloading groceries, was on my way to return the cart and while holding on to the cart with both hands for balance with no warning, my legs finally gave out, and I fell, scraping both of my knees. I still have scars to this day,” said Rachel, who was diagnosed with late onset Tay-Sachs at age 29.

Kirsten, who lives with late onset Tay-Sachs talked about the ongoing fear of falls, saying “I never knew when I was going to fall and that was very frightening to me.” She talked about how a previous fall caused her to “fracture both knees and patella tendons,” going on to say that “it's really taken a toll physically, as well as emotionally, the fear of not knowing.”

Speech struggles: Dealing with speech difficulties

Adults living with late onset disease shed light on the pervasive impact of speech difficulties on social interactions and professional opportunities. From enduring challenges in finding employment to facing social isolation, their accounts underscored the repercussions of speech impairment.

“Her speech problems and awkwardness affected her social life starting in middle school going through her entire life. It also affected her ability to find a job in spite of her good education. It was very difficult for her to be interviewed,” said Sophia, who takes care of her 50-year-old daughter Vera living with late onset Tay-Sachs. “It not only interferes with her social life, it's also dangerous that she would not be able to be understood if something happened.”

Rachel, living with late onset Tay-Sachs, said that her speech is “very affected,” and that people think she has a hearing problem or intellectual disability, despite her holding two master’s degrees and being bilingual in Spanish and English. She noted that although her speech seems to be slowly improving due to speech therapy, “it still affects me mentally where people are nasty towards me just based off the way I speak.”

Inside the mind: Understanding the devastating mental impact

Panelists and participants shared the profound mental health impact of living with late onset GM2. Their stories spanned everything from feelings of emptiness to managing severe psychiatric issues, highlighting the complex interplay between physical and mental health.

Katie, living with late onset Tay-Sachs, said: “Some days I have a high and low of emotional breakdown, depression sometimes. Why me? Why does this happen? It's not fair that it's just so rare. Why does this happen to me?”

Sonja, who lives with late onset Tay-Sachs said, “Since the age of 18, I have [had] countless stays in psychiatric clinics due to psychosis.”

Patricia, mother to two adult children with late onset Tay-Sachs, talked about the severe impact of mental health effects on her children, such as anxiety faced in going to places. “What can I do? How can I use the bathroom? Are people going to look at me? How are they going to think about me or see me or view me? That's what it affects them every day.”

Struggling to connect: Missed moments and the emotional toll

GM2 can result in adults with late onset GM2 feeling disconnected from others. Participants shared frustrations and fears around missing out on important activities, as well as the heavy emotional toll that the disease can bring.

“My son James plays football, and some of the fields can only be accessed by walking down a steep grass bank to reach the field. When James was younger, I could carefully walk down the inline sideways to lessen the gradient, but I can no longer do this and only now attend his game if I can park my car alongside the football field,” said Michael, 54 years old living with late onset Sandhoff disease.

Lee wrote about her fears for daughter Allie, living with late onset TaySachs, “I worry that she will not be able to have her own babies. This is something that Allie wants with all her heart…to have children and be a mother.”

While Jenny wrote about the impact that her adult son Stephen living with late onset Tay-Sachs has had on the whole family. “It has been a very isolating experience having a family member diagnosed with a rare disease. There is no one to talk to that knows what he is going through.”

“I try and stay upbeat, but I've started to deteriorate mentally. As the quality of life deteriorates, so have I,” Ken, 57-years-old and living with late onset Tay-Sachs, talked about the emotional impact despite having a strong support network.

Fears for the future: Losing independence and becoming a burden

Adults with late onset GM2 and caregivers reveal their fears and worries for the future. Their accounts reveal deep uncertainties about losing independence, becoming dependent on others, and burdening loved ones.

Sophia explained how her 50-year-old daughter Vera had to go on disability when “she couldn't drive, started to need help in everyday living and was getting tired very fast.” Sophia went on to say, “Vera's conditions now are even more severe,” and that she often chokes while eating, needs help in and out of bed, and spends most of the time in a wheelchair.

Allie, 28 years old, a former college athlete now living with late onset Tay-Sachs, said: “I'm a really independent person, really active, so it really scares me to think that those things could be slowly taken away from me.”

“Now I'm a caretaker for my daughters. If something happened to me, how will that affect them?” said Rachel, who was diagnosed at age 29 with late onset Tay-Sachs when pregnant with her first child.

“Late onset GM2 results in progressive disability and greater dependence on caregivers for the activities of daily living,” said Cynthia Tifft, MD, PhD, Deputy Clinical Director and Senior Clinician at the National Human Genome Research Institute of the National Institutes of Health.

Current and Future Treatments for GM2

With no disease-modifying treatments available for GM2, patients and caregivers resort to a range of assistive devices and therapies to manage symptoms, all of which were deemed inadequate in controlling all symptoms sufficiently. In a meeting poll, 88% of participants say treatments for symptoms only help “somewhat” or “very little.” Parents and patients have hopes that future disease-modifying treatments will help them preserve even basic abilities to improve quality of life, with many willing to take considerable risks in the quest for an effective treatment.

“How do we treat these diseases? Unfortunately, there's no disease-altering treatment available for these children. I want to emphasize that there are no FDA-approved drugs for this condition,” said Florian Eichler, MD, Director of the Center for Rare Neurological Diseases at Massachusetts General Hospital.

Symptom management is falling short

The top worry about GM2 is that symptoms will get worse.

Meeting polls and discussions reflected a wide range of treatments being used, including seizure and pain medication, antibiotics, feeding tubes, nebulizer treatments, respiratory therapy and antidepressants/antianxiety medications, along with other supplements. Physical and occupational therapy were often cited by parents and patients as being helpful for strength and flexibility, while Botox was cited by several parents as being helpful in secretion management. Additional therapies such as speech, music, equine therapy and others provide further support. Despite diligent efforts to manage the disease, these interventions serve as temporary measures for a progressive condition that will inevitably worsen over time.

Chart 5

Participants were asked about the biggest drawbacks of their or their loved one ’ s current treatment/symptomatic approaches

Lisajane, mother to son Mathew who passed away from infantile Tay-Sachs, said: “From speech therapy, physical therapy and respiratory therapy, to feeding tubes, seizure medications and the suction machine. All of it helped to a point, but the disease always continued to get worse.”

“His life became machines and medications,” said Kim, mother to Greyson who died from infantile Tay-Sachs just before his third birthday.

Mobility devices are a constant

Parents of children with GM2 and adults with late onset GM2 talk about the range of mobility devices needed to support their daily lives. This includes ankle-foot orthosis (AFOs) to support the foot and ankle alignment, as well as canes, walkers and wheelchairs.

“I have three walkers. I have one upstairs, one in the basement, and as well as an electric stair lift to get to the basement. I have a power wheelchair, and I keep one in my truck. That's pretty much what my life has become,” said John, 59 years old, living with late onset Tay-Sachs.

G-tubes become a way of life

Many parents discuss transitioning their children to a G-tube to guarantee proper nutrition. However, this decision is challenging for all involved, as it deprives the children of the joys of tasting and enjoying food, yet they may not be getting sufficient nutrients due to the challenges of eating. This leaves parents burdened with guilt for having to make such a choice.

Aaron, who lost his daughter Annabella to juvenile Tay-Sachs just after her fifth birthday, described the gradual decline in her ability to eat, leading to increased coughing and danger of aspiration. “Giving her the G-tube almost killed us, she was such a great eater before. She ate everything that we gave her, and she loved pizza or cookies… and she loved drinking juice, and then she couldn't do that anymore. We tried to keep it going as long as we could until it was just getting too dangerous.”

Challenges with medication trade-offs and administration

“The child lives a life of therapy just so that we can keep her just sustaining because there is no way our children are going to make gains. The word ‘gain’ is not in our vocabulary. We sustain until we regress,” said Yasmina, mother to 11-yearold Lily with juvenile TaySachs.

Parents talked about the trade-offs with certain medications, such as seizure medications causing extreme sleepiness and difficulties in dosing and administration.

Reita, mother of 18-month-old Palmer with infantile Tay-Sachs recounts that: “It is very hard to tell the right amount to help him, and it is constantly changing. These medications also tend to make him drowsy, which is a negative as he already has very low energy. We also had to thicken his medications when he was still consuming things by mouth as he would otherwise choke on them.”

Sonja talked about tradeoffs, noting that, "For many adults with psychiatric disorders, the biggest problem is that many antipsychotics worsen neurological symptoms.”

Additional devices

Participants talked about a broad range of additional devices used to assist them in daily life including communication devices, home modifications, oxygen machines, vital signs monitors, adaptive seating items and much more.

Kirsten, who had previously worked as a parole officer, noted that now she cannot move around her home “without touching a wall, piece of furniture or using a four-wheeled walker,” and describes the various accommodations for her house. “My bathroom has been modified with a higher toilet, grab bars and a shower with a low lip. I cannot dress or undress without using a grab bar located right next to the shower. A mat on the shower floor gives me traction and stability along with two grab bars located within it.”

Some families choose the path of low intervention

With no treatments that can change the course of disease, some families focus on making the most of the time left rather than seeking extensive treatments for symptoms.

Carla, whose daughter Talia died from infantile Tay-Sachs at 23 months old, said: “Our family made the choice not to intervene with any life extending treatments like a feeding tube, and instead to allow us to follow Talia's body as her brain ceased functioning. The only intervention we allowed were those to mitigate pain. We enlisted the help of palliative care to help us see a path forward where our daughter could focus on the things that made her happy, like being held, going on hikes and laying in her bouncer chair at the family table where her siblings ate and laughed.”

Shannon wrote a similar sentiment saying that although a high intervention approach was recommended by the medical teams, they took a different approach and “chose to be as low intervention as possible.” She went on to question the “intense focus on keeping these kids alive as long as possible. At a certain point, the question becomes, at what cost? Why do we allow parents to admit these kids to the hospital for weeks when they get sick? That doesn't seem humane when the outcome of this disease is always death.”

Hopes for future treatments

Parents and patients affected by GM2 share a common hope for future treatments that can halt or slow disease progression (Chart 6). To reach that goal, participants expressed a readiness to undertake greater risks in hopes of finding a disease-modifying treatment. Short of a cure, the significance of modest achievements - such as the capacity to grasp a hand, communicate thoughts effectively or reduce the incidence of falls - cannot be overstated for individuals living with GM2. These small victories are profoundly meaningful, offering tangible improvements in quality of life and a sense of control against the condition.

Chart 6

Participants were asked what top three specific things they would look for in an ideal treatment for GM2, short of a complete cure

Desperation for a disease-modifying treatment that can slow or stop disease progression

With no treatment that can target the root cause of GM2, parents and patients experience profound frustration and helplessness as they grapple with the inability to halt the relentless progression of the disease.

“What frustrates me the most is that there's no way for me to stop the progression of this disease. There is literally nothing I can do to save my son,” said Kate, mother to three-year-old Felix who lives with infantile Tay-Sachs.

Allie, 28 years old, a former college athlete now living with late onset TaySachs, said: “I want to stop this so I can keep my life being as normal as I could, but it's just getting worse and worse and worse.”

Jennifer, mother of 12-year-old Madelyn with juvenile Sandhoff disease said: “I wish that we could just stop, freeze time. Of course, I wish we could go back and regain when she could independently walk or run or do all of those things, but at this point there's so few options that I just wish there was a way to just stop it or slow it down more so that she can keep these abilities…and we don't lose our children more than we already have.”

“One of the things that really sticks out in my mind is when we got him enrolled in hospice. He’s a two-year-old kid in hospice,” said Kim, whose son Greyson succumbed to infantile Tay-Sachs just before his third birthday.

Quality of life goals are different for everyone, but quality is the

key

Amidst the challenges of managing Tay-Sachs and Sandhoff diseases, a common goal is to preserve a patient’s quality of life. What that looks like differs from person-to-person but a common thread emerged, which was a desire for a life that allows children to engage with the world, enjoy simple pleasures, and minimize pain and discomfort, rather than merely surviving.

Carla, whose young daughter died from infantile Tay-Sachs at 23 months old said: “If the interventions could help Talia to have a healthy mind, to help her to know us and allow us to fully know her, then I would support it. If the interventions' mark of success was the ability to keep her body functioning without addressing her mind's deterioration, then it would not be something I would want for her.”

Kevin R., whose son Mathew died from infantile Tay-Sachs at seven years old, said: “Quite frankly, a good day was when we weren't in intensive care and we were able to have our child home with us.”

Kevin L., who has two adult children with late onset Tay-Sachs said: “An ideal treatment would be to stop the slow deterioration and wasting away of leg muscles” along with an ability to “smooth out the rough mental health episodes.”

Small gains would have a big impact

Parents and patients underscored the profound significance of even modest advancements in quality of life. They expressed the relief and joy found in simple gestures and interactions. Whether it's the ability to hold hands, enjoy time at home, witness a smile, or achieve basic motor skills, these accounts emphasize the transformative power of small gains amidst the realities of GM2.

Lorelei, mother to a 13-year-old son Isaac with infantile Tay-Sachs, who had a stem cell transplant at 10 months old, said that for her a huge win would be “to see him smile consistently and/or verbalize anything would be amazing at this point” and for her son, he would most benefit from getting off some of his respiratory treatments which take up much of his day.

Abby, mother to young son with infantile Tay-Sachs wrote: “I think the biggest improvement to Levi's quality of life would come from a greater ability to interact and respond to the people around him.”

Dan, father to Amélie who died from infantile Tay-Sachs disease at eight years old, noted a key treatment goal would be “the ability to reach out and grab something, grab a toy, grab food, even holding a hand.” He goes on to talk about the importance that holding hands gives to both the child and the parent and how preserving that could make a big difference.

People are willing to take on more risks but need transparency

“One of our most difficult moments was when our daughter couldn’t reach out and hold our hand. You don't realize who it’s comforting; that small action is for both of you and your child until they are no longer able to do it,” Patricia recounted of her experience with her daughter Amélie who died from infantile Tay-Sachs disease at eight years old.

In the pursuit of treatments for GM2-related diseases, a prevailing sentiment among caregivers and patients emerged: the willingness to embrace risk in hopes of improving outcomes. A demand for transparency was also clear, not just around informed consent in the moment but also as a way to mitigate any future regrets the family may have about treatment choices.

Carla, whose young daughter died from infantile Tay-Sachs said that “parents are grasping at anything to improve survival even before we're able to slow down and have real discussions about what survival truly means. There must be time built into any treatment for more than one fully transparent discussion before any life-altering treatment is given. Survival means something different to each family, and discussions that get to the heart of the patient's wishes, while being transparent about the treatment's ability to meet them, is almost as important as the treatment itself. Only with full transparency can future regret be mitigated, and regret can be more corrosive than grief.”

Lorelei, mother to 13-year-old Isaac who has infantile Tay-Sachs, said: “We knew 100% that Tay-Sachs was fatal if we didn't do anything. 100%, we were going to lose him. So a 50% chance of losing him during this process [of a stem cell transplant] versus maybe saving his quality of life and giving him not just quantity but good quality, that was what tipped it for us.”

Heath said: "If a current trial has been paused because of seeing a possible side effect that patients experience anyway, why can parents not make the choice to continue with the trial? I would rather deal with a possible side effect from medication that could slow or stop the progression than have my child develop the same thing and not slow or stop the progression."

People are willing to take on more risks but need transparency (cont’d)

Allie, a 28-year-old living with late onset Tay-Sachs, said, “I'm willing to try anything. I've even thought about prosthetics, robotic limbs, as extreme as having an amputation in order to have legs that work that can carry me without fear of falling.”

And while some are willing to accept greater risks to gain a new treatment, others questioned clinical trial participation and what it means for them. Ken, 57 years old, with late onset Tay-Sachs shared, “My biggest issue with clinical trials is that after I participated in one, then that eliminates me from any future trials. If there's a washout period, that is fine. However, if I participate in a more serious type of trial that involves a more permanent change to me, then I'm no longer considered a prime candidate for any future trials, and this to me is hard to accept.”

Patients and parents beg for expedited timelines

Sophia wrote about the need for an expedited timeline for trials, asking, “Could a new system of testing be developed with shorter [timelines] (e.g. six months) with a small number of patients to try new medications? Patients are getting worse every day.”

Vera wrote, “As someone living with late onset Tay-Sachs, my condition is progressively getting worse, and I don't have seven years to wait for a clinical study. I would like to have the ability to try medications or treatments approved for other conditions or perhaps take part in a smaller study. Because the longer I wait and let things continue ‘as is’, the greater chance I have of significant injury.”

Rick’s daughter Krystie, who had a stem cell transplant, passed away from infantile Tay-Sachs at the age of nine: “As more and more children are diagnosed with these horrible diseases, time is not our friend.”

Promise in new treatments

As experimental new treatments show some promise, a family impacted by GM2 shared their experience. Lauren writes, “We are five months post gene therapy and looking back we would make the same decisions to participate again. One of the biggest benefits we have seen from it is that Daphne is still able to take all her food and drink by mouth. Tay-Sachs has taken so much from our daughter and being able to maintain her ability to eat is a very important piece to her quality of life. We feel lucky at the timing of her diagnosis that she was able to receive gene therapy and hope that the research and availability is more widespread in the future.”

Incorporating Patient Input into a Benefit-Risk Framework for GM2

Benefit-risk assessment is the foundation for FDA’s regulatory review of human drugs and biologics. This framework provides a context for regulatory decision-making and includes valuable information for weighing the specific benefits and risks of a particular medical product under review.

The chart below was assembled based on input from the GM2 EL-PFDD meeting on February 15, 2024, including discussion during the meeting, polls taken and comments submitted afterwards. This sample framework may help inform the FDA’s Benefit-Risk Assessment for urgently needed GM2 treatments.

Evidence and Uncertainties

GM2, known as Tay-Sachs and Sandhoff diseases, is a rare neurodegenerative disorder characterized by the progressive degeneration of nerve cells in the brain and spinal cord.

Conclusion and Reasons

GM2 exhibits a relentless progression from onset, fatal in children and lifelimiting in adults.

Analysis of Conditions

Individuals with GM2 experience a decline in abilities and may ultimately lose all functional capabilities.

Those affected by GM2 are profoundly impacted by a wide range of symptoms with many losing abilities they once had, including their capacity to walk, talk and eat.

Individuals with GM2 become wholly reliant on caregivers for their daily needs

Parents grapple with numerous concerns for their loved ones, particularly around the decline of quality of life, inevitable loss of independence and the deadly course of childhood GM2

Current Treatment Options

There are no disease-modifying treatments, only symptom management which doesn’t always fully address symptoms.

These treatments may encompass seizure, secretion and pain management, among others. Patients also rely heavily on intensive physical and occupational therapy, as well as specialized equipment to assist with breathing, mobility and feeding needs.

Treatments that can stop or slow disease progression are urgently needed.

Patients recognize that any improvement in quality of life would be profoundly welcome, even if a complete cure remains elusive.

Incremental improvements such as preserving the ability to hold one’s hand, eat independently, communicate clearly and have some mobility, would be incredibly meaningful. In exchange for the hope of maintaining quality of life, patients and parents would be open to taking considerable risks.

Conclusion

The Externally-led Patient-Focused Drug Development meeting on February 15, 2024, was an important platform for the FDA and others to hear directly from those impacted by the three different onsets of GM2 gangliosidosis. Parents and patients shared their intense journeys with Tay-Sachs and Sandhoff diseases while mourning a life that could have been. They shared their frustration at dealing with ineffective symptom management while watching themselves or their loved ones fade away until they finally succumb to GM2.

The desperate need for a treatment that can stop or slow progression of GM2 is clear. Even the smallest improvements would make a huge difference in the lives of those impacted by Tay-Sachs and Sandhoff diseases.

NTSAD is grateful for this opportunity to share the experiences of patients and parents during the EL-PFDD meeting and in this “Voice of the Patient” report. We are continually inspired by the strength and courage of the GM2 community. We hope that learning about the love, loss and legacy of these families will spark change and create a brighter future for those impacted by Tay-Sachs or Sandhoff diseases.

APPENDIX I – Meeting Agenda and Discussion Questions

MEETING AGENDA

TIME

TOPIC PRESENTER

9:30 – 9:35 AM Welcome

Kathleen Flynn, CEO, NTSAD

9:35 – 9:45 AM FDA Opening Remarks Jacqueline Karp, MD

9:45 – 9:50 AM

Meeting Format and Overview James Valentine, JD, MHS Meeting Moderator

9:50 – 10:00 AM Demographic Polling

James Valentine, JD, MHS Meeting Moderator

Topic 1A: Living with Infantile/Juvenile GM2 – Symptoms and Impact on Daily Life

10:00 – 10:10 AM Clinical Overview Florian Eichler, MD

10:10 – 10:30 AM Patient/Caregiver Panel

10:30 – 11:20 AM

Audience Polling and Moderated Discussion

Pre-recorded statements from Jennifer, Crystal, Kelly, Kate

Kathleen Flynn, James Valentine - Moderators

Topic 1B: Living with Late Onset GM2 – Symptoms and Impact on Daily Life

11:20 – 11:30 AM Clinical Overview Cynthia Tifft, MD, PhD

11:30 – 11:45 AM Patient/Caregiver Panel

11:45 – 12:30 PM

Audience Polling and Moderated Discussion

12:30 – 1:00 PM Break

Pre-recorded statements from Rachel, Michael, Sophia

Kathleen Flynn, James Valentine - Moderators

Topic 2: Current and Future Treatments for GM2

1:00 – 1:25 PM Patient/Caregiver Panel

1:25 – 2:20 PM

Audience Polling and Moderated Discussion

2:20 – 2:55 PM Meeting Summary

Pre-recorded statements from Mandy, Carla, Ken, Allie, Reita

Kathleen Flynn, James Valentine - Moderators

Larry Bauer, RN, MA, Hyman, Phelps, & McNamara, P.C.

2:55 – 3:00 PM Closing Remarks Kathleen Flynn, NTSAD

DISCUSSION QUESTIONS

If you are a parent or caregiver of a child with GM2 (Tay-Sachs or Sandhoff):

Which GM2 symptoms have the most significant impact on your child’s life?

How does GM2 affect your child on his/her best and worst days? Describe his/her best and worst days.

What specific activities is your child is unable to do at all or has difficulty doing because of GM2?

How have your child’s symptoms changed over time? How has his/her/your ability to cope with the symptoms changed over time?

What do you fear the most as your child progresses? What worries and frustrates you most about his/her condition?

What are you currently doing to manage your child’s GM2 symptoms?

How well do your current disease management interventions address your child’s most significant symptoms of GM2?

What are the most significant downsides to your child’s current interventions and how do they affect your daily life?

Short of a complete cure, what specific things would you look for in an ideal treatment for GM2?

If you are an adult living with GM2 (Tay-Sachs or Sandhoff):

Which GM2 symptoms have the most significant impact on your life?

How does GM2 affect you on your best and worst days? Describe your best and worst days. What specific activities, that are important to you, that you cannot do at all or as fully as you would like because of GM2?

How have your symptoms changed over time? How has your ability to cope with the symptoms changed over time?

What do you fear the most as you get older? What worries and frustrates you most about your condition?

What are you currently doing to manage your GM2 symptoms?

How well do these disease management interventions address the most significant symptoms of your GM2?

What are the most significant downsides to your current interventions and how do they affect your daily life?

Short of a complete cure, what specific things would you look for in an ideal treatment for GM2?

APPENDIX II – Polling Results

DEMOGRAPHIC POLLING QUESTIONS

1: Are you:

B. Parent/Caregiver of a chid living with GM2 (Tay-Sachs and Sandhoff)

C Parent/Caregiver of an adult living with GM2 (Tay-Sachs and Sandhoff)

2: Where do you currently reside?

3: Are you or your loved one with GM2:

4: How old are you or your loved one with GM2?

5: At what age were you or your loved diagnosed with GM2?

6: What type of GM2 have you or your loved one been diagnosed with?

TOPIC 1A: POLLING QUESTIONS

LIVING WITH GM2: SYMPTOMS AND DAILY IMPACT (Infantile/Juvenile GM2)

1: Which of the following GM2-related health concerns has your loved one ever had?

RESPONSE OPTIONS

2: Select the TOP 3 most troublesome GM2-related health concerns that your loved one has ever had. Select up to 3.

OPTIONS

3: What daily life activities, that are important to your loved one, are they NOT able to do or struggle with due to GM2? Select TOP 3.

RESPONSE OPTIONS

4: What worries you most about your loved one’s condition in the future? Select TOP 3.

RESPONSE OPTIONS

TOPIC 1B: POLLING QUESTIONS

LIVING WITH GM2: SYMPTOMS AND DAILY IMPACT (Late Onset GM2)

1: Which of the following GM2-related health concerns have you or your loved one ever had? Select ALL that apply.

RESPONSE OPTIONS

2: Select the TOP 3 most troublesome GM2-related health concerns that you or your loved one have ever had. Select up to 3.

OPTIONS

3: What daily life activities that are important to you or your loved are you/they NOT able to do or struggle with due to GM2? Select TOP 3.

RESPONSE OPTIONS

4: What worries you most about your or your loved one’s condition in the future? Select TOP 3.

TOPIC 2: POLLING QUESTIONS

PERSPECTIVE ON CURRENT AND FUTURE APPROACHES TO TREATMENT

1: What medications or medical treatments have you or your loved one used (currently or previously) to treat symptoms associated with GM2? Select ALL that apply.

medication or

2: Besides medications and treatments, what have you or your loved one used (currently or previously) to help manage the symptoms of GM2? Select ALL that apply.

3: How well does your or your loved one’s current regimen manage the most significant symptoms of GM2?

OPTIONS

4: What are the biggest drawbacks of your or your loved one’s current approaches? Select up to 3.

RESPONSE OPTIONS

5: Short of a complete cure, what TOP 3 specific things would you look for in an ideal treatment for GM2? Select up TOP 3.

APPENDIX III – IN THEIR WORDS: SUBMITTED COMMENTS ONLINE

Organized alphabetically by first name and unedited

Name, Country Comments

Which GM2 symptoms have the most significant impact on your child’s life? Seizures have been the most difficult symptom to control, and have had the most disruptive effect on his quality of life

How does GM2 affect your child on his/her best and worst days? Describe his/her best and worst days On his best days, Levi gets good rest, is comfortable, and alert and enjoys being with his favorite people. At this stage, his best might be a slight smile or momentary giggle. On his worst days, he has seizures that require extra medication which make him sleepy but he isn't able to get quality rest.

What specific activities is your child is unable to do at all or has difficulty doing because of GM2? Laugh and smile is the hardest one He has very little voluntary movement, so no walking, sitting up without support, etc He can't speak He is on a g-tube keto diet, so no food for fun

How have your child’s symptoms changed over time? How has his/her/your ability to cope with the symptoms changed over time? The disease onset was marked by lack of speech and rapid decline in mobility Around 22 months old his seizures started all at once and were identified as epileptic encephalopathy He required an extended hospital stay to titrate medications At this stage, our ability to cope with symptoms is most challenged by respiratory issues He requires frequent respiratory therapies throughout the day

Abby, USA

What do you fear the most as your child progresses? What worries and frustrates you most about his/her condition? His disease has largely taken away his ability to laugh and smile Lack of speech, mobility, and eating by mouth are all manageable symptoms He was a very very happy baby who loved to laugh with his brother, and seeing that taken away has had a huge impact on our quality of life as a family.

What are you currently doing to manage your child’s GM2 symptoms? We have an excellent team comprised of physical therapy, home nursing, palliative care, pulmonary and neurology, as well as GI to a lesser extent At home we manage with cough assist, nebulizer treatments, BiPap, gtube pump, home oxygen, and a vital signs monitor as well as multiple adaptive seating items- a P Pod chair, bath chair, and tumbleform chair with wagon stroller We administer a 12-hour continuous feed during the day, use the BiPap at night, and respiratory therapies throughout the day as well as meds He has something like a dozen prescriptions Care goes from about 7am to 11pm daily

How well do your current disease management interventions address your child’s most significant symptoms of GM2? We are lucky to have a pediatric neurologist who specializes in epilepsy who has crafted a relatively effective combination of meds for Levi Respiratory interventions can be difficult to keep up with and really have to be done right away in the morning and last thing at night Gtube management has been the easiest Traveling with all of our necessary machines and supplies is a big challenge.

Name, Country Comments

Abby, USA (cont’d)

What are the most significant downsides to your child’s current interventions and how do they affect your daily life? Respiratory interventions are a challenge because he needs constant monitoring Issues with swallowing, secretion management, shallow breathing, need to be addressed repeatedly throughout the day Seizure medications have been somewhat successful, but took many months of trial and error as well as necessary changes over time with weight gain, and have not been able to create a seizure-free quality of life.

Short of a complete cure, what specific things would you look for in an ideal treatment for GM2? I think the biggest improvement to Levi's quality of life would come from a greater ability to interact and respond to the people around him

Alan, USA

The late onset Tay-Sachs' (LOTS GM2) symptoms that have the most significant impact on my life are currently mobility (stiff/straight legs), balance and energy level (use more energy to accomplish simple tasks On my best days, GM2 seems a mere bump in the road, with challenges that are not difficult to complete, while on my worse days, GM2 feels like an "unlucky curse, " causing me to feel trapped The worse days are infrequent, occurring once or twice a month. Having come to terms with my rare diagnosis, worse days are more like worse moments, as the day is usually not ruined completely, enabling me the opportunity to reframe the "roadblock" or negative feeling into a challenge to be overcome or modified I enjoyed working, hiking, dancing, walking immersed in nature, and other activities that I can no complete due to my physical limitations My symptoms have improved within the last few months due to, frequent exercise (2 times per week with a physical therapist, 3 times a week walking indoors at the mall, listening to music, going to concerts, podcasting, etc Diagnosed in December, 2015, I had a very difficult time coping with and accepting my diagnosis Learning more about GM2, sharing experiences with friends I've made through NTSAD and the passage of time have enabled me to cope more effectively almost a decade later As I get older, I am actually less afraid of my GM2 diagnosis While some things in my life become more challenging, other things become easier I view GM2 as both a positive and a negative, but tend to focus on the positive, so as not to get bogged down by the negative Plus, I have grown to believe, life is to be lived and enjoyed as much as possible and my diagnosis is not my identity--I am a man living with GM2; I am NOT GM2

Alejandra, Argentina

One of the most difficult things for me as a mother of two children with Tay-Sachs and two healthy children is watch how two of my children advanced and improve some abilities as talk, play and make friends while my children affect with Tay-Sach are unable to do that kind of things, that really breaks my heart

Allie, USA

Becky, USA

I do hot yoga 2-3 times a week and workout with a trainer once a week. Even when I do hot yoga once, I notice a significant improvement in my coordination for about 1 week. I believe the heat makes a difference because when I have tried doing regular yoga, I have not noticed the same benefit. Working out with my trainer helps to maintain and improve my muscle strength

When our daughter was diagnosed with infantile Tay-Sachs in 2009, preexisting conditions were still a very real consideration for medical insurance As I stayed home to care for her, one way this factor impacted our entire family is that my husband could not take a new job at another company or our daughter would then be considered ineligible for medical coverage due to her Tay-Sachs diagnosis as a preexisting condition. It was frustrating and we felt stuck.

Name, Country Comment

All of the patients are suffering to one degree or another

Other than saying "hire more people" to speed up the approval process for (potential) drugs that enter the pipeline, I'm not sure enumerating our symptom list is much help

David, USA

Galo, Ecuador

Even with fast tracking novel therapies or authorizing off-label use, aren't patients with an orphan disease still at the mercy of "capitalism" ?

Not enough patients to justify development of a specialized drug. there's better chance that some already existing drug can be used off label

The newer therapies are some of the most expensive drugs in the world Miglustat is $30K/month

My daughter have some difficult meanwhile eat, and she can't move by himself, now we traying to care without a lot information about Tay Sach, she is 1 year 10 month, it's a baby, in family we need know what we do for Sofi's care... Thanks Pd. In My country talk Spanish.

Heath, USA

Jenny, Australia

If the current Azafaros trial has been paused because of seeing a possible side effect, that patients experience anyway, why can parents not make the choice to continue with the trial? I would rather deal with a possible side effect from medication that could slow or stop progression than have my child develop the same thing and not slow or stop progression.

Thank you for accepting my submission regarding our family’s experiences of a GM2 diagnosis My name is Jenny, and my son Steven was diagnosed with late onset Tay-Sachs last year Steven is 31 years old, and we live in Melbourne Australia Steven has 2 siblings, an older sister and a younger brother

In hindsight, Steven’s symptoms began in his teenage years But they have accelerated substantially in the last 4-5 years As a teenager, he was never particularly interested in sport, preferring to play electronic games – very much a Nintendo expert He was a little clumsy, but nothing particularly unusual He did have a hand tremor, which was noted on a medical report when he was about 13 years old In his younger years he was actually physically advanced if anything – walking when he was only 9 months old

When Steven was 13 years old he was diagnosed with Aspergers – Neurodivergent the current term, having earlier been diagnosed as being on the spectrum. I mention this as I believe it has contributed to a delayed diagnosis for LOTS

Thank you for accepting my submission regarding our family’s experiences of a GM2 diagnosis My name is Jenny, and my son Steven was diagnosed with late onset Tay-Sachs last year Steven is 31 years old, and we live in Melbourne Australia Steven has 2 siblings, an older sister and a younger brother

Name, Country Comment

In his early to mid 20’s Steven’s symptoms were starting to be noticeable, though at the time we didn’t recognise them His gait started to change – he walked very heavily – almost stomping This gradually changed further to having the wider stance as he walked – like he was trying to keep his balance (which we now know he was) I started to notice that when getting up from a chair he would not stand straight up, but instead turn and push himself up with his arms He also started to lock his knees back when standing. He would avoid exercise and stairs, and struggled to clean his room. He never complained that he was physically having trouble, so we all just assumed he was being lazy. He was also starting to fall – though he didn’t always tell us.

We would comment to Steven about trying to walk “properly” and encourage him to do more exercise In frustration one day I remember saying that if he couldn’t walk properly then perhaps he needed to see a doctor He did actually go see his General Practitioner (GP) at that point But the doctor just said he had weak quads and should do more exercise – more squats This just reinforced our view that he was just lazy In late 2019 Steven agreed to see a Personal Trainer, as we believed his issues were due to lack of exercise This was only a few months before COVID, so he did not go for long He hated it of course as he clearly found everything very difficult

Jenny, Australia (cont’d)

By now we witnessed him struggling up a ramp near our home to get to the train station, needing to pull himself up on the handrails and stop regularly Another day he commented that he needed to go slowly down a hill – it was just the decline between the footpath and the road He would lean on anything he could, never just stand up without holding something It became extremely obvious there was a problem when he walked along a short length of footpath outside his new apartment grabbing trees, cars and whatever he could, to get to where we had parked the car. I was totally confused as to what was going on. Steven still never complained about anything being difficult – he just avoided doing anything that was difficult instead of questioning why it was difficult. This I believe was due to his neuro divergence

Mid 2021 Steven purchased his own apartment and moved out of home Knowing how little housework he did in our home – I was concerned about him looking after his new home And himself I wanted to ensure he had cleaners come and any other help he needed We are very lucky in Australia to have the National Disability Insurance Scheme (NDIS) I learned that Aspergers was considered a disability they would cover – so I started the process to have him accepted As part of this process he had to see a GP again This time he saw a different GP – one who noticed his gait and wanted to refer him to a neurologist The earliest appointment wasn’t until November – about 6 months away

In the meantime we progressed his NDIS application On the morning of his appointment with the neurologist we received news that his NDIS application was successful! Steven saw the neurologist in the afternoon only to be told that he needed to see a more specialised neurologist And she would come in to see him the next day -on her day off. Alarm bells started to ring.

Name,

Country Comment

The second neurologist said that yes there was definitely something not right. And she sent us home with a handful of referrals. I swear nearly every part of his body was scanned poked and prodded over the following months. An initial working diagnosis of some kind of muscular dystrophy was given – though we knew that wasn‘t quite right. But we used that to have Steven’s physical needs added to his NDIS plan. Then after an MRI of his brain showed a severely atrophied cerebellar we were given a diagnosis of spinocerebellar ataxia. This diagnosis was a better fit, but still not right.

Steven then saw a geneticist, for the second time. He was surprised Steven could even walk given the extent of the atrophy of his cerebellar. He then managed to have Steven accepted into a research project where they could do whole genome sequencing. About 12 months later – May 2023 - we were contacted and told they had discovered that Steven had late onset Tay-Sachs. To formally confirm the diagnosis Steven underwent a blood test to check his HEXA level. June 2023 it was confirmed that Steven definitely had late onset Tay-Sachs. Everything then made sense. Steven’s father and I felt a little in shock. Both the uncertainty of what was ahead of Steven and realising that we were carriers. It took some time to come to terms with – still not sure I have. Steven on the other hand, just took it all in his stride. “It is what it is” was his comment to the geneticist when given the diagnosis.

Jenny, Australia

(cont’d)

Thanks to the NDIS Steven has a power wheelchair that he uses when outside the home. It has been lifechanging – he can now independently get to work or the shops or visit friends– things he could not do easily before, or at all. The NDIS has paid for bathroom modifications – there are grab rails in the shower and strategically placed in the bathroom. He has a cleaner come regularly and often has meals delivered –all thanks to the NDIS.

NDIS would also cover any Physio and Occupational Therapy that Steven wanted to do, but he chooses not to. I accept that he has multiple disabilities, so respect his choice. He will soon get a tilt recliner through NDIS so that he can easily get up out of his armchair. While the NDIS is certainly making life easier for Steven, his life is of course limited in other ways now. He doesn’t always like the intrusion of having a cleaner come. And I am sure he will not enjoy it when he does require carers on a daily basis. The inconvenience of relying on maxi taxis or public transport to get around – as we can’t fit his power chair in our car. Relying on a wheelchair has highlighted just how inaccessible our world is. He misses out on some events if they are held in inaccessible venues.

It has been a very isolating experience having a family member diagnosed with a rare disease.There is no one to talk to that knows what he is going through. Steven himself doesn’t really talk about it either. I have only been in contact with one other person in Australia with LOTS. NTSAD put us in touch – thank you. So the PFDDM was fabulous opportunity to hear from other LOTS patients and learn about the issues they face. It certainly helps to know what to look for with Steven’s symptoms as they progress.

We have concerns for Steven’s future . What will happen if we can’t be around to support him. If his speech regresses and particularly if psychosis issues start. The NDIS is great, but it helps to have an advocate to navigate the system. And Steven doesn’t complain about things - he just accepts everything. I regularly remind him to let me know if things get hard. We can find a solution. But he doesn’t ask for help often. Our Hopes for future? A treatment to stop or slow the progression of this disease. Thank you, Jenny, Steven’s mum

Name, Country Comment

Jessica, USA

I was never informed about the [Intra Bio] trial My doctor left without telling me and we never heard whether the trial was successful or not I felt the medication helped my symptoms and would like to know if the FDA ever approved it

What do you fear the most as your child progresses? What worries and frustrates you most about his/her condition? PAIN Phillip is constantly in pain and it breaks my heart I wish the progression did not create more pain and discomfort for him

Kaitlyn, USA

Joseph, UK

Which GM2 symptoms have the most significant impact on your life? Respiratory Daily struggle with secretions Mobility Constant state of discomfort from limited movement Seizures Child suffers from multiple seizures a day, making it difficult to do simple activities

My wife, Nicole, is diagnosed with late onset She has mobility difficulties that we mitigate with ADA accessibilities in our home Recently she experienced severe psychiatric issues Her birth control was changed in March and she went on to have psychotic episodes once a month around her cycle This was brought up to her OBGYN and she was put back on a stable series of birth control I believe that the hormones women experience can have a growing effect on psychiatric issues associated with TaySachs I take no merits in that belief other than what I have seen living with my wife and the struggles she has had to endure She maintains a happy life and enjoys art and being creative

Kate, USA Other top 3 biggest fears/concerns would be death. Losing them forever.

Kathy, USA

Kenan, USA

I am Rachel's mother who spoke earlier She and my son, Brian, were diagnosed in 2021 My biggest concern is for Brian He is 28 years old and single, living with me I am 69 years old My concern is for his ability to independently live when I'm unable to assist him Rachel and their other brother will be able to help, but they will have their own lives As a parent who had no idea that I was a carrier, I also carry a lot of guilt

It is very hard to find doctors who can help you put a plan together to manage your systems Not many are familiar with these diseases

Both of my adult children (son is 32, daughter is 29) have LOTS. Both were diagnosed in 2012, having to travel to the Mayo Clinic in Rochester, MN for the diagnosis. We struggled for 2+ years seeking a diagnosis, and incredibly no hospital or doctor in our Pittsburgh area knew what was wrong. How do pediatricians and general practitioners and those in the mental health industry not look for this when an adults gait and mental health are simultaneously failing them?

Kevin, USA

The most significant and everyday struggle is now becoming simple walking Neither of my children can even step over a curb let alone use any steps, and the danger of frequent falls constantly hangs over us As time marches on, they both struggle more and more with simple everyday tasks as this awful disease progresses For example, if they fall they cannot get up, if they drop anything they cannot bend over to pick items up, tie their shoes or carry anything Coping everyday with the fear of a serious injury from falling is very difficult for them as well as for my wife and I

Our biggest fear is how are they going to be able to go on and take care of themselves when my wife and I are gone? Who will intervene when mental health issues periodically arise?

Name, Country Comment

In terms of managing symptoms, both take Seroquel XR (800 mg daily) in an attempt to thwart mental health issues (but they still occur periodically)

Kevin, USA

(cont’d)

Kirsten, USA

How do we get the word out to doctors at children’s hospitals, mental health facilities, so people know and are aware of this disease? The misdiagnosis and whirlwind tour of doctors and hospitals , in addition to managing their safety was and is the part that has to be brought to top of mind for health care professionals.

While we have our diagnosis, the prognosis is devastating for all members of our family….An ideal treatment would be to stop the slow deterioration and wasting away of leg muscles, and to find a suitable pharmaceutical that can smooth out the rough mental health episodes Please help us!

To whom it may concern:

Yesterday I was a part of the discussion panel, just prior to lunch I feel it’s of notable importance to share a few additional bits of information and know your time is precious and limited so I’ll be as succinct as possible.

I lived a very normal life prior to the age of 30 5 years, regarding Tay Sachs I worked full-time as a juvenile Probation Officer in my county, prior to entering the police academy I expressed having left due to a broken finger I’d suffered during Defensive Tactics, but there was much more going on behind the scenes It’s their job to tear you down before building you back up I didn’t stay past 8 weeks and therefore didn’t experience the latter part

I did however start to feel and see I couldn’t do walking lunges to the extent others in the Academy could do and that I myself, had previously been able to do I tried to put it out of my mind and returned to Probation Unexpected falls came and went and my lower body strength at the gym showed itself

It was a long and extensive three year journey, from my first visit to my PCP to Ohio State uncovering my accurate diagnosis The first doctor I saw after the Tay Sachs diagnosis informed my Mum and I that I didn’t have a serious case, and at that time I was having difficulties with stairs.

Over the years I worked at Probation until Nov 2017, when I retired due to the effects of the Tay Sachs. My employer had been wonderfully supportive as had my husband, who I’d met at Probation. My disability was like an ocean with waves which ebbed and flowed; sometimes stable and sometimes quite active, physically and mentally

I’ve been in counseling for many years as a result of my Mum’s death, my Depression and LOTS Added to it is anxiety The feelings have been immensely dark and intense I didn’t ever see myself losing my fierce independence but there came a breaking point when I couldn’t function without the help and support of others, starting on medication for my mental health around Sept 2022, and relying on various equipment (ramps, grab bars, walkers, wheelchair etc )

Name, Country Comment

Today, I cannot get around any part of my ranch style home I’ve had since March 2009 without touching a wall, piece of furniture or using a 4-wheeled walker My bathroom has been modified with a higher toilet, grab bars and a shower with a low lip I cannot dress or undress without using a grab bar located right next to the shower, A mat on the shower floor gives me traction and stability along with 2 grab bars located within it

Kirsten, USA

(cont’d)

I’ll wrap this up but wanted to also mention that for the last 2 years I’ve been utilizing Life Alert. There was an incident where I was stuck/trapped on the 3 stairs of our house, leading from the back door up to the kitchen. I’d let the dogs in and used grab bars to get up 2 of the 3 steps. My body was shaking uncontrollably as I had my left leg on the top step but couldn’t move the right leg It was utterly terrifying as I knew I could fairly easily fall down those stairs and momentum would lead to many more stairs leading into the basement I was beyond fortunate that I had my cell phone in my pocket and somehow could call my husband at work, and he was at his desk If not, 911 would’ve been next My body was utterly exhausted as he got home 20 minutes later and lifted me up to the top step, right leg and all I got Life Alert right after that for safety and piece of mind for both my husband and myself I also no longer do stairs of any kind

There is much more I tell you but I believe a picture has been created to try and help you understand what a portion of my life has been like In sharing, I very much hope it will lead to a better understanding about life I take life day by day, and sometimes moment by moment It is the simplest things I’m so grateful for and didn’t appreciate prior to my diagnosis

Tay-Sachs was never a part of my vocabulary prior to March 26, 2021 I lived blissfully unaware of what Tay-Sachs was and how it would change the course of my entire life My son, Greyson, was diagnosed with infantile Tay-Sachs March 26, 2021 We noticed he was regressing in the milestones he had previously accomplished and was incredibly lethargic, which was out of the norm for our sweet boy It took us 4 months to find his diagnosis, and compared to others in our shoes, our search was shorter than most

Kim, USA

Greyson began have the exaggerated startle reflex, which led to seizures He was forced to get a gtube because his body was failing him and he was unable to safely eat We never got to see him crawl or walk. We only heard his sweet voice say " mama " a few times before Tay-Sachs robbed him of everything. His muscles began to become weak. He lost the ability to hold his own head up or move when he became uncomfortable. His life became machines and medications.

We were lucky with Greyson's medical team They were honest with us in admitting they had never seen a patient with Tay-Sachs before We leaned hard on our NTSAD family to help us with what equipment, medication, specialties, and programs we needed to start obtaining to survive this There were no resources available to us at the genetics office to help guide us and we were lost There needs to be more for these families There needs to be support and resources available to help them through this

Name, Country Comment

At the time of his diagnosis, my biggest fear was losing him I have never loved another human the way I loved Greyson and the fear of him not being physically here with me was terrifying The other reality of Tay-Sachs is the fear of Greyson's quality of life My two year old never played at a park He never had the chance to be a kid Tay-Sachs took that opportunity away from him It also took away my motherhood experience that I had envisioned for my life I am so thankful to be Greyson's mother, but I wish there was more to give me a chance to give Greyson the childhood he deserved. The absolute best of everything I could give him. He is my soulmate and I would give anything to have given him more out of this life.

Kim, USA

(cont’d)

Lauren, USA

We lost Greyson 9/6/2022 It was 2 months and 1 day shy of his 3rd birthday My sweet boy died in my arms surrounded by our family My life shattered and I'm still trying to find the pieces My fears have changed since losing my son I fear my life without him but I also fear the new families receiving that diagnosis I fear for them because this diagnosis is earthshattering I fear for the children I have met through NTSAD knowing one day, they will no longer be here I fear for their parents because no one, no one, should feel the heartbreak I do every single day without my son We need to continue to work to find a cure, a treatment, something to help provide hope for these children and adults suffering from Tay-Sachs and Sandhoff diseases We need to work together to find a way to make sure no other families need to go through this pain and heartache that we feel every day

Myself and my husband wanted to submit our thoughts about participation in clinical trials since we are unable to attend live

Research and clinical trials are so important to the progression of treatments for Tay-Sachs and Sandhoffs Having gene therapy treatment that’s approved and available would be a huge step for families just like ours Timely decisions by the FDA on treatments, like the gene therapy our daughter received, is imperative with Tay-Sachs since they start regressing quickly and don’t take to the treatment as well the older they get

We are 5 months post gene therapy and looking back we would make the same decisions to participate again One of the biggest benefits we have seen from it is that Daphne is still able to take all her food and drink by mouth Tay-Sachs has taken so much from our daughter and being able to maintain her ability to eat to us is a very important piece to her quality of life. We feel lucky at the timing of her diagnosis that she was able to receive gene therapy and hope that the research and availability is more widespread in the future.

My daughter Allie age 28 was diagnosed in 2021

Her condition has significantly increased since her diagnosis

Lee, USA

1 The symptoms I see that have most affected her lifestyle are difficulty walking, going up stairs and ability to get up out of a seated position 2. I do not see her daily so unable to respond.

Name,

Country Comment

3 Activities she is now no longer able to do are: walk long distances, jog, go into the ocean, snow ski and play Tennis All activities she enjoyed her entire life

4 What has changed the most for Allie since she was diagnosed is her ability to walk and exercise like she did before her diagnosis Allie is coping by finding new ways to work out such as playing wheelchair tennis, light weight training, stationary bike and yoga Additionally, Allie has purchased a wheelchair to have if needed for long distance walking and outings. Allie wants to be able to live her life to the fullest and not let her diagnosis be restrictive. Therefore she purchased the wheelchair. She has an admirable amount of courage and strength!

5. As Allie’s condition progresses, what I fear the most is her losing her ability to walk on her own. I am also worried with how her condition has progressed quicker than expected

Lee, USA

(cont’d)

Lucía, Ecuador

Additionally, I worry that she will not be able to have her own babies This is something that Allie wants with all her heart to have children and be a mother

6/7/8 Not applicable She is an adult and lives on her own

I have suggested that she try to adopt an clean anti-inflammatory type of nutrition to help with her joints and overall well-being

9 At this point with no cure

I would like to see a medication that can slow down the progression

Any studies or suggestion with nutrition or anti-inflammatory foods/diet that can help

There should be additional health insurance allotments for PT to help affected patients strengthen the muscles they can use I feel Allie should be able to have PT 2-3 times per week paid by insurance This should be considered preventative and helpful in dealing with the progression of the disease

Saludos desde Ecuador, mi hija Sofi tiene 1 año 11 meses después de varios exámenes, chequeos de especialistas y una revisión oftalmologica le detectaron manchas rojo cereza en sus ojos, de ahí que hicimos lo posible por acceder a un exoma que no lo realizan en nuestro país Determinando en dicho estudio: Tay Sach cuando tenía 1 año, a transcurrido el tiempo y la falta de información, investigación donde vivimos nos lleva a acudir a revisiones médicas en la capital, en donde neurólogos pediatras, gastroenterología y otras especialidades, han llevado nuestro caso en función a los síntomas que se van presentando, actualmente estamos con aumento de dosis de medicamentos para las crisis epilépticas, las mismas que han causado un gran retroceso en su desarrollo

En medio de la angustia diaria, la falta de apoyo y empatía de personas cercanas, continuamos en pie de lucha para brindarle mejor condición de vida por medio de terapias físicas, estimulación temprana y de lenguaje, apoyándonos en el círculo familiar con la esperanza de que un milagro ayude a nuestra pequeña hija.

Confiamos que Dios permitirá que médicos, investigadores, farmacéuticas vuelquen su mirada a estos casos poco frecuentes de seres extraordinarios (niñas y niños, bebés) que luchan a diario por sobrevivir Estamos seguros que el abordar está enfermedad desde la experiencia de otras familias es de gran ayuda para apoyarnos en cómo podríamos actuar, por eso queremos ser parte de este grupo, estar en contacto y ser escuchados

Saludos cordiales Atte Lucía Pazmiño

Name, Country Comment

Michael, New Zealand

Patricia, UK

I'm living with late onset Sandhoff Disease Since diagnosis I have come to realise that every year this condition has a growing impact on my everyday life I have had to begrudgingly accept this whilst remaining positive about my future against all odds

One of the most difficult moments was when our daughter was no longer able to reach out and hold our hand - we really struggled with that progression of the disease You don't realise who comforting that small action is for both you and your child until they no longer do it

AWARENESS IN SOCIETY!!!!

People, even general doctors, have never heard of these diseases or only infantile forms. People may be unaware what the disease is but haven't even heard of it. People have heard of ALS, Multiple Sclerosis, Muscular dystrophy, but no one has even heard of Tay Sachs or Sandhoff, or the different forms There needs to be some kind of awareness in society for just the name of the disease and how impactful to our lives it is

Rachel, USA

Reita, USA

Thank you for sharing Nate in regards to the handicapped sticker, I have late onset Tay-Sachs, I get glares every time I use the handicapped spot when needed

It's interesting, I was diagnosed with late onset GM2 Taysachs at age 31, and in listening to the juvinille, the first and second woman to speak, I have many similarities Although I was not diagnosed until age 31 my neurologist presumed I had this disease at juvinille teen age, just figured out coping mechanisms

I worry about being ill-prepared for when symptoms increase I know that they are going to, and I worry about how I will treat them and try to keep Palmer as comfortable and healthy as I can

Our daughter – sweet, loving, funny, and lover of music is one of only a few children diagnosed with this illness annually across the country that affects the brain and nervous system and will eventually take away her ability to talk, walk, eat, see--- to live. We have mourned for who Chloe would have been in the future, but we continue to mourn our Chloe now, who she was just a few months ago, weeks ago, and even days ago, as we slowly see her skills and abilities deteriorate. We ask you do everything in your power to prioritize support and review of research impacting these conditions Thank you for allowing us to share our experiences

USA

As parents of a rare child, we advocate for support to prioritize understanding and action around rare illnesses – to make sure that families are supported in this difficult journey by:

1) Prioritizing research and funding for cures and treatments -- there are no effective treatments for Tay Sachs, there is no cure

2) Educating for providers on early signs and symptoms of these life-limiting conditions

3) Improving access to specialty care

4) Designing integrated care that supports families as they navigate and secure medical care while they grieve and take care of their ill child

5) Ensuring medical care that will guarantee quality of life to best fit the needs of the child irrespective of ability to pay

Rennie,

Name, Country Comment

Rick, USA

Krystie was born on a sunny winter morning in So California in 2006 She was perfect The dark clouds of GM2 would not set in until she was about 9 months old and falling behind in her development After several wrong diagnoses, the eye doctor confirmed Tay-Sachs disease at about one of age Like any loving parents, we searched all over the world for a treatment; any treatment We finally sold our home and moved to Minneapolis for a cord blood stem cell transplant procedure in hope that her Hex A levels would improve and cross the blood brain barrier. While the treatment helped, and Krystie lived to be 9, she lead a challenging life that included many hospitalizations. That treatment gave us hope, and was quite experimental at the time. Every parent and every child deserves to have that hope. GM2, as it currently stands, offers little hope for either the parent or the afflicted child

We urge the FDA to work with both academia and industry to find treatments and a cure for both Tay-Sachs and Sandhoff disease They are 100% fatal, and private foundations can only fund a fraction of the immediate need As more and more children are diagnosed with these horrible diseases, time is not our friend

Ma fille souffre de la maladie de Tay Sachs. Nous la stimulons tous les jours le.plus possible pour qu 'elle conserve ses facultés le.plus longtemps.possible. nous savons que la science avance à grand pas pour ces maladies dévastatrices mais pas assez vite Un des laboratoires vient d'annoncer la fin de la phase 2 de leur essai mais la phase 3 n 'est prévu que pour 2025 en Europe Nous ne pouvons pas nous permettre d'attendre Le temps est notre ennemi C'est très frustrant pour les personnes impactées par la maladie et pour les familles Cela fait deux ans qu ' on nous parle de plusieurs essais et malheureusement Mathilde n ' a pu en intégrer aucuns Ou parce que ils n ' ont pas marcher ou parce qu 'elle est trop jeune, ou parce que ce n 'est pas en Europe C'est très dur de savoir qu'il existe des choses qui fonctiinnent et que nous ne pouvons pas y avoir accès D'autant plus que nous voyons l'état de notre fille se dégradé mois après mois Merci de me permettre de m 'exprimer C'était le cri du coeur d'une maman désespérée Je vous félicite pour toutes vos actions et votre travail sans relâche Merci encore une fois

Sandra, France

(French to English Translation) We live with this disease day by day Mathilde no longer speaks but her look says a lot She still walks and is not in a wheelchair We spend a lot of time on therapies, physiotherapist, occupational therapy, speech therapist, balneotherapy, equitherapy... our family's life revolves around Mathilde. We try to maintain Mathilde's condition but unfortunately, the illness manages to take over. We have a lot of hope and we believe with all our might that science will find something for this terrible disease. This hope allows us to move forward and not give up.

Nous vivons avec cette maladie au jour le jour Mathilde ne parle plus mais son regard en dit long Elle marche encore et n 'est pas en fauteuil roulant Nous passons beaucoup de temps sur les thérapies, kinésithérapeute, ergothérapie, orthophoniste, balnéothérapie, equitherapie la vie de notre famille tourne autour de Mathilde Nous essayons de maintenir l'état de Mathilde mais malheureusement, la maladie réussie à prendre le dessus Nous avons beaucoup d'espoir et nous croyons de toute nos forces que la science va trouver quelque chose pour cette terrible maladie Cet espoir nous permet d'avancer et de ne pas baisser les bras

Name, Country Comment

In our experience, high intervention was pushed by most of the medical team we encountered We had a radically opposite approach to our son ' s disease and chose to be a low intervention as possible I think the pros and cons of both need to be presented to families, instead of such an intense focus on keeping these kids alive as long as possible At a certain point, the question becomes, at what cost? Why do we allow parents to admit these kids to the hospital for weeks when they get sick? That doesn't seem humane when the outcome of this disease is always death.

Shannon, USA

Sonja, Germany

I think the seizures and associated neurological issues were the most difficult to handle as a caregiver. As our son ' s GM2 progressed, he made it clear to us that his body could not handle much in the way of sensory stimulation He would get agitated going to the grocery store with the lights, sounds, and being touched He eventually struggled with temperature regulation and could not handle being outside This resulted in keeping him home where he was most comfortable at all times, but this was a huge strain on us as caregivers We have to find a way to alleviate these symptoms and also provide more respite for caregivers

Adult living with GM2: Since the age of 18, I have countless stays in psychiatric clinics due to psychosis. My increasing neurological problems were seen as a side effect of the antipsychotic drugs. At the age of 35, the neurological symptoms were so evident that I was finally sent to a medical centre for rare diseases I was finally diagnosed with LOTS there

For many adults with psychiatric disorders, the biggest problem is that many antipsychotics worsen neurological symptoms

For 2 5 years I was on a clinical trial for IB1001 that helped me well But it is not yet approved because the FDA wants another trial with placebo Tay Sachs patients can not participate

I have now lost hope and can see that my symptoms are getting worse and worse I now use a wheelchair outside and my entire body is getting weaker and weaker Getting up, walking, eating and drinking and speaking are becoming more and more difficult I am now 42 years old and I am very anxious about my life in a few years ' time

Sophia, USA

I would like to ask FDA about their plans after this meeting Will there be any changes in FDA approach to find/try treatments for ultra rare diseases? As follows from Dr Tiffs presentation, people with LOTS differ significantly Will it be possible to use patients as their own controls, especially considering that there has been a disease history study done? There are a number of general neurological drugs that have been in development, however 2 years study with placebo controls are turning majority of companies way from trying those drugs on LOTS patients Could a new system of testing be developed with a shorter (e g 6 months) with a small number of patients to try new medications? Standard clinical study as was noticed today take 7 years Patients are getting worse every day and can not wait for each drug to be tested 7 years

Name, Country Comment

Susan, USA

Vera, USA

Wendy, USA

I find I am getting very tired at doing nothing My balance and walking not great My speech is not great I would like to find out new things that are going on with new GM2 research

As someone living with LOTS, my condition is progressively getting worse and I don't have 7 years to wait for a clinical study I would like to have the ability to try medications or treatments approved for other conditions or perhaps take part in a smaller study Because the longer I wait and let things continue " as is", the greater chance I have of significant injury Please take this into consideration

Victor's diagnosis was devastating for us, but seeing the progress of his illness little by little is even more so, how he smiled less and less every day, how he stopped moving little by little, how we realized that his eyesight is getting worse and worse. How this damn disease is stealing our beautiful son from us little by little is really hard, the hardest and most painful thing in life.On his best days Víctor stays wide awake, with his eyes wide open, he makes some funny and tender noise in his own way of communicating, on his worst days he also makes some noise, but of discomfort, of pain, his heart rate is very elevated and its secretions uncontrollable Currently we feed Victor through a G tube, 24 hours a day, 35 ml/hr, 75% formula and 25% water, we do it this way because it is the only way he tolerates food, we have tried to feed him dividing it into 4 meals a day , 85ml/hr for 2 hours each meal, but unfortunately I can't tolerate it, I started to have fever, pain, and too many secretions It is very frustrating for me to see how my son ' s symptoms are progressing and getting worse and it is even more frustrating to not be able to help him Currently Víctor takes 12 medications, including 3 anticonvulsants that have really helped him control his episodes, he receives physical and occupational therapy, early stimulation, and we want to believe that in some way that helps him, even if just a little What we fear most is that Victor will reach a point where he will not be able to breathe on his own, because we would not want to have to subject him to further surgery We know and are convinced that in the future, researchers, scientists, laboratories, pharmaceutical companies will find some medicine that, although it does not cure children and patients with Tay Sachs, Sandhoff and Canavan, can at least help them reduce the symptoms, if they could. Finding some medicine that would help gradually eliminate or drain the toxic material that accumulates in the brain to reduce neurological deterioration, I think many families or all of us would try this

Wendy Tapia, Victor Sanchez's mom

Patient with infantile Tay Sachs

I am a 36-year-old mother and wife who was diagnosed with an ultra rare progressive genetic neuromuscular disease late onset Tay-Sachs LOTS at 21 years old I had never heard of the disease before my diagnosis and I didn’t know what it meant for my life.

Zoe, USA

It took me 3 years to be diagnosed after going through endless tests and doctor appointments. A muscle biopsy where I laid on an operating table unmedicated as the muscle on my right leg was sliced into as I was screaming, crying, and gripping the nurses hands From that I was misdiagnosed with Spinal Muscular Atrophy SMA and sent on to another hospital for more tests Eventually I was given one simple blood test that indicated I had late onset Tay-Sachs A few years later my eldest sister was also diagnosed with LOTS we had similar but very different major symptoms Mine being more physically related and hers more related to her mental health

Name,

Country Comment

When I look back on my childhood very simple things stick out to me as unordinary Being clumsier and less coordinated than my average peers I hated ice skating and the falling that went hand in hand with it because of the balance it required Jumping on trampolines always felt unnatural because I couldn’t bend my knees when jumping On the playground being unable to hold on strong enough to go down the fireman pole with clear memories of falling Or being able to pump my legs hard enough to go as high as everyone else on the swings. I always had terrible handwriting and difficulty gripping a pencil properly.

Can openers were difficult to use because of my hand strength. In high school when I was on the swim team it became difficult to climb out of the swimming pools and it always felt difficult to kick to my full potential Although I always found freedom in water, I knew something was wrong With friends we joked about how I couldn’t jump And how I got myself off the ground was unusual In my first year of college I started adjusting where I parked on campus so that I could avoid stairs and could avoid people seeing me go up stairs because I was struggling and using my arms to pull myself up each step Tripping became very normal thing

Zoe, USA

(cont’d)

Being able to get up became harder and harder and then impossible I lost a job after not being able to stand up from the toilet after doing a morning workout because my muscles were exhausted I stopped being able to drive because I feared for the safety of others and myself when moving my foot to and from the gas and break I stopped being able to walk without assistance in public and became reliant on a wheelchair I then stopped being able to walk without assistance in my home Living with constant anxiety if somewhere will be accessible or not And a constant fight with depression about what my life could have been and what I miss out on because of this disease. After my pregnancy I can no longer get off the toilet by myself. I have had to get a new bed that operates like a hospital bed that lowers and rises help me get in and out of the bed. Most of my days are spent sitting or laying down.

As a mom it changes how I can care for my daughter being unable to bend over to give her a bath Or simply pick her up off the ground, or run around the playground with her

The progression of LOTS has been a huge life adjustment for my husband, our daughter, and myself as the challenges are constantly changing I never thought I would be jealous of sheep But I think about the sheep that have been treated with gene therapy everyday and I just want it to be my day The day for adults with LOTS to have a real treatment that could mean life changing opportunities I go to doctors appointments and I feel like a science experiment Many doctors have heard of Tay-Sachs but won’t ever see a patient with it so they tell me I get to teach them Even in physical therapy they don’t really understand the weakness to the extremes that it affects certain muscle groups and not others I always say there isn’t anything in my life Tay-Sachs hasn’t touched

I would be a different person and have a completely different life if it weren’t for this disease I dream of just one day without Tay-Sachs and its hard to even imagine what one day of freedom physically and mentally would be. I have more hope that there will be a real treatment and cure for this disease that causes havoc in every minute of every day for those of us with LOTS and for all of our families who have been touched by this disease. We deserve the right to have the chance for science and medicine to treat and or cure this disease There isn’t any other option for us with LOTS