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João Gonçalves, PhD – Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

Derralynn Hughes, BM BCh – Professor, Experimental Hematology, Lysosomal Disorders Unit, Royal Free London NHS Foundation Trust and University College London, London, UK

Eric Wallace, MD – Professor of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA

The management of Fabry disease continues to evolve as clinicians gain deeper insight into disease biology and as new therapeutic approaches expand the treatment landscape. In this expert-led discussion, faculty provide a comprehensive overview of Fabry disease—from underlying pathophysiology to clinical variability and emerging treatment strategies—highlighting both progress and persistent challenges in care.

Understanding Disease Burden and Heterogeneity
Fabry disease is an X-linked lysosomal storage disorder caused by deficiency of the enzyme α-galactosidase A. This leads to progressive accumulation of globotriaosylceramide (Gb3) and its derivative lyso-Gb3 across multiple organ systems. The result is a highly heterogeneous disease with manifestations that may include renal dysfunction, cardiac involvement, neuropathic pain, and cerebrovascular complications.

A key theme throughout the discussion is the variability in disease presentation. While classic Fabry disease often presents earlier in life with more severe symptoms, later-onset variants may primarily affect the heart or kidneys and can remain undiagnosed for years. This heterogeneity complicates both diagnosis and management, requiring clinicians to maintain a high index of suspicion—particularly in patients with unexplained left ventricular hypertrophy, proteinuria, or early stroke.

The Challenge of Delayed Diagnosis
Delayed diagnosis remains a significant barrier to optimal outcomes. Because Fabry disease symptoms often overlap with more common conditions, patients may experience years—or even decades—of misdiagnosis before receiving appropriate evaluation.

Panelists emphasized the importance of increased awareness among healthcare providers, particularly cardiologists, nephrologists, and neurologists who are most likely to encounter Fabry-related complications. Family screening and genetic testing also play a critical role, given the hereditary nature of the disease.

Early diagnosis is not simply academic—it has direct implications for treatment. Initiating therapy before irreversible organ damage occurs is essential to preserving long-term function.

Treatment Landscape: Enzyme Replacement and Beyond
Enzyme replacement therapy (ERT) remains a cornerstone of Fabry disease management. By supplementing deficient α-galactosidase A, ERT aims to reduce substrate accumulation and slow disease progression.

However, the panel highlights several limitations associated with traditional ERT approaches. These include infusion burden, variability in tissue penetration, and the potential development of anti-drug antibodies, which may impact treatment efficacy.

Emerging Therapies and Innovation
One of the most important developments in Fabry disease is the emergence of therapies designed with enhanced stability and longer half-life, aimed at improving clinical durability and patient convenience. These therapies reflect a broader trend toward “rational design,” where treatments are engineered to optimize performance within the body.

In addition to improved ERTs, gene therapy represents a promising frontier. By enabling sustained endogenous production of α-galactosidase A, gene-based approaches have the potential to transform Fabry disease from a chronically managed condition into one that may be treated with a single intervention. While still under investigation, early data are encouraging.

The panel also discussed the importance of biomarkers, particularly lyso-Gb3, in monitoring disease activity and treatment response. Biomarkers are increasingly being used to guide clinical decision-making and assess therapeutic effectiveness over time.

Managing Multisystem Disease
Effective management of Fabry disease requires a multidisciplinary approach. Given the multisystem nature of the condition, coordination among specialists is essential to address the full spectrum of disease manifestations.

Renal monitoring is particularly important, as kidney disease is a major contributor to morbidity. Similarly, cardiac imaging and evaluation are critical for detecting and managing hypertrophic cardiomyopathy and arrhythmias. Neurologic assessment is also necessary, given the increased risk of stroke and transient ischemic events.

The panel emphasized that treatment decisions should be individualized, taking into account disease severity, organ involvement, and patient-specific factors. There is no single treatment pathway that applies to all patients.

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João Gonçalves, PhD – Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

Derralynn Hughes, BM BCh – Professor, Experimental Hematology, Lysosomal Disorders Unit, Royal Free London NHS Foundation Trust and University College London, London, UK

Eric Wallace, MD – Professor of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA

The treatment landscape for Fabry disease continues to evolve as next-generation enzyme replacement therapies (ERTs) aim to address longstanding limitations in durability, tolerability, and clinical outcomes. In this expert discussion, faculty highlight the clinical rationale and emerging data supporting the use of pegunigalsidase alfa as a novel approach to disease management.
Fabry disease is caused by a deficiency of α-galactosidase A, leading to the accumulation of glycosphingolipids in multiple organ systems, including the kidneys, heart, and nervous system. This progressive buildup drives significant morbidity, with renal and cardiovascular complications representing major contributors to long-term outcomes.

A Next-Generation Approach to Enzyme Replacement
Pegunigalsidase alfa is a PEGylated, recombinant form of α-galactosidase A designed to enhance stability and prolong circulation time. This “bio-better” approach to ERT reflects a shift toward optimizing how therapies behave in vivo, rather than simply replacing the deficient enzyme.
By extending half-life and maintaining sustained enzyme activity, pegunigalsidase alfa aims to improve tissue exposure and reduce fluctuations between infusions. This is particularly relevant in a chronic disease like Fabry, where consistent substrate clearance is critical to slowing disease progression.

Approved for use in adults, the therapy is administered via intravenous infusion and is intended for long-term disease management.

Clinical Data and Real-World Relevance
Emerging clinical data suggest that pegunigalsidase alfa may provide durable disease control, particularly in stabilizing renal function—one of the most clinically meaningful endpoints in Fabry disease. Long-term observations indicate that patients treated with the therapy can maintain relatively stable kidney function over time, with a favorable safety profile.

Additional studies have demonstrated reductions in key biomarkers, including lyso-Gb3, supporting the therapy’s biological activity and its role in reducing disease burden. Early-phase and Phase 3 data also suggest potential benefits in patients who transition from other ERTs, highlighting its relevance in real-world clinical scenarios.

Importantly, the discussion emphasizes that these outcomes are not solely driven by efficacy, but also by improved pharmacokinetics and tolerability—factors that directly influence long-term adherence and treatment success.

Addressing Limitations of Traditional ERT
While conventional ERTs have transformed Fabry disease care, challenges remain. These include infusion burden, variability in tissue uptake, and the development of anti-drug antibodies, which may impact treatment response.

Pegunigalsidase alfa is designed to mitigate some of these limitations through its molecular structure and extended half-life. Panelists note that this may translate into more consistent enzyme activity and potentially improved patient experience, although continued real-world data will be critical in validating these advantages.

Positioning Within the Evolving Treatment Landscape
As new therapies emerge—including chaperone therapies and gene-based approaches—clinicians are increasingly faced with complex treatment decisions. Pegunigalsidase alfa represents an important addition to the therapeutic toolkit, particularly for patients who may not be optimally managed on existing therapies.

The panel underscores the importance of individualized treatment strategies, taking into account disease severity, organ involvement, and patient-specific factors. In this context, therapy selection is becoming less about a single standard of care and more about matching the right treatment to the right patient.

Looking Ahead
The development of pegunigalsidase alfa reflects a broader trend in rare disease therapeutics: leveraging rational design to improve clinical performance and patient outcomes. As more data become available, its role in long-term Fabry disease management will continue to be refined.
For clinicians, the key takeaway is clear—innovation in ERT is not only expanding treatment options, but also redefining expectations for disease control. In a condition as complex and heterogeneous as Fabry disease, these advances represent meaningful progress toward more durable and personalized care.

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João Gonçalves, PhD – Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

Derralynn Hughes, BM BCh – Professor, Experimental Hematology, Lysosomal Disorders Unit, Royal Free London NHS Foundation Trust and University College London, London, UK

Eric Wallace, MD – Professor of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA

As the treatment landscape for Fabry disease continues to evolve, next-generation enzyme replacement therapies (ERTs) are aiming to address key limitations of earlier approaches. In this expert discussion, faculty examine the clinical role of pegunigalsidase alfa and its potential to improve long-term disease management through enhanced pharmacologic design.

Fabry disease is driven by deficiency of α-galactosidase A, resulting in progressive accumulation of glycosphingolipids and multisystem involvement, particularly affecting renal, cardiac, and neurologic function. While traditional ERTs have significantly improved outcomes, challenges such as infusion burden, immunogenicity, and variability in response remain.

A Rationally Designed ERT
Pegunigalsidase alfa (Elfabrio) is a PEGylated recombinant α-galactosidase A engineered to improve stability and prolong circulation time. Pegunigalsidase alfa This design enables sustained enzyme activity, with the goal of maintaining more consistent substrate clearance between infusions.

Experts in the discussion emphasize that this represents a shift from simple enzyme replacement toward optimizing pharmacokinetics and tissue exposure—an important consideration in a lifelong disease requiring chronic therapy.

Clinical Impact and Renal Outcomes
A major focus of the discussion is renal disease progression, a key determinant of morbidity in Fabry disease. Data presented highlight that patients treated with pegunigalsidase alfa demonstrate stabilization of kidney function over time, particularly when therapy is initiated before advanced damage occurs.

In addition to renal outcomes, reductions in biomarkers such as lyso-Gb3 support the therapy’s biological activity and its role in addressing underlying disease burden.

Dosing Flexibility and Patient-Centered Care
Another important consideration is treatment burden. Traditional ERTs are typically administered every two weeks, which can be challenging for patients over the long term. Emerging data suggest that pegunigalsidase alfa may allow for extended dosing intervals in certain patients, potentially improving convenience and adherence.

The panel highlights that reducing treatment burden is not simply a quality-of-life issue—it may directly influence long-term outcomes by supporting consistent therapy.

Positioning in a Growing Treatment Landscape
With the availability of multiple ERTs, as well as chaperone therapies and investigational gene therapies, treatment decisions in Fabry disease are becoming increasingly individualized. Pegunigalsidase alfa is positioned as an important option, particularly for patients who may benefit from improved pharmacokinetics or who are transitioning from other therapies.
Experts emphasize the importance of tailoring treatment based on disease severity, organ involvement, and patient-specific factors, rather than relying on a one-size-fits-all approach.

Looking Ahead
The development of pegunigalsidase alfa reflects a broader trend in rare disease therapeutics—leveraging rational design to improve durability, tolerability, and real-world effectiveness. Approved in both the United States and Europe, it represents a meaningful addition to the Fabry treatment armamentarium.

For clinicians, the key takeaway is clear: advances in ERT are not only expanding treatment options but also redefining expectations for disease control. As more real-world data emerge, therapies like pegunigalsidase alfa are poised to play an increasingly important role in optimizing long-term outcomes for patients living with Fabry disease.

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The US Food and Drug Administration (FDA) has approved Filspari (sparsentan) to reduce proteinuria in patients with focal segmental glomerulosclerosis (FSGS). The indication includes adult and pediatric patients ages 8 years and older without nephrotic syndrome.

In the clip below, Howard Trachtman, MD, of the University of Michigan, discusses FSGS and the clinical data that led to sparsentan’s approval.

FSGS is a rare kidney disorder characterized by scar tissue that forms in the glomeruli. Signs and symptoms include protein in the urine, elevated levels of creatinine, and swelling. In many cases the cause can not be determined. Some cases are thought to be associated with congenital kidney defects, urine backing up into the kidneys, obesity, obstructive sleep apnea, sickle cell anemia, or viruses.

Sparsentan is a dual endothelin and angiotensin II receptor antagonist that reduces kidney inflammation and proteinuria. It was originally approved for the treatment of IgA nephropathy and is now the first and only medicine approved by the FDA for the treatment of FSGS.

The approval is based on results from the phase 3, global, randomized, multicenter, double-blind, parallel-arm, active-controlled DUPLEX clinical trial (NCT03493685). The trial enrolled 371 patients ages 8 to 75 years with FSGS.

Patients treated with sparsentan in the overall study population experienced a statistically significant reduction of 46% in proteinuria from baseline to week 108, compared to 30% in patients treated with maximum labeled dose irbesartan. In patients without nephrotic syndrome, a 48% reduction in proteinuria from baseline to week 108 was observed, compared to 27% in those treated with irbesartan. Additionally, patients treated with sparsentan demonstrated a benefit in estimated glomerular filtration rate (eGFR) with a treatment difference of 1.1 mL/min/1.73 m^2 based on mean change from baseline to week 108.

Across both adult and pediatric patients, sparsentan was generally well tolerated, with a safety profile comparable to irbesartan and consistent across clinical programs.

CHAPTERS
Introduction 00:00
FSGS Overview 00:21
Sparsentan Overview 2:11
Clinical Data 3:37
Effect on Clinical Practice and Patients 5:14
Educational Priorities 9:32

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Jennifer Ibrahim, Head of North America, Rare Disease Medical Affairs at Sanofi, discusses the Breakthrough Therapy designation of venglustat for the treatment of neurological manifestations in Gaucher disease type 3 (GD3).

Gaucher disease refers to a group of inherited metabolic diseases in which harmful amounts of lipids accumulate in the body. It is caused by genetic changes in the GBA gene that lead to reduced levels of glucocerebrosidase. 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 three main forms of the disease: GD1, characterized by lack of central nervous system involvement; GD2, marked by rapid neurological decline and severe neurocognitive symptoms; and GD3, marked by slower and more variable progression and symptom severity.

Venglustat is a novel, investigational oral glucosylceramide synthase inhibitor (GCSi) that reduces abnormal accumulation of glycosphingolipids. It is designed to cross the blood-brain barrier to target the underlying pathology causing the neurological effects of GD3.

The Breakthrough designation is based on data from the LEAP2MONO phase 3 double-blind, double-dummy, active-comparator, two-arm study (NCT05222906). Patients receiving venglustat demonstrated statistically significant improvements in neurological symptoms measured by a global test score that included assessments for ataxia (mSARA) and cognition (RBANS) compared with patients receiving the enzyme replacement therapy (ERT), imiglucerase. In the study, venglustat was well tolerated overall with no new safety signals compared with previous studies. The most commonly reported adverse events were headache, nausea, spleen enlargement, and diarrhea.

FDA Breakthrough Therapy designation is designed to expedite the development and review of medicines in the US that target serious or life-threatening conditions. Medicines qualifying for this designation must show preliminary clinical evidence that the drug may demonstrate substantial improvement on clinically significant endpoints over available medicines.

CHAPTERS
Introduction 00:00
Gaucher Disease Types 00:15
Gaucher Disease Presentation 1:29
Physicians Involved in Care 3:45
Limitations of Current Treatment 8:35
Venglustat Overview 9:22
LEAP2MONO Clinical Trial 11:35
Next Steps 14:20

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Ben Zimmer, CEO of Priovant Therapeutics, discusses results from the recent phase 3 study testing brepocitinib for the treatment of dermatomyositis (DM).

DM is a rare autoimmune condition that causes skin changes and muscle weakness. Symptoms can include a red skin rash around the eyelids, red bumps around the joints, and muscle weakness in the arms and legs. Muscle weakness gets worse over time and can lead to stiff joints and muscle wasting. Current approved treatment options include steroid medications and intravenous immunoglobulin.

Brepocitinib is a dual selective inhibitor of TYK2 and JAK1 administered orally once daily. The medication targets and suppresses the signaling of pathogenic cytokines known to cause disease activity in dermatomyositis. Results from the phase 3 VALOR clinical trial of brepocitinib were recently presented in the New England Journal of Medicine.

The study enrolled a total of 241 patients globally. Subjects were randomized to brepocitinib 30 mg, brepocitinib 15 mg, and placebo, with one-year of double-blind treatment. The primary endpoint was the difference at week 52 between brepocitinib and placebo in mean Total Improvement Score (TIS).

Brepocitinib 30 mg achieved a week 52 mean TIS of 46.5 compared to 31.2 for placebo. A statistically significant difference between brepocitinib 30 mg and placebo on mean TIS was seen at all time points, including as early as week 4. Brepocitinib also demonstrated clinically meaningful and statistically significant improvement over placebo on all nine key secondary endpoints. Dose-dependent response between brepocitinib 30 mg and brepocitinib 15 mg was seen consistently across the primary and secondary endpoints.

Approximately 75% of patients were on background steroids at enrollment, with a mean baseline dose of 12.2 mg/day in the brepocitinib 30 mg arm and 11.3 mg/day in the placebo arm. Of these patients, 62% of brepocitinib 30 mg patients achieved a steroid dose less than or equal to 2.5 mg/day by the end of the study, compared to 34% for placebo. Additionally, 42% of brepocitinib 30 mg patients were able to come off steroids, compared to 23% for placebo.

In the brepocitinib 30 mg arm, clinically meaningful and statistically significant improvements relative to placebo on the CDASI (skin), MMT-8 (motor strength) and HAQ-Disability Index (patient questionnaire around daily living activities requiring functional muscle strength, like getting dressed or walking up five steps) were observed. More than two-thirds of these patients experienced at least a moderate response, and about half experienced a major response. Among patients who entered the trial with moderate-to-severe skin disease, 44% on brepocitinib 30 mg achieved cutaneous clinical remission by week 52, compared to 21% on placebo.

The safety profile of brepocitinib 30 mg was consistent with previous brepocitinib clinical trials. Adverse events of special interest, including malignancy, cardiovascular events, and thromboembolic events, did not occur with greater frequency in the brepocitinib 30 mg arm than the placebo arm.

In March 2026, the US Food and Drug Administration (FDA) accepted the New Drug Application (NDA) for brepocitinib for the treatment of DM and granted the application Priority Review. A Prescription Drug User Fee Act (PDUFA) target action date has been assigned in the third quarter of 2026. The company expects to launch the drug in the United States at the end of September 2026.

CHAPTERS
Introduction 00:00
Dermatomyositis Overview 00:48
Physicians Involved in Care 4:02
Phase 3 Trial Results 5:39
Next Steps 9:57
What Should Physicians Know 11:20

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Prem Subramanian, MD, PhD, Chief of Neuro-Ophthalmology at the University of Colorado Anschutz, discusses Tepezza (teprotumumab-trbw) for the treatment of thyroid eye disease (TED).

TED is a chronic endocrine, autoimmune disease characterized by immune-mediated orbital inflammation that greatly impacts a person’s vision. The condition often occurs in people with hyperthyroidism or Graves’ disease, but also can occur in association with hypothyroidism, euthyroidism, and Hashimoto’s thyroiditis. Graves’ disease affects approximately 1% to 2% of the adult population, with an estimated 40% of patients subsequently developing TED over the course of their lifetime. The onset of TED typically occurs between 30 and 50 years of age, with the disease course more severe after the age of 50. Common symptoms can include ocular discomfort, upper eyelid retraction, dry eyes, tearing, inflammation, erythema, light sensitivity, and sensation of a foreign body present in the eye.

At the NANOS Annual Meeting 2026 recently held in Boston, MA pooled data from four clinical trials were presented on teprotumumab in patients with TED. Teprotumumab is a fully human monoclonal antibody that targets and blocks insulin-like growth factor-1 (IgG1) receptor, reducing inflammation, orbital fibroblast activation, and expansion of fat and muscle tissue behind the eye.

The data presented was from a pooled post-hoc analysis of four randomized trials and their open-label extensions that evaluated teprotumumab in patients with short duration TED (diagnosed for less than one year) and longer duration TED (diagnosed for one year or longer).

Results indicated that patients experienced improvements across all endpoints regardless of disease duration or baseline disease activity. This includes improvements in proptosis, diplopia, clinical activity score (CAS) and overall response. At 24 weeks, 82% of patients treated within one year achieved proptosis reduction versus 72% with longer disease duration, with mean eye bulging reductions of −3.0 mm and −2.6 mm, respectively. Additionally, diplopia improved in 66% of patients treated within one year and 57% of those with longer disease duration, with complete resolution achieved in 50% and 47% of patients, respectively.

CHAPTERS
Introduction 00:00
Thyroid Eye Disease Overview 00:26
Diagnosis of TED 3:03
Treatment of TED 4:34
Tepezza Overview 6:33
Clinical Trial Analysis 9:13

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Stevie Ringel, CEO of Nome Therapeutics, discusses the US Food and Drug Administration’s (FDA) Plausible Mechanism Framework and its effect on rare disease therapy development.

On November 12, 2025, the US Food and Drug Administration (FDA) released the Plausible Mechanism Framework guidance. The purpose of this guidance is to outline recommendations to help developers of individualized therapies generate sufficient clinical safety and efficacy data for the intended use, and that the product can be manufactured to regulatory quality standards. The data is used to support approval or licensure of an individualized therapy for a specific indication. This includes a careful evaluation of the results of nonclinical and clinical data and chemistry, manufacturing, and controls data.

This framework has the opportunity to cut approval timelines, lower costs, and make drug development for rare diseases economically viable.

Mr. Ringel, also a rare disease patient, was told at the age of 17 that he'd go blind and there was no cure for his disease. Over the next 16 years, he realized the science existed but the system couldn't deliver a treatment efficiently. In response, he built precision medicine business units at Tempus, GeneDx, and Sema4, learning the operational infrastructure of this industry. In October 2025, he launched Nome Therapeutics with an artificial intelligence (AI)-powered orchestration platform that strives to solve the execution problem the recent FDA guidance created.

Historically, genetic medicine has focused on drug development that leads to patient recruitment, which has posed difficulties in meeting enrollment goals and clinical endpoints.

Nome Therapeutics’ model takes this into consideration, using AI systems that scour databases of a whole patient population and find those that will benefit from certain therapies and develop from there. The company currently has five preclinical programs across gene therapies and ASOs in neurology and retinal disease. The objective is to help patients figure out the path forward with blueprints that use AI in addition to science to look for and synthesize all potential options for each patient; then ongoing procurement and program management to develop therapies. This is done with the goal of vetting patients to then move forward to clinical trials.

CHAPTERS
Introduction 00:00
FDA's Plausible Mechanism Framework 2:45
Shifting Industry Trends 5:09
Real-Life Examples 7:28
Patient Population Focus 10:07
Personalized Medicine and Business Models 11:50

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