WHY SPINRAZA/LATER-ONSET EFFICACY
Pivotal trial:
CHERISH3,5
Study: A phase 3, multicenter, randomized (2:1), double-blind, sham procedure–controlled trial
Treatment duration: 15 months
Participants: 126 patients with later-onset SMA, aged 2 to 9 years at screening
Primary endpoint: Change in motor function as measured by HFMSE
Secondary endpoint: Clinically meaningful change in HFMSE ≥3 points and change in upper limb function as measured by RULM
Study limitations: Differences in dosing compared to the approved SPINRAZA schedule
Safety: The most common side effects were fever (43%), headache (29%), vomiting (29%), and back pain (25%)
Significant improvements seen in overall motor function3
HFMSE=Hammersmith Functional Motor Scale—Expanded.
Motor function began to steadily improve in just 6 months compared to untreated group
Learn more about the mobility measures used in the SPINRAZA clinical trials
Learn more about the mobility measures used in the SPINRAZA clinical trials
Review the warnings and precautions, including thrombocytopenia, coagulation abnormalities, and renal toxicity
Independent
observational study
from The Lancet
Neurology7
Study design: An independent, prospective, multicenter, observational cohort study
Study duration: Up to 14 months. Assessments made at 6, 10, and 14 months
Participants: 139 patients with genetically confirmed 5q later-onset SMA, aged 16 to 65
Primary endpoint: Change from baseline in motor function measured by HFMSE at 6, 10, and 14 months. Patients with missing baseline HFMSE scores were excluded from these analyses
Secondary endpoints: Change from baseline in upper limb and walking ability measured by RULM and 6MWT at 6, 10, and 14 months
Study limitations: No control group; observational design. Study powered on primary endpoint only. Statistics for other endpoints are descriptive only
Safety: The majority of adverse events (AEs) were generally consistent with those reported in the SPINRAZA clinical trials. Other reported AEs were:
- Nausea
- Diffuse pain
- Constipation
- Vertigo
- Bladder disorder not otherwise specified
- Infection
- Meningitis, aseptic
- Tinnitus, aggravated
Not a Biogen-sponsored study. Biogen-sponsored pivotal trials for SPINRAZA did not
include adults with SMA.
One of the largest real-world studies of SPINRAZA included 139 adults with later-onset SMA up to age 657
HFMSE=Hammersmith Functional Motor Scale—Expanded.
*Lower bound of 95% CI not shown.
SPINRAZA significantly increased mean HFMSE scores compared to baseline
139 patients completed an assessment at 6 months, 105 at 10 months, and 61 at 14 months. Patients not included at 10-month and 14-month assessments were those who had not reached the assessment time point (30 at month 10, 44 at month 14), were missing baseline or assessment values (15, 13, and 4 at month 6, 10, and 14, respectively), had an adverse reaction or procedure-related event (n=2), or withdrew consent (n=2). Greater improvement of motor function was correlated with lower severity of disease at baseline. 14 of 124 patients (11%) showed worsening motor function under treatment as measured by HFMSE.
†Exploratory endpoint.
≥3-point increase is considered clinically meaningful for HFMSE. A 1-2–point increase could be considered a positive outcome in a disease where natural history has shown a progressive decline.7,9
SPINRAZA improved mean upper limb function and walking distance compared to baseline at every study time point7
RULM=Revised Upper Limb Module.
‡Lower bound of 95% CI not shown.
- 75% (21/28) who saw clinically meaningful improvements in RULM at 6 months maintained these milestones at 14 months
- At 6 months, 28 (23%) of 120 patients showed ≥2-point improvement in RULM from baseline (ie, a clinically meaningful improvement), whereas 74 (61%) showed no meaningful change, 18 (15%) showed a decline of 1 point or more, and 10 (8%) showed a decline of ≥2 points
6MWT=6-Minute Walk Test.
§Lower bound of 95% CI not shown.
A >30-meter increase surpasses the definition of clinically meaningful on the 6MWT4
Independent,
observational study
from The Journal of
Neurology,
Neurosurgery and
Psychiatry6
Study design: An independent, retrospective, multicenter, observational cohort study
Study duration: Up to 14 months. Assessments made at 6, 10, and 14 months
Participants: 116 patients with later-onset SMA Type 2 (n=13) and Type 3 (n=103), aged 18-72
Primary outcomes: Change from baseline in motor function measured by HFMSE, RULM, and 6MWT at 6, 10, and 14 months
- Clinically meaningful response was defined as a ≥3-point increase in HFMSE, ≥2-point increase in RULM, or ≥30-meter increase in 6MWT
Study limitations: No control group; retrospective observational design; missing data for some clinical assessment variables; and a small number of patients with SMA Type 2 (n=13)
Safety: The majority of adverse events (AEs) were generally consistent with those in the SPINRAZA clinial trials
- The most frequently reported AEs were postprocedural headache (37.1%) and lumbar pain (8.6%)
- 5 patients were hospitalized for headache
- Other reported AEs were transient worsening of existing hand tremor (2 patients) and renal colic (1 patient)
Not a Biogen-sponsored study. Biogen-sponsored pivotal trials for SPINRAZA did not
include adults with SMA.
One of the largest real-world studies of SMA Type 3 to date included 103 adults6
HFMSE=Hammersmith Functional Motor Scale—Expanded.
Statistically significant improvement seen as early as 6 months and up to 14 months in patients with SMA Type 3
Positive trends toward improvement in patients with SMA Type 2, even though improvements were not statistically significant
Statistically significant improvement seen as early as 6 months and up to 14 months in patients with SMA Type 3
SPINRAZA improved median upper limb function and median
walking distance in SMA Type 3 subgroups6
RULM=Revised Upper Limb Module.
- Positive trends toward improvement in patients with SMA Type 2, with a 2-point increase seen at 14 months (3/5, range 0 to 3)
The Type 3 SMA cohort showed an increase by a median 0.5 points in RULM score at 14 months compared to baseline (44/102, range -6 to 6)
6WMT=6-Minute Walk Test.
The Type 3 SMA cohort showed an increase by a median 0.5 points in RULM score at 14 months compared to baseline (44/102, range -6 to 6)
Critical literature
review and meta-
analysis from
Orphanet Journal
of Rare Diseases9
Study design: A real-world, independent critical review and meta-analysis assessing the efficacy of SPINRAZA in Type 2 and Type 3 SMA patients based on 19 peer-reviewed publications:
- Critical literature review and meta-analysis performed on structured assessments of SPINRAZA efficacy in later-onset SMA patient cohorts (all publications up to Jan 2021 included)
- Subgroup analyses conducted to further verify and estimate the influence of age, SMA type, and motor function on pooled results of treated population
- Publications containing SMA natural history outcomes were also included
Motor outcomes measured: Hammersmith Functional Motor Scale—Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT)
Study limitations:
- Small numbers of participants in some studies and subgroups
- Respiratory function or safety concerns were not addressed in all studies
- Confidence intervals were often broad, and high variability observed in the cohorts required a conservative analysis of the data
- Due to variability across the studies, a direct comparison with studies reporting data from untreated patients cannot be made
- Other variables, such as age, SMN2 copies, or functional ability at baseline could not be analyzed due to missing data
- This review only focused on functional motor abilities, as these were the measures most commonly used
Safety: Safety was not critically evaluated in this publication. Adverse events (AEs) reported in individual studies are included in the publication’s Supplemental Information section. AEs were generally consistent with those seen in the SPINRAZA pivotal trials5,9
Not a Biogen-sponsored study. Biogen-sponsored pivotal trials for SPINRAZA did not
include adults with SMA.
The largest independent critical literature review and meta-analysis of
SPINRAZA in adult and pediatric patient cohorts with later-onset SMA to date9
Using PRISMA guidelines—a 4-phase approach to guide the identification, screening, eligibility, and inclusion of studies into a meta-analysis—databases were searched to identify articles reporting on SPINRAZA efficacy using structured assessments in Type 2 and 3 SMA. After screening, 13 articles (out of 14,627 identified hits) were included in the meta-analysis of HFMSE results.
All 13 publications in this analysis reported improved mean HFMSE scores for treated groups. Overall, treated patient cohorts had a statistically significant improvement in functional motor scores as shown by the 2.27-point increase in the HFMSE pooled mean score from baseline (95% CI, 1.41-3.13).
HFMSE subgroup analysis results
Results remained consistent when studies with 10, 12, 14, or 24 months of follow-up were analyzed.
