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 function and upper limb 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
RULM=The Revised Upper Limb Module evaluates limb function and strength in individuals with later-onset SMA who are unable to walk. It is scored from 0-37 points, with higher scores indicating better function.
HFMSE was developed specifically for SMA and is a widely used and well-validated scale for measuring clinical benefit in later-onset SMA.6,7
Supportive trials:
CS2/CS124
Study: A phase 1b/2a, open-label, multiple-dose, dose-escalation integrated analysis of CS2 and CS12 trials
Treatment duration: ~3 years (38 months)
Participants: 28 ambulatory and nonambulatory patients with SMA aged 2 to 16 years at time of first dose
Primary endpoint: Safety of SPINRAZA
Study limitations: Differences in dosing compared to the approved SPINRAZA schedule and no control group
Safety: Adverse reactions were similar to those reported in the pivotal trials
Individuals saw improvements in overall motor function, upper limb function, and
walking distance4
ULM=The Upper Limb Module evaluates limb function and strength in individuals with later-onset SMA who are unable to walk. It is scored from 0-18 points, with higher scores indicating better function.
100% (7/7) who achieved meaningful improvements in their walking distance maintained these milestones through
year 36†
†Clinically meaningful is defined as ≥30-meter increase in walking ability.
SPINRAZA may help patients gain or regain the ability to walk.
- At least 1 of 11 patients with Type 2 SMA gained the ability to walk for the first time
- At least 2 of 4 patients with Type 3 SMA regained the ability to walk
†Clinically meaningful is defined as ≥30-meter increase in walking ability.
In multiple independent, observational studies, SPINRAZA demonstrated a clinical benefit in adults with later-onset SMA7,8
The Lancet
Neurology
independent,
observational
study7
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 ages 16-65
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
The largest real-world study 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 6MWT4,7
The Journal of
Neurology,
Neurosurgery and
Psychiatry
independent,
observational
study8
Study design: An independent, retrospective, multicenter. observational cohort study
Study duration: Up to 14 months. Assessments made at 6, 10, and 14 months
Participants: 115 patients with later-onset SMA Type 2 (n=13) and Type 3 (n=103) aged 18-72
Primary outcomes: Change from beselice 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, restrospective 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 Biogen-sponsored studies. SPINRAZA pivotal trials did not include adults with SMA.
The largest real-world study of SMA Type 3 to date included 103 adults
HFMSE=Hammersmith Functional Motor Scale—Expanded.
- 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
Statistically significant improvement seen as early as 6 months and up to 14 months in patients with SMA Type 3
SPINRAZA significantly improved median upper limb function and median
walking distance in SMA Type 3 subgroups8
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)
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)
