Complementing Treatments for Myasthenia Gravis

This binding opens a central pore within the receptors, allowing sodium and calcium ions to rush in and cause muscle contraction. Images of healthy endplates reveal a complex structure with deep, finger-like folds that increase the surface area for acetylcholine-receptor binding. In people with myasthenia gravis, however, the muscle endplates have a compromised architecture that is significantly smoother and with much fewer acetylcholine receptors than their healthy counterparts. This destruction of the endplates in the absence of a toxic agent pointed to one prime suspect – the immune system. And it orchestrates a dramatic attack. When rogue antibodies attach themselves to the endplate’s acetylcholine receptors (and to a smaller extent, other transmembrane proteins), the immune system wrongly identifies the receptors as foreign and then attracts an arsenal of other immune cells and molecules to the endplate, initiating the destruction of the receptors. Loss of acetylcholine receptors impairs neuromuscular transmission, which manifests as progressive fatigue and muscle weakness. “Think of the malfunctioning immune system’s response as a full-scale military attack,” said Greene. “You have different branches of the immune system, all having the goal of killing the perceived intruder, but they do it using different tools, different weapons and vantage points. They all work together.”

Setting a Target for Better Treatment

The impetus for personalized medicine has ushered in an era of therapies where genes and proteins highly specific to a particular disease are targeted for treatment. For myasthenia gravis, an attractive therapeutic target is a family of proteins called complement that are activated after antibodies have attached to the acetylcholine receptors. Like a chain of dominoes, complement proteins activate sequentially to form the membrane attack complex, a straw-like pore that pierces into the cell membrane, allowing water to flow in and build pressure until the cell ultimately bursts open. “With complement, we're downstream, and so we're targeting proteins that do the actual damage. The footman on the ground, so to speak,” said Greene. “This is great because the more upstream you suppress the immune system, there is going to be more collateral damage or more side effects.” In Greene’s clinical study, the two drugs being tested, Soliris (eculizumab) and Ultomiris (ravulizumab), inhibit the terminal complement protein, C5. The medications, differing mainly in their frequency of dosing, block C5, arresting the formation of the membrane attack complex thereby thwarting an immune response at the muscle endplate.

An Old Drug with a New Purpose

Incidentally, early clinical studies tested eculizumab as a treatment not for myasthenia gravis but for individuals with rheumatoid arthritis, lupus and those with coronary artery bypass graft surgery. In 2002, eculizumab was tested in a Phase II pilot study for a rare blood disorder called paroxysmal nocturnal hemoglobinuria, another autoimmune condition where the immune system attacks the red blood cells and platelets. Successful clinical studies resulted in the FDA approval of the drug in 2007, but it was only in 2017 when eculizumab, sold by the name Soliris, was approved for treating myasthenia gravis. Since then, the drug has cleared Phase III testing and is now being assessed at Houston Methodist and other centers for long-term outcomes and safety. The ongoing study follows adult participants diagnosed with myasthenia gravis, over 5 years. These patients are either on Soliris or Ultomiris for their symptoms. So far, Greene views the drug as a valuable addition in pushing back against the debilitating disease. "We now have another option to help patients lead a more fruitful life,” she said. “With complement inhibitors, people with myasthenia gravis who had accepted suboptimal living for many years can now return to work, attend PTA meetings and travel with family. They no longer need to take a nap every day to function."

Supporting Research with Education

Even with the very favorable therapeutic effects of complement 5 inhibitors, the drugs on their own aren’t enough, Greene noted. Most patients still require a combination of treatments that includes Soliris (or Ultomiris) to tackle all of their symptoms. But the efforts to better treat myasthenia gravis are ongoing: currently, there are more than 50 active clinical studies for myasthenia gravis, a testament to the endeavors in improving care for the disease. In addition to bringing awareness to myasthenia gravis through research, Greene is deeply committed to educating both healthcare professionals and patients about the disease. She is the program director of the neuromuscular residency fellowship at Houston Methodist and serves as the co-director of the Annual Myasthenia Gravis Patient Education Conference that brings together specialists and patients to discuss disease identification, management and treatments. “By having FDA-approved drugs and more on the way, it brings an awareness not only in the community but for doctors who in the past have not had many options for their patients,” said Greene. “This is an important era for myasthenia gravis, and it's only going to get better.”