Miquel Vila-Perello, PhD, co-founder and CEO of SpliceBio, discusses an investigational dual adeno-associated virus (AAV) gene therapy in development for patients with Stargardt disease.

Stargardt disease is a genetic eye disorder characterized by progressive vision loss caused by abnormal accumulation of lipofuscin in the cells within the macula. Patients with Stargardt disease also have problems with night vision and color vision. It is most commonly caused by genetic changes in the ABCA4 gene but, in rare cases, may be caused by genetic changes in other genes. There are currently no approved treatments for this disease.

Difficulties in developing therapies, especially for those that address the underlying cause of Stargardt disease, are due to the size of the ABCA4 gene. As Dr. Vila-Perello explains, AAVs have limited cargo capacity and the ABCA4 gene is larger than what can fit. This causes challenges in delivering a healthy copy of the gene to patients and effectively treating their underlying disease.

SB-007 is an investigational dual AAV gene therapy designed to restore expression of a functional, full-length ABCA4 protein in the retina. A novel protein splicing platform uses two AAV serotype 8 (AAV8) vectors to overcome the size limitations of conventional AAVs, reconstituting biologically active ABCA4 through protein trans-splicing in target photoreceptor cells. SpliceBio has received Orphan Drug designation for SB-007 from the US Food and Drug Administration (FDA) and the European Commission.

In preclinical models, SB-007 demonstrated robust pharmacological activity, durable retinal expression, and a favorable safety profile.

SpliceBio is currently enrolling participants in ASTRA, a phase 1/2 multicenter, global clinical trial designed to evaluate the safety, tolerability and efficacy of SB-007. The company expects to enroll approximately 57 patients aged 12 to 65 with Stargardt disease into Part B. Part A of the study evaluated three dose levels of subretinal SB- 007 in an open-label, dose-escalation design. Part B is randomized, controlled and masked, and will evaluate two dose levels of subretinal SB-007 compared to an untreated control group, with a follow-up of 96 weeks. The primary endpoint is safety and tolerability, assessed by the incidence and severity of ocular and nonocular adverse events.

CHAPTERS
Introduction 00:00
Stargardt Disease Overview 00:39
Challenges to Effective Treatment 2:24
SB-007 Dual AAV Gene Therapy 4:13
Pre-Clinical Data 5:12
Next Steps 6:44

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Richard A. Furie, MD, Chief of the Division of Rheumatology at Northwell Health, discusses nipocalimab for the treatment of systemic lupus erythematosus (SLE).

SLE is an autoimmune disease characterized by inflammation in the connective tissues, leading to multisystem involvement and potentially significant morbidity and mortality. Genetic, immunological, endocrine, and environmental factors influence the loss of immunological tolerance against self-antigens leading to the formation of pathogenic autoantibodies that cause tissue damage through multiple mechanisms. Common signs and symptoms include severe fatigue, malaise, fever, loss of appetite, weight loss, joint pain and swelling, butterfly rash, and muscle pain and weakness.

Nipocalimab has been granted US Food and Drug Administration (FDA) Fast Track designation as a potential treatment for adults with systemic lupus erythematosus (SLE). Nipocalimab is an immunoselective investigational therapy that lowers harmful immunoglobulin G  (IgG) while preserving key immune functions.  The Fast Track designation program is designed to expedite the development and review timelines of drugs that demonstrate the potential to treat serious conditions, aiming to deliver therapeutics to patients more quickly in areas where unmet needs remain.

Following positive results from the phase 1b JASMINE clinical trial (NCT04882878), which illustrated nipocalimab’s ability to reduce SLE disease activity and potential for steroid sparing, patient enrollment for the phase 3 GARDENIA (NCT07438496) clinical trial has been initiated. GARDENIA is a randomized, double-blind, placebo-controlled, multicenter study of nipocalimab in adults with moderate to severe SLE.

CHAPTERS
Introduction 00:00
Nipocalimab Overview 00:31
JASMINE Clinical Trial 2:51
Next Steps 3:30
Safety Concerns 4:15

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Jack Johnson, Co-Founder and Executive Director of Fabry Support and Information Group (FSIG), discusses the organization’s 30 year anniversary.

Fabry disease is a rare lysosomal storage disease characterized by a deficiency in the enzyme alpha-galactosidase (alpha-GAL). Alpha-GAL helps break down a fatty acid called globotriaosylceramide (GL3). Symptoms of Fabry disease may include episodes of pain, especially in the hands and feet, clusters of small angiokeratomas, hypohidrosis, corneal opacity, and hearing loss. Internal organs, such as the kidney, heart or brain, may also be affected, leading to progressive kidney damage, heart attacks, and strokes. Fabry disease is caused by changes in the GLA gene.

2026 marks the 30th anniversary of FSIG, a patient-driven nonprofit organization dedicated to improving the lives of those affected by Fabry disease. FSIG was founded in 1996 by Mr. Johnson and his family to address the unmet needs of patients with Fabry disease in a time of diagnostic uncertainty and limited therapeutic options.

The group works with patients, caregivers, clinicians, researchers, and industry leaders on education, advocacy, and newborn screening initiatives. Their focus is on advancing awareness, research, equitable access to care worldwide, and, importantly, providing a place for patients and families to find community.

Nowadays, in an era of scientific advancement and industry innovation that has led to emerging gene-therapies and next-generation approaches, FSIG works to elevate the patient voice in informing research priorities, clinical trial design, and treatment development. FSIG hosts national conferences, regional meetings, educational webinars and peer-to-peer connections, to build relationships between patients, clinicians, and industry partners.

Through partnership with “Testing for Tots,” the organization’s newborn screening advocacy program, FSIG is expanding awareness of Fabry disease and advancing earlier diagnosis. The group also partners closely with clinicians and researchers to reduce disparities in care, particularly among women and underrecognized patient populations, ensuring that lived patient experience informs ongoing clinical and therapeutic development.

Priorities for the organization going forward include:
- Expanding newborn screening advocacy through Testing for Tots
- Strengthening patient education and peer connection opportunities
- Advancing health equity and closing gaps in diagnosis and treatment
- Encouraging sustained industry investment in innovative therapies
- Supporting collaborative research initiatives that accelerate progress

CHAPTERS
Introduction 00:00
Fabry Disease Landscape 00:32
Advice for Newly Diagnosed Patients 3:27
Patient Involvement in Clinical Trials 4:09
What Physicians Should Know 5:04
FSIG Overview 6:22
The Future of FSIG 11:31
Take Home Message 12:59

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Joanne Donavan, MD, PhD, Chief Medical Officer at Edgewise Therapeutics, discusses the MESA extension study of sevasemten for the treatment of patients with Becker muscular dystrophy (BMD).

BMD is a genetic condition characterized by a lack of working dystrophin protein resulting in the gradual damage and loss of muscle fibers in the heart and skeletal muscles. Symptoms of this disease may begin in childhood to adulthood and slowly worsen over time. Complications of BMD may include cardiomyopathy, difficulty or inability to walk, cognitive changes, kidney, lung, and liver problems, scoliosis, contractures, arrhythmia, and heart failure. BMD is caused by a genetic change in the DMD gene and primarily affects males.

Sevasemten is an investigational fast skeletal myosin inhibitor designed to protect muscle from contraction-induced damage. MESA (NCT06066580) is an open-label extension study evaluating sevasemten long-term safety, tolerability, and efficacy in adults and adolescents with BMD previously treated in sevasemten clinical trials. Patients enrolled in the extension included those previously enrolled in ARCH, CANYON/GRAND CANYON, and DUNE. Long-term data was presented at the 2026 MDA Clinical and Scientific Conference.

North Star Ambulatory Assessment (NSAA) functional scores of ARCH and CANYON trial participants treated with sevasemten remained stable after 3.5 years and 2 years, respectively. CANYON participants on placebo who rolled into the MESA study also had increasing NSAA functional scores during the first year after switching to sevasemten.

This stabilization in function contrasts with natural history data that shows once functional decline begins, its course typically continues along that downward trajectory. Multiple natural history studies in BMD report NSAA scores declining by an average of 1.0 to 1.7 points annually, equating to an expected average functional decline of 3.0 to 5.1 points over 3 years.

Additionally, in MESA, the NSAA scores observed in the sevasemten treatment arm diverged from predicted natural history declines:
- CANYON over 2 years: +0.1 improvement (treated) vs. -2.9 decline (predicted natural history)
- ARCH over 3.5 years: +0.1 improvement (treated) vs. -5.3 decline (predicted natural history)

Top-line results of the sevasemten placebo-controlled pivotal cohort, GRAND CANYON in is expected to be announced in quarter four of 2026. If data is positive, the goal is to advance sevasemten toward a marketing application to seek approval as the first targeted therapy for patients with BMD.

CHAPTERS
Introduction 00:00
Becker Muscular Dystrophy Overview 00:18
Relationship to Duchenne Muscular Dystrophy 1:20
Diagnostic Pathway 3:01
Sevasemten Overview 4:28
Clinical Trials 5:46
Starting Clinical Trials in Earlier Ages 10:35
What Physicians Should Know 12:22

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Carlos A. Bacino, MD, Professor of Molecular and Human Genetics, Baylor College of Medicine and Texas Children’s Hospital, discusses the accelerated approval of Yuviwel (navepegritide) for patients with achondroplasia.

Achondroplasia is a disorder of bone growth that prevents the changing of cartilage to bone, particularly in the long bones of the arms and legs. It is characterized by dwarfism, limited range of motion at the elbows, macrocephaly, small fingers, and normal intelligence. Achondroplasia can cause health complications such as apnea, obesity, recurrent ear infections, and lordosis. More serious problems include spinal stenosis and hydrocephalus. Some patients may have delayed motor development early on, but cognition is normal. Achondroplasia is caused by genetic changes in the FGFR3 gene.

The US Food and Drug Administration (FDA) recently granted Accelerated Approval to navepegritide for the treatment of children 2 years of age and older with achondroplasia. As Dr. Bacino explains, this is the first and only once-weekly treatment and it is indicated to increase linear growth in patients with open epiphyses and the only treatment to provide continuous systemic exposure to C-type natriuretic peptide (CNP) over the weekly dosing interval.

Navepegritide is a prodrug of CNP administered once weekly, designed to provide continuous exposure of active CNP to receptors on tissues throughout the body to counteract the overactive FGFR3 signaling in achondroplasia.

The approval was largely based on the safety and efficacy data from three randomized, double-blind, placebo-controlled clinical trials and up to three years of open-label extension data. The pivotal ApproaCH Trial data is available in JAMA Pediatrics.

Navepegritide is expected to be available in the US in the second quarter of 2026. Continued approval for this indication, which was based on an improvement in annualized growth velocity (AGV), may be contingent upon verification and description of clinical benefit in confirmatory trials.

Alongside this approval, the FDA also issued a Rare Pediatric Disease Priority Review Voucher (PRV), which confers priority review to a subsequent drug application that would not otherwise qualify for priority review. This program is designed to encourage development of new drugs and biologics for the prevention or treatment of rare pediatric diseases.

CHAPTERS
Introduction 00:00
Achondroplasia Overview 00:44
Disease Nomenclature 3:17
Diagnostic Pathway 4:27
Treatment With CNPs 7:22
Navepegritide Overview 8:39
Clinical Trial Data 9:40
Ongoing Research 12:29

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Paul Romness, CEO of OS Therapies, discusses the Plausible Mechanism Framework draft guidance and how it will affect the approval process of OST-HER2 LM for the treatment of osteosarcoma.

Osteosarcoma is the most common type of bone cancer, typically occurring in adolescence. Although osteosarcoma tends to occur in the larger bones, such as the shin, thigh, and upper arm, it can occur in any bone. A number of variants of osteosarcoma exist, including conventional types (osteoblastic, chondroblastic, and fibroblastic), telangiectatic, multifocal, parosteal, and periosteal. The exact cause of osteosarcoma is not known, however, at least one gene has been linked to increased risk.

The OST-HER2 LM vaccine is an immunotherapy that targets HER2-positive cancers such as osteosarcoma, breast, and esophageal cancer. It is designed to activate the immune system, triggering T cells to seek out and destroy cancer cells. The immunotherapy shows potential in preventing or eliminating recurrences of osteosarcoma, particularly through translational research and trials involving canines diagnosed with the disease. OST-HER2 LM is currently under review via the US Food and Drug Administration’s (FDA) Plausible Mechanism Framework.

The FDA’s Plausible Mechanism Framework:

The US FDA’s Center for Biologics Evaluation and Research and Center for Drug Evaluation and Research recently issued the Plausible Mechanism Framework draft guidance. The guidance is designed for sponsors seeking approval for targeted individualized therapies by generating substantial evidence of effectiveness and safety when randomized controlled trials are not feasible due to small patient populations. The goal is to remove barriers and exercise regulatory flexibility to encourage scientific advances and the delivery of more cures and meaningful treatments for patients suffering from rare diseases.

The guidance focuses on therapies that target a specific genetic, cellular or molecular abnormality and are designed to address the underlying cause of disease. Key criteria include:
Identifying the disease-causing abnormality.
Demonstrating the therapy targets the root cause or proximate biological pathway.
Relying on well-characterized natural history data in untreated patients.
Confirming successful target drugging or editing.
For traditional approval, therapies should demonstrate improvement in clinical outcomes, disease course, or biomarkers if they are established to predict clinical benefit.

OS Therapies has an upcoming Type B meeting with the FDA to discuss biomarker data and accelerated approval of OST-HER2 LM. Following that meeting, Mr. Romness noted that there are plans for a phase 3 global trial to start by September 2026. In addition to being involved in the Plausible Mechanism Framework, OST-HER2 LM has also received Orphan Drug, Fast Track, and Rare Pediatric Disease Designations.

CHAPTERS
Introduction 00:00
Osteosarcoma Overview 00:53
OST-HER2 LM Immunotherapy 3:09
FDA’s Plausible Mechanism Framework 4:19
Next Steps 6:44

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Merlin G. Butler, MD, Medical Geneticist and Professor, Departments of Psychiatry & Behavioral Sciences and Pediatrics, University of Kansas Medical Center, Kansas City, and one of the pioneers in Prader–Willi syndrome research, discusses the clinical features of this very rare disease and the critical importance of early identification.

Prader–Willi syndrome was first reported in 1956, and deletions in chromosome 15 were first identified in the 1980s. Dr. Butler has been working on the genetics of Prader–Willi syndrome since that decade.

Dr. Butler said that Prader–Willi syndrome was the first example of a disorder caused by “genetic imprinting,” in which it matters whether genes are contributed by the mother or the father. In 70% of the cases of this disorder, the father’s contribution is missing from chromosome 15q13, and 25% of cases are the result of both copies of chromosome 15 being from the mother (referred to as “disomy”).

Babies born with this genetic anomaly have severe hypotonia, and they have no interest in sucking or feeding. They often have decreased muscle mass and energy. “These infants look like they have a major problem at birth,” stated Dr. Butler. They need to be tube-fed. Once a genetic cause is suspected, Prader-Willi syndrome is quickly diagnosed; it is a very rare disease that also has very unique features. Pediatricians may see only one of these patients every 10 years. Therefore, according to Dr. Butler, “it is the parents who oftentimes make the diagnosis, through what they have seen on the Internet, prompting genetic testing.”

Despite their problems with feeding in the neonatal period, infants with Prader–Willi syndrome will begin to gain an interest in feeding by around age 2 to 3 years. By age 6 years, they develop hyperphasia. “Once their appetite is turned on,” he said, “it is never off.” Uncontrolled, this results in obesity and life-threatening conditions, such as type 2 diabetes and stomach rupture.

Early identification is key, and determining the genetic subtype is extremely important to building a multidisciplinary care team. There are seven different genetic subtypes, which can impact outcomes and management. Typically, the care team will include the medical geneticist and genetic counselors, endocrinologists (to manage the use of growth hormone and diabetes-related treatment), dietitians to manage and monitor caloric intake, mental health experts to address behavioral issues and the risk of self-injury, gastroenterologists, and potentially even sleep medicine professionals. The specialists comprising the care team will change over the patient’s lifespan; occupational therapy and speech therapy may well be required as the patient ages.

The treatment of hyperphagia associated with Prader–Willi syndrome, the number 1 issue, is a particularly active area of research. The idea is to avoid the onset of obesity, which can lead to most of the comorbidities and complications.

CHAPTERS
Introduction 00:00
Prader-Willi Syndrome Overview 00:48
Diagnostic Odyssey 6:30
Multidisciplinary Approach to Management 8:42
Emerging Therapies and Research 10:21
Key Message for Clinicians 11:58
Advice for Newly Diagnosed Families 17:37

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Cem Akin, MD, PhD, Professor, Allergy and Immunology at the University of Michigan, discusses with CheckRare systemic mastocytosis, and the results of the phase 2 PIONEER study, which tested the tyrosine-kinase inhibitor avapritinib (Ayvakit) against placebo in symptomatic patients. These results were presented at the 2026 AAAAI meeting in February 2026.

Mastocytosis is an incurable, heterogeneous disorder that is classified into two forms: cutaneous mastocytosis (seen in children) and systemic mastocytosis (mainly seen in adults). The systemic form is associated with an acquired (not inherited) genetic variant called KIT D816V, which is found in stem cells of more than 95% of affected patients.

Less than 15% of patients with systemic mastocytosis have advanced disease; the rest have nonadvanced types. Advanced disease is associated with decreased life expectancy and survival, whereas the other forms are not. However, patients with the more-common indolent or smoldering forms present with chronic symptoms (e.g., skin lesions, gastrointestinal and neurocognitive symptoms, osteopenia/osteoporosis). These symptoms are most often managed with antihistamines, leukotriene inhibitors, and mast-cell stabilizers. Due to the heterogeneity of the disorder, symptom burden may be relatively low or great; it can truly affect patients’ quality of life, daily activities, social life, and personal relationships.

Dr. Akin described the phase 2 PIONEER study, a double-blind, placebo-controlled investigation to evaluate the safety and efficacy of a selective tyrosine-kinase inhibitor avapritinib, which targets the KIT mutation. PIONEER had three components: (1) a dose-finding investigation, which settled on 25 mg/day orally as the primary dose tested; (2) the 6-month, randomized, placebo-controlled trial in patients with symptoms that were inadequately controlled with other medications; and (3) a long-term (follow-up is ongoing, up to 5 yr), open-label extension trial, which included switching the patients who receive placebo previously to active treatment with avapritinib.

The randomized, controlled portion of PIONEER proved that the avapritinib was clinically effective, as shown by various primary and secondary endpoints, including clearance or clinical improvement in skin lesions, reduction in symptoms scores, lower mast-cell load, and improvements in other biologic markers of the disease. Dr. Akin pointed out that the extension portion of PIONEER showed that these benefits were durable for up to 5 years with continued use.

In terms of safety, no additional safety concerns were observed through the extended follow-up phase. Peripheral and periorbital dema was seen in about 10% of patients (not serious, and no patient discontinued as a result).

In the open-label extension, a group of patients were allowed to increase their dose to 50 mg/mg based on their symptom burden, mast-cell markers, and the perceived patient response to the medication. Patients with the higher dose continued to improve symptomatically, with no additional safety concerns (their follow-up was up to 1 yr at this point).

Dr. Akin said that the PIONEER study provided confidence that the mutation is in fact the main driver of the disease, and if we can suppress expression of the mutation, we can change the outcome of systemic mastocytosis. “When disease markers and symptoms improve, we expect the response to be durable,” he stated. “Avapritnab kills the stem cells carrying the mutation, and when therapy is stopped, we expect that the systemic mastocytosis symptoms and markers will return. It is important to make the point that this is a chronic therapy.” PIONEER provided the reassurance that avapritinib is safe and effective over the long term.

CHAPTERS
Introduction 00:00
Mastocytosis Overview 00:42
Burden of Disease 2:30
PIONEER Clinical Trial Design 3:37
Four-Year Follow-Up Data 5:13
Durability of Symptom Improvements 8:40
GI Symptoms, Bone Health, and Other Manifestations 9:31
Effect of Ayvakit on Underlying Disease 11:58
Selection of Patients 13:39
Unanswered Questions for Future Studies 17:12

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CheckRare conducted a joint interview with two key opinion leaders in spinal muscular atrophy (SMA), Kristin J. Krosschell, DPT, MA, Professor of Physical Therapy and Human Movement Sciences, Pediatrics and Nancy L. Kuntz, MD, Child Neurologist and Professor, Pediatrics (Neurology and Epilepsy), both at Ann and Robert H. Lurie Children's Hospital of Chicago & Northwestern Feinberg School of Medicine. Dr. Kuntz is also Medical Director of the Mazza Foundation Neuromuscular Disorders Program, the PPMD Duchenne Care Center and the MDA Care Center at the Children’s Hospital. In this interview, Drs. Krosschell and Kuntz describe how disease-modifying therapies have changed the landscape of SMA management, discuss their study on the impact of newborn screening and early treatment, and reflect on some of the challenges facing SMA patient care today.

Summary copy:
The ability of providers to diagnose, treat, and manage SMA is dramatically different than 10 years ago, said Dr. Kuntz. “Not only are some of these new treatments very effective in improving outcomes, but timing of their administration is critical.” In fact, those infants who receive a confirmed genetic diagnosis of SMA before symptoms are apparent, and who begin treatment have better outcomes than infants who only receive these new therapies after the emergence of symptoms. Newborn screening is extremely effective, identifying 95% to 97% of all infants with SMA.
Dr. Krosschell added that the objective of their latest study was to determine what difference early treatment meant to motor function development and progression. The investigation comprised 21 infants who received care at the Ann and Robert H. Lurie Children’s Hospital in Chicago. All were diagnosed at younger than 3 months of age. Among this study group were three infants who were diagnosed with SMA prenatally and received treatment within the first 3 weeks postdelivery.
Based on the results of the CHOP INTEND, TIMPSI, and WHO Motor Milestone surveys, all infants demonstrated gross motor function improvements, and their progression followed a normative development curve, but at a slightly lower level.
It appears that increasing access to genetic testing and reducing the time to obtain testing are very important variables in obtaining optimal outcomes in SMA. They acknowledge that if the fetus cannot be tested prior to delivery, testing within the first 2 weeks of delivery is crucial.
Now that prenatal diagnosis is possible, work is just beginning on whether any specific prenatal care may be additionally useful in these patients. Drs. Kuntz and Krosschel acknowledge that the individual treatments now available are not curative, but knowing whether a particular therapy would be appropriate upon delivery would be time-saving. For example, some mothers may have antibodies to the viral vector used in gene therapy, which may help better guide treatment choices for the baby.
Dr. Krosschel added that we now know it is beneficial to treat SMA as early as possible. “We need longer-term studies in real-world settings to identify where there may be treatment delays and gaps. We need to understand what slows down the process” of getting these SMA-confirmed patients into treatment.
Dr. Kuntz said that based on the research and presentations at the MDA meeting, “It’s an incredibly exciting time. It’s not the end of the journey, only the beginning.”




CHAPTERS
Introduction 00:00
Understanding the Current Landscape of SMA 1:12
Effects of Disease Modifying Treatments 2:35
Real World Data of Early Treated Infants 2:59
The Future of SMA Screening and Treatment 13:22
Take Home Message 19:32

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