Stabilizing long COVID POTS<\/p>\n
Efgartigimod was first approved under the name Vyvgart as a treatment for the rare disease myasthenia gravis. Like POTS, myasthenia gravis involves a breakdown in communication between the nervous system and the rest of the body. The drug works on the neonatal Fc receptor (FcRn), which transports antibodies. Blocking FcRn can stop certain autoantibodies that interfere with the body\u2019s communication from reentering circulation.<\/p>\n
So researchers at Argenx, Vyvgart\u2019s manufacturer, thought Vyvgart might be able to treat POTS as well. The company sponsored a trial that enrolled 53 patients, including Delli Gatti.<\/p>\n
Vyvgart was a game changer for Delli Gatti. While she was on the drug, midodrine and compression socks no longer felt necessary. She went months without a flare-up, although she sometimes felt like she was on the brink of one. At school, she was able to manage a full course load again, and when summer rolled around, she picked up a physically demanding job, staining wood in the summer heat.<\/p>\n
Other patients in the trial reported similar improvements. Nicole Barrick, a nurse with long COVID POTS who\u2019d previously been unable to stand for more than 1 min without developing extreme fatigue, gradually got her strength back and began working part time again. Others saw improvements in their energy levels. Their heart rates evened out. Their fatigue began to dissipate.<\/p>\n
When the initial study period ended, Argenx launched an open-label extension so that participants could stay on the drug, or transition to it if they\u2019d been in the placebo group, and many did. Some of the participants got to know each other through a group on the messaging app Discord. Barrick estimates that at least 12 study participants responded well to Vyvgart.<\/p>\n
As far as anyone could tell, things were going well. Then, in June 2024, one of the patients in the Discord group spotted a paragraph halfway down a press release highlighting Argenx\u2019s upcoming R&D day<\/a>. In the long COVID POTS trial, Vyvgart had shown \u201cno clinically meaningful improvement compared to placebo,\u201d the release read. Argenx would not move forward with development.<\/p>\n The press release dropped less than 24 h before Delli Gatti was supposed to go in for her next Vyvgart infusion. About an hour after the Discord message, Delli Gatti\u2019s patient coordinator called and canceled her appointment at the clinic.<\/p>\n \u201cThe communication piece was kind of trash,\u201d Delli Gatti says. \u201cI have no idea where the patient coordinator heard about it. But they had no warning. . . . She was scrambling.\u201d (The clinic has since closed, and attempts to reach former employees were unsuccessful.) A research assistant at Barrick\u2019s clinical site was apparently scrambling too. The assistant called Barrick early in the morning, asking if she\u2019d \u201cseen the press release yet,\u201d according to Barrick. Other trial participants began contacting their respective clinical sites to \u201cfind out what was going on,\u201d she says. They felt they\u2019d been left in the dark, without access to their own data or a path forward for treatment.<\/p>\n Ben Petok, a spokesperson for Argenx, says that when the study ended, the company communicated in writing and verbally with patient advocacy groups and clinical trial investigators. The company also put together a question-and-answer document, which Petok shared with C&EN. \u201cWe did learn that some patients felt better while participating in this clinical trial and we see that in the data,\u201d the Q&A reads. \u201cWhat we don\u2019t see in the data is that efgartigimod was the reason those patients felt better during the trial as there was no meaningful difference in the proportion of patients who felt better on efgartigimod versus placebo.\u201d<\/p>\n Stanford Medicine neurologist Mitchell Miglis, one of the site investigators, says by email that there was an unexpectedly high placebo response. Petok tells C&EN that the trial\u2019s control arm used a 0.9% saline solution, which he describes as a \u201cstandard placebo.\u201d (Intravenous saline can reduce symptoms in POTS<\/a>, since it increases blood volume.)<\/p>\n Miglis says he doesn\u2019t know how Argenx decided to stop the trial or communicate with patients. \u201cIt is very common for companies to halt trials when results are negative,\u201d he writes in an email. \u201cI do recall it was fairly abrupt, but I\u2019m not sure this is unusual in clinical trials.\u201d Patient advocates disagree. \u201cThat is poor form on the part of any pharma company,\u201d says Lauren Stiles, president of Dysautonomia International, a nonprofit that advocates for people with POTS and other autonomic nerve disorders.<\/p>\n Stiles says she reached out to Argenx on behalf of the trial participants, asking if patients who responded well to Vyvgart could stay on the drug through a compassionate-use protocol. The company declined the request, according to Stiles and Barrick. Petok says he is not aware of any formal compassionate-use requests Argenx received after the trial.<\/p>\n \u201cI never heard back after that,\u201d Barrick says.<\/p>\n Postviral illnesses beyond POTS<\/p>\n Long COVID takes many forms. It disrupts people\u2019s bodies in different ways, depending on the individual. Some people end up with lower natural killer (NK) cell activity, others with mitochondrial dysfunction; plenty endure both, among other physiological changes. Researchers have chronicled more than 200 symptoms that can crop up in the wake of a COVID-19 infection, ranging from loss of smell and gastrointestinal changes to autonomic dysfunction\u2014like POTS\u2014and, perhaps most seriously, a profound, all-encompassing fatigue brought on by even the mildest activities.<\/p>\n Ramiro Valdes falls into the last camp. A lawyer in Miami, he got COVID-19 in March 2020 and, like so many first wavers\u2014people who were infected in the initial wave of the pandemic\u2014\u201cbecame ill, and the symptoms never left,\u201d he says. Valdes spent the next few years mostly bedbound. He continued working remotely, using medical leave from time to time, before finally quitting in 2023. \u201cI was crashing way too much, and I used all my [medical leave],\u201d Valdes says.<\/p>\n Valdes was diagnosed with long COVID and myalgic encephalomyelitis, or ME, which is sometimes referred to as chronic fatigue syndrome (CFS) or by the hybrid abbreviation ME\/CFS. In 2023, a friend told him about a trial near Miami testing Ampligen, a drug approved for ME\/CFS in Argentina, to see whether it would treat long COVID. Valdes enrolled and started getting infusions around July of that year.<\/p>\n Rintatolimod is a double-stranded RNA made up of a single polyinosine strand hydrogen bonded with a single polycytosine strand containing a uridine (red) that appears once every 12 cytosines. The hydrogen-bonding mismatch between inosine and uridine creates thermodynamic instability.<\/p>\n Valdes describes dramatic improvements around the 2-month mark. He went from being able to walk a maximum of 2,000 steps a day to consistently hitting anywhere between 8,000 and 10,000 steps. Unfortunately, the gains didn\u2019t stick around after he stopped taking Ampligen when the study period ended in October 2023. By December of that year, Valdes\u2019s baseline had started to decrease again. For the next 12 months, he was once again bedbound 23 h a day. He now relies on disability income and parental support.<\/p>\n Ampligen, or rintatolimod, is an unusual molecule. It\u2019s been around since the 1970s, when researcher William A. Carter modified a double-stranded RNA molecule. Ampligen is a toll-like receptor 3 (TLR3) agonist. It stimulates TLR3, a protein critical to immune responses, and in turn induces interferons, cytokines that interfere with viral replication.<\/p>\n Carter joined Hemispherx Biopharma in 1978 to develop Ampligen for market, believing that its immune-stimulating properties could make it a potent treatment for viruses, cancer, and chronic conditions, including ME\/CFS.<\/p>\n But the going has been slow\u2014and fraught. Hemispherx has been trying and failing to get the FDA to approve Ampligen as an ME\/CFS treatment since 2007. The agency refused to even consider its first application, citing deficiencies including missing and inadequate data, database discrepancies, and inconsistencies in statistical analysis. Hemispherx\u2019s attempts to address those concerns didn\u2019t yield much: the FDA rejected a revamped application in 2009.<\/p>\n As far as the agency was concerned, Hemispherx needed to run another, better trial. But instead, Hemispherx reanalyzed its existing data and presented it to the FDA and an advisory committee in 2012. It appeared by then that Ampligen had helped improve exercise tolerance in at least some patients<\/a>, as measured by time on a treadmill, but the FDA and the committee agreed that Hemispherx\u2019s data weren\u2019t statistically significant.<\/p>\n Since the FDA\u2019s last denial<\/a> 13 years ago, Hemispherx, which rebranded as AIM ImmunoTech in 2019<\/a>, has not initiated any new placebo-controlled trials of Ampligen in ME\/CFS. Instead, it has run expanded-access programs, which allow qualifying ME\/CFS patients to enroll in unblinded studies where they know they are receiving Ampligen. Insurance companies pay for the care team. Patients cover the cost of the drug, which is around $40,000 a year. The expanded-access studies have become established as the only way for people with ME\/CFS\u2014and long COVID, which has an overlapping set of symptoms\u2014to get access to Ampligen in the absence of FDA approval. Only Argentina has approved Ampligen for treatment of severe ME\/CFS.<\/p>\n AIM\u2019s expanded-access model is basically identical to the compassionate-care protocol that the Vyvgart trial participants sought from Argenx. But it isn\u2019t particularly useful for regulatory submissions. When a patient knows they are taking a drug, and when that drug isn\u2019t compared with a placebo, it\u2019s difficult to prove that any improvements are attributable to the drug and not some confounding factor.<\/p>\n The stories of Vyvgart and Ampligen illustrate an ethical minefield that manufacturers must navigate. Launch an expanded-access program, and you can\u2019t get the kind of data that FDA reviewers care about, imperiling a drug\u2019s chances at approval. Spend years trying to get funds, clinical trial sites, and a study protocol that satisfies regulators, and you leave patients in limbo. Some drug companies die in the interim. Some patients do too.<\/p>\n Daniel Peterson is a physician and ME\/CFS expert who\u2019s been giving patients Ampligen through various studies since 1987. \u201cPatients told me they were grateful for the years they\u2019d been on the drug under whichever protocol they\u2019d been on, but there was no way to continue it,\u201d he says. \u201cFor many years, it was, \u2018We\u2019ll wait and see, and we\u2019ll get FDA approval.\u2019 \u201d<\/p>\n But the expanded-access studies \u201cwould never be the appropriate route for doing more trials or even to open a treatment center,\u201d Peterson says. FDA approval has not happened, and the expanded-access studies are on borrowed time.<\/p>\n \u201cWhy the company has never found a way to do a decent follow-up trial in the past 40 years or so, I don\u2019t know,\u201d says Cort Johnson, an ME\/CFS patient who runs an online ME\/CFS and fibromyalgia resource called Health Rising. AIM has maintained that data from the expanded-access studies could support future studies or FDA submissions.<\/p>\n Ampligen access dwindles<\/p>\n Without Ampligen, Valdes\u2019s condition was seriously deteriorating. His father called a research site in North Carolina that was running an Ampligen study in ME\/CFS. Valdes says his father spoke with a receptionist a few times, but \u201che never got any straight answer\u201d about how exactly to move forward.<\/p>\n \u201cHe stopped trying to contact them because nothing was clear,\u201d Valdes says.<\/p>\n Then, in late 2025, some patients noticed that the official record for the ME\/CFS expanded-access study on ClinicalTrials.gov was adorned with a dark red flag. The study, the site said, was \u201ctemporarily not available,\u201d and patients didn\u2019t know why.<\/p>\n As it turns out, the reason comes down to corporate resources. AIM is running out of money. The expanded-access studies don\u2019t bring in much revenue, and the company has stopped trying to sell Ampligen in Argentina, because hyperinflation has made selling the drug cost prohibitive.<\/p>\n AIM\u2019s leaders recently decided to devote all the company\u2019s resources to a single program developing Ampligen as a pancreatic cancer treatment. Everything else\u2014including placebo-controlled trials, like the one Valdes was in for long COVID, and the expanded-access studies for ME\/CFS\u2014has been \u201cplaced on hold,\u201d according to AIM spokesperson Jenene Thomas. AIM categorizes the ME\/CFS expanded-access program as \u201cactive,\u201d but it is not enrolling any new patients.<\/p>\n A person lies on the ground as part of a \u201cdie-in\u201d demonstration in 2022 calling for better access to care for people with long COVID and myalgic encephalomyelitis.<\/p>\n Credit: The pancreatic cancer trial is the top priority because it could \u201clead to the most lucrative outcome,\u201d AIM says in a recent securities filing<\/a>, but the company doesn\u2019t have enough money to complete even that study. At the end of March, the company estimated that its short-term financial needs were between $7.2 million and $10.8 million\u2014far more than the $5.9 million cash it had on hand at the time. Its revenues were only $22,000 in the first quarter of this year; the company posted a $3 million net loss in the same period.<\/p>\n For patients who\u2019d come to rely on the expanded-access studies to get Ampligen, the situation is dire. By April, only four participants were taking Ampligen for ME\/CFS. That number held true in July. \u201cThere is no projected completion date yet\u201d for the pancreatic cancer trial and thus no projection of when other studies might resume, says Charles Lapp, a physician and ME\/CFS expert in Charlotte, North Carolina, whose clinic has been a site for an expanded-access study. Lapp is also a consulting medical officer for AIM.<\/p>\n Mark Stewart was one of Lapp\u2019s ME\/CFS patients. He participated in the expanded-access study in North Carolina between August 2023 and February 2025. Like Valdes\u2019s, Stewart\u2019s condition improved significantly while he was on Ampligen. \u201cIt was, for my physical capacity, miraculous,\u201d he says. \u201cFor my cognitive capacity, it\u2019s harder to tell.\u201d But 18 months was all Stewart could afford. He hoped Ampligen would have a lasting effect, but after 6 weeks off the drug, he lost everything he\u2019d gained.<\/p>\n “Just to not feel sick is wonderful. When I relapse, I feel sick again.”<\/p>\n Mary Schweitzer, patient with myalgic encephalomyelitis\/chronic fatigue syndrome<\/p>\n Share Relapsing is common, according to Peterson. His patient Mary Schweitzer first started on Ampligen for her ME\/CFS around 30 years ago at a hospital in Delaware, where she lived at the time with her husband and kids. She set three goals as benchmarks for her recovery: put her feet in the ocean, read a book, and dance at her son\u2019s wedding. She did all three within 6 months of starting Ampligen. But Schweitzer was forced to stop and restart the drug several times over the next few years as the Ampligen studies changed hands, and she relapsed each time she went off the drug.<\/p>\n \u201cWhen you\u2019re sick with this, you feel sick 24 hours a day, 60 minutes an hour, 60 seconds a minute,\u201d Schweitzer says. \u201cJust to not feel sick is wonderful. When I relapse, I feel sick again.\u201d<\/p>\n In 2010, Schweitzer moved to Incline Village, Nevada, so she could consistently see Peterson, who by then was one of the only doctors in the country administering Ampligen. But she and other patients were only ever able to buy the drug a month or two at a time, and Peterson has warned with increasing urgency about low supply.<\/p>\n The people who had hoped for an Ampligen approval\u2014or at least a lower price tag for the expanded-access protocol\u2014are beginning to make other plans. One has identified a retirement community close to family members who can offer physical support. Others have looked into other drugs. Valdes, for instance, enrolled in a study testing the monoclonal antibody sipavibart in long COVID, although he says it hasn\u2019t made a difference for him.<\/p>\n Stewart recently had surgery to remove a growth on his thymus, a small organ where immune cells develop, and his condition briefly improved. But after about 2 weeks, it began deteriorating again. Some days, Stewart cannot think straight enough to talk to his mother, who\u2019s become his caretaker. Other days, his thoughts turn bleak.<\/p>\n \u201cI don\u2019t know if this is something I would pull the trigger on if I got approved, but just to give you a sense of my quality of life, I have been actively exploring and researching assisted-suicide options in Switzerland,\u201d Stewart says.<\/p>\n Patients are left in limbo<\/p>\n Corporate realities often do not align with the needs of very sick people.<\/p>\n AIM has tried and failed to get additional funding to test Ampligen in long COVID and related conditions. Former scientific officer Chris McAleer told C&EN in 2024<\/a> that the company expanded into long COVID in part because he and his peers thought there would be money from the US National Institutes of Health\u2019s RECOVER program. But RECOVER has not prioritized drug trials. McAleer left AIM last year.<\/p>\n Peterson believes that AIM\u2019s decision to deprioritize long COVID and ME\/CFS drug development comes down to \u201ccorporate pharmaceutical\u201d realities. \u201cIt\u2019s just what it is,\u201d he says. \u201cI think, for example, if someone came to AIM and said, \u2018I want to run a trial for, let\u2019s say, $1.2 million, and here\u2019s the money. You produce the drug and monitor it,\u2019 I think they would be happy to go along with that.\u201d<\/p>\n According to Barrick, the nurse who participated in the Vyvgart trial for long COVID POTS, Argenx has told patient advocates that an independent researcher or medical facility would need to do the legwork for an additional study. Argenx spokesperson Petok says the company has no intention of running another trial of Vyvgart in long COVID POTS, based on the previous trial results. \u201cI think most drug developers would follow similar protocols,\u201d he says. \u201cI don\u2019t think that it is in anybody\u2019s interest to continue to provide therapies once they have been demonstrated not to work.\u201d<\/p>\n “The reason why so many trials get stopped or paused is because of mediocre results.”<\/p>\n Sadie Whittaker, chief scientific officer, Solve ME<\/p>\n Share Some patients are still mobilizing to get researchers on board with a new and different trial. In October, Delli Gatti, Barrick, and five others who say their symptoms improved during the Vyvgart trial in long COVID POTS published an op-ed<\/a> in The Sick Times, a nonprofit publication covering long COVID and postinfectious diseases, asking the US government to pick up where Argenx left off and study the drug.<\/p>\n Crucially, they write, a new study will need a different design from the one for the Argenx-sponsored trial. That trial used two clinically validated questionnaires as primary end points to measure efficacy: Composite Autonomic Symptom Score 31, or COMPASS 31, and the Malm\u00f6 POTS Symptom, or MAPS, score. Both are commonly used in POTS trials. Argenx\u2019s Q&A describes them as \u201cthe most widely recognized clinical tools for POTS.\u201d<\/p>\n But these end points missed a critical part of the picture, Delli Gatti and Barrick say. Patients may have continued to experience symptoms including dizziness and fatigue, but it took much more to trigger those symptoms, allowing several participants to return to work, school, and exercise. \u201cWe continued to have symptoms, but they were manageable,\u201d Barrick says.<\/p>\n Miglis, the Stanford investigator, says in an email that while the trial \u201cwas well designed,\u201d researchers \u201cneed more specific end points and biomarkers for these kinds of trials.\u201d Argenx\u2019s scientific team has submitted results to a peer-reviewed journal, but they have not yet been published.<\/p>\n At the Icahn School of Medicine at Mount Sinai, the neuroscientist and long COVID expert David Putrino is collecting blood samples from some of the patients who responded well to Vyvgart. He hopes the samples could enable better immune phenotyping so clinicians can predict whether a person with long COVID might respond to Vyvgart or similar drugs.<\/p>\n![\"Chemical](\"https:\/\/www.newsbeep.com\/ie\/wp-content\/uploads\/2026\/07\/FEATURE--Long-Covid-drug-development-falters--confuses-patients---540699.webp\")
\n Chemical structure of rintatolimod.<\/p>\n![\"A](\"https:\/\/www.newsbeep.com\/ie\/wp-content\/uploads\/2026\/07\/FEATURE--Long-Covid-drug-development-falters--confuses-patients---538500.webp\")
\n A person wearing a white KN95 mask lies on grassy ground. At their head is a gravestone made from cardboard with the words \u201cDIED FROM COVID\u201d handwritten on it.<\/p>\n
\n Bryan Olin Dozier\/NurPhoto via Associated Press<\/p>\n
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