Tony and Kelly Mantoan, with their boys Teddy and Fulton, who both suffer from SMA, a genetic disorder that makes walking, swallowing, and breathing progressively difficult.
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.
She figured the pain would go away. But instead, it intensified that night. Kamil's husband drove her to the Cedars-Sinai hospital, where she was admitted to the coronary care unit. It turned out she wasn't having a heart attack after all. Instead, she was diagnosed with a much less common but nonetheless dangerous heart condition called takotsubo syndrome, or broken heart syndrome.
A heart attack happens when blood flow to the heart is obstructed—such as when an artery is blocked—causing heart muscle tissue to die. In takotsubo syndrome, the blood flow isn't blocked, but the heart doesn't pump it properly. The heart changes its shape and starts to resemble a Japanese fishing device called tako-tsubo, a clay pot with a wider body and narrower mouth, used to catch octopus.
"The heart muscle is stunned and doesn't function properly anywhere from three days to three weeks," explains Noel Bairey Merz, the cardiologist at Cedar Sinai who Kamil went to see after she was discharged.
"The heart muscle is stunned and doesn't function properly anywhere from three days to three weeks."
But even though the heart isn't permanently damaged, mortality rates due to takotsubo syndrome are comparable to those of a heart attack, Merz notes—about 4-5 percent of patients die from the attack, and 20 percent within the next five years. "It's as bad as a heart attack," Merz says—only it's much less known, even to doctors. The condition affects only about 1 percent of people, and there are around 15,000 new cases annually. It's diagnosed using a cardiac ventriculogram, an imaging test that allows doctors to see how the heart pumps blood.
Scientists don't fully understand what causes Takotsubo syndrome, but it usually occurs after extreme emotional or physical stress. Doctors think it's triggered by a so-called catecholamine storm, a phenomenon in which the body releases too much catecholamines—hormones involved in the fight-or-flight response. Evolutionarily, when early humans lived in savannas or forests and had to either fight off predators or flee from them, these hormones gave our ancestors the needed strength and stamina to take either action. Released by nerve endings and by the adrenal glands that sit on top of the kidneys, these hormones still flood our bodies in moments of stress, but an overabundance of them could sometimes be damaging.
Elaine Kamil
A study by scientists at Harvard Medical School linked increased risk of takotsubo to higher activity in the amygdala, a brain region responsible for emotions that's involved in responses to stress. The scientists believe that chronic stress makes people more susceptible to the syndrome. Notably, one small study suggested that the number of Takotsubo cases increased during the COVID-19 pandemic.
There are no specific drugs to treat takotsubo, so doctors rely on supportive therapies, which include medications typically used for high blood pressure and heart failure. In most cases, the heart returns to its normal shape within a few weeks. "It's a spontaneous recovery—the catecholamine storm is resolved, the injury trigger is removed and the heart heals itself because our bodies have an amazing healing capacity," Merz says. It also helps that tissues remain intact. 'The heart cells don't die, they just aren't functioning properly for some time."
That's the good news. The bad news is that takotsubo is likely to strike again—in 5-20 percent of patients the condition comes back, sometimes more severe than before.
That's exactly what happened to Kamil. After getting her diagnosis in 2013, she realized that she actually had a previous takotsubo episode. In 2010, she experienced similar symptoms after her son died. "The night after he died, I was having severe chest pain at night, but I was too overwhelmed with grief to do anything about it," she recalls. After a while, the pain subsided and didn't return until three years later.
For weeks after her second attack, she felt exhausted, listless and anxious. "You lose confidence in your body," she says. "You have these little twinges on your chest, or if you start having arrhythmia, and you wonder if this is another episode coming up. It's really unnerving because you don't know how to read these cues." And that's very typical, Merz says. Even when the heart muscle appears to recover, patients don't return to normal right away. They have shortens of breath, they can't exercise, and they stay anxious and worried for a while.
Women over the age of 50 are diagnosed with takotsubo more often than other demographics. However, it happens in men too, although it typically strikes after physical stress, such as a triathlon or an exhausting day of cycling. Young people can also get takotsubo. Older patients are hospitalized more often, but younger people tend to have more severe complications. It could be because an older person may go for a jog while younger one may run a marathon, which would take a stronger toll on the body of a person who's predisposed to the condition.
Notably, the emotional stressors don't always have to be negative—the heart muscle can get out of shape from good emotions, too. "There have been case reports of takotsubo at weddings," Merz says. Moreover, one out of three or four takotsubo patients experience no apparent stress, she adds. "So it could be that it's not so much the catecholamine storm itself, but the body's reaction to it—the physiological reaction deeply embedded into out physiology," she explains.
Merz and her team are working to understand what makes people predisposed to takotsubo. They think a person's genetics play a role, but they haven't yet pinpointed genes that seem to be responsible. Genes code for proteins, which affect how the body metabolizes various compounds, which, in turn, affect the body's response to stress. Pinning down the protein involved in takotsubo susceptibility would allow doctors to develop screening tests and identify those prone to severe repeating attacks. It will also help develop medications that can either prevent it or treat it better than just waiting for the body to heal itself.
Researchers at the Imperial College London found that elevated levels of certain types of microRNAs—molecules involved in protein production—increase the chances of developing takotsubo.
In one study, researchers tried treating takotsubo in mice with a drug called suberanilohydroxamic acid, or SAHA, typically used for cancer treatment. The drug improved cardiac health and reversed the broken heart in rodents. It remains to be seen if the drug would have a similar effect on humans. But identifying a drug that shows promise is progress, Merz says. "I'm glad that there's research in this area."
This article was originally published by Leaps.org on July 28, 2021.
