Myasthenia Gravis: Patient Choice, Cultural Change
Packed Early-Development Pipeline
Regarding early-stage projects, said Dr. Howard, the pipeline is packed with compounds that target various aspects of the immune system. “The real question with those is, what’s going to be the side effect profile? All of the trials are very early. We need bigger trials with much longer observation for safety, durability, and degree of efficacy.”
The next potential B cell–targeting game changer, he said, is chimeric antigen receptor (CAR) T cell–based therapy. In a phase 2b trial of Descartes-08 (Cartesian Therapeutics), 71% of treated patients experienced clinically meaningful improvement in MG Composite score at 3 months vs 25% for placebo.14
In early clinical trials, said Dr. Howard, patients treated with Descartes-08 — which uses autologous mRNA to target B-cell maturation antigen — have shown “exceptional improvement” lasting 20 or more months. Because the drug is not ingrained permanently into the genome, Descartes-08 avoids potentially severe side effects of DNA-targeting CAR T candidates. Dr. Howard hopes a phase 3 trial will commence around January 2025.
The tolerance approach exemplified by CNP-106 (COUR Pharmaceuticals) and a myasthenia gravis tolerogen (Toleranzia) seeks to prevent the immune system from recognizing and reacting to the NMJ abnormalities that produce myasthenia gravis, potentially providing a cure. “We look forward to those trials as they come online in the next 1-2 years,” said Dr. Howard.
Unmet Needs
Historically, neurologists believed that all myasthenia gravis symptoms stemmed from muscle fatigue — the more active the muscle, the weaker it gets. However, said Dr. Kaminski, some patients might lack measurable weakness but still complain of fatigue.
Elevated levels of cytokines such as interleukin (IL)–6 or IL-17 also can produce fatigue, he noted. “With the drugs we’re using, certainly the new ones, we’re not specifically targeting this fatigue phenomenon, which has been studied in a very limited fashion.”
In the RAISE-XT zilucoplan trial, participants experienced significant improvement in fatigue scores for up to 60 weeks.15 Although zilucoplan does not address fatigue directly, said Dr. Howard, improving myasthenia gravis overall helps reduce fatigue.
The Myasthenia Gravis Symptoms Patient Reported Outcome (MG Symptoms PRO), which Dr. Kaminski helped develop, includes questions designed to distinguish muscular fatigue from overall physical fatigue.16 “I’m very interested in some of the information that’s coming out on long COVID and its effect on muscle,” Dr. Kaminski added. “We might be able to learn from there that there’s still some pathology going on beyond the neuromuscular junction.”
What the field desperately needs, said Dr. Howard, are biomarkers to identify which patients will and will not respond to certain therapeutics. “We’re not there yet.” Such biomarkers are at least 3-7 years from becoming clinical reality.
Promising antibody-independent serum markers include circulating microRNAs. For example, miRNA-150-5p and miRNA-21-5p are elevated in generalized AChR-positive myasthenia gravis and early-onset myasthenia gravis (occurring before age 50) and decline after immunosuppression and thymectomy.17
Among diagnostic modalities for patients with seronegative myasthenia gravis, said Dr. Kaminski, single-fiber EMG is the most sensitive, at approximately 95%. “It’s not perfect.” Moreover, he said, performing this test accurately requires a highly experienced expert, which many treatment centers lack.
Presently, added Dr. Kaminski, orbital MRI is neither specific nor sensitive enough to be clinically useful. “One needs to be careful with these specialized tests that are published from the best laboratory in the world that does the test, and does it repetitively.” As the search for effective myasthenia gravis biomarkers continues, avoiding false-positive results is as important as avoiding false negatives.
References
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14. Cartesian Therapeutics. Cartesian Therapeutics announces positive topline results from phase 2b trial of Descartes-08 in patients with myasthenia gravis. 2024 Jul 2. https://ir.cartesiantherapeutics.com/news-releases/news-release-details/cartesian-therapeutics-announces-positive-topline-results-phase.
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