Treating SMA in Australia ‘Complex’ Mix of Opportunity, Ethical Issues
The availability of early genetic testing and approval of several spinal muscular atrophy (SMA) treatments has dramatically changed disease outcomes, while introducing ethical issues in terms of screening, predicting SMA severity, and patient access to therapy.
As such, appropriate information and support should be given to parents and patients to help them in making decisions, and a patient-centered approach is essential.
These are the conclusions of the study, “Ethical aspects of the changing landscape for spinal muscular atrophy management in Australia,” published in the Australian Journal of General Practice.
SMA is caused by mutations in both copies of the SMN1 gene, which provides instructions to produce SMN, a protein essential for motor neuron and muscle health. SMN deficiency leads to motor neuron death that results in muscle weakness and wasting.
A second SMN gene, SMN2, can partly compensate for the loss of SMN1-derived SMN, with a higher number of SMN2 gene copies associated with a milder disease. However, disease severity may be influenced by factors other than SMN2 copy number, challenging predictions of SMA severity before symptom onset — which helps in determining SMA types.
As such, SMA-specific genetic tests can be given to couples before conception, and to the baby during pregnancy and shortly after birth. These tests can help with reproductive decisions and in identifying newborns with the disease before any symptoms become apparent — a time when treatment initiation has been shown to result in optimal outcomes.
Three disease-modifying therapies for SMA — Biogen’s Spinraza (nusinersen), Novartis’ Zolgensma, and Roche’s Evrysdi (risdiplam) — have become available since late 2016 in several countries, including Australia.
All of these therapies work by increasing SMN levels, but they have different mechanisms of action, as well as distinct administration routes and regimens.
In Australia, Spinraza is available at low cost for infants genetically diagnosed with SMA but not yet showing symptoms (pre-symptomatic) and who carry one to two copies of SMN2 — suggestive of SMA type 1. It is also available to those showing clinical symptoms prior to 3 years of age, including types 1–3.
Evrysdi is reimbursable to children between 2 months and 18 years of age who develop symptoms before age 3. The one-time gene therapy Zolgensma, the most expensive treatment in the world, was approved in Australia for infants up to 9 months old who carry one to three SMN2 copies and is currently being considered for reimbursement.
Therefore, screening and treatment options “can be increasingly complex to navigate for both healthcare professionals and at-risk families,” the researchers wrote.
A team of researchers in Australia discussed the ethical aspects of identifying and treating SMA in the rapidly changing SMA landscape in that country.
These include protecting reproductive choice, considerations of the value of life with a disability, balancing benefits and harms with genetic screening, predicting SMA severity and treatment eligibility, evaluating a treatment’s cost-effectiveness, and managing parental expectations regarding treatments.
Genetic carrier screening provides couples with information about their chance of having a child with SMA, allowing them to “make reproductive decisions in accordance with their values,” the researchers wrote.
However, ethical issues argued in prenatal screening, or genetic testing during pregnancy to assess whether the baby will be affected by the disease, include that “is unjustly discriminatory,” as it carries “an implicit purpose of eradicating disability and diminishing diversity, thereby devaluing people living with genetic conditions such as SMA,” the team wrote.
As such, couples should have “access to balanced information, including testimony regarding the lived experience of SMA and caring for those with this condition” to help them “make decisions that are in line with their values,” they added.
Newborn screening (NBS) for SMA, done shortly after birth, is available for free in several countries and is likely to soon be available in Australia, based on a pilot study in two of the country’s regions.
While NBS allows a start of timely treatment, patients with three SMN2 copies are currently not eligible for funded treatment until symptom onset, and this “watch and wait” approach may be stressful for parents.
NBS also raises questions about how and when to intervene, particularly among infants with more than three SMN2 copies, for whom disease severity becomes more uncertain and who may not present symptoms until adulthood.
If a newborn screen for SMA comes back positive, families may also want to test older siblings. But if no symptoms are present, this is only recommended once siblings are old enough to exercise their own choice.
“A further issue is that older siblings may not be able to access the same treatment, as there are specific [reimbursement] restrictions for each therapy based on age and symptoms,” the researchers wrote.
“This scenario will require careful pre-test counselling and neurological assessment in partnership with pediatric multidisciplinary neuromuscular clinics and families,” they added.
Given that currently available SMA therapies are not a cure and cannot reverse already established motor neuron loss, “it is important to manage parental optimism and hope, and ensure that benefits are not overestimated while possible harms are underplayed,” the researchers wrote. Associated treatment burden and costs should also be part of these discussions.
These ethical considerations emphasized that “to work effectively with [parents and patients] pre- and post-testing, general practices should ensure they have resources to access relevant information regarding the various screening and treatment options in SMA,” the team wrote.
In addition, “care should be supported by referral or consultation with expert specialists in ‘grey’ or difficult cases,” and “patient-centered care that responds to each family’s preferences and their specific context is crucial” to help both parents and physicians “navigate these issues,” they concluded.