Application of RWE in Drug Access Decision Making Tuesday, April 19 @ 12:00pm EDT Angela Paradis, ScD, Medical Director, Biogen, Cambridge, MA, USA

1. Generating real-world evidence in rare
disease: The example of Spinal Muscular
Atrophy
Angela Paradis, ScD
Global Medical Director and Head of Data Generation,
Neuromuscular Diseases
Biogen
Cambridge, MA, USA
April 2022

2. Speaker disclosures
Angela Paradis is employee of and hold stock/stock options in Biogen.

3. CT, clinical trial; RDT, rare disease treatment; RWE, real-world evidence.
List of studies represents pivotal and key studies but is not a complete list.
Speaker’s own opinion.
RWD supplement evidence generated from CTs
RWD: Observational
vs.
CT: Interventional
CT
population
RWD
population
Real-world timeframe
Clinical trial timeframe

4. CT, randomized clinical trial; RWD, real-world data.
List of studies represents pivotal and key studies but is not a complete list.
1. Coratti G, et al. Orphanet J Rare Dis. 2021;16(1):430. 2. NCT02386553. 3. NCT02193074. 4. NCT04488133. 5. NCT02292537. 6. Darras BT, et al. Neurology. 2019;92:e2492-e2506. 7. NCT05067790. 8.
NCT04089566. 9. NCT03505099. 10. NCT03306277. 11. NCT02122952. 12. NCT03381729. 13. NCT03779334.14. NCT02913482. 15. NCT02908685. 16. NCT03032172. Available from: ClinicalTrials.gov. March 2022.
RWD supplement evidence generated from CTs
Pre-symptomatic Pediatric Adult
Nusinersen
Onasemnogene
abeparvovec
Risdiplam
NURTURE2
CS2/126
CHERISH5
RWD publications1
RESPOND4
DEVOTE8
ENDEAR3
SPR1NT9 STRIVE10 START11 STRONG12
RAINBOWFISH13
FIREFISH14
SUNFISH15
JEWELFISH16
Nusinersn study Onasemnogene abeparvovec study Risdiplam Study Ongoing trial
RWD: Observational
vs.
CT: Interventional
CT
population
RWD
population
Real-world timeframe
Clinical trial timeframe
ASCEND7

5. RDT, rare disease treatment; RWD, real-world data; RWE, rea-world evidence
1. Speaker’s own opinion. 2. Real-World Evidence. Available from: https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence. Accessed March 2022
There are diverse sources of RWD and ways of generating RWE2
Disease registries can be used to study real-world
effectiveness and safety of RDTs
Disease registry
approach1
Protocol driven studies
Claims and
billing
Electronic health
records (EHRs)
Mobile devices
Registries
Other sources
Treatment value across patient population
Treatment effectiveness vs. natural history
Predictor of /time to treatment outcomes
Indirect comparisons between treatments

6. EMA, European Medicines Agency; SMA, spinal muscular atrophy.
1. European Medicines Agency: Patient Registries. Available from: https://www.ema.europa.eu/en/human-regulatory/post-authorisation/patient-registries. Accessed March 2022. 2. Raynaud S, et al. Presented at
ICNMD 2021.
Biogen has broadly supported this approach with multiple partners, following the
inception of EMA Patient Registries Initiative in 20151,2
SMA disease registry network: a global collaboration
Improve the capacity
and capability of
registries to collect
patient-level data
Standardize data
across registries to
an internationally
aligned core data set
Provide financial
support for data
collection and
sustainability
1. Harmonize data collection across
a broad patient population to
generate high-quality data for SMA
community
2. Characterize natural history
3. Characterize treatment patterns
and outcomes
4. Supplement clinical trial data to
support post-authorization
commitments and payers’ data
needs.
Specific objectives3

7. ICNMD, international congress on Neuromuscular Diseases; HCP, healthcare provider; HTA, health technology assessment; SMA, spinal muscular atrophy.
Raynaud S, et al. Presented at ICNMD 2021.
Meeting the needs of the SMA community, HCPs, researchers, regulators, payors,
and Industry
Biogen-supported SMA registry collaborations
4,500 patients with SMA have been enrolled
across 18 registries/19 countries
Registries
Individual/collaborative
projects
Individual/aggregate
data
National/international
guidelines
Patient management and
standards of care
Scientific congresses,
meetings, and publications
Scientific congresses,
meetings, and publications
Regulators
HTA/payers

8. CT, clinical trial; EMA, European Medicines Agency; SMA, spinal muscular atrophy; SmPC, summary of product characteristics.
Speaker’s own opinion.
Utilizing data from SMA disease registries
Key advancements in
knowledge on the
natural history of SMA
Independent publications
on real-world
effectiveness,
supplementing CTs
Fulfill post-authorization
safety requirements
from regulatory bodies
Reimbursement
submissions to inform
treatment value in specific
patient populations

9. CT, clinical trial; EMA, European Medicines Agency; SMA, spinal muscular atrophy; SmPC, summary of product characteristics.
1. Nusinersen Managed Access Agreement treatment eligibility criteria evidence review: 5q Spinal Muscular Atrophy type III non-ambulant cohort. Available from:
https://www.nice.org.uk/guidance/ta588/evidence/external-assessment-centre-eac-report-pdf-9138885231. Accessed March 2022
Utilizing data from SMA disease registries
Key advancements in
knowledge on the
natural history of SMA
Independent publications
on real-world
effectiveness,
supplementing CTs
Fulfill post-authorization
safety requirements
from regulatory bodies
Reimbursement
submissions to inform
treatment value in specific
patient populations
Case:
Pooled European registry
analysis (2020) of data from
Italy, Germany and Spain helps
expand treatment access and
reimbursement for the adults
with SMA1

10. DMT, disease-modifying treatment.
Speaker’s own opinion.
Big data from large patient population allow for adequate matching of patients on
clinical characteristics and account for confounding variables
Registries provide opportunities for comparative
effectiveness analysis among DMTs
Challenges in comparing therapies
within clinical trials:
• Limited sample sizes
• Patient-level data not
retrievable
• Difference in trial design and
inclusion/exclusion criteria

11. RWD, real-world data.
Speaker’s own opinion.
Considerations for a disease registry to generating
robust RWD
Data Interoperability
•
Data standards and quality
•
Potential to pool data
Prespecified, flexible
statistical analysis plan
•
Transparent data
governance
•
Sustainability
Inclusion of patient-
relevant outcomes

12. Nusinersen in adults with 5q spinal muscular atrophy: a
non-interventional, multicentre, observational cohort
study
Hagenacker T, et al. Lancet Neurol. 2020;19(4):317-325.

13. Design & patients
HFMSE, Hammersmith Functional Motor Scale-Expanded; RULM, Revised Upper Limb Module 6MWT, 6-minute Walk Test
Hagenacker T, et al. Lancet. 2020;4;317-25.

14. Baseline characteristics
HFMSE, Hammersmith Functional Motor Scale-Expanded; RULM, Revised Upper Limb Module 6MWT, 6-minute Walk Test; SD, standard deviation
Hagenacker T, et al. Lancet. 2020;4;317-25.

15. Effectiveness findings
HFMSE, Hammersmith Functional Motor Scale-Expanded; RULM, Revised Upper Limb Module 6MWT, 6-minute Walk Test; CI, confidence interval
Hagenacker T, et al. Lancet. 2020;4;317-25.

16. Effectiveness findings
HFMSE, Hammersmith Functional Motor Scale-Expanded; RULM, Revised Upper Limb Module 6MWT, 6-minute Walk Test
Hagenacker T, et al. Lancet. 2020;4;317-25.

17. Subgroup analyses were performed using the Mann–Whitney U test.
BL, baseline; HFMSE, Hammersmith Functional Motor Scale-Expanded; SD, standard deviation.
Hagenacker T, et al. Lancet. 2020;4;317-25.
Changes in HFMSE score at 14-month analysis
Factors affecting response to treatment
Baseline HFMSE score Spondylodesis Ambulant SMA Type
High (≥ 35) Low (< 35) Y
es No Y
es No II III
n 22 35 14 43 23 34 20 37
Difference vs
BL (SD)
4.6 (4.2) 2.2 (3.7) 1.4 (1.3) 3.7 (4.4) 4.6 (4.4) 2.1 (3.4) 1.1 (1.4) 4.2 (4.5)
p value < 0.0001 < 0.0001 0.0078 < 0.0001 < 0.0001 < 0.0001 0.0059 < 0.0001
Preplanned subgroup analyses Post-hoc subgroup analyses

18. Safety
No new safety concerns
identified
AE, adverse event
Hagenacker T, et al. Lancet. 2020;4;317-25.

19. Strengths
• The largest real-world
independent study of
nusinersen use in
teenagers and adults
with SMA Type II or III
• Multicentre study:
10 clinical sites in
Germany with a follow-up
for up to 14 months
• Multiple outcomes
assessed
• Exploratory analyses: the
study allowed the
identification of different
responses in patients
with different functional
levels at baseline
Hagenacker T, et al. Lancet. 2020;4;317-25.

20. HFMSE, Hammersmith Functional Motor Scale-Expanded
Hagenacker T, et al. Lancet. 2020;4;317-25.
Limitations
• Descriptive observational
single-arm study with no
control or natural history
arm
• Heterogeneous cohort
(real-world study)
• Ceiling and floor effects
are not captured by
HFMSE (patients with
very poor and very strong
motor function)
ü

21. Author conclusions
This study shows the safety and efficacy of nusinersen treatment
in adult patients with 5q SMA, with statistically significant improvements
in motor function observed at all timepoints
Hagenacker T, et al. Lancet. 2020;4;317-25.

22. Nusinersen safety and effects on motor function in
adult spinal muscular atrophy type 2 and 3
Maggi L, et al. J Neurol Neurosurg Psychiatry. 2020;91(11):1166-1174

23. Design & patients
Maggi L, et al. J Neurol Neurosurg Psychiatry 2020;0:1-9.

24. Baseline characteristics
HFMSE, Hammersmith Functional Motor Scale-Expanded; RULM, Revised Upper Limb Module 6MWT, 6-minute Walk Test; FVC, forced vital capacity
Maggi et al. J Neurol Neurosurg Psychiatry 2020;0:1-9.

25. Effectiveness findings
HFMSE, Hammersmith Functional Motor Scale-Expanded; RULM, Revised Upper Limb Module 6MWT, 6-minute Walk Test; FVC, forced vital capacity
Maggi et al. J Neurol Neurosurg Psychiatry 2020;0:1-9.

26. Safety
• Two patients reported worsening of existing hand
tremor and 1 patient reported renal colic
requiring hospitalization
• Two patients discontinued nusinersen due to
insufficient balance between benefit and
tolerability of lumbar puncture
• No relevant changes related to nusinersen were
observed in laboratory tests, including serum
creatinine
AE, adverse event
Maggi et al. J Neurol Neurosurg Psychiatry 2020;0:1-9.

27. Limitations
• Retrospective design • Small SMA Type II
sample size
• Missing data for some
variables
• Nominal statistical
significance (this
observational study had
open recruitment and
was not formally
enhanced for
effectiveness)
ü
HOWEVER
Retrospective studies present real-world data outside the rigid setting of clinical trials.
The few patients included with SMA Type II reflect the small prevalence of this condition in adults.
Maggi et al. J Neurol Neurosurg Psychiatry 2020;0:1-9.

28. Author conclusions
This study provides further real-world evidence of nusinersen safety and
efficacy in adult patients with SMA Types II and III, with the efficacy benefits
in SMA Type III appearing to be cumulative over time.
Maggi et al. J Neurol Neurosurg Psychiatry 2020;0:1-9.

29. Motor function in patients with Type II and III SMA
treated with nusinersen: a critical review and meta-
analysis
Coratti G, et al. Orphanet J Rare Dis. 2021;16(1):430

30. Design & patients
Coratti G, et al. Orphanet J Rare Dis. 2021;16(1):430.

31. HFMSE mean (SD)
change in adults
All studies in nusinersen-treated patients
reported positive HFMSE changes
irrespective of the age, SMA type or
functional level of the cohorts studied.
Square = SMA Type II; circle = SMA Type III; diamond = ambulant SMA Type III; triangle = non-ambulant SMA Type III; Symbol = mixed
phenotypes; blue = ~10 mo from initiation of drug; green = ~12 mo from initiation of drug; white = ~24 mo from infusion; light green
shade = SMA Type II; white shade = SMA Type III; striped shade = mixed phenotypes; italics = median value; not italicized = mean value
*Mean/median of baseline population not excluding drop-outs at 10, 14, or 24 mo of follow-up
**Mean/median of baseline population of both SMA Types II and III combined
HFMSE, Hammersmith Functional Motor Scale-Expanded; SD, standard deviation
Coratti G, et al. Orphanet J Rare Dis. 2021;16(1):430.

32. HFMSE mean (SD) change in children
Square = SMA Type II; circle = SMA Type III; diamond = ambulant SMA Type III; triangle = non-ambulant SMA Type III; Symbol = mixed phenotypes; blue = ~10 mo from initiation of drug; green =
~12 mo from initiation of drug; white = ~24 mo from infusion; light green shade = SMA Type II; white shade = SMA Type III; striped shade = mixed phenotypes; italics = median value; not italicized
= mean value
*Mean/median of baseline population not excluding drop-outs at 10, 14, or 24 mo of follow-up**Mean/median of baseline population of both SMA Types II and III combined
HFMSE, Hammersmith Functional Motor Scale-Expanded; SD, standard deviation
Coratti G, et al. Orphanet J Rare Dis. 2021;16(1):430.

33. RULM mean (SD) change in adults
Square = SMA Type II; circle = SMA Type III; diamond = ambulant SMA Type III; triangle = non-ambulant SMA Type III; Symbol = mixed phenotypes; blue = ~10
mo from initiation of drug; green = ~12 mo from initiation of drug; white = ~24 mo from infusion; light green shade = SMA Type II; white shade = SMA Type III;
striped shade = mixed phenotypes; italics = median value; not italicized = mean value *Mean/median of baseline population not excluding drop-outs at 10,
14, or 24 mo of follow-up **Mean/median of baseline population of both SMA Types II and III combined
RULM, Revised Upper Limb Module; SD, standard deviation
Coratti G, et al. Orphanet J Rare Dis. 2021;16(1):430.

34. RULM mean (SD) change in children
Square = SMA Type II; circle = SMA Type III; diamond = ambulant SMA Type III; triangle = non-ambulant SMA Type III; Symbol = mixed phenotypes; blue = ~10 mo from initiation of drug; green = ~12 mo from initiation of drug; white =
~24 mo from infusion; light green shade = SMA Type II; white shade = SMA Type III; striped shade = mixed phenotypes; italics = median value; not italicized = mean value *Mean/median of baseline population not excluding drop-
outs at 10, 14, or 24 mo of follow-up **Mean/median of baseline population of both SMA Types II and III combined
RULM, Revised Upper Limb Module; SD, standard deviation
Coratti G, et al. Orphanet J Rare Dis. 2021;16(1):430.

35. Effectiveness findings
HFMSE, Hammersmith Functional Motor Scale-Expanded; RULM, Revised Upper Limb Module 6MWT, 6-minute Walk Test; CI,
confidence interval; SE, standard error
Coratti G, et al. Orphanet J Rare Dis. 2021;16(1):430.

36. Subgroup analysis
Subgroup analysis HFMSE score
pooled mean change
Pooled mean
change between the two populations
Age p = 0.320
Adult population 1.87, 95% CI 1.05–2.68
Paediatric population 2.98, 95% CI 0.97–4.99
SMA Type p = 0.780
SMA Type II 2.54, 95% CI 1.00–4.09
SMA Type III 2.26, 95% CI 1.06–3.47
Ambulatory status p = 0.730
ambulant 1.99, 95% CI 0.24–3.74
non-ambulant 2.39, 95% CI 0.99–3.79
All subgroups reported an increase in HFMSE scores
HFMSE, Hammersmith Functional Motor Scale-Expanded; CI, confidence interval
Coratti G, et al. Orphanet J Rare Dis. 2021;16(1):430.

37. Limitations
• Limited number of real-
world studies despite
robust search strategy
• Number of participants
overall and in the
subgroups
• Broad confidence
intervals indicating
variability between
groups
• Missing or incomplete
baseline data prevented
analysis of variables
such as age, SMN2 copy
number or functional
ability
• 62% of studies have 1 or
2 high risk domains for
bias
• Different durations of
follow-up
• Safety outcomes were
not systematically
addressed
ü
SMN, spinal motor neuron
Coratti G, et al. Orphanet J Rare Dis. 2021;16(1):430.

38. Author conclusions
• Nusinersen provides a favorable benefit in motor function across a wide
range of patients with SMA Type II and III over a 10- to 14-month
observation period
• Although a direct comparison with studies reporting data from untreated
patients cannot be made, the longitudinal changes in the motor functions
for the treated cohorts were consistently positive, whereas the changes in
the untreated cohorts were consistently negative
Coratti G, et al. Orphanet J Rare Dis. 2021;16(1):430.

39. HCP, healthcare provider, RWD, real-world data; SMA, spinal muscular atrophy.
Takeaways
RWD, generated
from diverse sources
in routine
healthcare, could fill
the evidence gaps in
assessing long-term
treatment outcomes
in real-world
population
Disease registry
approach, like the
SMA global registry
network, is important
to meet the needs of
patient community,
HCPs, researchers,
regulators, payors,
and industry
To generate reliable
RWD, it is critical to
ensure the quality
and sustainability of
data, robust analysis
plans and the
inclusion of patient-
relevant outcomes