Wolfe Authors NEJM Editorial on Myasthenia Gravis Study

In the editorial, published in June and titled “Myasthenia Gravis — Redemption for B-Cell Depletion,” Wolfe reevaluates previous research and clinical trials on B-cell depletion and details the more recent Phase 3 Myasthenia Gravis Inebilizumab Trial (MINT)’s promising results.

Wolfe, who was invited to write the editorial after having published in and served as a veteran reviewer for the journal, has long studied myasthenia gravis and other disorders of neuromuscular transmission.

In individuals with MG, the immune system produces immunoglobulins, specifically autoantibodies, that block the signals nerves send to muscles. These harmful autoantibodies are in turn produced by B-cells, a type of immune cell.

Therefore, researchers have believed for quite some time that depleting B-cells could treat MG.

“It makes complete sense that it should work, but we struggled in earlier trials,” Wolfe says.

Earlier treatments have used agents such as rituximab to deplete certain B-cells, Wolfe explains, which targets the CD20 marker found on many B-cells.

Yet these treatments have been ineffective for many patients. Why? CD20 may be the wrong target.

As B-cells continue to mature, they eventually become plasmablasts and then plasma cells, which are believed to secrete the autoantibodies behind MG, Wolfe says. As they're developing, the cells lose the CD20 marker; it is no longer expressed on differentiating plasmablasts and matured plasma cells.

So, the MINT Trial research team opted for a new target marker: CD19. Unlike CD20, CD19 is expressed earlier and more broadly throughout B-cell development, including on plasmablasts and plasma cells.

Using inebilizumab, a monoclonal anti-CD19 antibody, they were able to deplete a wider family of cells, including plasmablasts and plasma cells.

Compared to placebo, the MINT trial treatment group participants had a significantly greater reduction in their Myasthenia Gravis Activities of Daily Living (MG-ADL) scores, a validated outcome measure commonly used to assess the impact of MG on daily functions, among other positive results.

Wolfe notes that the therapeutic agent used in the MINT trial already has approval to treat another neurologic disorder. It could also be relatively low cost and involve fewer needle-based infusions to administer.

“This thinking behind B-cell depletion has been in place for several decades in myasthenia gravis, yet we still have not gotten an approval for B-cell depletion therapy,” Wolfe says. “But this trial, I think, opens the door for what could be new approvals for a new mechanism of action to treat the disease.”

Shahar Shelly, MD, chair of neurology at the Rambam Medical Center in Haifa, Israel, who worked with Wolfe during a sabbatical earlier this year, is co-author of the editorial.