Alan Percy, MD, Pediatric Neurologist at the University of Alabama at Birmingham, discusses results from the DAFFODIL study evaluating long-term safety of trofinetide in girls ages two to four years with Rett syndrome.

Rett syndrome is a neurodevelopmental condition primarily affecting girls. Patients with the disease appear to have normal psychomotor development during the first 6 to 18 months of life. This is followed by a developmental "plateau," and then rapid regression in language and motor skills. Additional signs and symptoms may include:

- Repetitive, stereotypic hand movements
- Fits of screaming and inconsolable crying
- Autistic features
- Panic-like attacks
- Teeth grinding
- Episodic apnea and/or hyperpnea
- Gait ataxia and apraxia
- Tremors
- Seizures
- Slowed head growth

Classic Rett syndrome is most commonly caused by genetic changes in the MECP2 gene and is usually inherited in an X-linked dominant manner.

The DAFFODIL study (NCT04988867) is an open-label study evaluating the long-term safety of trofinetide in girls ages two to four years with Rett syndrome. Trofinetide is a synthetic analog of the N-terminal tripeptide of insulin-like growth factor 1. It was approved by the U.S. Food and Drug Administration for the treatment of Rett syndrome in patients 2 years and older in 2023.

The key finding from this study was a safety profile in children ages two to four years of age similar to that observed in patients ages five years of age and older in the LAVENDER, LILAC-1, and LILAC-2 trials. Diarrhea and vomiting were the most common treatment-emergent adverse events, but were of mild to moderate severity. Additionally, the use of a diarrhea management plan (discontinuation of laxatives and initiation of increased fiber) led to a lower discontinuation rate caused by diarrhea, with only one discontinuation.

Other endpoints supported symptom improvement as observed in scores of CGI-I scale, CaGI-I scale, and change from baseline in ICND-QoL. Caregivers also noted significant improvement in patients’ ability to say new words, make eye contact, and use of hands.

Chapters:
Introduction 00:00
Trofinetide Overview 00:43
DAFFODIL Study 1:22
Symptom Improvement 4:04
New Learnings 5:14

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Alessandra Maleddu, MD, Sarcoma Specialist at the University of Colorado, discusses the misdiagnosis of desmoid tumors and provides some resources for patients.

Desmoid tumors are rare, benign, locally invasive, soft tissue tumors. They are commonly associated with a high recurrence rate, but with no metastatic potential. The tumors and tendril-like growths that they cause may be located anywhere in the body. Common symptoms include long-lasting pain, loss of physical function, and disfigurement. These symptoms can also often lead to anxiety, depression, and negative thoughts.

As Dr. Maleddu explains, women are two to three times more likely to be diagnosed with a desmoid tumor than men. The most common age of diagnosis is between 20 to 44 years of age. Due to the varying presentation of symptoms, desmoid tumors are often misdiagnosed, with an average misdiagnosis rate of 30% to 40%.

Recently, SpringWorks Therapeutics has updated their desmoid tumors website to include more resources for patients. This includes a doctor discussion guide and care option guide that can help patients find sarcoma centers, physicians, and treatment options best suited to their needs.

Chapters:
Introduction 00:00
Desmoid Tumors Overview 00:43
Diagnostic Journey 1:48
Importance of Early Diagnosis 3:18
Advice for Patients and Families 4:22
Current Management 5:07
Updated Resource Guide 6:38

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Kelly Guillo, Board Member of the Prader-Willi Syndrome Association in Georgia, discusses Prader-Willi syndrome (PWS) from the perspective of a caregiver.

PWS is a rare genetic condition that affects many parts of the body but its most dominant symptom is overwhelming hyperphagia. Infants with PWS also have severe hypotonia, feeding difficulties, slow growth, short stature, hypogonadism, developmental delays, cognitive impairment, and distinctive behavioral characteristics such as temper tantrums, stubbornness, and obsessive-compulsive tendencies. PWS is caused by missing or non-working genes on chromosome 15.

As noted earlier, the most prominent and debilitating symptom of PWS is hyperphagia, a chronic, intense, and insatiable feeling of hunger. This symptom in particular causes a variety of challenges in the everyday lives of patients and their families. Some of these challenges include:

- Persistent talking about or seeking food
- Bargaining, manipulating, or sneaking behavior to obtain more food
- Emotional distress when denied food
- Foraging or stealing food
- Risk of extreme overeating, leading to severe and life-threatening issues like gastric rupture

In addition to being a board member of the Georgia PWSA, Mrs. Guillo is also the parent of a daughter, Clementine, who has PWS. She shares how she and her family navigate life with PWS and how important it is to find a community of people who have been through similar experiences. This found community is a key element of the PWSA and their work of support and advocacy for patients with PWS and their families.

Chapters:
Introduction 00:00
Prader-Willi Syndrome Overview 00:54
Family Impact of Diagnosis 4:56
Advocacy Groups 6:55
Treatment Options and Clinical Trials 7:47
Measuring Hyperphagia 9:51

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Bruce Leuchter, MD, Co-founder and CEO of Neurvati Neurosciences and GRIN Therapeutics, discusses the Breakthrough Therapy designation for radiprodil for treatment of patients with GRIN-related neurodevelopmental disorders.

GRIN-related neurodevelopmental disorders are a family of rare genetic conditions caused by pathogenic mutations in the GRIN genes. These disorders are characterized by childhood-onset epilepsy, developmental delay, movement disorders, and features of autism spectrum disorder. The symptoms a child experiences and the severity of the disorder can vary widely. 

Radiprodil is a selective, potent negative allosteric modulator of the N-methyl-D-aspartate (NMDA) receptor subtype 2B (NR2B or GluN2B). The investigational drug has been shown to modulate GluN2B-NMDA and have an antiseizure effect.

Recently, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to radiprodil for the treatment of seizures associated with GRIN-related neurodevelopmental disorder with gain-of-function mutations. This designation grants access to the benefits of Fast Track designation alongside FDA guidance from senior management of drug development programs.

The Breakthrough Therapy designation followed positive data from the phase 1b Honeycomb clinical trial of radiprodil in patients with GRIN-related neurodevelopmental disorders. This included a 86% reduction in seizure frequency from baseline in patients with countable motor seizures treated with radiprodil versus anti-seizure medications. This frequency reduction was consistent across GRIN genotypes with gain-of-function variants.

Plans to initiate a phase 3 pivotal trial for radiprodil are set for early to mid-2025. The goal will be to evaluate the impact of targeted treatment on core aspects of the disease including seizures, behavioral abnormalities and functional outcomes.

Chapters:
Introduction 00:00
GRIN-Related Neurodevelopmental Disorders 1:18
Radiprodil Overview 3:34
Breakthrough Therapy Designation 4:57
Phase 3 Clinical Trial 7:17

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Steven Pipe, MD, Professor of Pediatrics and Pathology at the University of Michigan, discusses positive follow-up results in patients with hemophilia B treated with Hemgenix (etranacogene dezaparvovec-drlb).

Hemophilia B is a rare bleeding disorder that slows the blood clotting process. People with this disorder experience prolonged bleeding or oozing following an injury or surgery. In severe cases of hemophilia, heavy bleeding occurs after minor injury or even in the absence of injury. Serious complications can result from bleeding into the joints, muscles, brain, or other internal organs. Hemophilia B is caused by genetic changes in the F9 gene.

Etranacogene dezaparvovec-drlb is a AAV5 vector gene therapy that reduces the rate of abnormal bleeding in patients with hemophilia B by enabling the production of factor IX. It was approved by the U.S. Food and Drug Administration (FDA) as the first gene therapy for treatment of hemophilia B.

The HOPE-B clinical trial is an ongoing, phase 3, multinational, open label, single-dose, single-arm study evaluating the safety and efficacy of etranacogene dezaparvovec-drlb in adult patients with hemophilia B. The study enrolled 54 patients, 51 of which completed four years of follow-up.

The primary endpoint was annualized bleeding rate (ABR) 52 weeks following achievement of stable factor IX expression compared with the six-month lead-in period. The mean adjusted ABR for all bleeds was reduced by about 90% from lead-in compared to year four. Additionally, joint bleeds were reduced from a mean ABR of 2.34 at lead-in to 0.09 at year four.

Secondary endpoints included assessment of factor IX activity. Mean factor IX levels were 41.5 IU/dL at year one, 36.7 IU/dL at year two, 38.6 IU/dL at year three and 37.4 IU/dL at year four post-infusion. In year four, 94% of patients were able to remain free of continuous prophylaxis treatment.

No serious treatment-related adverse events were observed. The most common adverse event was increase in alanine transaminase.

Chapters:
Introduction 00:00
HOPE-B Clinical Trial Results 00:41
Next Steps 15:58

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Takayuki Shirakawa, PhD, Research Scientist at Mitsubishi Tanabe Pharma, discusses the effects of LRSAM1 on TDP-43 in patients with amyotrophic lateral sclerosis (ALS).

ALS, also referred to as "Lou Gehrig's disease," is a motor neuron disease that leads to muscle control and movement problems. There are various types of ALS that are distinguished by symptoms and, in some cases, genetic causes. Early symptoms may include muscle twitching, cramping, stiffness, or weakness, slurred speech, and/or difficulty chewing or swallowing. As the disease progresses, people become weaker and are eventually wheelchair-dependent.

Trans-activation response DNA-binding protein of 43 kDa (TDP-43) is a major component of ALS. The protein is responsible for mRNA and DNA binding, regulating mRNA splicing, stability, and translation, as well as gene transcription. As a possible driver of ALS pathophysiology, targeting this protein is thought to be a beneficial therapy pathway.

The goal of the study was to evaluate the effects of LRSAM1 on TDP-43 pathophysiology and cytotoxicity in patients with ALS. LRSAM1 causes the degradation of cytoplasmic TDP-43, reducing neuronal toxicity.

It was observed that LRSAM1 co-localizes with TDP-43 in neurons of postmortem human spinal cords. In patients with iPSC-derived neurons, LRSAM1 was able to improve TDP-43 pathophysiology, exert neuroprotective effects, and induce the degradation of cytotoxic C-terminal fragments of TDP-43.

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Daniel Lewi, Founder of the CATS Foundation, and Kathleen Flynn, CEO of the National Tay-Sachs & Allied Diseases Association (NTSAD), discuss an industry-advocacy collaboration to optimize clinical trial design through a patient-centric approach.

An estimated 30% of clinical trials fail due to design flaws such as inappropriate endpoints, poorly defined patient populations, and unaddressed patient needs. This is especially a challenge in the rare disease space where patient populations are smaller and more diverse, as well as difficulties defining adequate trial endpoints. This study aimed to collaborate with global advocacy groups in order to optimize clinical trial design.

By gathering data on patient perspectives, the goal was to effectively integrate this feedback into clinical trial design to ensure both unmet patient needs and scientific validity. Relationships were built through focus groups with patients and meetings with advocacy leaders to discuss real world experiences with trial eligibility, endpoints, and duration.

The collaborative approach of this study aided in increasing the transparency and relationship between companies and the patient community, better aligning mutual goals. By considering and integrating patient perspectives, the risk of clinical trial failing can be reduced, therefore improving the chances of successful outcomes.

Chapters:
Introduction 00:00
Tay-Sachs Disease Overview 1:04
Challenges of Treatment 2:26
WORLDSymposium Presentation 3:41
Take Home Message 7:52
Advice for Newly Diagnosed Families 8:41

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Reena Sharma, MD, Adult Metabolic Medicine at Salford Royal Hospital and University of Manchester, discusses plans for a phase 3 clinical trial evaluating FLT201 in patients with Gaucher disease.

Gaucher disease refers to a rare group of inherited metabolic diseases in which harmful amounts of lipids accumulate in various cells and tissues in the body. Signs and symptoms vary widely among affected individuals and may include skeletal disorders, hepatosplenomegaly, liver malfunction, anemia, low platelet counts, bone problems, and neurological problems. There are different types of Gaucher disease classified according to specific features and severity. Gaucher disease type 1 is the most common form. It is caused by genetic changes in the GBA gene.

FLT201 is an investigational adeno-associated virus (AAV) gene therapy in clinical trials for a potential one-time treatment for Gaucher disease. The treatment uses AAVS3 capsid to deliver GCase85, a longer-acting version of the deficient enzyme causing this disease.

The completed phase 1/2 GALILEO-1 clinical trial showed improvements in key biomarkers and clinical assessments such as reductions in the toxic buildup of substrate and a favorable safety and efficacy profile. Additionally, durable reductions were observed in glucosylsphingosine (lyso-Gb1), maintenance of normal hemoglobin levels, and sustained improvements or maintenance of platelet counts, spleen, and liver volume.

A phase 3 trial is supported by positive feedback from the U.S. Food and Drug Administration (FDA) in the end-of-phase 2 meeting. FLT201 faces the opportunity for accelerated approval based on the reductions in lyso-Gb1. Full approval would be based on the primary endpoint of maintenance or improvement in hemoglobin at one year in the phase 3 study. This study is expected to start in the second half of 2025.

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Majdolen Joleen Istaiti, Clinical Study Coordinator, Gaucher Unit at Shaare Zedek Medical Center, discusses insights into the cancer risk associated with Gaucher disease.

Gaucher disease refers to a rare group of inherited metabolic diseases in which harmful amounts of lipids accumulate in various cells and tissues in the body. Signs and symptoms vary widely among affected individuals and may include skeletal disorders, hepatosplenomegaly, liver malfunction, anemia, low platelet counts, bone problems, and neurological problems. There are different types of Gaucher disease classified according to specific features and severity. Gaucher disease type 1 is the most common form. It is caused by genetic changes in the GBA gene.

Past studies looking at the cancer risk associated with Gaucher disease have presented conflicting evidence. Some indicate an increased risk while others do not. Understanding this risk is essential for handling patient care and genetic counselling effectively.

The study presented at WORLDSymposium 2025 analyzed cancer risk in 709 patients with Gaucher disease over more than 30 years. From this cohort, 64 were diagnosed with cancer, 23 of which were diagnosed before or at the time of their first visit, while 41 patients developed cancer. The risk of cancer was associated with age. No association was found with sex, splenectomy, or Gaucher disease-specific therapies.

The standard incidence ratio (SIR) in patients with Gaucher compared to the Israel National Cancer Registry was 0.8. Multiple myeloma and non-Hodgkin lymphoma had significantly elevated SIR of 6.45 and 2.19, respectively.

Overall, no overall increased cancer risk was observed in patients with Gaucher disease. However, certain cancers, such as multiple myeloma and non-Hodgkin lymphoma should be closely monitored in these patients.

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