WHY SPINRAZA/LATER-ONSET STUDIES
Pivotal study:
CHERISH
Who: 126 individuals ages 2-9 years with later-onset SMA
Study time: 15 months
Primary outcome: Changes in motor function measured on the HFMSE
Secondary outcome: Changes in upper limb function measured on the RULM and percentage of individuals who had a clinically meaningful improvement of 3 or more points from baseline in HFMSE score
Safety: The most common side effects were:
- Fever
- Vomiting
- Headache
- Back pain
People on SPINRAZA had a 3.9-point improvement in overall motor function versus a 1.0-point decline in the control group.
The pivotal trial that proved SPINRAZA significantly improves
function in children with later-onset SMA versus control
Primary outcome: Change from baseline in HFMSE total score at 15 months
A 1- or 2-point improvement on HFMSE is considered a positive change, and ≥3-point improvement a clinically meaningful change
Secondary outcome: Change from baseline in upper limb function score at
15 months
Supportive studies:
CS2/CS12
Who: 28 individuals ages 2-16 years with later-onset SMA: 11 with Type 2 and 17 with Type 3
Study time: 3 years
Primary outcome: These supportive studies were designed to determine the safety of SPINRAZA
Other outcomes: The safety and longer-term effects of SPINRAZA on overall motor function, upper limb function and walking ability were also studied
Limitations: The dosing was different than the approved SPINRAZA schedule and these studies had no controls
Safety: Side effects were consistent with those reported in the pivotal trials
The longer-term effect of SPINRAZA on overall motor function, upper limb function, and walking ability was measured over 3 years
Changes in motor function
Changes in upper limb function in people with Type 2 SMA
56% (5/9) of people saw impactful
improvements by year 3
100% (7/7) who achieved meaningful improvements in their walking distance maintained these milestones through year 3.
1 individual with
Type 2 SMA gained
the ability to walk.
2 individuals with Type 3 SMA regained the ability to walk.
The SPINRAZA clinical trials in later-onset SMA did not include adults, but independent, observational studies in adults have been published. Two of these studies are listed below.
Adult independent,
observational study 1
Who: 139 adults ages 16-65 years with later-onset SMA: 2 with Type 1, 47 with Type 2, 89 with Type 3, and 1 with Type 4
Study time: 14 months
Primary outcome: Changes in motor function at 6, 10, and 14 months, measured on HFMSE
Secondary outcomes:
- Changes in upper limb function at 6, 10, and 14 months, measured on RULM
- Changes in walking ability measured on the 6MWT
Limitations
- No controls: Controls are people who don’t get the study drug. Controls can be compared to people who do get the study drug. This study had no controls
- No blinding: Blinding is when the doctors and nurses caring for those in the trial don’t know who is getting the study drug. This study was not blinded
- Measured for primary outcome only: Remember, primary outcomes answer the main question, or outcome, of a study. Secondary outcomes provide answers to other questions in a study
Safety: Most of the side effects were consistent with those in the SPINRAZA pivotal trials. The most common side effects in the trial were headache, back pain, and nausea. Others reported were:
- Nausea
- Diffuse pain
- Constipation
- Vertigo
- Bladder disorder not otherwise specified
- Infection
- Meningitis, aseptic
- Ear infection
An independent, observational study in adults ages 16-65 years with later-onset SMA
How do observational studies compare to
pivotal studies?
Pivotal studies: used to get FDA approval for a drug, and are conducted by the company seeking approval for the drug. They are designed so that we are very sure the efficacy and safety we see in the study are because of the drug.
Observational studies: designed to gain more knowledge about a drug after it has been approved by the FDA. These types of studies are valuable, but not as strong as pivotal studies.
Primary outcome: Average change in
HFMSE score from baseline
The number of individuals at each assessment varied. This is because 4 individuals withdrew from the study, and some had either missed assessments or had not received treatment long enough to be included.
Most adults stabilized or significantly improved their motor function. Some adults did not improve motor function.
- Those with less severe symptoms at the start of the trial had greater improvements in motor function
- 11% (14/124) showed worsening motor function while on treatment
Secondary outcome 1: Average change in
RULM score from baseline
On average, adults stabilized or improved their upper limb function
At 6 months, the majority of adults stabilized or improved their upper limb function, but some did see a decline.
After 6 months of treatment:
23% (28/120)
meaningfully improved their
current level of strength
61% (74/120)
stabilized their current
level of strength
15% (18/120)
showed a decline of 1 point or more and 8% (10/120) showed a decline of 2 points or more
Secondary outcome 2: Change from baseline in 6MWT at 6, 10, and 14 months
Most adults (24/37) improved their walking distance by month 10
Safety
Most of the side effects were consistent with those in the SPINRAZA pivotal trials. The most common side effects in the trial were headache, back pain, and nausea. Others reported were:
- Diffuse pain
- Constipation
- Vertigo
- Bladder disorder not otherwise specified
- Infection
- Meningitis, aseptic
- Ear infection
Adult independent,
observational study 2
Who: 116 adults ages 18-72 years with later-onset SMA; 13 with Type 2 and 103 with Type 3
Study time: 14 months
Primary outcomes: Changes in overall motor function measured on HFMSE, changes in upper limb function measured on RULM, and changes in walking ability measured on 6MWT
Limitations:
- No controls: Controls are people who don’t get the study drug. Controls can be compared to people who do get the study drug. This study had no controls
- Retrospective design: A retrospective study is one that uses the medical records and information of those who previously took the drug
- Missing data for some outcomes: Missing data may impact a study’s conclusion
- Small number of patients with SMA Type 2: Of the 116 adults who participated in the study, 13 had SMA Type 2
- These limitations could have introduced bias and affected outcomes
Safety: No new side effects were identified in this study; those that were reported were consistent with the safety profile of SPINRAZA.
The most common side effects were headache and back pain. Additionally:
- 41.4% of patients reported a side effect
- Most were generally mild to moderate and went away spontaneously in a few days
- 5 patients were hospitalized for headache
- 2 patients stopped therapy at 6 months. The reasons were that they felt no improvement and that they were unable to take the therapy
An independent, observational study in adults ages 18-72 with
later-onset SMA
How do observational studies compare to
pivotal studies?
Pivotal studies: used to get FDA approval for a drug, and are conducted by the company seeking approval for the drug. They are designed so that we are very sure the efficacy and safety we see in the study are because of the drug.
Observational studies: designed to gain more knowledge about a drug after it has been approved by the FDA. These types of studies are valuable, but not as strong as pivotal studies.
Primary outcome 1: Change from baseline in
HFMSE score at 6, 10, and 14 months
Primary outcome 2: Change from baseline in
RULM score at 6, 10, and 14 months
Nonambulatory adults with Type 3 SMA saw significant improvements in upper limb strength and motor function
When Type 3 individuals were analyzed based on their ability to walk, individuals:
- who could not walk (nonambulatory) had an improvement in upper limb function at months 10 (1 point) and 14 (2 points)
- who could walk (ambulatory) did not have an improvement at any time point (0 at all time points)
Primary outcome 3: Change from baseline in
6MWT score at 6, 10, and 14 months
Safety
Those that were reported were consistent with the safety profile of SPINRAZA. The most common side effects were headache and back pain. Additionally:
- 41.4% of patients reported a side effect
- Most were generally mild to moderate and went away spontaneously in a few days
- 5 patients were hospitalized for headache
- 2 patients stopped therapy at 6 months. The reasons were that they felt no improvement and that they were unable to take the therapy
Adults in the study saw clinically meaningful changes in 3 types of motor function
A clinically meaningful change can be described as the following:
+3 points on HFMSE,
which occurred in 49%
of adults by month 14
+2 points on RULM,
which occurred in 35%
of adults by month 14
+98 ft (30 m) on 6MWT,
which occurred in 42% of ambulatory
adults by month 14
“For me, it’s always been mind over matter; focusing on what you can do, and working around what you can’t.”