This document provides information on spinal muscular atrophy (SMA), including its genetics, epidemiology, classification, clinical features, diagnosis, management, and clinical trials of potential treatments. SMA is caused by a loss of motor neurons in the spinal cord due to a defect in the SMN1 gene and results in progressive muscle weakness. It is classified into five types based on age of onset and severity. Current management involves a multidisciplinary approach including nutritional and respiratory support as well as pharmacological treatments such as nusinersen, onasemnogene abeparvovec, and risdiplam which are being investigated in clinical trials as potential disease-modifying therapies.

2. DEFINITION
• Neuromuscular disorders that present in the
newborn period with hypotonia and weakness
can be caused by a variety of conditions that
affect the central nervous system (brain or spinal
cord), peripheral nervous system, or skeletal
muscle.
• Spinal muscular atrophy (SMA) is characterized by
degeneration of the anterior horn cells in the
spinal cord and motor nuclei in the lower
brainstem, which results in progressive muscle
weakness and atrophy.

3. GENETICS
• The inheritance pattern of chromosome 5q-
related SMA is autosomal recessive.
• The most common mutation of SMN1 is a
deletion of exon 7.
• The differences in SMN protein activity and
phenotypic expression appear to be related in
part to a modifying gene, called survival
motor neuron (SMN).

5. EPIDEMIOLOGY
• The incidence of spinal muscular atrophy
ranges from 4 to 10 per 100,000 live births,
• the carrier frequency of disease-causing SMN1
mutations ranges from 1:47 to 1:90.
• SMA is the most common monogenic cause of
infant mortality.

6. Carrier rate
• Approximately 1 in 54 people are carriers1
Birth rate
1. Kolb SJ & Kissel JT. Neurol Clin 2015;33:831–846; 2. About SMA: Overview. Available at: http://smafoundation.org/about-sma/, accessed March 2021
3. Verhaart I et al. J Neurol 2017;264:1465–1473; 4. Farrar MA et al. Ann Neurol 2017;81:355–368; 5. Verhaart I et al. Orphan J Rare Dis 2017;12:124.
SMA is a rare disease
Worldwide
~1 in 11,000 live births1,4
USA
~1 in 6000–10,000 live
births2
Europe
~1 in 3900–16,000 live
births3
There may be variation in the birth
rate between countries because
there is a difference in the
incidence of SMA between
ethnicities5

7. Classification
• These diseases are classified as types 0 through
4, depending upon the age of onset and clinical
course.
• SMA type 0 (prenatal onset) and SMA type 1
(infantile onset) are the most common and
severe types.
• SMA type 2 and SMA type 3 have a later onset
and a less severe course.
• SMA type 4 (adult onset) is the least severe type.

8. CLINICAL FEATURES
• The diagnosis of SMA should be suspected for any infant with
unexplained weakness or hypotonia.
• Weakness is usually symmetrical and more proximal than distal;
generally, it is greater in the legs than in the arms
• Additional clues suggesting the diagnosis in infants, children, or
adults include a history of motor difficulties, Impaired head
control, Weak cry and cough, progressive respiratory
insufficiency, Swallowing and feeding difficulty, sleep
disturbances, hyporeflexia or areflexia, tongue fasciculations,
and signs of lower motor neuron disease on examination.
• Sensitivity & and intellect are not affected.

9. Clinical classification of SMA
• Onset: 10–30 years
• Walk independently
– Ability may be
affected later in
life
• Normal life
expectancy
Type 0 Type 1 Type 2 Type 3 Type 4
• Onset: Prenatal
• Short life
expectancy
(usually <1
month)
• Onset: 0–6
months
• Never sit1
• Short life
expectancy (<2
years)
• Onset: <18 months
• Sit independently
• Never walk
• Survival into
adulthood (prognosis
dependent on
respiratory
involvement)
• Onset: >18 months
• Walk independently1
– Need assistance
– Lose the ability
over time
• Normal life
expectancy
Early onset Late onset

11. DIAGNOSIS
• Clinical : The diagnosis of SMA should be suspected for any
infant with unexplained weakness or hypotonia .
• Molecular genetic testing with targeted mutation analysis
can confirm the diagnosis of SMA by detection of
homozygous deletions of exons 7 of SMN1.
• Electromyography in SMA shows abnormal spontaneous
activity with fibrillations and positive sharp waves.
• Muscle biopsy reveals large groups of circular atrophic type
1 and 2 muscle fibers interspersed among fascicles of
hypertrophied type 1 fibers.
• SMA was added to the Recommended Uniform Screening
Panel (RUSP) for newborns in the United States in 2018,
and several states have begun newborn screening for SMA.

12. Early diagnosis of SMA is essential for best
patient outcomes
• Timely diagnosis is important in all types of SMA, as the success of treatments or medical interventions may
depend on identifying individuals as early as possible to begin treatment before irreversible
neuronal loss1
– For example, in infants with Type 1 SMA, loss of motor neurons occurs rapidly, within months of life1
– Type 1 SMA accounts for about 50% of individuals diagnosed with SMA
0–3 months
Rapid loss of
motor units
0–6 months
Severe denervation
>95% motor unit loss
Type 1 SMA2
Early diagnosis of SMA is critical

13. Management
• Conservative treatment.
• Pharmacological treatment

14. Occupational
therapist
Orthopaedic
consultant
Physiotherapist
Physician
Psychologist
Acute care
clinicians
Consultant
neurologist
Gastroenterologist
Neuromuscular
care specialist
Nutritionist
Pulmonologist
Speech-language
pathologist
The MDT can
consist of:
Conservative treatment
• A multidisciplinary approach is key for the management of individuals
with SMA
• In SMA, it is important to monitor the various aspects that are known to
be involved in disease progression and, when possible, provide
anticipatory care.

15. • Nusinersen
• Onasemnogene abeparvovec.
• Risdiplam.
Pharmacological treatment

16. • Since the 2000s, various therapeutics have been developed that aim to restore the physiological levels of SMN proteins.
This can be achieved in different ways:
FUNCTIONAL SMN PROTEIN LEVELS CAN BE RESTORED IN DIFFERENT WAYS
SMN, survival motor neuron.
1. Rao VK et al. J Manag Care Spec Pharm 2018;24:S3–S16; 2. Poirier A et al. Pharmacol Res Perspect 2018;6:e00447.
3.Butchbach MER. Front Mol Biosci 2016;3:7; 4. D'Amico A et al. Orphanet J Rare Dis 2011;6:71.
Gene therapy can beused to delivera functionalcopy ofhuman SMNgene to the patient’s
own cellstoreplace the missingor defective SMN1gene1
SMN2 expression from SMN2gene transcriptscan be increasedif the inclusionofexon 7is
promoted, thereby producing full-length,functional SMN2 protein2
Graphics createdwithBioRENDERsoftware
Viruscontaining
thecorrectSMN copy
SMN1 gene replacement therapy SMN2 gene transcript manipulation 2-
4

17. Drugs used for SMA
Nusinersen
Administered via lumbar puncture
Does not cross the blood–brain
barrier
The estimated cost of lifetime
nusinersen treatment is USD 6.3
million (2019)
Trained medical staff and hospital
facilities
are required for administration
Onasemnogene abeparvovec-xioi
Limited indication in the US and
Japan
for use in infants aged <2 years only
The initial cost of treatment is
USD 2.1 million for a single dose
IV administration is unsuitable for
older, heavier patients
Co-medication with steroids may be
required for up to ⁓3 months
Limited indication in Europe for use
in individuals with Type 1 SMA, or
affected individuals with ≤3 copies of
the SMN2 gene

18. 3’ss, 3’ splicing site; 5’ss, 5’ splice site; ESE, exonic splicing enhancer; snRNP, small nuclear RNA; SMA, spinal muscular
atrophy; SMN, survival of motor neuron.
Sivaramakrishnan M, et al. Nat Commun. 2017; 8:1476.
MECHANISM OF ACTION
• Risdiplam binds two sites in SMN2 pre-mRNA
– 5'ss of intron 7
– ESE2 in exon 7
• Binding to the 5’ ss of intron 7 improves
recognition by U1 snRNP
• U1 snRNP promotes inclusion of exon 7
• The unique specificity of binding two sites
increases levels of full-length SMN mRNA
and protein while reducing the impact on
splicing of other pre-mRNA
Maturefull-lengthSMN2mRNA
SMN2Pre-mRNA
Exon6 Exon8
Exon7
Intron6 Intron7
5’ss
ESE2
3’ss 5’ss 3’ss
Spliceosome recruitedto
initiatethesplicingprocess
ISS-N1
Exon6 Exon8
Exon7
Exon7is retainedandamature
full-lengthSMN2mRNAis generated
Bindingto 5’ssandimprovement
of
U1/5’ssinteraction
risdiplam
risdiplam
Bindingtothe exonic splicing
enhancer to promote
Exon 7 inclusion
Risdiplam

19. Risdiplam is being investigated
The FISH clinical program has enrolled individuals with SMA across a broad spectrum of
disease severity (Type 1–3), from newborns to 60-year-old adults, from pre-symptomatic
to very weak individuals, both treatment-naïve and previously treated, accounting for
the varied needs of the SMA population1–4
*Target enrolment, currently recruiting; †Actual subject number enrolled.
1. ClinicalTrials.gov NCT03779334, accessed March 2021; 2. ClinicalTrials.gov NCT02913482, accessed May 2020; 3.
ClinicalTrials.gov NCT02908685, accessed May 2020; 4. ClinicalTrials.gov NCT03032172, accessed March 2021; 5. Baranello G et al.
2019. Presented at the Cure SMA Annual Conference 2019, California, USA. Motor function; 6. Mercuri E et al. Presented at the
Cure SMA Annual Conference, 28 June–1 July 2019, Anaheim, CA, USA.
FIREFISH2
• Type 1 SMA
• 1–7 months old
• Dose finding (N=21)5
• Efficacy and safety
(N=41†)5
SUNFISH3
• Type 2 or 3 SMA
• 2–25 years old
• Dose finding (N=51)6
• Efficacy and safety
(N=180†)6
JEWELFISH4
• Type 1, 2 or 3 SMA
• 6 months–60 years old
• Previous SMA treatment
• PK/PD and safety (N=174†)
RAINBOWFISH1
• Pre-symptomatic SMA
• Birth–6 weeks old
• Efficacy and safety
(N=25*)
6 months 5 years 10
years
20
years
60 years
Age at enrolment
Birth
RAINBOWFISH
FIREFISH SUNFISH
JEWELFISH

20. FIREFISH is a two-part study that enrolled infants
aged 1–7 months with Type 1 SMA1
*A comprehensive list of the primary and secondary endpoints can be found at: https://clinicaltrials.gov/ct2/show/NCT02913482.
BSID-III, Bayley Scales of Infant and Toddler Development, Third Edition; CHOP-INTEND, Children’s Hospital of Philadelphia Infant Test
of Neuromuscular Disorders;
HINE-2, Hammersmith Infant Neurological Examination, Section 2; PD, pharmacodynamics; PK, pharmacokinetics.
1. ClinicalTrials.gov NCT02913482, accessed March 2021; 2. Servais L et al. Presented at a virtual meeting. 28 April 2020.
FIREFISH
Type 1 SMA
1–7 months old
Rationale1 Assess the safety and efficacy of risdiplam in infants with Type 1 SMA
aged 1–7 months
Primary
endpoints*1
Part 1
Determine the dose for
the confirmatory Part 2
Part 2
Proportion of infants who are sitting without support
at Month 12 (as assessed by item 22 of the BSID-III
Gross Motor Scale)
Key secondary
endpoints*
• Assess the safety,
tolerability and
PK/PD
of risdiplam1
• Evaluate motor function using the BSID-III, the
CHOP-INTEND and the HINE-2 at 12 months1
• Assess the time to death or permanent
ventilation1
• Evaluate the ability to swallow and feed orally at
Month 121,2
• Assess the safety, tolerability and PK/PD of
risdiplam1

21. Infants enrolled in FIREFISH with Type 1 SMA
from 15 countries1
1. ClinicalTrials.gov NCT02913482, accessed March 2021; 2. Bladen CL et al. J Neurol 2014;261:152–163.
• Belgium
• Brazil
• China
• Croatia
• France
• Italy
• Japan
• Poland
• Russia
• Saudi Arabia
• Serbia
• Spain
• Switzerland
• Turkey
• USA
Standards of care may vary between countries and may have an impact on patient outcomes2

22. FIREFISH Part 1 (Cohort B)*:Conclusions at 24 Month1
*High-dose cohort. † Event free in FIREFISH is defined as alive with no permanent ventilation (i.e. no tracheostomy or BiPAP ≥16 hours per day continuously for >3 weeks or continuous intubation >3 weeks, in the absence of, or
following the resolution of, an acute reversible event). ‡ As measured by HINE-2. § As measured by CHOP- INTEND. ǁ Safety statements are based on data from all infants in Cohort A and B. Data cut-off: 03 March 2020.
BSID-III, Bayley Scales of Infant and Toddler Development, Third Edition; CHOP-INTEND, Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; HINE-2, Hammersmith Infant Neurological Examination,
Module 2; SMA, spinal muscular atrophy.
1. Baranello G et al. FIREFISH Part 1: 24-month safety and exploratory outcomes of risdiplam (RG7916) in infants with Type 1 spinal muscular atrophy (SMA). Presented at the 25th International Annual Congress of the World
Muscle Society, 28th Semptember-2nd October 2020

23. Infants continued to
achieve motor
milestones, such as
sitting and standing with
support† which would never be
seen in natural history studies
*Event free in FIREFISH is defined as alive with no permanent ventilation (i.e. no tracheostomy or BiPAP ≥16 hours per day continuously for >3 weeks or continuous intubation >3 weeks, in the absence of, or following the resolution of, an acute reversible event).†As
measured by HINE-2.
‡Hospitalizations include hospital admissions ≥1 night. BiPAP, Bilevel Positive Airway Pressure; BSID-III, Bayley Scales of Infant and Toddler Development, third edition;
1. Darras BT, Masson R, Mazurkiewicz-Bełdzińska M, et al. FIREFISH Part 2: 24-month efficacy and safety of risdiplam in infants with Type 1 spinal muscular atrophy (SMA). Presentation at: American Academy of Neurology Annual Meeting; April 17-April 22, 2021; Virtual.
83%
(34/41)
of infants were event
free* at Month 24
of infants were alive and
93%
(38/41)
61%
(25/41)
All patients treated
with Risdiplam who
were able to sit without support
for 5 seconds at Month 12
maintained this ability at Month 24
of infants were
sitting without support for at least
5 seconds at Month 24, as
measured by the BSID-III
No drug-related safety findings led to withdrawal in FIREFISH Part 2
34%
(14/41)
of all infants did not
require hospitalization‡
during 24 months of
treatment
of infants alive were
able to swallow after
24 months of treatment
95%
(36/38)
FIREFISH Part 2: 24-months Data

24. SUNFISH is a two-part study which enrolled
individuals with Type 2/3 SMA, aged 2–25 years
SUNFISH
Type 2/3 SMA
2–25 years old
Rationale
Evaluate the safety and efficacy of risdiplam in individuals with Type 2/3 SMA
aged 2–25 years, which is representative of the diverse real-world patient population
Primary
endpoints*
Part 1
Determine the dose for
the confirmatory Part 2
Part 2
Evaluate motor function using the MFM-32 at 12 months
Key secondary
endpoints*
Assess the safety,
tolerability and PK/PD
of risdiplam
• Evaluate the proportion of participants achieving
stabilization or improvement in motor function as
assessed by the MFM at Month 12
• Evaluate motor function using the RULM and the
HFMSE at 12 months
• Assess independence using the SMAIS at 12 months
• Assess the safety, tolerability and PK/PD of risdiplam
*A comprehensive list of primary and secondary endpoints can be found at:
https://clinicaltrials.gov/ct2/show/ NCT02908685.
MFM, Motor Function Measure; PD, pharmacodynamics; PK, pharmacokinetics; RULM, Revised Upper Limb
Module.
ClinicalTrials.gov NCT02908685, accessed March 2021

25. Key exclusion criteria1
SUNFISH was designed to include a patient population
representative of the diversity of real-world individuals
living with Type 2/3 SMA1–3
A comprehensive list of inclusion/exclusion criteria can be found at: https://clinicaltrials.gov/ct2/show/study/NCT02908685.
SMN, survival of motor neuron.
1. ClinicalTrials.gov NCT02908685, accessed March 2021; 2. Mercuri E et al. Presented at the Cure SMA Annual Conference, 28 June–
1 July 2019, Anaheim, CA, USA;
3. Mercuri E et al. Presented at SMA Europe, 5–7 February 2020, Évry, France.
Key inclusion criteria1
Part 1 Part 2
• Previous participation in an SMN2-targeting
study or gene therapy study
• Planned (within 18 months) or previous
(<1 year prior) surgery for scoliosis or hip
fixation
Part 1 Part 2
• Confirmed genetic diagnosis of 5q-autosomal
recessive SMA
• Aged 2–25 years with Type 2/3 SMA
Type 2, or ambulatory
or non-ambulatory
Type 3 SMA
Type 2 or
non-ambulatory
Type 3 SMA
SUNFISH enrolled individuals with a broad functional and clinical range
including those with severe scoliosis or contractures2,3

26. SUNFISH enrolled individuals with Type 2/3 SMA
from 15 countries1
• Belgium
• Brazil
• Canada
• China
• Croatia
• France
• Germany
• Italy
• Japan
• Poland
• Russia
• Serbia
• Spain
• Turkey
• USA
Standards of care may vary between countries and may have an impact on patient outcomes2
1. ClinicalTrials.gov NCT02908685, accessed March 2021; 2. Bladen CL et al. J Neurol 2014;261(1):152–163.

27. Summary: SUNFISH Part 11
SUNFISH Part 1 is ongoing globally2
98% of individuals in
SUNFISH Part 1 have been
treated for at least 12
months.
1 dropout in the first 12 months
(not because of any safety reason.)
SUNFISH Part 1 helped to
determine the dose for Part
2 of the study (primary
endpoint for Part 1)
100% survival
No deaths or
drug-related safety
findings leading to
treatment
withdrawal
Exploratory MFM-32 results
indicate treatment with risdiplam
led to improvement in motor
function compared with
NatHis-SMA
A clinically meaningful increase
in the MFM-32 total score was
observed in individuals
independent of age or
functional status at baseline
Data cut-off for SUNFISH Part 1: 09 January 2019.
MFM, Motor Function Measure.
1. Mercuri E et al. Presented at the Cure SMA Annual Conference, 28 June–1 July 2019, Anaheim, CA, USA; 2.
ClinicalTrials.gov NCT02908685, accessed March 2021.

28. Individuals receiving risdiplam gain or maintain motor function
Risdiplam is the first SMA treatment to have positive pivotal placebo-controlled data
in a broad population of children, adolescents and adults—preserving and potentially
enabling motor function independence for individuals with Type 2 SMA
and non-ambulant Type 3 SMA
MFM-32 and RULM scores
showed that risdiplam
significantly improved
motor function after
12 months
versus placebo
No treatment-related safety
findings have led to
treatment withdrawal in
SUNFISH Part 2
Risdiplam improved
independence in activities
of daily living, as assessed using
the novel SMAIS measure
MFM, Motor Function Measure; RULM, Revised Upper Limb Module; SMAIS, SMA Independence Scale.
Mercuri E et al. Presented at SMA Europe, 5–7 February 2020, Évry, France.
Summary: SUNFISH Part 2

29. RAINBOWFISH is recruiting presymptomatic infants
with genetically diagnosed SMA (birth–6 weeks)
RAINBOWFISH1
Presymptomatic
Birth–6 weeks old
Rationale1 Assess the safety, efficacy, PK and PD of risdiplam in pre-symptomatic infants with
genetically diagnosed SMA (birth–6 weeks old)
Primary
endpoint*1
Proportion of participants with two copies of the SMN2 gene and a baseline CMAP†
≥1.5 mV who are sitting‡ without support at Month 12
Key secondary
endpoints*1
• Proportion of participants
developing clinically manifested
SMA
• Time to permanent ventilation
and/or death
• The achievement of motor
milestones defined in the BSID-III
and by
the HINE-2
• Change from baseline score in
the CHOP INTEND
• Growth measures
• Ability to swallow and amount of
solid food intake
• Degree of innervation by CMAP
• PK effects
• Respiratory effects by
plethysmography
*A comprehensive list of primary and secondary endpoints can be found at: https://clinicaltrials.gov/ct2/show/NCT03779334; †CMAP is the composite electrical
activity within the target muscle resulting from synchronous activation of a group of motor neurons within a nerve bundle.3 A low CMAP score indicates severe
denervation and high disease severity;4 ‡Sitting is defined as ‘sits without support for 5 seconds’, as assessed by Item 22 of the BSID-III Gross Motor Scale.
BSID-III, Bayley Scales of Infant and Toddler Development, Third Edition; CHOP INTEND, Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders;
CMAP, compound muscle action potential; HINE-2, Hammersmith Infant Neurological Examination, Section 2; PD, pharmacodynamics; PK, pharmacokinetics; SMN,
survival of motor neuron.
1. ClinicalTrials.gov NCT03779334, accessed March 2021; 2. Kolb SJ et al. Ann Clin Trans Neurol 2016;3(2):132–145; 3. . Treat NMD https://treat-nmd.org/wp-
content/uploads/2016/08/sma-SMA_M.2.2.002.pdf (accessed March 2021); ; 4. Lewelt AJ et al. Muscle Nerve 2010;42(5):703–708.

30. RAINBOWFISH is recruiting presymptomatic infants
with genetically diagnosed SMA (birth–6 weeks)1
RAINBOWFISH1
Presymptomatic
Birth–6 weeks old
Rationale1 Assess the safety, efficacy, PK and PD of risdiplam in presymptomatic infants with
genetically diagnosed SMA (birth–6 weeks old)
Primary
endpoint*1
Proportion of participants with two copies of the SMN2 gene and a baseline CMAP†
≥1.5 mV who are sitting‡ without support at Month 12
Key secondary
endpoints*1
• Proportion of participants
developing clinically manifested
SMA
• Time to permanent ventilation
and/or death
• The achievement of motor
milestones defined in the BSID-III
and by
the HINE-2
• Change from baseline score in
the CHOP INTEND
• Growth measures
• Ability to swallow and amount of
solid food intake
• Degree of innervation by CMAP
• PK effects
• Respiratory effects by
plethysmography
*A comprehensive list of primary and secondary endpoints can be found at: https://clinicaltrials.gov/ct2/show/NCT03779334; †CMAP is the
composite electrical activity within the target muscle resulting from synchronous activation of a group of motor neurons within a nerve bundle.3 A
low CMAP score indicates severe denervation and high disease severity;4 ‡Sitting is defined as ‘sits without support for 5 seconds’, as assessed by
Item 22 of the BSID-III Gross Motor Scale.
BSID-III, Bayley Scales of Infant and Toddler Development, Third Edition; CHOP INTEND, Children's Hospital of Philadelphia Infant Test of
Neuromuscular Disorders; CMAP, compound muscle action potential; HINE-2, Hammersmith Infant Neurological Examination, Section 2; PD,
pharmacodynamics; PK, pharmacokinetics; SMN, survival of motor neuron.
1. ClinicalTrials.gov NCT03779334, accessed March 2021; 2. Kolb SJ et al. Ann Clin Trans Neurol 2016;3(2):132–145; 3. Treat NMD https://treat-
nmd.org/wp-content/uploads/2016/08/sma-SMA_M.2.2.002.pdf (accessed March 2021); 4. Lewelt AJ et al. Muscle Nerve 2010;42(5):703–708.
• In 2016, a Natural History study was performed which assessed motor function and putative
electrophysiological, protein and molecular biomarkers in both affected and unaffected infants
aged <6 months2
• This study was useful when designing RAINBOWFISH as it provided several reference values
(particularly the cut-off baseline CMAP† value of ≥ 1.5 mV for the primary endpoint)2

31. 1. Risdiplam USPI

32. 1. Risdiplam USPI

33. Risdiplam Dosage
60 mg/80 ml
0.75mg/ml
Shelf-life: 64 days
after reconstitution;
2years for powder
2 Months 2 Years ≈7 Years/20kg Adult
0.2mg/kg/day 0.25mg/kg/day 5mg/da
y
1 bottle/≈60
days
1 bottle/≈20
days
1 bottle/max*
12 days
Risdiplam USPI
M-LB-00000264

34. Risdiplam is not yet registered in Iraq

35. THANKS FOR YOUR ATTENTION