The FDA recently approved nipocalimab (Imaavy) as a treatment for people living with generalized myasthenia gravis (gMG). Specifically, nipocalimab is for people with gMG who are 12 and older and who test positive for certain antibodies (AChR and MuSK). The drug works by reducing the levels of these antibodies in your body, which reduces disease symptoms.
Before any new treatment like nipocalimab hits pharmacy shelves, it goes through years of research and testing. It starts with lab studies, then moves to clinical trials with real people. These trials help the FDA see whether the treatment works, who benefits most from the treatment, and whether the treatment is safe.
After these tests, the FDA reviews this information to decide whether the drug should be approved. This is what that process was like for nipocalimab.
Step 1: Discovery and Development
When it comes to drug class, nipocalimab isn’t a breakthrough treatment for myasthenia gravis. It's the third monoclonal antibody in a class called neonatal Fc receptor agonists that the FDA has approved to treat the condition. Before this class of drugs entered the treatment scene, the only available therapies for gMG included cholinesterase inhibitors, immunomodulators, and immunosuppressants.
The FDA approved the previous treatments, rozanolixizumab (Rystiggo) and efgartigimod (Argenx, Vyvgart), in June 2023 and December 2021, respectively. All three Fc receptor agonists have the same underlying action for treating gMG.
“These drugs prevent the salvaging, or recycling, of immunoglobulin G, or IgG, by blocking the neonatal Fc receptor,” says Gil I. Wolfe, MD, SUNY distinguished professor and co-director of the neuromuscular/MDA program at University at Buffalo, SUNY.
IgG makes antibodies that help fight infection in the body, but it can also make antibodies that cause disease. Many autoantibodies in human disease are caused by IgG antibodies, says Wolfe.
“As far as we know, every autoantibody discovered in myasthenia gravis so far is an IgG molecule,” he says. “So these agents would have an obvious application in treating that disease — they prominently and quickly reduce the disease-causing IgG.”
Even though nipocalimab isn’t greatly different from the other Fc receptor agonists, researchers discovered it has a higher affinity than at least one of the other options. This means it binds more tightly and effectively to its specific target, which can mean it works just as well in lower doses than other drugs would.
Step 2: Testing in the Lab
When a drug class is brand new, researchers first test it on animals before trying it on humans. However, the FDA will soon phase out animal testing for monoclonal antibodies, instead relying on computer programs powered by artificial intelligence (AI) to predict whether a drug might be harmful, along with testing the drug on cells or mini versions of human organs (called organoids) in a lab to see how safe it is.
Step 3: Testing in People
In order to demonstrate a drug is safe, researchers conduct clinical trials with humans in progressive phases.
Phase I trials: This stage is mostly about checking the safety of the treatment. These trials are small, involving only around 30 to 80 volunteers who are generally healthy (i.e. don’t have the condition the drug treats) or in people who have tried all other options without success and are in end stages of their disease (cancer treatments are one example). These volunteers take the drug at low doses and researchers watch them closely for any side effects. Then they may increase the dose slowly.
Phase I usually lasts a few months to a year. About 70% of drugs move on from this phase to phase II.
Nipocalimab’s clinical trials took place in a study called Vivacity. In the study’s phase I trials, researchers found that people taking the treatment had very few adverse effects and tolerated the drug well.
Phase II trials: Phase II studies help researchers find out if a new drug — in this case nipocalimab — actually works for the specific illness or condition they intend it to treat. These trials usually include around 100 to 300 people and can last anywhere from a few months to two years.
Researchers also look at how much of the drug works best and how often people should take it. Most phase II trials are randomized. This means people are randomly assigned to different groups: one group gets the new drug, another gets an existing treatment or a placebo (a pill with no medicine in it).
This helps researchers fairly compare results. Many of these trials are also double-blind, which means neither the patient nor the doctor knows which treatment the person is getting. This keeps the results as accurate as possible.
Since more people are involved in phase II than in phase I, researchers also gather more information about side effects. About one-third of the drugs that pass both phase I and phase II will move on to phase III testing.
For nipocalimab, the Vivacity phase II trial showed that it reduced disease symptoms in people with gMG who hadn’t had success with other treatments.
“[Results were] based on a significant reduction versus the placebo arm on the MG Activities of Daily Living scale, or MG-ADL, which is a tool I helped create with my colleagues at University of Texas Southwestern Medical School in the late 1990s,” says Wolfe. “All three Fc receptor antagonists showed an improvement on that scale.”
Participants in phase II also continued to tolerate the drug well, with very few side effects.
Phase III trials: Phase III studies involve large groups of people — often hundreds or even thousands — who have the condition the drug is meant to treat. These trials take place at many different hospitals or clinics, which helps researchers see how the drug works in a wide range of people.
The Vivacity phase III trials happened in 81 myasthenia gravis outpatient centers in 17 countries in Asia-Pacific, Europe, and North America.
Results from these trials showed that people taking nipocalimab had a 4.70-point improvement on the MG-ADL scale. Experts consider a 2-point change on the scale “clinically significant,” which means it has a noticeable impact on a person’s health and well-being. Participants also continued to have very few negative side effects.
“As an overall class, these medications have really been quite safe,” says Wolfe. “There has been some suggestion of slightly increased infection rates on these agents versus placebo, and some of them have lowered albumin levels modestly, which may contribute to some swelling and some increase in lipid values, which is cholesterol and LDL, but these effects haven’t been dramatic.”
A second study outside of Vivacity also took place to test the treatment in children.
“It was a small study and it is still ongoing,” says Wolfe. “In an open-label study of nipocalimab, children also showed a positive clinical response, and therefore the FDA did approve it for childhood use from age 12 onwards. This is the first agent we have had that is actually approved in the pediatric population for MG.”
Step 4: Checking by Experts
After a drug company completes phase III studies, they can ask the FDA for permission to sell the drug by submitting a New Drug Application (NDA). This application includes all the scientific information collected during every stage of testing to show the drug's safety and effectiveness.
When the FDA approves a drug, it means the Center for Drug Evaluation and Research (CDER) has carefully reviewed data about how the drug works. If they decide the benefits of the drug are greater than the possible risks for the people it’s meant to treat, they approve the drug.
Step 5: Watching Over Time
The FDA uses a strict process to make sure a drug is safe and works well before approving it. Even after a drug is approved, the FDA keeps watching how it performs through a process called post-marketing surveillance.
“There is still, in a very rigorous fashion, data being collected on patients who have graduated from the randomized control portion of the trial and are still being followed,” says Wolfe.
“What is being followed are safety events as well as efficacy. What they want to know is, do people continue to show a favorable response from the medication over time? Do people have a sustained response to the agent? And it appears that most do,” he says.
