Sindhu Ramchandren, MD, Executive Medical Director, Neuroscience and Disease Cluster Lead for Neuroimmunology and Neuromuscular Disorders at Johnson & Johnson, discusses updated results from the Vivacity-MG3 clinical trial in patients with generalized myasthenia gravis (MG).

MG is a chronic autoimmune neuromuscular disease characterized by weakness of the skeletal muscles. Common symptoms include weakness of the muscles that control the eye and eyelid, facial expressions, chewing, talking, and swallowing. Weakness tends to increase during periods of activity and improve after periods of rest. The condition results from a defect in the transmission of nerve impulses to muscles, which is due to the presence of antibodies against acetylcholine receptors. The etiology of MG is not known.

The Vivacity-MG3 clinical trial (NCT04951622) was a phase 3, multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of nipocalimab in patients with antibody-positive generalized MG. There is also an ongoing open-label extension evaluating the long-term safety and efficacy of nipocalimab in patients with MG. Nipocalimab is an investigational monoclonal antibody designed to block FcRn and reduce levels of circulation immunoglobulin G (IgG) antibodies.

Results of the study showed that patients treated with nipocalimab plus standard of care maintained improvements in their MG-ADL and QMG scores over 84 weeks with sustained reductions in total IgG. The mean change in MG-ADL score was -5.64 from baseline after 60 weeks in the open-label extension participants receiving nipocalimab plus standard of care. The mean change in MG-ADL score for participants who transitioned from placebo and standard of care to nipocalimab plus standard of care was -6.01. 45% of patients in the antibody-positive population receiving steroids at baseline were able to decrease or discontinue use. The safety profile of nipocalimab was consistent and tolerable throughout the open-label extension.

Additionally, patients treated with nipocalimab plus standard of care achieved statistically significant improvements in QMG scores by -4.9 compared to placebo plus standard of care. Patients in the nipocalimab plus standard of care group were also four times more likely to sustain symptom improvement at 20 weeks compared to the placebo plus standard of care group. 36.4% of patients treated with nipocalimab versus 10.5% of patients on placebo spent greater than 75% of the study duration demonstrating improvements in QMG score.

Chapters:
Introduction 00:00
Myasthenia Gravis Overview 0:33
Nipocalimab Overview 2:21
Vivacity-MG3 Study 3:19
Take Home Message 7:45

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Michael Weiss, MD, Department of Neurology, University of Washington Medical Center, discusses results from the RAISE clinical trial in patients with myasthenia gravis (MG).

MG is a chronic autoimmune neuromuscular disease characterized by weakness of the skeletal muscles. Common symptoms include weakness of the muscles that control the eye and eyelid, facial expressions, chewing, talking, and swallowing. Weakness tends to increase during periods of activity and improve after periods of rest. The condition results from a defect in the transmission of nerve impulses to muscles, which is due to the presence of antibodies against acetylcholine. The exact reason this occurs is not known.

The RAISE clinical trial (NCT04115293) is a phase 3, multicenter, double-blind, placebo-controlled study evaluating zilucoplan in adult patients with MG. The primary objectives of the study were to evaluate the effect of zilucoplan on the Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores in patients with generalized MG. Zilucoplan is a macrocyclic peptide complement component 5 inhibitor and was administered as a daily subcutaneous injection at a dose of 0.3 mg/kg for 12 weeks.

At week 12, least-squares mean (LSM) change from baseline in MG-ADL total score was -4.39 for the zilucoplan treated group comopare to -2.30 for placebo. LSM change from baeline for QMG total score was -6.19 for zilucoplan and -3.25 for placebo. Mean change from baseline in AG-ADL subdomain scores in the zilucoplan versus placebo groups were: ocular, –1.5 vs –0.8 ; bulbar, –1.9 vs –1.1; respiratory, –0.4 vs –0.3; limb/axial, −1.2 vs –0.8. Mean CFB in QMG subdomain scores were: ocular, −2.0 vs −1.3; bulbar, −1.6 vs −1.1; respiratory, −0.6 vs −0.3; limb/axial, −2.9 vs −1.2.

These results further support zilucoplan’s ability to provide rapid and clinically meaningful improvements in MG-ADL and QMG scores compared to placebo.

Chapters:
Introduction 00:00
RAISE Clinical Trial 2:24
Choosing Treatment Options 4:02
AAN 2025 Talk 5:19

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Richard J. Nowak, MD, Director of the Myasthenia Gravis Clinic at Yale University, discusses positive data from the MINT clinical trial evaluating Uplizna (inebilizumab-cdon) in adults with generalized myasthenia gravis (gMG).

MG is a chronic autoimmune neuromuscular disease characterized by weakness of the skeletal muscles. Common symptoms include weakness of the muscles that control the eye and eyelid, facial expressions, chewing, talking, and swallowing. Weakness tends to increase during periods of activity and improve after periods of rest. The condition is due to the presence of antibodies against acetylcholine. The exact reason this occurs is not known.

The MINT study (NCT04524273) is a phase 3, randomized, double-blind, placebo-controlled, parallel-group clinical trial evaluating the safety and efficacy of inebilizumab in adults with gMG. Inebilizumab is an anti-CD-19 antibody that causes targeted and sustained depletion of CD19+ B cells that contribute to underlying disease progression.

The trial enrolled 238 patients with gMG, with 190 patients who are acetylcholine receptor autoantibody-positive (AChR+), and 48 who are muscle-specific kinase autoantibody-positive (MuSK+). The primary endpoint of this study is change from baseline in MG Activities of Daily Life (MG-ADL) score at week 26 in the combined population.

Results demonstrated a durable efficacy over the 52-week period in patients with AChR+ gMG with two doses per year after initial loading dose. Among the AChR+ population treated with inebilizumab, 72.3% had a 3 point or greater improvement in MG-ADL score, compared to 45.2% in the placebo group. Change from baseline in Quantitative MG score was also greater for patients treated with inebilizumab compared to placebo, with 69.2% of AChR+ patients improving by 3 or more points, compared to 41.8% in the placebo group.

Sustained efficacy was also observed with protocol-specified steroid taper. Starting at week4, all patients reduced prednisone use to 5 mg per day by week 24. Additionally, no new safety signals were identified. The most common adverse events were infusion-related reactions, nasopharyngitis, and urinary tract infections.

Chapters:
Introduction 00:00
Inebilizumab Overview 00:20
MINT Clinical Trial 1:53
Importance of Treatment Options 4:26

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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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Dawn Laney, Genetic Counselor at the Emory University School of Medicine, discusses a Fabry disease registry analysis that examined growth in children being treated with agalsidase beta.

Fabry disease is a rare lysosomal storage disease characterized by a deficiency of alpha-galactosidase (alpha-GAL). Alpha-GAL is important in the breaking down of globotriaosylceramide (GL3). Without enough alpha-GAL, the lysosomes become filled with GL-3 and can not work well. Symptoms of Fabry disease may include episodes of pain, especially in the hands and feet, 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. Milder forms of Fabry disease may appear later in life and affect only the heart or kidneys. Fabry disease is caused by genetic changes in the GLA gene.

The objective of this analysis was to assess the growth trajectories of pediatric patients with classic Fabry disease during the natural history and agalsidase beta treatment periods. Agalsidase beta is a recombinant human alpha-GAL indicated for the treatment of Fabry disease.

From the analysis, it was observed that male patients had significant improvements in the agalsidase beta treatment period when compared to the natural history. These patients had a mean increase of 6.7 percentiles for height and 5.5 percentiles for weight. While the change in BMI was also positive, it was not statistically significant. Height gains were the most notable in ages 14 to 20 years and weight gains most notable in ages 3 to 11 years.

For female patients, changes were more modest. However, significant height and weight improvements were observed in ages 3 to 11 years.

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Eric Wallace, MD, Professor of Nephrology at The University of Alabama at Birmingham, discusses an analysis of treatment comparisons between pegunigalsidase alfa versus other therapies for left ventricular mass index (LVMi) in Fabry disease.

Fabry disease is a rare lysosomal storage disease characterized by a deficiency of alpha-galactosidase (alpha-GAL). Alpha-GAL is important in the breaking down of globotriaosylceramide (GL3). Without enough alpha-GAL, the lysosomes become filled with GL-3 and can not work well. Symptoms of Fabry disease may include episodes of pain, especially in the hands and feet, 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. Milder forms of Fabry disease may appear later in life and affect only the heart or kidneys. Fabry disease is caused by genetic changes in the GLA gene.

The objective of this study was to indirectly compare the mean change from baseline in LVMi for pegunialsidase alfa with agalsidase alfa and migalastat in patients with Fabry disease by network meta-analysis (NMA) and simulated treatment comparison (STC). Pegunialsidase alfa is a pegylated recombinant form of human alpha-GAL, indicated as an enzyme replacement therapy for treatment of patients with Fabry disease.

Observations from the analysis included unanchored STC results mostly consistent with that of the NMA. However, no statistical difference was observed between pegunigalsidase alfa versus agalsidase alfa, placebo, or migalastat. The NMA demonstrated a nominal trend favoring pegunialsidase alfa, but with no statistical significance. Previous studies suggest that pegunialsidase alfa is comparable to other Fabry treatment options in terms of change from baseline in LVMi.

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Aneal Khan, MD, President of MAGIC Clinic (Metabolics and Genetics in Canada), discusses five year end-of-study results from the FACTs trial in patients in Fabry disease.

Fabry disease is a rare lysosomal storage disease characterized by a deficiency of the enzyme alpha-galactosidase (alpha-GAL), that helps break down GL3. Symptoms of Fabry disease may include episodes of pain, especially in the hands and feet, 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. Milder forms of Fabry disease may appear later in life and affect only the heart or kidneys. Fabry disease is caused by genetic changes in the GLA gene.

The goal of the Canadian FACTs clinical trial was to correct enzyme deficiency in patients with Fabry disease by transferring cDNA for alpha-GAL A into CD34+ hematopoietic stem cells. In total, five male patients with Fabry disease were treated

Following infusion with a recombinant lentivirus, circulating alpha-GAL activity was observed at day 6-8 and remained durable for 5 or greater years. Additionally, LV marking of peripheral blood cells has remained durable and polyclonal. Plasma lyso-Gb3 levels were significantly lower in four patients. All five patients were eligible to come off biweekly enzyme replacement therapy, with three doing so.

No sustained elevation of anti-alpha-GAL A antibodies were observed. Patient weight was stable in four patients and blood pressure and kidney symptoms were normal and stabilized in all patients. Overall, the therapy proved to be tolerable and durable.

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Carlo Antozzi, MD, discusses results from the phase 3 Vivacity-MG3 study of nipocalimab in antibody positive adults with generalized myasthenia gravis (MG).

MG is a chronic autoimmune neuromuscular disease characterized by weakness of the skeletal muscles. Common symptoms include weakness of the muscles that control the eye and eyelid, facial expressions, chewing, talking, and swallowing. Weakness tends to increase during periods of activity and improve after periods of rest. The condition results from a defect in the transmission of nerve impulses to muscles, which is due to the presence of antibodies against acetylcholine. The exact reason this occurs is not known.

The Vivacity-MG3 clinical trial (NCT04951622) was a phase 3, multicenter, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of nipocalimab in antibody positive adults with generalized MG. Nipocalimab is an investigational FcRn blocker designed to reduce levels of circulation immunoglobulin G (IgG).

In total, 199 patients, 153 of whom were antibody positive, enrolled in the trial. The primary endpoint, of demonstrating statistically significant and clinically meaningful improvement over 24 weeks in the MG Activities of Daily Living (MG-ADL) score, was met. Additionally, nipocalimab demonstrated a 75% reduction in median-pre-dose total IgG from baseline, as well as reduction in levels of antibodies such as AChR and MuSK. The safety profile of nipocalimab was also tolerable with no concerning adverse events compared to placebo.

A Biologics License Application has been submitted to the U.S. Food and Drug Administration as well as a Marketing Authorization Application to the European Medicines Agency for approval of this treatment.

Chapters:
Vivacity-MG3 Study Overview 00:00
FcRn Blockers 3:13
Treatment Utilization 4:22
Next Steps 6:25

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Keyur B. Shah, MD, Virginia Commonwealth University Health, discusses the approval of acoramidis for the treatment of patients with transthyretin amyloid cardiomyopathy (ATTR-CM).

AATR-CM is a rare amyloidosis caused by aging or genetic mutations. This results in the misfolding of TTR protein and accumulation of amyloid fibers in the cardiac myocardium. TTR fibrils build up in tissues, such as the peripheral nerves and heart, as well as the gastrointestinal tract, eyes, kidneys, central nervous system, thyroid, and bone marrow. This accumulation causes progressive dysfunction of these tissues. The disease eventually leads to heart failure.

Acoramidis is a near-complete stabilizer of TTR approved by the U.S. Food and Drug Administration for the treatment of adults with ATTR-CM. The approval follows positive results from the phase 3 ATTRibute-CM study where acoramidis demonstrated significant benefit on mortality, hospitalizations, and quality of life. Additionally, the treatment was generally well-tolerated.

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