‘Best Possible Outcome’ for SMA? Newborn Screening, Then Zolgensma

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by Marta Figueiredo PhD |

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Despite its high cost, giving the one-time gene therapy Zolgensma to an infant identified through newborn screening with spinal muscular atrophy (SMA) is cheaper in the long run than starting treatment with Spinraza (nusinersen) after symptom onset, according to a cost-effectiveness study in Australia.

Combining newborn screening (NBS) and early use of Zolgensma was not only associated with lower overall costs, but also with longer and better lives for these children.

“Pairing newborn screening with early gene therapy treatment will help save lives and improve the quality of life of babies born with SMA, as well provide cost savings for governments,” Sophy Shih, PhD, the study’s lead author and a health economist at the University of New South Wales (UNSW) Medicine & Health, said in a university press release.

“This is the best possible outcome from a cost-effectiveness study,” Shih added.

Findings support both the favorable cost-effectiveness profile of the Novartis’ gene therapy, and the importance of adding SMA to NBS programs, which are supported by the Australian government.

The study, “Newborn screening for spinal muscular atrophy with disease-modifying therapies: a cost-effectiveness analysis,” was published in the Journal of Neurology, Neurosurgery, and Psychiatry.

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SMA is the most common genetic cause of death in infants and children, affecting 1 in every 10,000 live births. It is caused mainly by mutations in both copies of the SMN1 gene, impairing the production of a key protein for motor neuron and muscle health called SMN.

“By the time an infant or child with SMA presents with symptoms, they’ve already lost 90 per cent of their nerves,” said Michelle Farrar, MD, PhD, one of the study’s authors and a pediatric neurologist based at UNSW and Sydney Children’s Hospital.

With the approval of the first SMA therapy — Biogen’s Spinraza — between 2016 and 2017 in several countries, and the proven importance of early diagnosis and treatment in preventing SMA-associated lifelong disability, an increasing number of countries have begun screening newborns for the disease.

After a successful NBS pilot program for SMA in two Australian states that account for one-third of all births nationally, conducted from August 2018 to July 2020, a submission to include the disease in the country’s NBS program was endorsed by the Australian government.

Each state and territory then decides whether to add SMA to its list of diseases screened at birth, considering the logistical and financial burdens of such a decision.

To help guide these decisions, Shih, Farrar, and colleagues compared the costs and associated health outcomes of NBS and early treatment with either Spinraza or Zolgensma to the current practice of diagnosing and treating  children with Spinraza after symptom onset.

Their analysis, the researchers noted, “was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.”

Both Spinraza, injected directly into the spinal canal three times a year (every four months after a loading period), and Zolgensma, given as a single into-the-vein infusion, work to increase SMN levels. But the former targets the “backup” SMN2 gene, and the latter delivers a healthy version of the SMN1 gene to cells.

Analyses included the estimated costs of screening, diagnosis, ongoing treatments and therapies, and of parents pausing their career to look after their child, as well as quality-adjusted life years (QALYs).

QALY measures the impact of life duration and quality over a specific time period, and is a standard measure in health economics to evaluate the monetary value of a given therapy.

Spinraza is subsidized in Australia for SMA patients under age 18, but a decision on Zolgensma’s reimbursement is still awaited, and its local market price is unknown. As such, the researchers considered a base cost of $1.54 million for the one-time gene therapy, up to its U.S. list price of $2.1 million.

Zolgensma was approved for use in Australia in March 2021 for infants up 9 months old, with mutations in both SMN1 gene copies and between one and three SMN2 gene copies.

NBS screening and treatment with either Zolgensma or Spinraza before symptom onset was associated with an additional 9.93 QALYs, compared with late treatment after symptoms are evident.

While early treatment with either therapy provided similar health outcomes, cost of Spinraza’s use was nearly twice that of Zolgensma over 60 years.

Compared with no screening and late Spinraza use, NBS and early treatment with Zolgensma was still cheaper, saving at least $24 per infant screened.

“In the long term, newborn screening for SMA coupled with gene therapy would save $US2.4 million per 100,000 babies screened — roughly the number of babies born in [New South Wales] each year,” Shih said.

Zolgensma was also associated with “an extra 85 life years in full health” per 100,000 newborns screened, Shih said, adding that these results make the combination of newborn screening and Zolgensma a “dominant intervention,” as it is both lifesaving and cost saving.

“NBS coupled with gene therapy improves the quality and length of life for infants with SMA and would be considered value-for-money from an Australian clinical and policy context,” the researchers wrote.

Even at its $2.1 million upper price, Zolgensma’s early use was considered cost-effective, with an incremental cost-effectiveness ratio of $21,000/QALY in the long-term, based on generally accepted willingness-to-pay thresholds of $50,000 per QALY.

“This is an innovative clinical and economic model, where a single administration of a gene therapy can potentially have a lifetime of benefits,” Farrar said.

“There’s a large up-front cost, but the burden of repeated treatments and costs over a lifetime aren’t present,” she added, noting the researchers are hopeful that Zolgensma’s health benefits will “continue over a lifetime.”

The researchers plans to test their model against new clinical trial and real-world data for Zolgensma, to determine whether its cost-effectiveness superiority is maintained.

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