Jud Broadhurst was 14 years old when he began to notice the symptoms.
Playing competitive soccer, Broadhurst would fall, seemingly "for no reason," he said. But there was one, lurking in his genes. Broadhurst had a form of spinal muscular atrophy, a rare neuromuscular condition that was causing his muscles to weaken over time.
At the time, no medicines were available to slow the relentless march of Broadhurst's disease. Doctors said he would be in a wheelchair by age 20, a prediction he swore to defy with a lifetime of healthy eating and exercise.
But, three decades later, the outlook for patients with SMA has changed dramatically. Broadhurst, still walking at age 46, has new options and decided earlier this year to receive his first infusion of Biogen's Spinraza.
"I will do anything humanly possible not to end up in a wheelchair," Broadhurst said in an interview.
Since 2016, three drugs have been approved to slow or stop the disease, from the most severe "Type 1" form that typically leads to death by age two to the more mild forms, like Broadhurst's, that can rob people of the ability to walk or swallow.
Each drug is dramatically different. Zolgensma, a gene therapy from Novartis, is a one-time treatment meant to produce long-lasting benefits. Spinraza, an RNA-based medicine, is infused at a clinic a few times a year. And Evrysdi, from Roche, is a daily medicine taken at home. Their arrival has transformed the expectations of patients, their families and the doctors who treat the disease.
"To see kids with SMA type 1 who are walking is just mind-blowing," said Elizabeth Kichula, a pediatric neurologist at Children's Hospital of Philadelphia.
But the availability of three such different drugs has left Kichula, Broadhurst and others in the SMA community with difficult choices, and not enough information to make those decisions. They must consider the cost of each treatment as well as the relative convenience each offers, and do so without knowing which is the most effective. None of them have been tested against another, and the long-term benefits of each are still being studied.
"The tricky part is that there are still a lot of unknowns," said Rebecca Scharf, a pediatric neurologist at the University of Virginia.
For the companies that make each drug, those unknowns, and how patients respond to them, will play a large role in how widely their treatments are adopted.
Choosing the right treatment
All three drugs can be used in infants younger than two years old, making each a potential option for those with Type 1, the most commonly diagnosed and deadly form of the disease. Only Spinraza and Evrysdi are approved for use by older patients, largely those with the more mild Types 2 and 3 that account for 88% of people living with the disease, according to the nonprofit SMA Foundation.
Each drug has its strengths and weaknesses, though.
As a gene therapy, Zolgensma is meant to permanently change the course of the disease with a single treatment. But because the longest patient exposure so far is only six years, patients' families have limited information on whether it could be considered a cure, and whether any safety problems might arise much later on. Zolgensma also costs $2.1 million, the highest per-dose price of any medicine in the world.
Spinraza and Evrysdi, by comparison, are chronic therapies. Biogen's drug is infused into the spine and costs $125,000 per use. Patients need six doses over the first year and three every year afterwards. Roche's medicine, a once-daily oral liquid, costs a maximum of $340,000 per year, though the actual price is tied to a patient's weight.
The choice between treatments looks different for each patient.
Cheryl Yoder's son Jase, now five years of age, was enrolled in a study of Spinraza as an infant and has been receiving infusions since he was one month old. While driving to a recent appointment, "I told the Lord I would love it if we wouldn't have to do this all the time. If there could be a one-time thing that would be amazing," she said.
Jase is now too old to receive Zolgensma.
The "intrathecal" injections, or spinal taps, used for Spinraza are also invasive procedures that must be done under specialized care in a healthcare facility, requiring local, or in some cases general, anesthesia. The injections can be an annoyance for some or a barrier to use for others, depending on age or overall condition.
Repeated sedation is potentially worrisome in infants and children because of possible long-term effects on developing brains. And younger children in some cases must be taken out of school before their Spinraza infusions to avoid upper respiratory infections that can make it risky to receive general anesthesia.
Older patients on Spinraza who spoke with Biopharma Dive had more modest concerns.
Broadhurst, who flies from his home in Colorado to Phoenix to receive Spinraza treatment, doesn't view the spinal injections as overly burdensome. Twice, he's gotten a dull, aching headache. "The infusion takes five minutes, tops," he said. "Every now and then they'll brush up against a nerve, and it feels like a lightning bolt."
Janelle Fiesta, 24, was diagnosed when she was one year old, and as a result of the condition has had a spinal fusion and a metal rod placed into her back.
She began taking Spinraza a year ago, and each infusion means a trip to the hospital radiology department to help physicians access her spinal canal. But even though the procedure can be painful, "for the most part the treatment goes really smoothly and they're able to do it without any issues," she said.
A big business
These differences are why analysts who cover Novartis and Biogen have generally expected Zolgensma to become the therapy of choice for a majority of infants with SMA, and Spinraza for older patients. But the approval of Evrysdi in August has led some to take a more cautious outlook for Spinraza, a crucial drug for Biogen that generated $2.1 billion in sales last year.
Salim Syed, an analyst at Mizuho Securities USA, forecast last month that Spinraza sales could decline by $700 million a year by the mid 2020s due to the rival therapies' emergence.
Competition already appears to be affecting Spinraza use. Roche in September said two-thirds of the patients to start treatment with Evrysdi previously got Biogen's drug or Zolgensma.
While the apparent convenience of oral administration would appear to give Evrysdi an edge over Spinraza, the reality is more complex. Roche's drug must be reconstituted and the dosage for children has to be based on their weight. This makes treatment less straightforward than taking a pill or capsule.
Additionally, patients may be hesitant to stop taking a drug they believe is helping.
Since starting on Spinraza, Fiesta said she can now sit upright without toppling over, lift heavier items and breathe more deeply than she could before treatment. While curious about Evrysdi and the prospect of avoiding trips to the hospital, she doesn't plan to switch anytime soon.
"For now I'm receiving Spinraza and I feel like I'm benefiting from it," she said.
Broadhurst said he finds peace of mind with Spinraza because he's concerned about the effectiveness of an oral medicine. "It doesn't get more precise than" an injection into the spinal fluid, he said.
In review documents posted following the approval of Evrysdi, the Food and Drug Administration called the effects observed in testing of Type 2 and 3 patients "relatively modest," noting that statistically significant benefits on motor function were largely driven by several study sites in Poland.
Brian Abrahams, an analyst at RBC Capital Markets, wrote in a September note to clients that if physicians were to view Evrysdi's data the same way, uptake could be limited in less severe patients.
On the other hand, if older patients with Type 2 or 3 have concerns about Spinraza's intrathecal administration, Evrysdi could win converts, Kichula of Children's Hospital said.
"When you're talking to young adults or adults they care more about their quality of life," she said. If there are "fewer uncomfortable procedures," she added, they may accept a drug with modest benefits.
Reaching for gene therapy?
Due to the age restrictions in Zolgensma's label, the gene therapy is out of reach for Broadhurst, Fiesta and a large number of patients with SMA.
Novartis wants to expand its use, but that effort — involving an intrathecal injection of Zolgensma rather than a blood infusion — has been slowed twice by the FDA. The agency is requiring Novartis run a new study. Even if successful, analysts don't expect a regulatory submission for an expanded approval for another two years.
Nonetheless, Zolgensma might reach these patients in the coming years, which could prompt a review of their treatment choices. While many patients like the idea of a once-and-done option, their enthusiasm is tempered by worries over the long-term impact and possible side effects of an essentially irreversible, ultra-expensive treatment.
"If they're going to put a huge price tag on it like there is and say it's a one-time dose, they really should know whether it is or not," Yoder said. "But it hasn't been studied long enough to know that."
While acknowledging the promise of Zolgensma, physicians are equally cautious, in part because of lingering concerns over a potential reaction to the engineered virus used to deliver the treatment. Scharf, of the University of Virginia, noted she's seen the liver enzymes of some children spike "very high" after treatment, indicative of possible liver damage.
"There's a lot unknown about the very long-term course of gene therapy," she said, "so that's another thing you have to think through."
All of which could leave Biogen's drug, the most firmly entrenched of the three available options, with perhaps more staying power among patients than previously thought.
Jase Yoder, now four years into treatment with Spinraza, likes to bike and run, his mother said, the kind of thing once never thought possible for an infant with Type 1 SMA.
"He is not as strong as his peer group. If we're honest they can run circles around them," she said. "In his heart, he's there … he believes he can run really fast."