WHY SPINRAZA/REAL-WORLD EVIDENCE
Pivotal Trial: CHERISH
The efficacy of SPINRAZA for later-onset SMA was demonstrated in CHERISH, a phase 3, sham-controlled pivotal trial that measured change in motor function as measured by the HFMSE. Study duration was 15 months and enrolled 126 patients with later-onset SMA aged 2 to 9 years at screening. Least-squares mean change from baseline in HFMSE score at 15 months was 3.9 in the SPINRAZA group and -1.0 in the untreated group. The most common side effects were fever, vomiting, headache, and back pain.2
Łusakowska et al. Orphanet Journal of Rare Diseases
This real-world evidence study in older children and adults on SPINRAZA evaluated functional assessments and patient-reported outcomes over 30 months4
Study Design: Prospective, observational study that assessed 130 patients who were treated with SPINRAZA between March 2019 and January 2022 with SMA (Types 1c-3), at 2 centers in Poland. Final analysis included 120 treatment-naïve patients. Seven patients were excluded due to insufficient follow-up, and 3 discontinued, which includes a fatality that was considered unrelated to treatment.4
Study limitations4:
- Open-label, multicenter study in Poland without a control group
- Treatment practices may vary by country
- Number of patients with Type 1c and Type 2 were limited
- Data for later time points were limited as many patients had not yet reached those time points
- Missing assessments on some endpoints (eg, 6MWT) due to COVID-19 restrictions
- CHOP INTEND is not validated in adults
- Differences in dosing compared to approved SPINRAZA dosing schedule
- PGI-I is subjective, patient-reported, and not validated in SMA
End points4:
- Mean change in HFMSE vs baseline up to 30 months
- Mean change in CHOP INTEND score vs month 0 and month 26
- Mean change in RULM score vs baseline up to 30 months
- Mean change in 6MWT score vs baseline up to 30 months
- PGI-I assessment at subsequent time points of treatment
Safety: The study safety profile is generally consistent with the safety reported in the SPINRAZA clinical trials1,4
- The most frequent adverse event was post-lumbar puncture syndrome (PLPS), reported in 198 patients (19%)4
- All patients with PLPS reported headache, mainly of mild intensity4
- Cerebrospinal fluid leak was observed after CT-guided injection at month 10 for 1 patient4
- The leak stopped within 1 hour without intervention4
SEE ADDITIONAL SPINRAZA
SAFETY
6MWT=6-minute walk test; CHOP INTEND=Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; COVID-19=coronavirus disease 2019; CT=computed tomography; HFMSE=Hammersmith Functional Motor Scale—Expanded; PGI-I=Patient Global Impression-Improvement; RULM=revised upper limb module; SMA=spinal muscular atrophy.
In the observational study, mean HFMSE score improved compared with baseline at each time point4
HFMSE patient population (n=73*)4:
- Mean age: 31 years (SD, 15.6 years; range, 5–66 years)
- Mean disease duration: 23.7 years (SD, 14 years; range, 4–62 years)
- SMA Type 2: 6 patients (4 children)
- SMA Type 3: 67 patients (10 children)
RESULTS4:
- Mean HFMSE score increase of 5.1 points at month 30 (n=28)
- In 15% of patients (11/73), the HFMSE score improved by ≥10 points during the study4
*One patient with SMA Type 2 did not undergo assessment at day 180 (month 6) but was assessed at the subsequent 4 time points. Therefore, he was included in the analysis. At month 30, 28 patients were evaluated using the HFMSE.
HFMSE=Hammersmith Functional Motor Scale—Expanded; SD=standard deviation; SMA=spinal muscular atrophy.
At month 30, the HFMSE score showed improvement or no change in 96% of patients (27/28) on treatment with SPINRAZA4
Mean CHOP INTEND score improved compared with baseline at each time point4
CHOP INTEND patient population (n=47†)4:
- Mean age: 33.7 years (SD, 11.0; range, 13–66 years)
- Mean disease duration: 31.7 years (SD, 9.5; range, 3.0–58.0 years)
- SMA Type 1: 12 patients‡
- SMA Type 2: 13 patients
- SMA Type 3: 22 patients
RESULTS4:
- Mean CHOP INTEND score increased by 5.6 points at month 26 vs baseline
- Clinically meaningful improvements (≥4 points) in the CHOP INTEND score were seen in 20.5% of patients (9/44) at month 6 and in 65% of patients (11/17) at month 26
- 5 patients were available for assessment at month 30; the mean difference was 9.4 points
The CHOP-ATTEND test validated for adult patients with severe symptoms was not available at the time of the study. For this reason, the CHOP INTEND test, which is not validated in adults, was used.4
†Forty-four patients were assessed at least twice (at month 0 and month 6).
‡Baseline CHOP INTEND score was not available for 3 adults with SMA Type 1 who started treatment abroad within the Expanded Access Program (EAP). They started study evaluation at month 10, month 14, and month 18, respectively. Assessment was available up to month 30 for 2 of these patients.
§Low patient numbers (n=5) at 30 months preclude meaningful interpretation at this time point.
CHOP-ATTEND=Children's Hospital of Philadelphia Adult Test of Neuromuscular Disorders; CHOP INTEND=Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; SMA=spinal muscular atrophy.
94% of patients (16/17) noted improvement by at least 1 point at month 26 vs baseline4
RULM score improved compared with baseline at each time point4
RULM patient population (n=51)4:
- Mean age: 27 years (SD, 14; range, 5–66 years)
- Mean disease duration: 22 years (SD, 12.8; range, 3.8–62.0 years)
- SMA Type 2: 9 patients
- SMA Type 3: 43 patients
RESULTS4:
- Mean RULM score increased by 1.96 points at month 30 vs baseline
- During treatment, the proportion of patients who showed improvement in upper limb function was 61% (14/23) at month 30
RULM=revised upper limb module; SD=standard deviation; SMA=spinal muscular atrophy.
Clinically meaningful improvements (≥2 points) in RULM score was seen in 43.5% (10/23) of patients at month 304
6MWT showed improvement or stabilization for the majority of patients4
6MWT patient population (n=27ll)4:
- Mean age: 27 years (SD, 13; range, 6–59 years)
- Mean disease duration: 18 years (SD, 10; range, 4–33 years)
- SMA Type 3: 27 patients
RESULTS4:
- Mean 6MWT improved by 27.0 meters at month 30 vs baseline
- A relatively large number of patients experienced worsening in each point of treatment: 40% of patients (6/15) at month 6 and 33% of patients (4/12) at month 30
llThe lack of a fairly significant number of ratings in the 6MWT was mainly due to patients’ fear of staying too long in the hospital and contacting medical staff and other patients during the pandemic.
6MWT=6-minute walk test; SD=standard deviation; SMA=spinal muscular atrophy.
Clinically meaningful improvement (≥30 meters increase in walking distance) was observed in 33% of patients (5/15) at month 6 and was 50% (6/12) at month 304
Improvements were seen across all functional assessments up to 30 months4
- Clinically meaningful improvement was defined as a change in HFMSE score of ≥3 points, change in CHOP INTEND score of ≥4 points, and change in RULM score of ≥2 points. For patients able to walk independently, significant improvement in the 6MWT was defined as an increase in walking distance by at least 30 meters
¶Three patients who did not undergo assessment at month 0 were excluded. Only 5 patients were evaluated for CHOP INTEND at month 30.
Patients and caregivers assessed and self-reported their status, and most reported improvement or stabilization while on treatment4#
- While no patients reported feeling much worse or very much worse at each time point, between 2 and 5 patients reported feeling minimally worse at various time points during the study
#PGI-I data was subjective and patient reported.
6MWT=6-minute walk test; CHOP INTEND=Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; HFMSE=Hammersmith Functional Motor Scale—Expanded; PGI-I=Patient Global Impression-Improvement; RULM=revised upper limb module; SD=standard deviation.
After 26 months of SPINRAZA treatment, 96.5% of patients (62/64) reported subjective improvement or stabilization/no change, which was also reported at month 30 in 100% (47/47) of the patients4
Independent, observational study
from
The Lancet Neurology5
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.
Safety: The majority of AEs were generally consistent with those reported in the SPINRAZA clinical trials. Other reported AEs were:
- Nausea
- Diffuse pain
- Constipation
- Infection
- Meningitis, aseptic
- Vertigo
- Tinnitus, aggravated
- Bladder disorder not otherwise specified
SEE ADDITIONAL SPINRAZA
SAFETY
6MWT=6-minute walk test; AEs=adverse events; HFMSE=Hammersmith Functional Motor Scale—Expanded; RULM=revised upper limb module; SMA=spinal muscular atrophy.
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 653,5
SPINRAZA increased mean HFMSE scores compared with baseline
14 of 124 patients (11%) showed worsening motor function under treatment as measured by HFMSE. 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.
**Lower bound 95% CI not shown.
††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.5,6
HFMSE=Hammersmith Functional Motor Scale—Expanded; SMA=spinal muscular atrophy.
SPINRAZA improved mean upper limb function and walking distance compared with baseline at every study time point5
- 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
‡‡Lower bound of 95% CI not shown.
§§For individuals with later-onset SMA, clinically meaningful was defined as an improvement in RULM score of a least 2 points.
RULM=revised upper limb module.
llllLower bound of 95% CI not shown.
6MWT=6-minute walk test.
Independent, retrospective, observational study from The Journal of Neurology, Neurosurgery and Psychiatry1,3
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 to 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 AEs were generally consistent with those reported in the SPINRAZA clinical 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)
SEE ADDITIONAL SPINRAZA
SAFETY
6MWT=6-minute walk test; AEs=adverse events; HFMSE=Hammersmith Functional Motor Scale—Expanded; RULM=revised upper limb module; SMA=spinal muscular atrophy.
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 adults3
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.
HFMSE=Hammersmith Functional Motor Scale—Expanded; SMA=spinal muscular atrophy.
SPINRAZA improved median upper limb function and median walking distance in SMA Type 3 subgroups3
The Type 3 SMA cohort showed an increase by a median 0.5 points in RULM score at 14 months compared with baseline (n=44/102, range -6 to 6)
Positive trends toward improvement in patients with SMA Type 2, with a 2-point increase seen at 14 months (n=5, range 0 to 3)
RULM=revised upper limb module; SMA=spinal muscular atrophy.
6MWT=6-minute walk test; SMA=spinal muscular atrophy.
Critical literature review and meta-analysis from Orphanet Journal of Rare Diseases1,6
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 or structured assessments of SPINRAZA efficacy in later-onset SMA patient cohorts (all publications up to January 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: HFMSE, RULM, and 6MWT
Study limitations:
- Small number 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 conservation 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 the publication. AEs reported in the individual studies are included in the publication’s Supplemental Information section. AEs were generally consistent with those seen in the SPINRAZA pivotal trials
SEE ADDITIONAL SPINRAZA
SAFETY
6MWT=6-minute walk test; AEs=adverse events; HFMSE=Hammersmith Functional Motor Scale—Expanded; RULM=revised upper limb module; SMA=spinal muscular atrophy.
Not a Biogen-sponsored study. Biogen-sponsored pivotal trials for SPINRAZA did not include
adults with SMA.
Coratti et al is the largest critical literature review and meta-analysis of SPINRAZA studies to date6
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.6,8
All 13 publications in this analysis reported improved mean HFMSE scores for treated groups. Overall, treated patient cohorts had an improvement in functional motor scores as shown by the 2.27-point increase in the HFMSE pooled mean score from baseline (95%).
Results remained consistent when studies with 10, 12, 14, or 24 months of follow-up were analyzed.
Interpreting the pooled mean change in HFMSE data:
No difference between adult and pediatric
SPINRAZA was shown to be effective in both adults and children6
No difference reported in SMA Type 2 and SMA Type 3
SPINRAZA was shown to be effective regardless of SMA Type in later-onset patients6
No difference between ambulant vs nonambulant
SPINRAZA was shown to be effective regardless of ambulatory status6
HFMSE=Hammersmith Functional Motor Scale—Expanded; PRISMA=Preferred Reporting Items for Systematic reviews and Meta-Analyses; SMA=spinal muscular atrophy.