$2 Million Gene Therapy
An effective rare disease therapy is overshadowed by the cost, while pharma rakes in cash
Grassroots funding by the rare disease community and foundational publicly funded science through NIH directly supported incredible advances in therapy for SMA, but pharmaceutical companies are driving exorbitant costs and making bank.
ProPublica released a story on gene therapy that I know well: Zolgensma (brand name for onasemnogene1). The last three letters in the drug “sma” reference the disease the gene therapy treats - spinal muscular atrophy (SMA).
Zolgensma is the latest in a string of incredible advancements in treatment for SMA. It stands out, not only because it’s a gene therapy but because of its outrageous price tag:
The one-time-only intravenous gene therapy Zolgensma costs $2 million.
The drug is credited with decreasing infant SMA mortality by two-thirds.
What is Spinal Muscular Atrophy?
Spinal muscular atrophy (SMA) is a genetic condition where the primary gene needed to make Survival Motor Neuron proteins (SMN1) in the spinal cord is missing or not working properly. This protein is a key part of the SMN complex that supports motor neurons—the nerve cells in the spinal cord and brainstem that send signals to muscles, allowing movement. People with SMA progressively lose muscle function, unable to move the muscles needed to walk, talk, breathe, and swallow. Thinking and feeling remain intact.
When I was a pediatric anesthesiology fellow, there was no treatment for SMA. We could only offer supportive care and resources - whatever could be done to maintain quality of life as muscle function faded away. While these kids needed some hospital care, much of the work to keep them healthy and well for as long as possible rested on their parents’ shoulders. Children with the most severe forms that showed up in infancy often didn’t live to their second birthday. Children with more copies of SMN2 would live longer. Since I work at a pediatric hospital, I see kids with a range of symptoms and severity.
Spinal Muscular Atrophy is a variable disease, and it’s not a death sentence for people who have more copies of SMN2 and access to supportive resources. While some patients don’t survive childhood, many others will live long lives with supportive care. Author Ben Mattlin has written extensively about his life as an adult with SMA.
One of the things that struck me was how many of these kids are exceptionally witty and mature at a young age. Lacking the ability to move much of his body, one of my former patients, at 4 years old, his neck supported in his wheelchair, would tell me pretty complex jokes and wiggle his little eyebrows to make everyone laugh. He could still move his hands to control his iPad. He used every available tool to make the most of each day.
I took care of quite a few children with this rare condition when they were in the ICU, often with their disease so advanced they needed a ventilator to breathe and a tube in their stomach because they could no longer swallow. In the later stages of the disease, the ability to communicate becomes harder and harder. My ability to assess patient needs, pain control, and other vital questions eventually means relying on parents’ interpretations of subtle signs they are used to looking for but don’t stand out to me.
The First SMA Treatment: Nusinersen
In late 2016, an SMA researcher reached out to me and my ethics colleagues with a unique question: a first of it’s kind SMA therapy would be approved soon, but only some facilities would have the space and staff to administer the medication to patients’ spinal fluid (intrathecal injections). How would we decide who to treat and in what order? It was a new version of an old rationing dilemma - when you can’t treat everyone, who do you treat? Plus, the drug was expected to be extremely expensive. Would insurance cover it? Who would pay for it?
The drug, injected into the cerebral spinal fluid, increases the body’s production of SMN2 proteins, which can make up for the nonfunctional SMN1 gene.
The researcher showed us videos of toddlers who’d gotten the experimental therapy and achieved motor function far beyond what could be expected without treatment. They showed up tables of the motor function of treated kids. Kids who were not expected to be able to sit up or roll over were starting to walk. Having cared for kids who could no longer communicate beyond blinking and crying, it took my breath away. This was a real chance to increase how long kids with SMA could live and improve their quality of life.
The drug would be called Nusinersen (trade name Spinraza).
At the time, Nusinersen became one of the most expensive drugs on the market at $125,000 per injection. Treatment involves multiple injections, costing $750,000 for the first year and $375,000 annually afterward. In addition to these costs are the costs of administration - a sterile room to give the medicine and a team to inject it safely.
Shortly after the drug was approved, my colleagues and I wrote about ethical issues with this first drug to treat spinal muscular atrophy and its outrageous price tag.
When I’m in the operating room caring for a kid having their nusinersen injection, we make sure to get every last drop of drug out of the vial - we’re all paranoid that we will waste it. We also had to return the empty vial to the pharmacy to prove it had all been used. When my university magazine wanted to cover the issue and wanted a photo of me holding the drug, I had to beg a pharmacist to give me an empty bottle for an hour.
My colleagues and I were initially surprised that there wasn’t more outcry from SMA advocacy groups about the high cost.
That was until we understood that those same groups had raised the money to push for early research.
Unlike treatments for common conditions like high blood pressure or common cancers, rare diseases, by their nature, do not offer a large pool of patients to treat. Advocacy groups depended on the scientific teams in start-up companies to develop novel therapies in an environment that often eschewed the risks of studying rare diseases. There are many failed attempts along the way, so when one drug stands out, then a larger pharmaceutical company can come in to license the product.
More treatments were expected to follow nusinersen, including a gene therapy (onasemnogene) and an oral therapy (risdiplam2). Within a few short years, multiple treatment options would exist for a small pool of patients. The market would face new questions about how to care for SMA patients.
I spent years attending conferences with neurologists, other clinicians, and SMA advocates to discuss the evolving ethical issues in SMA treatment. As new treatments emerged, we knew the ethical issues would continue to grow.
I sat on panel after panel, where the number one topic of conversation and audience questions was the extreme cost of these emerging therapies.
We have all been waiting for backlash against these outrageous costs to patients.
Taxpayer-Funded Research and Advocacy Groups
Major pharmaceutical companies did not lead the way in creating these drugs, upending the myth that massive drug prices are required to drive pharmaceutical innovation.
The success of SMA therapies is thanks to foundational tax-payer-funded research (in the US and other countries), combined with grassroots funding and advocacy by groups like Cure SMA (formerly Families of SMA), the SMA Foundation, and the Muscular Dystrophy Association.
The National Institute of Neurological Disorders and Stroke is a part of the U.S. National Institutes of Health, has a helpful timeline to show the long path to SMA treatment. From Lefebvre’s French scientific team’s discovery of the SMN1 gene in 1995, to numerous NIH-funded and international studies identifying and characterizing the role of SMN2, to the NIH-funded discovery of the antisense oligonucleotide (ASO) that would become nusinersen - drugs to treat SMA are not pharma company inventions. From 2003 to 2006, Cure SMA provided the very first research funding needed to investigate augmenting SMN2 production using as ASO. Early trials of nusinersen for adults were also funded by Cure SMA.
Sophia’s Cure Foundation funded early research into onasemnogene (Zolgensma). ProPublica’s story about Sophia Gaynor’s parents and their experiences with researchers after supporting the gene therapy for SMA is heartbreaking. Here is a brief excerpt from the article:
The Gaynors’ daughter Sophia had been diagnosed with SMA five years earlier. Since then, they’d raced to fund research to save her. Their charity, Sophia’s Cure, was covering a substantial portion of the costs of the trial.
They’d helped raise about $2 million for a program at Nationwide run by Brian Kaspar, a leading researcher. Gaynor, a New York City construction worker, had forged a tight bond with Kaspar, speaking frequently with him by phone, sometimes deep into the night.
But their relationship had started to fray when — with success in sight — Kaspar became part owner of AveXis, a biotech startup that had snapped up the rights to his SMA drug. Billions of dollars were at stake.
When Kaspar walked into the cafeteria that day, Gaynor said, the scientist didn’t acknowledge him or his wife before sitting down a short distance away. Neither did the man with him, the startup’s CEO.
“It was like they didn’t know us,” Gaynor recalled.
Pharma Makes Bank
After Nusinersen’s approval and my introduction to the world of SMA advocacy, I began following SMA drug pricing regularly. There’s a whole world of biotech funding that is far more business-y than medical. I found myself more closely following the business side and watching the companies that swallowed the original research start-ups make boatloads of money.
FiercePharma’s 2020 ranking of top drug launches since 2017 included both Sprinraza (Nusinersen, #5) and Zolgensma (Onasemnogene, #7).
In 2018, Biogen reported the launch of Spinraza (Nusinersen), contributed $884 million in global revenues. That same year, pharma giant Novartis bought AveXis (the maker of onasemnogene/Zolgensma) for $8.7 billion dollars - preparing to cash in on the future of gene therapy. Sales for both drugs have leveled out, given the small pool of patients. Biogen hopes to increase their market share with the anticipated approval of higher doses of Spinraza. Risdiplam sales reached nearly $1.8 billion in 2024 - a rising leader due to convenience.
I’m so happy patients have access to effective therapies. But how are these costs acceptable? Insurers have chosen to cover the costs for some patients. So many children and adults with SMA rely on publicly funded healthcare programs like Medicaid, Children's Health Insurance Program (CHIPs), and MediCal, which means that it’s again the public taxpayer funding the cost of these drugs. How is this what the market will bear?
In addition to driving massive drug costs in the US, the costs of these drugs are out of reach for people with SMA in middle- and low-income countries.
Since the cost of onasemnogene (Zolgensma) has been tolerated - $2 million has become a standard cost for newer gene therapies.
Massive Drug Costs Don’t Cover Supportive Care
Compounding the absurdity of the cost of treatments for SMA, is that despite these massive costs, they do not negate the need for supportive care. SMA treatments don’t mean that SMA doesn’t exist anymore - but can reduce symptoms. Patients still need lots of support, including therapies, mobility aids, care givers, and specialty transportation (like disability equipped vans).
My colleagues spoke to adults with SMA and parents of children with SMA about nusinersen. Below is a particularly compelling excerpt from a paper they published in 2019. An adult patient with SMA describes the cost of nusinersen compared to what could be done with that same amount of funding:
“I’m 40 years old, right. . . . Based on my progression, what I can see, I’ve given myself 20 good years. If I took that 20 years and I put that towards Spinraza, like if I took 20 years of Spinraza, then it would amount to about I think close to eight million dollars, right. If I had eight million dollars handed to me and somebody said, “you can either take Spinraza and you might be able to open the hell out of this Ziploc container . . . or you can take this eight million dollars and get all the intended care you need to never have to fight to get a new wheelchair. You can swim in a pool. You can have an accessible home. You can go anywhere you want to go. You never have to worry about your van breaking down.” Everything that I could ever need that would help me stay healthy and independent, I could buy with this eight million dollars, right, over being able to open a Ziploc container really well. I would be more cured if I put $8 million towards that than to this drug. To me, the priority is very medically-driven . . . the cost, it really hurts me, it hurts people and it hurts our world because it’s putting a value on the idea of a cure that really isn’t really there... an overall idea of disability being so atrocious that being able to open a Ziploc container is more important than having a full life that you can engage with.” – an Adult with SMA III, from an interview study of adults with and parents of children with SMA (emphasis added by me)
We keep shelling out millions of dollars to the pharmaceutical industry, but that isn’t helping patients get some of the basic tools they need to maximize their ability to be part of society. When we are paying so much for drugs, what are we not paying for?
The story of the evolution of treatments for SMA brings all these issues into focus.
Patients should not have to choose between effective therapy and basic needs. We need drug prices that center on patients rather than pharmaceutical company profits. When we address the needs of patients with rare diseases, we can’t be limited to the fanciest, most expensive options. We need to fight these massive costs without making disabled people the targets of cost-cutting. Disability justice is about so much more than drugs - it’s about enhancing every person’s capacity to live a meaningful life.
Sources
Fields R. What a $2 Million Per Dose Gene Therapy Reveals About Drug Pricing.
Burgart AM, et al. Ethical Challenges Confronted When Providing Nusinersen Treatment for Spinal Muscular Atrophy. JAMA Pediatr. 2018 Feb 1;172(2):188-192. doi: 10.1001/jamapediatrics.2017.4409. PMID: 29228163.
Iyer AA, Barzilay JR, Tabor HK. Patient and family social media use surrounding a novel treatment for a rare genetic disease: a qualitative interview study. Genet Med. 2020 Nov;22(11):1830-1837. doi: 10.1038/s41436-020-0890-6. Epub 2020 Jun 30. PMID: 32601388.
Pacione M, Siskind CE, Day JW, Tabor HK. Perspectives on Spinraza (Nusinersen) Treatment Study: Views of Individuals and Parents of Children Diagnosed with Spinal Muscular Atrophy. J Neuromuscul Dis. 2019;6(1):119-131. doi: 10.3233/JND-180330. PMID: 30594933.
I have no doubt drug makers were happy to have a completely unpronounceable name for the gene therapy. I work hard to use the non-trade named of drugs, but these pharm folks love making it hard.
A liquid oral drug Risdiplam (trade name Evrysdi) came on the market in 2020. While considered “low cost,” the drug itself costs as much as Nusinersen maintenance annually. The oral dosing, however, is more convenient than nusinersen for patients and does not require the costs, pain, or inconvenience of frequent hospital-based procedures. Oral tablets were also recently released.