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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David Warnock, MD, Professor of Medicine (Emeritus), University of Alabama at Birmingham, discusses the Fabry disease landscape.

Fabry disease is a rare genetic, multisystemic lysosomal disease characterized by specific cutaneous, neurological, renal, cardiovascular, cochleo-vestibular, and cerebrovascular manifestations.

Dr. Warnock describes recent advancements in the treatment of Fabry disease, including two enzyme treatments and a chaperone therapy. While these treatment options provide hope for patients and a base for research, there are still unmet clinical needs in this population.

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Jack Johnson, Co-Founder and Executive Director of the Fabry Disease Support and Information Group, and VP of the Fabry International Network, discusses the phase 3 BRIGHT study testing Elfabrio (pegunigalsidase alfa-iwx) in patients with Fabry disease.

Fabry disease is a rare lysosomal storage disease caused by a deficiency of the enzyme alpha-GAL which helps break down the fatty acid, 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. Fabry disease is caused by genetic changes in the GLA gene.

The BRIGHT study is a phase 3, open-label, multinational, switchover, 12-month study evaluating the pharmacokinetics, safety and efficacy of 2 mg/kg pegunigalsidase administered every four weeks. Pegunigalsidase is a PEGylated α-Gal A enzyme replacement therapy that is approved at 1mg/kg every two weeks for the treatment of adults with Fabry disease.

29 patients completed the study. No new safety concerns were observed and pegunigalsidase alfa median plasma concentrations were above the lower limit of quantification after each 4-week dosing interval. Median estimated glomerular filtration rate remained stable with change from baseline of -1.9 mL/min/1.73m2/year after 12 months of treatment. Additionally, plasma globotriaosylsphingosine concentrations were low and stable in women involved, with men demonstrating a slight increase compared to baseline.

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Anne Marie Morse, DO, of Geisinger Health, discusses the U.S. Food and Drug Administration (FDA) approval of Lumryz (sodium oxybate) for the treatment of cataplexy or excessive daytime sleepiness in patients with narcolepsy ages 7 years and older.

Narcolepsy is a rare, chronic, neurological disorder affecting the brain’s ability to control sleep-wake cycles. Common symptoms include excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hallucinations, and fragmented sleep and insomnia. These symptoms can greatly affect daily activities and may partially improve over time but will never go completely away.

As Dr. Morse explains, in a normal sleep cycle, a person enters rapid eye movement (REM) sleep after about 60 to 90 minutes. People with narcolepsy frequently enter REM sleep rapidly, within 15 minutes of falling asleep. Also, the muscle weakness or dream activity of REM sleep can occur during wakefulness or be absent during sleep.

Lumryz is an FDA approved extended-release sodium oxybate and the only once-at-bedtime treatment for narcolepsy in those ages 7 years and older. The approval follows results from the REST-ON clinical trial, a phase 3, randomized, double-blind, placebo-controlled study in adults with narcolepsy. In this study, statistically significant and clinically meaningful improvements were observed in the three primary endpoints when compared to placebo. These endpoints included EDS, clinicians’ assessment of patient functioning, and cataplexy attacks.

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Sabrina Sacconi, MD, PhD, Head of Neuromuscular Disease at Nice University Hospital, discusses recent guidelines for myasthenia gravis (MG).

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

- Eye and eyelid
- Facial expressions
- Chewing
- Talking
- Swallowing

As Dr. Sacconi notes, the therapeutic landscape for MG is rapidly changing with the advent of new therapies such as anti-FcRn and anti-complement receptors. With guidelines being updated across the world, recommendations now include the use of these novel therapies in addition to traditional first line treatments. (e.g., https://pmc.ncbi.nlm.nih.gov/articles/PMC11266451/ and https://pmc.ncbi.nlm.nih.gov/articles/PMC11236053/) These guidelines hope to produce minimal symptom expression in patients.

Dr. Sacconi also discusses a recent pooled analysis looking at the use of rozanolixizumab, an anti-FcRn receptor that was recently approved for MG. The analysis included data from the phase 3 MycarinG study as well as the MG0004 and MG0007 open-label extensions.

In the initial study, participants were treated with one cycle consisting of six once-weekly infusions of rozanolixizumab. It was observed that this treatment significantly improved MG outcomes versus placebo. Response to treatment was also sustained over the cycle. For patients who didn’t respond in the first cycle, greater than 50% responded in the second cycle and response was sustained.

Patient reported outcome measures were all positive. These measures included MG-Activities of Daily Living (MG-ADL) and Quantitative MG (QMG) response rates. Scores in the MG-ADL were improved by 2 or greater points and the QMG scores were improved by 3 or greater points.

Overall, patients receiving rozanolixizumab demonstrated a high response rate over multiple cycles.

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Richard Nowak, MD, and Director of Myasthenia Gravis Clinic at Yale University, discusses data from the MINT study for myasthenia gravis (MG).

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

- Eye and eyelid
- Facial expressions
- Chewing
- Talking
- Swallowing

The MINT clinical trial is a phase 3, randomized, double-blind, placebo-controlled, parallel-group trial evaluating the efficacy and safety of inebilizumab in adults with generalized MG (gMG). Inebilizumab is a B-cell-depleting monotherapy that binds to the cell surface of CD19+ B lymphocytes. It is currently approved for the treatment of neuromyelitis optica spectrum disorder (NMOSD).

The trial included 238 adults with gMG, 190 of which are acetylcholine receptor autoantibody-positive (AChR+) and 48 who are muscle-specific kinase autoantibody-positive (MuSK+). The study met its primary endpoint of statistically significant change from baseline in MG Activities of Daily Living (MG-ADL) score at week 26 with a score of -4.2 with inebilizumab and -2.2 for placebo.

Inebilizumab also illustrated significant change from baseline compared to placebo in secondary endpoints of Quantitative MG (QMG) score (inebilizumab: -4.8, placebo: -2.3), MG-ADL score in the AChR+ group (inebilizumab: -4.2, placebo: -2.4), QMG score in the AChR+ group (inebilizumab: -4.4, placebo: -2.0), and MG-ADL score in the MuSK+ group (inebilizumab: -3.9, placebo: -1.7)

Overall, patients being treated with inebilizumab demonstrated continued improvement through week 26. Patients who began the trial taking corticosteroids were tapered down starting at week 4 to 5 mg of prednisone per day by week 24. Additionally, safety results were consistent with the known profile.

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Ratna Bhavaraju-Sanka, MD, Chief of Neuromuscular Medicine at UT Health San Antonio, discusses Vyvgart’s (efgartigimod alfa) impact on myasthenia gravis (MG) patients.

MG is a chronic autoimmune neuromuscular disease characterized by weakness of the skeletal muscles. The condition is due to the presence of antibodies against the acetylcholine receptor. Weakness tends to increase during periods of activity and improve after periods of rest. Common symptoms include weakness of the muscles that control the eyes, mouth and face, but any set of skeletal muscles can be impacted.

Efgartigimod alfa is a neonatal FcRn blocker that is approved by the U.S. Food and Drug Administration (FDA) for the treatment of generalized MG as well as chronic inflammatory demyelinating polyneuropathy (CIDP). Data presented at the 2024 American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) conference examined the treatment’s long-term and real-world effects.

Efgartigimod alfa continues to show consistent improvement in various MG patient subgroups. Real-world data indicated that at one-year post initiation of the treatment, 55% of patients reduced their corticosteroid use by 5 or more mg/day and 42% achieved steroid doses of 5 or less mg/day. Additionally, the safety of the therapy continues to be consistent and favorable with no increase in adverse events.

Additional studies are currently ongoing to test the efficacy of efgartigimod alfa in other MG populations including seronegative MG and ocular MG.

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James F. Howard, Jr., MD, The University of North Carolina at Chapel Hill, discusses the interim analysis of the RAISE-XT extension study for myasthenia gravis (MG).

MG is a chronic autoimmune neuromuscular disease characterized by weakness of the skeletal muscles. The condition results from a defect in the transmission of nerve impulses to muscles, which is due to the presence of antibodies against the acetylcholine receptor. The exact reason this occurs is not known.

The RAISE-XT extension study is an ongoing, multicenter, open-label extension of a phase 3 study evaluating the long-term safety, tolerability, and efficacy of zilucoplan in patients with AChR+ generalized MG. Zilucoplan is a C5 complement inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of MG.

The 200 patients enrolled in the open-label extension and received daily, self-administered subcutaneous 0.3 mg/kg of zilucoplan. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs) and secondary endpoints included change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score.

94% of patients experienced a TEAE, the most common being MG worsening and COVID-19. However, improvements to MG-ADL scores were observed in those who received zilucoplan in the parent study and those who switched from placebo in the parent study to zilucoplan in the extension. Overall, the treatment demonstrated a favorable long-term safety profile and tolerability as well as sustained efficacy.

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Tuan Vu, MD, Professor of Neurology at the University of South Florida, discusses positive results in Vivacity-MG3 study evaulating the safety and efficacy of nipocalimab for myasthenia gravis (MG).

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

- Eye and eyelid
- Facial expressions
- Chewing
- Talking
- Swallowing

Nipocalimab is a fully human monoclonal antibody targeted at FcRn, a protein that attenuates the degradation of circulating IgG. By blocking FcRn activity, the net result is a reduction in circulating IgG antibody levels and thereby reducing the autoimmune pathophysiology that causes MG.

The Vivacity-MG3 study is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial further evaluating the efficacy and tolerability of nipocalimab. 153 adults with generalized MG who had an inadequate response to standard of care treatment were enrolled. The primary endpoint of this study was improvement in MG Activities of Daily Life (MG-ADL) score with Quantitative Myasthenia Gravis (QMG) score. Key secondary endpoints included MG-ADL responder rates, or the percentage of patients with a 2 or greater point improvement on average in MG-ADL scores.

Results include a statistically significant improvement in MG-ADL and QMG scores from baseline versus placebo with an average change of -4.7. MG-ADL responder rate was 68.8% in the nipocalimab group compared to the 52.6% in the placebo group. Additionally, the nipocalimab group saw greater sustained response to the treatment with 46.8% demonstrating a 50% or greater improvement in MG-ADL, versus 25% in the placebo group.

Overall, nipocalimab illustrated positive efficacy and safety in a broad population of MG patients.

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