Treatment with Spinraza (nusinersen) may cause some alterations in the cerebrospinal fluid — that which surrounds the brain and spinal cord — in adults with spinal muscular atrophy (SMA), a study reported.

Changes recorded, like in total protein, were “mild” and without affect on treatment tolerability, the researchers wrote, and likely due to the lumbar punctures given to administer Spinraza than to the therapy itself. Still, they noted a need for further monitoring.

The study, “Cerebrospinal Fluid Parameters in Antisense Oligonucleotide-Treated Adult 5q-Spinal Muscular Atrophy Patients,” was published in Brain Sciences.

Spinraza, by Biogen, was the first SMA treatment to be approved in the U.S. It works by increasing levels of SMN protein, the lack of which causes SMA.

Because Spinraza cannot cross the blood-brain barrier — which, as its names suggests, limits what substances can pass from the blood into the brain — it must be administered by intrathecal injection. This is an injection directly into the cerebrospinal fluid (CSF) via a lumbar puncture — an injection directly into the spinal cord.

Some studies have indicated that treatment with Spinraza can lead to certain changes in the CSF, such as the amount of protein in the fluid. However, these effects are poorly understood.

A research team with Hannover Medical School in Germany took and analyzed CSF-related measures from 28 adults with SMA who were treated with Spinraza between 2017 and 2019. Among the patients, 10 had type 2 SMA, 17 had type 3, and one had type 4. Their median age was 36, and 64.3% were male.

Patients were given Spinraza, as recommended, first in loading doses and then as a maintenance treatment. During the loading period, Spinraza was administered via lumbar puncture on days 0, 14, 28, and 63; as maintenance, it’s given once every four months.

Prior to each injection, the researchers took CSF samples and reported detailed analyses of how various CSF parameters changed over time. Not all data was available for every patient at every time point, they noted.

Collectively, the 28 patients received 179 lumbar punctures. Consistent with prior findings, Spinraza’s use was generally safe, the researchers wrote, with no side effects reported across the majority (58%) of treatments given.

Side effects that did occur were mostly (80.2%) classified as being related to the procedure. That is, they were likely a result of the lumbar puncture rather than the medication.

“Our results confirm the notion that intrathecal administration of nusinersen [Spinraza] in adult SMA patients is generally safe and well tolerated,” the researchers wrote.

The team found several noteworthy trends in CSF measures. For example, total protein levels in the CSF and CSF/serum albumin quotient (QAlbumin) were often elevated. Both CSF protein levels and QAlbumin are markers of blood-brain barrier dysfunction. In other words, these changes suggest that this barrier is “leakier” in SMA patients than is typical.

These parameters were most often elevated toward the start of treatment, during or near the roughly two-month loading phase, when three of four lumbar punctures are given 14 days apart.

“We suggest that a short interval between repeated LPs [lumbar punctures] is more likely to result in an elevation of CSF protein parameters, especially against the background of numerous repeated LPs,” the team wrote.

They also noted that it is not possible to distinguish between the effects of Spinraza itself, and the effects of its administration, since every patient is treated via a lumbar puncture.

CSF parameters were often atypical in SMA patients, even in the absence of treatment, the researchers added. For example, 28% of these patients had higher-than-normal CSF protein levels before first use of Spinraza. The team suggested this may be due to the underlying disease, or to cut-off values that poorly determine what constitutes “higher-than-normal” protein levels.

Patients’ CSF protein levels also closely associated with age and other factors, and researchers suggested these factors may need to be accounted for in future analyses to ensure accuracy.

Various statistical analyses were done to look for associations between CSF parameters and measures of disease severity and clinical function, but generally no significant associations were found. While a few patients had rare inflammation-associated markers in their CSF, these were not linked with poorer Spinraza-related outcomes.

This study “confirms the previous findings on mild changes in CSF routine parameters in adult SMA patients under nusinersen treatment,” the researchers concluded.

“Conspicuous pre-treatment CSF findings … had no impact on the tolerability of nusinersen,” they added, although “it is important to further investigate and monitor CSF routine parameters.”

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