ѻý

What's on the Horizon for Myasthenia Gravis

<ѻý class="mpt-content-deck">— Cell-based therapies, broader B-cell targeting, and immune tolerance are all in the works
MedpageToday
 A computer rendering of autoantibodies blocking the acetylcholine transmitters in myasthenia gravis

While the medical armamentarium for generalized myasthenia gravis (gMG) has blossomed in the last several years, further advances are headed down the pipeline.

Atop standard therapies, including acetylcholinesterase inhibitors, steroids, broad immunosuppressants, and thymectomy, a number of targeted immunotherapy agents have been approved for adults with gMG since 2017. These C5 and neonatal Fc receptor inhibitors block the autoantibody attack against the neuromuscular junction that causes the disease's characteristic fluctuating muscle weakness. Clinical trials are with in both of those two classes.

However, "the ultimate therapeutic goal of complete disease control can be reached only in a subset of people with the disease," noted a commentary by Andreas Meisel, MD, of Charité Universitaetsmedizin Berlin in Germany.

"Complete elimination of the harmful autoantibodies and their effects is impossible with these therapeutic approaches alone," he wrote. "Therefore, new safe and effective immunotherapies are urgently needed that specifically target the immune machinery that produces the autoantibodies."

That's what new strategies still early in development in gMG aim to do.

Cell-based Therapy

Cellular-based therapies are "super exciting" with promising results in antibody-mediated disease, said Richard Nowak, MD, director of the Yale Myasthenia Gravis Clinic in New Haven, Connecticut.

Earlier this year, the first clinical data in gMG emerged for Descartes-08, an autologous RNA chimeric antigen receptor T-cell (rCAR-T) therapy that targets B-cell maturation antigen expressed on plasma cells.

Meisel called it an "elegant" approach that doesn't require potentially harmful lymphodepletion chemotherapy as has standard DNA-based CAR T-cell therapy used in advanced cancers.

The phase Ib/IIa MG-001 trial used the Descartes-08 rCAR-T agent to target and selectively destroy plasma cells with just the standard immunosuppressive therapies used in gMG. Thus, there were no study-related serious adverse events or dose-limiting toxicity, neurotoxicity, cytokine release syndrome, or hematological adverse effects among the 14 patients treated open-label with a variety of dose schemes in the trial.

Most study participants had significant improvements in MG disease severity that persisted for the median 6 months of follow-up. Mean improvements from baseline to week 12 included a 6-point gain on Myasthenia Gravis-Activities of Daily Living (MG-ADL) score and a 14-point gain on Myasthenia Gravis Composite (MGC) score, which are three- and more than fourfold greater than the minimal clinically meaningful improvement on those scales, respectively.

Meisel noted that the only partial destruction of plasma cells by rCAR-T (with slightly decreased concentrations of total IgG, vaccine antibodies, and autoantibodies) was good news for maintaining protection against infection.

Despite the small numbers, the results were "sort of mind-boggling," said James Howard Jr., MD, of the University of North Carolina at Chapel Hill, who was senior author on the trial and has been involved in clinical trials developing complement and neonatal Fc receptor inhibitors as well.

"We have patients who have gone 12 months in remission, 18 months in remission following just six weekly infusions of engineered cells," he told ѻý.

Broader B-Cell Targeting

Rituximab (Rituxan) is an anti-CD20 B-cell depleting monoclonal antibody used off-label in gMG, because anti-muscle-specific tyrosine kinase (MuSK) and anti-acetylcholine receptor (AChR) antibodies common in gMG are produced by a subset of B cells.

But inebilizumab (Uplizna) is "now being looked at to supplant rituximab, because we've seen mixed results with rituximab in AChR-positive MG," Howard noted. "That drug targets a much broader group of B cells than rituximab does."

Inebilizumab is an anti-CD19, B-cell depleting monoclonal antibody given as a twice-yearly maintenance infusion after initial doses. It is approved to treat another rare autoimmune disorder, neuromyelitis optica spectrum disorder, in adults who are anti-aquaporin-4 antibody positive.

Nowak's group has a phase III trial, dubbed , underway with the drug in some 270 MG patients who are positive for AChR or MuSK antibodies.

Reestablishing Immune Tolerance

Pharmaceutical companies are also developing antigen-specific therapy as well in the hopes of reversing autoimmunity and restoring immune tolerance in myasthenia gravis.

"That could be considered the holy grail of autoimmune therapy, where you can induce tolerogenic signals, where the disease can actually go into a durable remission," noted Nowak. "And I think that is quite exciting."

Toleranzia is that contains the protein component AChR for MG, although not yet in clinical trials. Cour Pharmaceuticals has an investigational agent dubbed aimed at reprogramming T cells in a phase 1b/2a trial for MG. (Nowak is involved in that research.)

"If it pans out, it'll be phenomenal. But like everything else, you never know until you see the proof," said Howard. Altogether, the field is primed for real change, he projected. "Prior to 2007, we were sort of like the turtle making slow methodical steps. And since then we're the Saturn rocket going through the stratosphere. It's going to continue."

Disclosures

Howard disclosed research funding to his institution from Alexion AstraZeneca Rare Disease, argenx, Cartesian Therapeutics, CDC, MGFA, the Muscular Dystrophy Association, NIH, PCORI, Ra Pharmaceuticals/UCB Bioscience, and Takeda Pharmaceuticals as well as honoraria or consulting fees from AcademicCME, Alexion AstraZeneca Rare Disease, argenx, Biologix Pharma, F. Hoffmann-LaRoche, Horizon Therapeutics, Medscape CME, Merck EMD Serono, NMD Pharma, Novartis Pharma, PeerView CME, PlatformQ CME, Regeneron Pharmaceuticals, Sanofi U.S., and Zai Labs.

Nowak disclosed grant or research support from the NIH, MGFA, Grifols, Alexion, Genentech, argenx, Ra Pharma (now UCB), Momenta (now Janssen), Immunovant, Annexon, Viela Bio (now Horizon Therapeutics) and consulting or advisory relationships with Alexion, Cabaletta, Cour Pharmaceuticals, Ra Pharma, Momenta (now Janssen), argenx, Immunovant, and Viela Bio.

Meisel reported relationships with Alexion Pharmaceuticals, Argenx, Axunio, Desitin, Grifols, Hormosan Pharma, Janssen, Merck, Octapharma, UCB, Xcenda, and the German Myasthenia Gravis Society.