After years of being exposed to germs as manager of a clothing store in La Jolla, CA, Leah Gaitan-Diaz thought her immune system was impenetrable. But in 2014, she noticed something was not right. She was slurring her words, had double vision, and felt so weak she needed one arm to support the other when she put on mascara. And swallowing became a problem. She choked on everything, including her saliva. A doctor she went to see had no idea what was wrong and wrote a prescription for antibiotics, which made things worse.
After an ear, nose, and throat physician ordered a swallowing test and ruled out any physical blockages in her throat, Gaitan-Diaz's primary care doctor referred her to a neurologist, who ordered other tests but still couldn't find anything wrong. Months later, Gaitan-Diaz broke down in the neurologist's office, explaining how she could barely eat and could no longer lift her arms to display merchandise in the store. The neurologist ordered a blood test that revealed she had myasthenia gravis (MG), a rare condition in which the immune system produces antibodies that attack the part of the body where the nerves connect to the muscles, causing weakness and fatigue. The test further revealed that Gaitan-Diaz had muscle-specific tyrosine kinase (MuSK) myasthenia gravis, which means her immune system attacks MuSK proteins essential for muscles and nerves to communicate.
In the years since her diagnosis in 2015, Gaitan-Diaz has been hospitalized several times and required intubation and mechanical ventilation when the muscles she needs to breathe have stopped working. Recently, however, she's had reason to be upbeat: She has enrolled in a clinical trial investigating a new treatment for her type of MG. “I feel excited, scared, and happy all at the same time,” says the 47-year-old, who now lives in central Texas and is traveling to Portland, OR, for the study. “Mostly, I can't wait because I have faith it's going to go well.”
Gaitan-Diaz is one of hundreds of people with myasthenia gravis who sign up for clinical trials every year. Their participation is crucial to determining if a new treatment is safe and effective for humans.
Clinical Trial Basics
Research starts in the laboratory where scientists investigate the cellular processes of a disease, hoping to better understand it and possibly find targets for treatment. This type of research led to the identification of some of the antibodies that play a role in MG. During this phase, scientists can observe the effects of potential therapies on cells in human tissue samples and then in animals.
If a treatment—which may include a drug, device, or surgical procedure—has promise, the next step is to test it in a clinical trial, which requires approval from the U.S. Food and Drug Administration (FDA), and oversight from the Institutional Review Board, a group that ensures that the rights, welfare, and privacy of clinical trial participants are protected.
Clinical trials happen in three phases. Phase 1 evaluates safety and dosage and involves a small group of about 20 to 80 people. Phase 2 includes more people, typically a few hundred, to determine if the treatment is effective as well as safe. Most phase 3 trials are randomly assigned, placebo-controlled and involve a few hundred to thousands of participants. For rare diseases like myasthenia gravis, fewer people are included in phase 2 and 3 clinical trials, which are designed to compare results in people who are given the treatment with those who are given a placebo. In these trials, neither the researchers nor the participants know who is getting the treatment or the placebo.
“We don't know which treatments will fail or succeed until we actually do clinical research,” says Henry Kaminski, MD, FAAN, endowed professor of neurology at George Washington University School of Medicine & Health Sciences in Washington, D.C. “Then we can say with confidence, ‘We understand that this is going to help you, and these are the potential complications.’”
Research on Myasthenia Gravis
Clinical trials have drastically changed treatment options for myasthenia gravis, according to Dr. Kaminski. “Ten years ago, nearly every treatment in myasthenia gravis was based on expert opinion rather than research,” he says. A good example is thymectomy, a surgery in which a person's thymus gland is removed. Doctors have observed since the early 1900s that removing the thymus in some people with myasthenia gravis reduces their symptoms or stops them altogether.
A study published in 2016 in the New England Journal of Medicine provided the first concrete scientific evidence that the procedure works. The phase 3 clinical trial comparing thymectomy plus the steroid prednisone with prednisone alone showed that people who underwent thymectomy and took the steroid were less likely to need prednisone and were hospitalized fewer times than people who didn't undergo the surgery. That work led to guidelines that established which patients were the best candidates for thymectomy.
Interest in clinical trials for myasthenia gravis has increased in the past decade as doctors are better able to diagnose people with specific antibodies that contribute to the disease. “If we know which antibodies are associated with a patient's myasthenia gravis, we can determine which studies to enroll the person in,” says Alejandro Tobon, MD, FAAN, chief of neurology at the South Texas Veterans Health Care System and associate professor of neurology at the University of Texas, both in San Antonio. Neurologists and people with the disease have pushed for new treatments and strategies, which has also spurred research, says Dr. Tobon.
And participating in studies has become easier, says Gil Wolfe, MD, FAAN, Irvin and Rosemary Smith chair of the department of neurology at the University at Buffalo Jacobs School of Medicine and Biomedical Sciences. Researchers no longer require volunteers to go off their medication during the trial. In the past, people risked flare-ups if they participated. Nowadays, some study outcomes can be conducted at home through an eight-question survey called the MG-Activities of Daily Living, which helps researchers assess the effects of various drugs. “We've learned how to design studies and recruit better, and we're now seeing the results from those efforts,” Dr. Wolfe says.
Recent clinical trials have led to the development of a new class of medications called monoclonal antibodies, which target specific parts of the immune system instead of the whole system as immunosuppressants do. Drugs in this class include eculizumab (Soliris), which was approved in 2017; efgartigimod (Vyvgart), approved in 2021; and ravulizumab (Ultomiris), approved in 2022.
And other drugs are either currently being considered for approval by the FDA or will be shortly, says Dr. Wolfe. He also thinks therapeutic agents that work in other ways may be available in the next decade or two.
Enrollment Tips
Cindy Streltzov finds out about clinical trials by searching online databases, attending support groups, and talking to her neurologist. The 71-year-old, who lives in Oakland, CA, was diagnosed with myasthenia gravis in 2019 and has not yet found a treatment that works for her. “I am what they call refractory, which means I'm not really responding to anything and am trying everything out,” Streltzov explains. In 2021, she enrolled in a phase 3 trial at the University of California, San Francisco for a monoclonal antibody drug called rozanolixizumab. When the trial ended, she continued in an “open label” study, which allowed her to get the experimental drug for a period of time.
For his own clinical trials, Dr. Tobon and his research team alert patients, advertise on websites and in newspapers, and reach out to leaders of support groups. They also inform other neurologists and primary care physicians who may refer their own patients for the study.
Before joining a trial, most people have some concerns, says Dr. Kaminski. “Almost every patient asks, ‘Is this safe for me to be doing?’” he says. He explains that while clinical trials are experiments, they all have rules and regulations that protect participants. And in clinical trials, patients are monitored by doctors much more closely than they would be normally. “Most patients see their doctor every three or four months,” Dr. Kaminski says. “In a trial, participants are seen every few weeks, with formalized evaluations.” In addition, research coordinators regularly evaluate and call patients to schedule appointments, check in with them, and answer any questions.
Dr. Tobon recommends asking about the type of therapy, risks, compensation, and time commitment. They should inquire about whether clinic, lab, or telehealth visits are required; if hospitalization is involved; and who pays for hospitalization if a volunteer has severe side effects. Finally, he suggests they ask about the odds of getting a placebo instead of the treatment, and whether access to the treatment is allowed once the study is completed.
“It's essential that patients be able to say, ‘I'd love to be in the trial, but I can't do it because of this and that,’ and then ask if their needs can be accommodated,” Dr. Kaminski says. “I know that some trials reimburse up to a certain level for lost work time, arrange lodging near a medical center, or move visits to virtual.”
All potential volunteers go through an informed consent process overseen by an ethics committee or Institutional Review Board to ensure that patients know what participation would entail and the potential risks. Dr. Tobon recommends asking how medical information will be collected and protected and whether participants can drop out at any point, if necessary. He encourages patients to bring a friend or family member to these meetings to take notes and remind them of any questions they may have forgotten. “The last thing that you want is to start a trial and then realize that you weren't aware of something or something unexpected happens,” Dr. Tobon says.
Clinical trials can be time-consuming. For the study at UCSF, Streltzov traveled to the research site once a week for six weeks. Each all-day visit involved getting blood and urine tests done and having her muscle strength assessed. The study sponsor paid for a taxi from her home in Oakland to San Francisco. After six weeks off, she repeated the process for another six weeks. The entire experience, from the randomized control trial to the open label study, took 10 months.
Gaitan-Diaz's trial-related expenses—flights from Texas to Oregon and hotel accommodations—are paid for by the sponsoring pharmaceutical company. Because it's a phase 1 study—testing the safety and best dosage for a drug called MuSK-CAART—Gaitan-Diaz will receive the drug rather than a placebo. Even if she were in a trial that randomized some people to placebo, she would still participate. “A lot of people hesitate when they notice the placebo thing, but we need to put ourselves out there,” she says. “I have few options, so here I go on my new adventure.”
Dr. Wolfe applauds attitudes like Gaitan-Diaz. “Thanks to people participating, we are learning, the field is advancing, and a future generation of patients with that same disease may very likely benefit.’
3 Promising New Drug Trials
A phase 3 trial of zilucopan randomly assigned 174 people with generalized myasthenia gravis to receive a daily injection of zilucoplan or a placebo. The results, published in The Lancet Neurology in May 2023, showed that after 12 weeks, those who received zilucopan had better scores on the MG-Activities of Daily Living questionnaire than people who received placebo.
Rozanolixizumab was tested in a phase 3 trial that included 200 people with acetylcholine receptor or muscle-specific tyrosine kinase (MuSK) autoantibody positive MG. Participants were assigned to receive one of two doses of the injectable drug or placebo for six weeks. After 43 days, the people who received the drug, whether the lower or higher dose, had better MG-Activities of Daily Living scores than those on placebo, according to results published in The Lancet Neurology in May 2023.
Another drug, rituximab, was studied in a phase 3 trial of people newly diagnosed with generalized MG. Participants were randomized to receive one intravenous infusion of the drug or placebo. After 16 weeks, people who received the drug had fewer flare-ups than those on placebo, according to results published in JAMA Neurology in 2022.
Resources for Clinical Trials
ClinicalTrials.gov
The U.S. National Library of Medicine runs this database of privately and publicly funded clinical studies. In the spring of 2023, the site showed more than 40 myasthenia gravis studies that were recruiting participants.
Myasthenia.org
The Myasthenia Gravis Foundation of America publishes a list on its website of clinical trials that are recruiting.
