Ethical Challenges of Nusinersen: Considerations When Counseling on Treatment

Although regarded as a miracle drug to some, nusinersen comes with some troublesome strings attached.

Spinal muscular atrophy (SMA), the leading cause of genetic death in infants, affects an estimated 1 in 6000 to 10,000 people in the United States. Until late 2016, physical therapy and palliative care were the only treatment options available for patients with SMA.

However, in December 2016, the US Food and Drug Administration (FDA) approved nusinersen (Spinraza), the first drug approved to treat SMA types 1, 2, and 3. SMA is caused by a faulty SMA1 gene that cannot encode the survival motor neuron protein essential for nerves carrying signals from the spinal cord to the body’s muscles. Nusinersen works by altering a different gene enough that it can produce the survival motor neuron protein instead.

Although not a cure, the drug represents a tremendous leap in treating SMA, as it is the first opportunity to interrupt the disease’s progression. And with its approval a few days before Christmas, it may have felt like a miracle to some families.

But miracles are sometimes too good to be true. Although the drug’s approval brought much-needed hope to patients and families dealing with the diagnosis, nusinersen’s arrival also brought with it a host of ethical concerns that neurologists, pediatricians, bioethicists, parents, and others must wrestle with. The ethical quandaries nusinersen poses are not new, but underscore the importance of carefully considering risks, benefits, and costs in physician-caregiver shared decision-making.

“Families need to know more about what it means to live with SMA and with the benefits and burdens of the available treatment,” wrote Nancy M. P. King, JD, a professor of social sciences and health policy and codirector of the Center for Bioethics, Health, & Society, and Christine Bishop, MD, an assistant professor of pediatrics and director of neonatal/perinatal palliative care, both from Wake Forest School of Medicine in Winston-Salem, North Carolina. Their review of ethical considerations for nusinersen was published in 2017 in Gene Therapy.1

“Parents of affected children — and later, more and more children themselves — face high-stake decisions about chronic treatment and potential aggressive life-prolonging therapies,” King and Dr Bishop wrote. “Without considering the ethical, psychosocial, financial, and quality-of-life aspects of SMA and its treatment, physicians and families run the risk of treating patients without fully understanding how to care for them.”

Among the first issues they address is the uncertainty about nusinersen resulting from limited data, including the risk of “overestimating potential benefits and underestimating potential harms.”

“As important as it is to acknowledge and celebrate progress, it is equally essential that all stakeholders — scientists, physicians, journalists, families, advocacy groups, and the public — keep trying to distinguish between justifiable hope and undue hype,” they wrote.

“[I]t is essential to avoid considering Spinraza a curative treatment,” they add. Instead, they recommend calling it a palliative intervention, as it can slow, but not stop, disease progression and cannot restore lost function.

Uncertainty of the Evidence

Clinical trials for nusinersen showed favorable enough improvements in symptoms that 2 trials switched to open-label so any enrollee could receive the drug. But the studies remained small, with fewer than 200 patients receiving the drug in trials before approval, and concerns about the drug’s effectiveness remain.

“Four issues weaken the claims of efficacy,” wrote Gerrity et al2 about ENDEAR, the drug’s key randomized controlled study. First, the primary endpoint was switched from “overall survival free of permanent mechanical ventilation” initially to, 22 months later, “the dichotomous outcome of motor milestone responder vs nonresponder, regardless of the timeframe.” This switch and use of interim analysis data “increased the risk of bias and overstated estimates of benefit,” the researchers wrote.

Second, “motor milestone responder” has not previously been used as an outcome to establish a drug’s efficacy and has uncertain clinical relevance compared with outcomes such as ventilator-free survival or ability to sit or walk. Although 6% of the patients who received nusinersen could sit unassisted, most could not, and none could stand or walk.

Gerrity et al also noted that nusinersen was approved for multiple types of SMA when the ENDEAR trial only enrolled participants with SMA1. King and Dr Bishop also expressed concern about generalizability, as trial participants “were least likely to be disadvantaged by trial participation and most likely to provide good study data” without the characteristics or comorbidities real-world patients might have.

“Long-term follow-up is essential to determine whether the slowing of progression continues with continued treatment, whether there are significant effect differences for patients affected with different degrees of severity, and whether any potential harms manifest over the long term,” wrote King and Dr Bishop.

Long-term concerns are justified, given nusinersen’s route of delivery: After an initial 6 injections into the spinal canal, patients receive injections every 4 months thereafter, for life. Each injection is painful and requires patient immobilization. Sedation, pain management, and adverse effects such as thrombocytopenia and nephrotoxicity, although not seen much in the clinical trials, carry risks.

Further, “[b]oth disease progression and repeated lumbar punctures for intrathecal injections may compromise access to the intraspinal space over time,” King and Dr Bishop wrote. “[T]his could eventually make injection of the drug for ongoing therapy impossible for some patients.”

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That’s assuming they can afford it. Nusinersen currently costs $750,000 in the first year and $375,000 each year thereafter, for life. The total cost could actually be considerably higher for some patients if administration is more complex because of “weakness, bulbar dysfunction, respiratory insufficiency, scoliosis, spinal fusion, or other sequelae of SMA,” wrote Burgart et al in a December 2017 article about nusinersen’s ethical challenges.3

The difficulty of administration and potential need for advanced airway management, fluoroscopy, ultrasonography, and overnight hospitalization also raise questions about treatment allocation, depending on local resources and whether a “logistical bottleneck could cause a delay in drug administration,” Burgart et al wrote.

Informed Consent and Decision-Making

The concerns carry implications for informed consent, too. Parents’ values play a role in assessing the benefits of the drug’s effects, tolerance for the drug’s possible toxicity, and possible treatment cessation. In addition, discussions about treatment options may involve other research studies that may or may not allow nusinersen’s concurrent use, Dr Bishop told Neurology Advisor.

“For physicians, being honest about what is known and what is not known, being open about the potential burdens and benefits of the treatment, and being open to discussing goals of care and the concept of quality of life are important,” Dr Bishop told Neurology Advisor. “Then, the healthcare team must really listen to families’ concerns, investigating what their concept of a good quality of life is, and try to help the family choose the what they think is the best plan of care for their child.”

The same benefit — slowing disease progression and potentially extending survival — can be perceived very differently by different families.

“These can be agonizing decisions for families, and it should be recognized that good parents who love their children very much can make different decisions in this situation,” Dr Bishop added.

That’s precisely why pediatricians should not see nontreatment with nusinersen as potential “medical neglect,” King told Neurology Advisor, as the question of treatment is far more complicated.

“Treatment decision-making depends on the child’s age, precise diagnosis, severity of manifestations of SMA, and available data about the magnitude, likelihood, and anticipated persistence of nusinersen’s effect on symptom progression in a given patient,” she said. “Everyone should recognize that nusinersen is not a magic bullet, and whether the possibility of benefit is worth the burdens of this treatment is a very individualized decision for patients and families.”

She told Neurology Advisor the decision-making process should be “careful, thoughtful, and based on evidence and families’ experiences and values,” and then “revisited periodically, whatever the decision is, to reassess.”

“Reluctant parents may decide to start nusinersen as they see symptoms develop, or as they feel better able to overcome financial and logistical hurdles, and eager parents may later decide to stop if they don’t see benefits that outweigh the burdens to the child and the family,” King said.

Specific examples of things providers may want to discuss with families include travel times for treatment, potential associated costs, childcare and potential lost wages, and insurance changes.

An added challenge to communication between providers and parents is what parents may hear about a drug elsewhere, including from advocacy organizations. Nusinersen’s development involved partnership with CureSMA, and such organizations can be “real lifelines for newly diagnosed families,” Dr Bishop said.

But as she and King wrote, “it is also well established that a close relationship between funders and researchers can run the risk of distorting information and even data.” CureSMA’s role “in supporting both families and drug discovery may unintentionally give rise to conflicts of interest and increase the likelihood of therapeutic misconception.”

It is therefore helpful for physicians to be aware of advocacy groups and their goals, Dr Bishop said, so they can discuss the groups and any possible concerns with families. She often conducts an internet search of a condition online before meeting with a patient to see what the patient likely saw when they searched for information online themselves.

“It helps me to open the conversation with them about what they may see or encounter online and to discuss how differently information can be presented depending on the source,” Dr Bishop told Neurology Advisor. “Just being really upfront with families about these potential biases can help raise their awareness of it and also keep the lines of communication between physician and patient/family open.”

King and Dr Bishop report no disclosures.


  1. King NMP, Bishop CE. New treatments for serious conditions: ethical implications. Gene Ther. 2017(9):534-538.
  2. Gerrity MS, Prasad V, Obley AJ. Concerns about the approval of nusinersen sodium by the US Food and Drug Administration. JAMA Intern Med. 2018;178(6):743-744.
  3. Burgart AM, Magnus D, Tabor HK, et al. Ethical challenges confronted when providing nusinersen treatment for spinal muscular atrophy. JAMA Pediatr. 2018;172(2):188-192.