An Astounding Treatment at an Astounding Price: Who Gets to Benefit?
Kelly Mantoan was nursing her newborn son, Teddy, in the NICU in a Philadelphia hospital when her doctor came in and silently laid a hand on her shoulder. Immediately, Kelly knew what the gesture meant and started to sob: Teddy, like his one-year-old brother, Fulton, had just tested positive for a neuromuscular condition called spinal muscular atrophy (SMA).
The boys were 8 and 10 when Kelly heard about an experimental new treatment, still being tested in clinical trials, called Spinraza.
"We knew that [SMA] was a genetic disorder, and we knew that we had a 1 in 4 chance of Teddy having SMA," Mantoan recalls. But the idea of having two children with the same severe disability seemed too unfair for Kelly and her husband, Tony, to imagine. "We had lots of well-meaning friends tell us, well, God won't do this to you twice," she says. Except that He, or a cruel trick of nature, had.
In part, the boys' diagnoses were so devastating because there was little that could be done at the time, back in 2009 and 2010, when the boys were diagnosed. Affecting an estimated 1 in 11,000 babies, SMA is a degenerative disease in which the body is deficient in survival motor neuron (SMN) protein, thanks to a genetic mutation or absence of the body's SNM1 gene. So muscles that control voluntary movement – such as walking, breathing, and swallowing – weaken and eventually cease to function altogether.
Babies diagnosed with SMA Type 1 rarely live past toddlerhood, while people diagnosed with SMA Types 2, 3, and 4 can live into adulthood, usually with assistance like ventilators and feeding tubes. Shortly after birth, both Teddy Mantoan and his brother, Fulton, were diagnosed with SMA Type 2.
The boys were 8 and 10 when Kelly heard about an experimental new treatment, still being tested in clinical trials, called Spinraza. Up until then, physical therapy was the only sanctioned treatment for SMA, and Kelly enrolled both her boys in weekly sessions to preserve some of their muscle strength as the disease marched forward. But Spinraza – a grueling regimen of lumbar punctures and injections designed to stimulate a backup survival motor neuron gene to produce more SMN protein – offered new hope.
In clinical trials, after just a few doses of Spinraza, babies with SMA Type 1 began meeting normal developmental milestones – holding up their heads, rolling over, and sitting up. In other trials, Spinraza treatment delayed the need for permanent ventilation, while patients on the placebo arm continued to lose function, and several died. Spinraza was such a success, and so well tolerated among patients, that clinical trials ended early and the drug was fast-tracked for FDA approval in 2016. In January 2017, when Kelly got the call that Fulton and Teddy had been approved by the hospital to start Spinraza infusions, Kelly dropped to her knees in the middle of the kitchen and screamed.
Spinraza, manufactured by Biogen, has been hailed as revolutionary, but it's also not without drawbacks: Priced per injection, just one dose of Spinraza costs $125,000, making it one of the most expensive drugs on the global market. What's worse, treatment requires a "loading dose" of four injections over a four-week period, and then periodic injections every four months, indefinitely. For the first year of treatment, Spinraza treatment costs $750,000 – and then $375,000 for every year thereafter.
Last week, a competitive treatment for SMA Type 1 manufactured by Novartis burst onto the market. The new treatment, called Zolgensma, is a one-time gene therapy intended to be given to infants and is currently priced at $2.125 million, or $425,000 annually for five years, making it the most expensive drug in the world. Like Spinraza, Zolgensma is currently raising challenging questions about how insurers and government payers like Medicaid will be able to afford these treatments without bankrupting an already-strained health care system.
To Biogen's credit, the company provides financial aid for Spinraza patients with private insurance who pay co-pays for treatment, as well as for those who have been denied by Medicaid and Medicare. But getting insurance companies to agree to pay for Spinraza can often be an ordeal in itself. Although Fulton and Teddy Mantoan were approved for treatment over two years ago, a lengthy insurance battle delayed treatment for another eight months – time that, for some SMA patients, can mean a significant loss of muscular function.
Kelly didn't notice anything in either boy – positive or negative – for the first few months of Spinraza injections. But one day in November 2017, as Teddy was lowered off his school bus in his wheelchair, he turned to say goodbye to his friends and "dab," – a dance move where one's arms are extended briefly across the chest and in the air. Normally, Teddy would dab by throwing his arms up in the air with momentum, striking a pose quickly before they fell down limp at his sides. But that day, Teddy held his arms rigid in the air. His classmates, along with Kelly, were stunned. "Teddy, look at your arms!" Kelly remembers shrieking. "You're holding them up – you're dabbing!"
Teddy and Fulton Mantoan, who both suffer from spinal muscular atrophy, have seen life-changing results from Spinraza.
(Courtesy of Kelly Mantoan)
Not long after Teddy's dab, the Mantoans started seeing changes in Fulton as well. "With Fulton, we realized suddenly that he was no longer choking on his food during meals," Kelly said. "Almost every meal we'd have to stop and have him take a sip of water and make him slow down and take small bites so he wouldn't choke. But then we realized we hadn't had to do that in a long time. The nurses at school were like, 'it's not an issue anymore.'"
For the Mantoans, this was an enormous relief: Less choking meant less chance of aspiration pneumonia, a leading cause of death for people with SMA Types 1 and 2.
While Spinraza has been life-changing for the Mantoans, it remains painfully out of reach for many others. Thanks to Spinraza's enormous price tag, the threshold for who gets to use it is incredibly high: Adult and pediatric patients, particularly those with state-sponsored insurance, have reported multiple insurance denials, lengthy appeals processes, and endless bureaucracy from insurance and hospitals alike that stand in the way of treatment.
Kate Saldana, a 21-year-old woman with Type 2 SMA, is one of the many adult patients who have been lobbying for the drug. Saldana, who uses a ventilator 20 hours each day, says that Medicaid denied her Spinraza treatments because they mistakenly believed that she used a ventilator full-time. Saldana is currently in the process of appealing their decision, but knows she is fighting an uphill battle.
Kate Saldana, who suffers from Type 2 SMA, has been fighting unsuccessfully for Medicaid to cover Spinraza.
(Courtesy of Saldana)
"Originally, the treatments were studied and created for infants and children," Saldana said in an e-mail. "There is a plethora of data to support the effectiveness of Spinraza in those groups, but in adults it has not been studied as much. That makes it more difficult for insurance to approve it, because they are not sure if it will be as beneficial."
Saldana has been pursuing treatment unsuccessfully since last August – but others, like Kimberly Hill, a 32-year-old with SMA Type 2, have been waiting even longer. Hill, who lives in Oklahoma, has been fighting for treatment since Spinraza went on the U.S. market in December 2016. Because her mobility is limited to the use of her left thumb, Hill is eager to try anything that will enable her to keep working and finish a Master's degree in Fire and Emergency Management.
"Obviously, my family and I were elated with the approval of Spinraza," Hill said in an e-mail. "We thought I would finally have the chance to get a little stronger and healthier." But with Medicare and Medicaid, coverage and eligibility varies wildly by state. Earlier this year, Medicaid approved Spinraza for adult patients only if a clawback clause was attached to the approval, meaning that under certain conditions the Medicaid funds would need to be paid back. Because of the clawback clause, hospitals have been reluctant to take on Spinraza treatments, effectively barring adult Medicaid patients from accessing the drug altogether.
Hill's hospital is currently in negotiations with Medicaid to move forward with Spinraza treatment, but in the meantime, Hill is in limbo. "We keep being told there is nothing we can do, and we are devastated," Hill said.
"I felt extremely sad and honestly a bit forgotten, like adults [with SMA] don't matter."
Between Spinraza and its new competitor, Zolgensma, some are speculating that insurers will start to favor Zolgensma coverage instead, since the treatment is shorter and ultimately cheaper than Spinraza in the long term. But for some adults with SMA who can't access Spinraza and who don't qualify for Zolgensma treatment, the issue of what insurers will cover is moot.
"I was so excited when I heard that Zolgensma was approved by the FDA," said Annie Wilson, an adult SMA patient from Alameda, Calif. who has been fighting for Spinraza since 2017. "When I became aware that it was only being offered to children, I felt extremely sad and honestly a bit forgotten, like adults [with SMA] don't matter."
According to information from a Biogen representative, more than 7500 people worldwide have been treated with Spinraza to date, one third of whom are adults.
While Spinraza has been revolutionary for thousands of patients, it's unclear how many more lives state agencies and insurance companies will allow it to save.
Scientists aim to preserve donkeys, one frozen embryo at a time
Every day for a week in 2022, Andres Gambini, a veterinarian and senior lecturer in animal science at the University of Queensland in Australia, walked into his lab—and headed straight to the video camera. Trained on an array of about 50 donkey embryos, all created by Gambini’s manual in vitro fertilization, or IVF, the camera kept an eye on their developmental progress. To eventually create a viable embryo that could be implanted into a female donkey, the embryos’ cells had to keep dividing, first in two, then in four and so on.
But the embryos weren’t cooperating. Some would start splitting up only to stop a day or two later, and others wouldn’t start at all. Every day he came in, Gambini saw fewer and fewer dividing embryos, so he was losing faith in the effort. “You see many failed attempts and get disappointed,” he says.
Gambini and his team, a group of Argentinian and Spanish researchers, were working to create these embryos because many donkey populations around the world are declining. It may sound counterintuitive that domesticated animals may need preservation, but out of 28 European donkey breeds, 20 are endangered and seven are in critical status. It is partly because of the inbreeding that happened over the course of many years and partly because in today’s Western world donkeys aren’t really used anymore.
“That's the reason why some breeds begin to disappear because humans were not really interested in having that specific breed anymore,” Gambini says. Nonetheless, in Africa, India and Latin America millions of rural families still rely on these hardy creatures for agriculture and transportation. And the only two wild donkey species—Equus africanus in Africa and Equus hemionus in Asia—are also dwindling, due to losing their habitats to human activities, diseases and slow reproduction rates. Gambini’s team wanted to create a way to preserve the animals for the future. “Donkeys are more endangered than people realize,” he says.
There’s much more to donkeys' trouble though. For the past 20 or so years, they have been facing a huge existential threat due to their hide gelatin, a compound derived from their skins by soaking and stewing. In Chinese traditional medicine, the compound, called ejiao, is believed to have a medicinal value, so it’s used in skin creams, added to food and taken in capsules. Centuries ago, ejiao was a very expensive luxury product available only for the emperor and his household. That changed in the 1990s when the Chinese economy boomed, and many people were suddenly able to afford it. “It went from a very elite product to a very popular product,” says Janneke Merkx, a campaign manager at The Donkey Sanctuary, a United Kingdom-based nonprofit organization that keeps tabs on the animals’ welfare worldwide. “It is a status symbol for gift giving.”
Having evolved in the harsh and arid mountainous terrains where food and water were scarce, donkeys are extremely adaptable and hardy. But the Donkey Sanctuary documented cases in which an entire village had their animals disappear overnight, finding them killed and skinned outside their settlement.
The Chinese donkey population was quickly decimated. Unlike many other farm animals, donkeys are finicky breeders. When stressed and unhappy, they don’t procreate, so growing them in large industrial settings isn’t possible. “Donkeys are notoriously slow breeders and really very difficult to farm,” says Merkx. “They are not the same as other livestock like sheep and pigs and cattle.” Within years the, the donkey numbers in China dropped precipitously. “China used to have the largest donkey population in the world in the 1990s. They had 11 million donkeys, and it's now down to less than 3 million, and they just can't keep up with the demand.”
To keep the ejiao conveyor going, some producers turned to the illegal wildlife trade. Poachers began to steal and slaughter donkeys from rural villages in Africa. The Donkey Sanctuary documented cases in which an entire village had their animals disappear overnight, finding them killed and skinned outside their settlement. Exactly how many creatures were lost to the skin trade to-date isn’t possible to calculate, says Faith Burden, the Donkey Sanctuary’s director of equine operations. Traditionally a poor people’s beast of burden, donkey counts are hard to keep track of. “When an animal doesn't produce meat, milk or eggs or whatever edible product, they're often less likely to be acknowledged in a government population census,” Burden says. “So reliable statistics are hard to come by.” The nonprofit estimates that about 4.8 million are slaughtered annually.
During their six to seven thousand years of domestication, donkeys rarely got the full appreciation for their services. They are often compared to horses, which doesn’t do them justice. They’re entirely different animals, Burden says. Built for speed, horses respond to predators and other dangers by running as fast as they can. Donkeys, which originate from the rocky, mountainous regions of Africa where running is dangerous, react to threats by freezing and assessing the situation for the best response. “Those so-called stubborn donkeys that won’t move as you want, they are actually thinking ‘what’s the best approach,’” Burden says. They may even choose to fight the predators rather than flee, she adds. “In some parts of the world, people use them as guard animals against things like coyotes and wolves.”
Scientists believe that domestic donkeys take their origin from Equus africanus or African wild ass, originally roaming where Kenya, Ethiopia and Eritrea are today. Having evolved in the harsh and arid mountainous terrains where food and water were scarce, they are extremely adaptable and hardy. Research finds that they can go without water for 72 hours and then drink their fill without any negative consequences. Their big jaws let them chew tough desert shrubs, which horses can’t exist on. Their large ears help dissipate heat. Their little upright hooves are a perfect fit for the uneven rocky or other dangerous grounds. Accustomed to the mountain desert climate with hot days and cold nights, they don’t mind temperature flux.
“The donkey is the most supremely adapted animal to deal with hostile conditions,” Burden says. “They can survive on much lower nutritional quality food than a cow, sheep or horse. That’s why communities living in some of the most inhospitable places will often have donkeys with them.” And that’s why losing a donkey to an illegal skin trade can devastate a family in places like Eritrea. Suddenly everything from water to firewood to produce must be carried by family members—and often women.
Workers unloading donkeys at the Shinyanga slaughterhouse in Tanzania. Fearing a future in which donkeys go extinct, scientists have found ways to cryopreserve a donkey embryo in liquid nitrogen.
TAHUCHA
One can imagine a time when worldwide donkey populations may dwindle to the point that they would need to be restored. That includes their genetic variability too. That’s where the frozen embryos may come in handy. We may be able to use them to increase the genetic variability of donkeys, which will be especially important if they get closer to extinction, Gambini says. His team had already created frozen embryos for horses and zebras, an idea similar to a seed bank. “We call this concept the Frozen Zoo.”
Creating donkey embryos proved much harder than those of zebras and horses. To improve chances of fertilization, Gambini used the intracytoplasmic sperm injection or ICSI, in which he employed a tiny needle called a micropipette to inject a donkey sperm into an egg. That was a step above the traditional IVF method, in which the egg and a sperm are left floating in a test tube together. The injection took, but during the incubating week, one after the other, the embryos stopped dividing. Finally, on day seven, Gambini finally spotted the exact sight he was hoping to see. One of the embryos developed into a burgeoning ball of cells.
“That stage is called a blastocyst,” Gambini says. The clump of cells had a lot of fluids mixed within them, which indicated that they were finally developing into a viable embryo. “When we see a blastocyst, we know we can transfer that into a female.” He was so excited he immediately called all his collaborators to tell them the good news, which they later published in the journal of Theriogenology.
The one and only embryo to reach that stage, the blastocyst was cryopreserved in liquid nitrogen. The team is waiting for the next breeding season to see if a female donkey may carry it to term and give birth to a healthy foal. Gambini’s team is hoping to polish the process and create more embryos. “It’s our weapon in the conservation ass-enal,” he says.
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.
Too much of this ingredient leads to autoimmune diseases, new research shows. Here's how to cut back.
For more than a century, doctors have warned that too much salt in your diet can lead to high blood pressure, heart disease and stroke - and many of the reasons for these effects are well known. But recently scientists have been looking deeper, into the cellular level, and they are finding additional reasons to minimize sodium intake; it is bad for immune cells, creating patterns of gene expression and activity seen in a variety of autoimmune diseases such as multiple sclerosis, lupus, rheumatoid arthritis, and type-1 diabetes.
Salt is a major part of the ocean from which life evolved on this planet. We carry that legacy in our blood, which tastes salty. It is an important element for conducting electrical signals along nerves and balancing water and metabolites transported throughout our bodies. We need to consume about 500 milligrams of salt each day to maintain these functions, more with exercise and heavy sweating as that is a major way the body loses salt. The problem is that most Americans eating a modern western diet consume about 3400 milligrams, 1.5 teaspoons per day.
Evidence has been accumulating over the last few years that elevated levels of sodium can be harmful to at least some types of immune cells. The first signal came in monocytes, which are immune cells that travel to various tissues in the body, where some of them turn into macrophages, a subset of white blood cells that can directly kill microorganisms and make chemical signals that bring other types of immune cells into play.
Two years ago, Dominik N. Müller from the Max-Delbrueck-Center in Berlin, Germany and Markus Kleinewietfeld, an immunologist at Hasselt University in Belgium, ran a study where they fed people pizza and then measured their immune cell function. “We saw that in any monocytes, metabolic function was down, even after a single salty meal,” Kleinewietfeld says. It seemed to be the cellular equivalent of the sluggish feeling we get after eating too much. The cells were able to recover but more research is needed to answer questions about what dose of sodium causes impairment, how long the damage lasts, and whether there is a cumulative effect of salt toxicity.
Kleinewietfeld and his colleagues have hypothesized that too much salt could be a significant factor in the increased number of autoimmune diseases and allergies over the last few generations.
The latest series of experiments focused on a type of T cell called T regulatory cells, or Tregs. Most T cells release inflammatory mediators to fight pathogens and, once that job is done, Tregs come along to calm down their hyperactive brethren. Failure to do so can result in continued inflammation and possibly autoimmune diseases.
In the lab, Kleinewietfeld and his large team of international collaborators saw that high levels of sodium had a huge effect on Tregs, upregulating 1250 genes and downregulating an additional 1380 genes so that they looked similar to patterns of gene expression seen in autoimmune diseases.
Digging deeper, they found that sodium affected mitochondria, the tiny organelles inside of cells that produce much of its energy. The sodium was interfering with how the mitochondria use oxygen, which resulted in increased levels of an unstable form of oxygen that can damage cell function. The researchers injected those damaged Tregs into mice and found that they impaired the animals' immune function, allowing the inflammation to continue rather than shutting it down.
That finding dovetailed nicely with a 2019 paper in Nature from Navdeep Chandel's lab at Northwestern University, which showed in mice that inhibiting the mitochondrial use of oxygen reduced the ability of Tregs to regulate other T cells. “Mitochondria were controlling directly the immunosuppressive program, they were this master regulator tuning the right amount of genes to give you proper immunosuppression,” Chandel said. “And if you lose that function, then you get autoimmunity.”
Kleinewietfeld's team studied the Treg cells of humans and found that sodium can similarly decrease mitochondrial use of oxygen and immunosuppressive activity. “I would have never predicted that myself,” Chandel says, but now researchers can look at the mitochondria of patients with autoimmune disease and see if their gene expression also changes under high salt conditions. He sees the link between the patterns of gene expression in Tregs generated by high salt exposure and those patterns seen in autoimmune diseases, but he is cautious about claiming a causal effect.
Kleinewietfeld and his colleagues have hypothesized that too much salt could be a significant factor in the increased number of autoimmune diseases and allergies over the last few generations. He says a high salt diet could also have an indirect effect on immune function through the way it affects the gut microbiome and the molecules made by microbes when they break down food. But the research results are too preliminary to say that for sure, much less parse out the role of salt compared with other possible factors. “It is still an exciting journey to try to understand this field,” he says.
Additionally, it is difficult to say precisely how this research in animals and human cell cultures will translate into a whole human body. Individual differences in genetics can affect how the body absorbs, transports, and gets rid of sodium, such that some people are more sensitive to salt than are others.
So how should people apply these research findings to daily life?
Salt is obvious when we sprinkle it on at the table or eat tasty things like potato chips, but we may be unaware of sodium hidden in packaged foods. That's because salt is an easy and cheap way to boost the flavor of foods. And if we do read the labeled salt content on a package, we focus on the number for a single serving, but then eat more than that.
Last September, the U.S. Food and Drug Administration (FDA) began a process to update labels on the content of food, including what is meant by the word “healthy” and how food manufacturers can use the term. Many in the food industry are resisting those proposed changes.
Chandel cautions against trying to counter the effects of salt by reaching for foods or supplements full of antioxidants, which, in theory, could reduce the harmful effects on mitochondria caused by a heavy hand with the salt shaker.
Until labels are updated, it would be prudent to try to reduce sodium intake by cutting down on packaged foods while making your own food at home, where you know just how much salt has been added. The Mayo Clinic offers guidance on how to become more aware of the sodium in your diet and eat less of it.
Chandel thinks many people will struggle with minimizing salt in their diets. It’s similar to the challenge of eating less sugar, in that the body craves both, and it is difficult to fight that. He cautions against trying to counter the effects of salt by reaching for foods or supplements full of antioxidants, which, in theory, could reduce the harmful effects on mitochondria caused by a heavy hand with the salt shaker. “Dietary antioxidants have failed in just about every clinical trial, yet the public continues to take them,” Chandel says. But he is optimistic that research will lead us to a better understanding of how Tregs function, and uncover new targets for treating autoimmune diseases.