Evidence Points to Benefits of Newborn Screening for SMA, German Researchers Say

Researchers in Germany have found that newborn screening for spinal muscular atrophy (SMA) would likely be beneficial, based on evidence that early diagnosis and treatment leads to better motor development such as walking and sitting independently, less need for permanent ventilation, and lower mortality. 

The Institute for Quality and Efficiency in Health Care (IQWiG) in Germany published its findings in a final report, on behalf of the Federal Joint Committee (G-BA).

The G-BA is the highest healthcare decision-​making body in Germany which oversees the IQWiG, the agency responsible for assessing the quality, effectiveness, and safety of medical treatments.

Right now, newborn screening in Germany does not include SMA. And because there were no studies that specifically compare early-stage treatments with those given at a later stage, the IQWiG conducted its own research, looking for supporting evidence of the potential benefits of screening infants for SMA in existing medical literature. 

“No direct evidence was available for this benefit assessment, i.e., there were no comparative intervention studies of the screening chain,” said IQWiG project manager Andrea Steinzen, PhD, in a press release. “We therefore had to compile the evidence ourselves, using various pieces of the puzzle from treatment and diagnostic studies and following the so-called ‘linked evidence’ approach.”

They found evidence in a randomized and double-blind, sham-procedure-controlled Phase 3 clinical trial (NCT02193074) called ENDEAR, which evaluated the safety and efficacy of Spinraza (nusinersen; developed by Biogen) in 121 infants diagnosed with SMA (most likely to have SMA type 1).

SMA is primarily caused by mutations in the SMN1 gene that results in low or no SMN protein production, which is critical for muscle health. Spinraza is designed to compensate for the loss of SMN protein by stimulating a second survival motor neuron gene (SMN2). It is administered intrathecally, meaning an injection directly into the spinal canal. 

Within this trial, a subgroup analysis found that infants benefited from early treatment initiation (given at most 12 weeks after symptom onset), compared with a later treatment start, in terms of achievement of motor milestones and time to death or permanent ventilation, the study’s primary measures.

By request of the IQWiG, Biogen conducted a comparison between presymptomatic and early symptomatic start of therapy. These data came from the ongoing NURTURE study (NCT02386553), a Phase 2 trial that includes 25 infants, most likely to have SMA type 1 or 2, who were genetically identified with SMA mutations at less than 6 weeks of age and treated with Spinraza before symptoms started to develop. 

Early results of the study presented at the 2019 American Academy of Neurology Annual Meeting showed that none of the treated infants required permanent ventilation or tracheostomy (a tube to help with breathing difficulties), all were able to sit without support and swallow, and some were able to walk with assistance while some could walk on their own. 

“For the final report, at our insistence the manufacturer provided a crucial piece of the puzzle to assess the effects of starting treatment earlier, which ultimately led to an indication of a benefit of newborn screening,” Steinzen said. “The earlier treatment can start, the more positively the course of the disease is influenced.”

No differences were found in adverse effects in either study when comparing the timing of treatment. Furthermore, as both studies lasted less than one year, conclusions on long-term effects were not available. 

Current testing procedures were found to be suitable for newborn screening as supported by the review of four additional studies. 

One of the limitations of newborn screening is that data on children with infantile SMA cannot be extrapolated to other forms of SMA. Additionally, early screening measures may evoke ethical issues in those identified with probable late-onset disease regarding the benefits of presymptomatic treatment. 

Currently, in the U.S., newborn screening programs for SMA are available in 18 states with more in the process of doing so.