US Medical Data Show Higher Mortality in SMA Patients Before DMT Era

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Before the emergence of Spinraza (nusinersen) — the first disease-modifying therapy (DMT) approved for spinal muscular atrophy (SMA) — patients of all ages and types of the disease showed greater all-cause mortality than their peers who did not have SMA and the general population, according to a large study based on U.S. medical records.

These findings highlight that even those with type 3, a milder later-onset form of SMA thought to be associated with normal life expectancy, had an increased risk of death in the pre-DMT era, the researchers noted.

Given that this study did not have access to information on cause of death, future studies are needed to better understand the causes of this reduced life expectancy in patients with this milder form of the disease.

The study, “Comparative All-Cause Mortality Among a Large Population of Patients with Spinal Muscular Atrophy Versus Matched Controls,” was published in the journal Neurology and Therapy.

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SMA is characterized by progressive muscle weakness and wasting that affects mainly the muscles involved in movement, but also those that support breathing.

The disease is divided into five main types — 0, 1, 2, 3, and 4  — based on the age of symptom onset and the highest motor milestone achieved. Type 0 is the most severe form of the disease, with onset before birth, while type 4 is its mildest form, with an adult onset.

It is commonly accepted that severe forms are associated with a shorter lifespan, but patients with milder, later-onset forms, “who often live to older ages, have a mortality rate similar to the general population,” the researchers wrote.

However, “there is little information about survival of spinal muscular atrophy (SMA) patients into adulthood,” and survival studies in SMA patients in large and diverse medical settings are rare, they added.

To address this, researchers at Biogen, Spinraza’s developer, retrospectively analyzed electronic health records (EHR) from the U.S. Optum database to estimate age-specific, all-cause mortality rates from Jan. 1, 2007 to Dec. 22, 2016 (the day before Spinraza’s U.S. approval) in SMA patients and individuals without the disease.

The Optum database is one of the largest de-identified EHR data assets in the U.S., with records covering about 100 million people.

Using specific health codes, the researchers identified 5,179 SMA patients diagnosed during that period, who were matched by age, sex, and first diagnostic code date to 51,152 people without the disease (used as controls).

“This is one of the first studies to examine mortality in patients with SMA compared with a representative sample of age-matched controls in a large, real-world sample,” the researchers wrote.

All individuals were divided into nine age groups: less than 1 year old, between 1 and 2, 2–12, 13–20, 21–30, 31–40, 41–50, 51–60, and older than 60 years.

The mean age of the SMA patients was 45.1 (range, 0–86 years), and about 12% were younger than 13 years at the time of the first diagnostic code, while 31% were older than age 60. Most (77%) were Caucasian and over half (52.6%) were male.

A total of 66 people had been diagnosed with SMA type 3, and their mean age was 38.9 years.

Both SMA patients and controls were followed for a mean of 7.7 years.

Results showed that 746 (14%) SMA patients died during the follow-up period, compared with 4,227 (8.3%) deaths in the control group.

The occurrence of all-cause deaths per 100,000 person-years (the gathered follow-up years of all individuals in the study) was 1,926 among SMA cases and 1,099 among controls, reflecting a significantly increased risk of death (by 1.76 times) in the SMA group.

The overall mortality rate in SMA patients was also two times higher than that of the U.S. general population in 2012 (810 deaths per 100,000 person-years), which more closely resembled that of the control group.

Differences between the control group and the general population may be related to differences in age and sex distribution, as well as the EHR-based nature of the study, which may have included individuals requiring more medical care than the general population.

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An increased risk of all-cause death among SMA patients was observed in both males (1.69 times higher) and females (1.85 times higher), and across all age groups (between 1.26 and 44 times higher).

Particularly, the largest SMA-associated increase in mortality risk was seen among individuals younger than age 1, “which is not surprising given that these were mostly patients with SMA type [1], who have poor survival when untreated,” the researchers wrote.

Among individuals older than 60 years, SMA patients still showed a 1.26 higher risk of death relative to unaffected individuals.

People with SMA type 3 also had a greater all-cause mortality rate relative to controls (1,059 vs. 603 deaths per 100 person-years), but this difference did not reach statistical significance.

These real-world findings from the pre-DMT period highlighted that “SMA patients of all ages have a higher mortality rate than the general population, including older patients who survive into adulthood and those with SMA type [3],” the researchers wrote.

“In the future, it is recommended that mortality studies of patients with SMA include a detailed analysis of cause of death and genetic confirmation of SMA, which will provide detailed mortality rates in clinical studies and elucidate the potential reason for higher mortality in SMA patients,” the team wrote.

The data also suggest “the need for improvements in the care and management of patients with SMA, regardless of age or SMA type,” the researchers concluded.