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Clinical research

Complementing Treatments for Myasthenia Gravis

Complement protein 5 inhibitors have emerged as a new line of treatment for the debilitating neuromuscular disorder. Now, a clinical study at Houston Methodist is testing the drugs’ long-term efficacy and safety.

In the spring of 1644, a violent clash between the Native Americans and the English in the Virginian tidewaters culminated in the capture of the Powhatan chief, Opechancanough. Almost 100 years old during his imprisonment, the once formidable warrior is described by chroniclers as having had “excessive fatigue” with sinews lacking “tone and elasticity” and requiring attendants to “lift his eyelids” to see. The chief’s incurable malady, experts now believe, is the first-ever recorded case of myasthenia gravis, an autoimmune disease that wreaks havoc on the muscles of the body. With a prevalence of 14-20 in a population of every 100,000, myasthenia gravis is considered a rare disease. The neuromuscular disorder often affects women under the age of 40, men older than the age of 50 and occasionally children. Unless diagnosed, patients often mistake the life-long condition as general fatigue that hinders everyday activities.
"Some patients are unable to comb their hair without their arms getting weak. Others are unable to talk without their tongue becoming paralyzed or swallow without choking on food or saliva,” said Ericka Greene, MD, professor of clinical neurology and an expert in neuromuscular disorders. “In a few cases, the breathing mechanism can also become fatigued, and if significant, patients can develop a ‘myasthenia crisis’ for which they need to be evaluated immediately for treatment.”
Ericka Greene, MD Professor of Clinical Neurology
Houston Methodist
The disease is, however, manageable with therapies, and many symptoms can be stabilized without the need for hospitalization. But myasthenia gravis patients still have to adjust to living a new normal. "Clinicians realized that what we viewed as 'stable' and 'normal' with our cachet of therapies was not what our patients experienced in their day-to-day lives,” said Greene. “However, treatments for myasthenia gravis are now changing.” Targeted therapies for myasthenia gravis have improved the strength and function of patients, something previously not thought possible. As a result, a drug’s impact on myasthenia gravis patient’s daily life is now considered a primary measure for FDA approval.
Subtypes of myasthenia gravis. Image adapted from (Gilhus, 2017).
Joining the effort in closing the gap in treatment, Greene’s team is leading a prospective clinical study at Houston Methodist that records the clinical outcomes and safety of medications that selectively inhibit the immune protein C5, an important player in the pathology of myasthenia gravis.
Coexisting conditions with myasthenia gravis. Image adapted from (Gilhus, 2017).
Case of Mistaken Identity
Myasthenia gravis was first clinically documented in 1672 by English physician Thomas Willis in his book “De Anima Brutorum” where he describes patients as healthy in the morning but fatigued toward noon. Yet, it was only in the 20th century that scientists were able to definitively pin the disease to the neuromuscular junction. In this tiny space, acetylcholine molecules released by motor nerve endings traverse a synapse and attach themselves to receptors studded on structures called endplates on the muscle fiber.
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.”
Antibodies to acetylcholine receptors at the muscle endplate trigger the complement pathway responsible for muscle weakness in myasthenia gravis. Inhibitors to the C5 complement protein can prevent the complement pathway from progressing. Image designed by Rachael Whitehead
To dial down the immune machinery’s mayhem, Greene turns to a variety of immunosuppressive therapies for her myasthenia gravis patients. But she is quick to acknowledge that most current treatments shut down the immune system with a sledgehammer, and this approach is far from ideal. “Steroids, for example, affect almost every aspect of the immune system, and they come with many short- and long-term side effects, including weight gain, osteoporosis and diabetes,” said Greene. “Chemotherapy drugs suppress your immune system with fewer side effects than steroids, yet there remains a risk of organ damage and infections because often they weaken more than one part of the immune system.”
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.”
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Vandana Suresh, PhD
May 2023
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