We thought our younger son was healthy at birth, and we had high hopes for his future. His weak movements and excessive fussiness raised our concerns, leading to an unsuspected, devastating diagnosis of type 1 spinal muscular atrophy (SMA). The US Food and Drug Administration had recently approved nusinersen, the first disease-modifying treatment for SMA, but its supporting evidence and steep list price made the drug controversial. We made the decision to treat him, despite limited available information. My roles of father and physician soon became inextricably linked; pulse oximetry alarms needed attention at home like in the emergency department, and sometimes the commute from work to our son’s bedside involved only a brief elevator ride to the PICU. This experience offered an unexpected perspective on the benefits and costs of nusinersen therapy for type 1 SMA.
Consider the patient impact of 1 end point of the ENDEAR trial1 (identifier NCT02193074 at www.clinicaltrials.gov): motor-milestone response, assessed by using the Hammersmith Infant Neurologic Examination, section 2 (HINE-2). The HINE-2 quantifies infant motor development by assigning scores to various abilities,2 including head control, rolling, and sitting. The use of this end point was motivated by the natural history of type 1 SMA; children rarely gain new motor milestones after symptom onset, and loss of previously achieved milestones is expected instead.3 The value of motor-milestone response may not be self-evident, but for our son, what seem like minor changes in the HINE-2 led to major improvements in function.
Our son fit the population enrolled in the ENDEAR trial, initiating therapy after symptom onset and before 6 months of age.1 He never developed antigravity movement of the extremities and lost swallow function shortly before initiating therapy. The loading doses of nusinersen appeared to halt the progression of his motor deficits, and after a long quiescent period, the expected deterioration of his illness began to reverse. First, he gained the ability to lift his head; the HINE-2 quantifies this with 2 points gained, yet from our son’s perspective, he gained the ability to look at his mother’s face whenever he wished. Next, he developed the abilities to grasp and roll, which translated into newfound autonomy in choosing his own toys for play. Later, he began sitting upright next to his older brother while watching cartoons, offering an unexpected glimpse of normalcy. Now, past the age of 24 months when 90% of untreated infants progress to death or ventilator dependence,4 he is beginning to recite the alphabet and count to 10. If untreated, he would have been expected to remain nonverbal because of the onset of respiratory failure before speech acquisition. Motor improvements with nusinersen appeared gradually, requiring prolonged rehabilitation efforts like other neurologic injuries, including strokes and spinal cord trauma. Our son’s response was generally consistent with results from the ENDEAR trial: he attained motor milestones that would have been unexpected without treatment, and this response conferred meaningful patient-centered outcomes that may not be fully described by the HINE-2. The power granted by self-expression and the autonomy of movement according to one’s own intents and purposes are outcomes with value far exceeding 1 author’s claim that nusinersen is a “marginal” therapy.5
Consider also the significance when a historically nonsurvivable disease becomes treatable. Like type 1 SMA, type 1 diabetes mellitus implied a grim prognosis nearly 100 years ago. Before insulin was discovered, common treatments used calorie-restricted, low-carbohydrate diets with little benefit. In the 1910s, it was believed that “pancreatic extracts have no clinical value whatsoever” for treating diabetes.6 However, Banting and Best isolated the yet-unnamed insulin from proteolytic enzymes within pancreatic tissue, and this extract revealed therapeutic potential in animal models.6 They described, in a case series published in 1922, 7 children treated with insulin who showed normalization of blood glucose, cessation of ketonuria, and “a subjective sense of well-being and increased vigor.”6 The quality of evidence offered by this publication was low by modern standards, given its uncontrolled design and small sample size. Like insulin at that time, more studies are needed to determine the long-term effects of nusinersen. However, the anticipation of future research does not diminish the responsibility of physicians to use the best-available evidence to advocate for patients at the time of illness.
Current knowledge indicates that some availability of survival of motor neuron protein, like insulin, is essential for human life. Both insulin and nusinersen represented first-available therapies for illnesses, offering hope where little previously existed. The comparison between these drugs is not meant to imply equivalent efficacy between them nor that nusinersen offers a cure for SMA. The ENDEAR trial, however, demonstrated substantial mortality benefit with nusinersen that favored early initiation of therapy: children receiving nusinersen had an absolute risk reduction of 29% for death or ventilator dependence compared with those in the placebo group.1 This improved to 44% for the subgroup of children with shorter disease duration at screening. Absolute risk reductions of this magnitude, for mortality-related end points, are uncommonly achieved in translational research. Like insulin in the 1920s, nusinersen offers the potential for improvement where deterioration and death would otherwise be expected, and in my view, this reversal is the success of nusinersen’s approval.
The list price of nusinersen is high ($750 000 for the first year and $375 000 annually thereafter), rivaling the most expensive orphan drugs. Without intending to defend or criticize it, I consider this price a result of our for-profit system of pharmaceutical development. By design, this system divides the benefits of marketing approval between patients and financial stakeholders. Without financial incentives spurring development, nusinersen would not likely exist; and as parents, we are grateful that it does. How can we price our son’s childhood and the milestones he has gained? The price of nusinersen is difficult to accept, however. Tension exists between cost and access to health care. Consider insulin again, which remains expensive today despite being priced orders of magnitude lower than nusinersen. Too frequently I treat patients with diabetic ketoacidosis, caused when they rationed insulin because of financial constraints. When this happens, I wonder if our son will someday face an economic decision between nusinersen and his other priorities.
All family members were affected in varying ways by our son’s illness and treatment, as families of children with other serious illnesses might relate. When my wife and I decided to pursue nusinersen therapy, the rest of the family supported our decision. My wife stopped working because of the time commitment required for our son’s care, including airway clearance and physical, occupational, and speech therapy. Despite having no medical background, she quickly became adept with his complex needs. At work, the residents seek my feedback before changing ventilator settings; but now at home, the hierarchy differs: I have to ask for my wife’s permission. When our son was younger and more fragile, after each visit, his grandparents were grieved by wondering if he would survive until the next visit. It was deeply saddening when I explained to our older son, in preschool terms, that he might outlive his little brother and we should be grateful for each day. Uncertainty about long-term outcomes with nusinersen makes planning for the future challenging: Do we save money for higher education when survival to kindergarten is not assured? Will our home require disability accommodations for a wheelchair, walker, or neither?
We cannot presume anything about our son’s future, whether he will experience adulthood or even adolescence, but we do have the opportunity to spend time together now. Perhaps future innovations will influence his outcome, but regardless, we are grateful for the present. Our son has been given the opportunity to live his childhood and explore the world in a way that was unexpected after the diagnosis of type 1 SMA. We are so proud of his inquisitive mind, his newfound voice, his contagious laughter, and his favorite pastimes: trucks and coloring. He routinely achieves what was believed to be impossible, and he does not yet realize it. He was never expected to sit, yet in a sense, now he stands on the shoulders of the researchers who developed nusinersen.
I sincerely thank Leah Hoot for her dedication as a wife, mother, and caregiver.
Dr Hoot was responsible for this work in its entirety, and he approved the final manuscript as submitted and agrees to be accountable for all aspects of the work.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The author acknowledges the potential conflict of interest in having a family member treated with nusinersen.
FINANCIAL DISCLOSURE: The author has indicated he has no financial relationships relevant to this article to disclose.