This document provides information about therapeutic options for spinal muscular atrophy (SMA). It first defines SMA as a genetic disorder that causes degeneration of motor neurons in the spinal cord, resulting in muscle weakness. It then discusses the four main types of SMA based on severity and age of onset. The causes and diagnosis of SMA are also outlined. The therapeutic options section summarizes gene replacement therapies like nusinersen and onasemnogene abeparovec, which aim to increase SMN protein levels. It also mentions the small molecule risdiplam and ongoing clinical trials evaluating these treatment approaches.

1. Therapeutic options for Spinal Muscular
Atrophy
Presenter:-
Dr Monica Jain,
Professor & Head,
Department of Pharmacology,
SMS Medical College,Jaipur

2. Outliners
What is SMA?
Types of SMA
Causes of SMA
Incidence of SMA
Diagnosis
Therapeutic Options
References

3. What is Spinal Muscular Atrophy?
• Spinal muscular atrophy (SMA) is a rare autosomal recessive disease
that deteriorates NM functioning of the body by causing motor neurons
loss and associated muscle weakness.(when muscles get smaller).
• The disease was first described in the 1890s by Werdnig and by
Hoffmann.
• Spinal muscular atrophy (SMA) is characterized by degeneration of the
alpha motor neurons of the spinal cord anterior horn cells, leading to
progressive proximal muscle weakness & atrophy and in the most
severe types, paralysis.

4. • Spinal muscular atrophy linked to chromosome 5q (SMA) is a recessive,
progressive, neuromuscular disorder caused by bi-allelic mutations in
the SMN1 gene, resulting in motor neuron degeneration and variable
presentation in relation to onset and severity.
• SMA can affect a child's ability to crawl, walk, sit up, and control head
movements.
• Severe SMA can damage the muscles used for breathing and
swallowing.

5. There are four types of SMA on the basis of disease’s severity and age
when symptoms begin.
Types Age Characteristic Features
1.SMA-I
(Most severe)
(Werdnig-
Hoffmann
disease)
Up to 6 weeks Severe, progressive muscle weakness and flaccid or reduced
muscle tone (hypotonia) &Bulbar dysfunction includes poor
suck ability, reduced swallowing, and respiratory
failure,patient never sit and SMA-I is rapid motor neuron loss
result in death or permanent ventilator support in >90% of
patients.
2.SMA-II
(Moderate to
More Severe)
Intermediate
Between 7 to 18
months
Difficulties with sitting independently or failure to stand by 1
year of age and pseudohypertrophy of the gastrocnemius
muscle, musculoskeletal deformities, and respiratory failure
can occur and patient is live with ventilatory support.
3.SMA-III
(Mildest)
Kugelberg-
Welander disease
18 months to 35
years
Slowly progressive proximal weakness & most children can
stand and walk but have trouble with motor skills, such as
going up and down stairs and stand & walk during adulthood.
4.SMA-IV
(Very Less
Severe or Adult)
After 35 months Symptoms mimics to SMA –III but patients have a normal life
expectancy and walk unaided.

6. Causes of SMA?
• It is caused by a genetic defect in survival motor neuron(SMN)-1 gene
which encodes the SMN protein. (People have two SMN1 genes).
• SMA genes is located in the long arm of the chromosome 5, in the
5q13.2 region.
• A mutation in the SMN1 gene leads to a deficiency of a motor neuron
protein called SMN.

7. • As its name implies, this protein is responsible for gene expression
necessary for normal motor neuron function.
• A consequent decrease in the SMN protein leading to lower motor
neuron degeneration and progress into muscle atrophy and finally
muscle are paralyzed.
• In SMA,mainly respiratory and skeletal muscles are involved,so
patients are complaints difficulty in breathing and they unable to sit and
walk independently.

8. Incidence of SMA
• The incidence of SMA is 1 in 10,000 to 11,000 live births throughout
the worldwide and carrier frequency of 1/40 to 1/60,so it is rare
disease.
• As per orphan drug amendment (1983) act of USA, a rare disease
/condition is one affects less than 0.2 million people in the USA.
• Though these drugs may be life saving for some patients,they are
commercially difficult to obtain as a medicinal product.
• Rare disease criteria is differ from country to country.

9. How is SMA diagnosed?
• Genetic testing: This is the most common way to test for SMA.
Testing checks for a deletion or variation in the SMN1 gene.
• A muscle biopsy: Take a small sample of muscle to check under a
microscope.

10. Therapeutic options
I.Gene replacement therapy
II.Small molecules
III.Muscle enhancing therapy
IV.Other therapies

11. I.Gene replacement therapy
1.Nusinersen:
In December 2016, the FDA approved nusinersen (Spinraza), the first
drug approved to treat children (including newborns) and adults with
SMA.
Nusinersen is an antisense oligonucleotide (ASO) designed to treat
SMA caused by mutations in chromosome 5q that lead to SMN protein
deficiency.
Using in vitro assays and studies in transgenic animal models of
SMA, nusinersen was shown to increase exon 7 inclusion in SMN2
messenger ribonucleic acid (mRNA) transcripts and production of
full-length SMN protein.

12. Pharmacology of Nusinersen
Mechanism of Action
An antisense oligonucleotide (ASO) designed to treat SMA caused by
mutations in chromosome 5q that lead to SMN protein deficiency.
Using in vitro assays and studies in transgenic animal models of
SMA, nusinersen was shown to increase exon 7 inclusion in SMN2
messenger ribonucleic acid (mRNA) transcripts and production of
full-length SMN protein.
Absorption
Through plasma levels relatively low, compared to trough CSF
concentration
Peak plasma time: 1.7-6 hrs

13. Distribution
CSF and peripheral tissues (eg, skeletal muscle, liver, kidney)
Metabolism
Metabolized via exonuclease (3’- and 5’)-mediated hydrolysis
Not a substrate for, or inhibitor, or inducer of CYP450 enzymes
Elimination
Half-life: 135-177 days (CSF); 63-87 days (plasma)
Excretion
Primary route of elimination is likely by urinary excretion; at 24 hr,
only 0.5% of the administered dose was recovered in the urine

14. Dosing
In Adults:
12 mg/5mL single dose vial intrathecally per administration
Initial: 4 loading doses; administer the first 3 doses at 14-day intervals
and the fourth dose 30 days after the third dose
Maintenance: One dose every 4 months
In Children:
12 mg intrathecally per administration
Initial: 4 loading doses; administer the first 3 doses at 14-day intervals
and the fourth dose 30 days after the third dose
Maintenance: One dose every 4 months

15. Clinical Trials:
• Nusinersen approval was based on the ENDEAR trial.
• After promising results for nusinersen in phase I and II trials in
children with SMA type II and III, two phase III, randomized, double-
blind, sham-procedure controlled studies were initiated consequently.
• ENDEAR (ClinicalTrials.gov identifier: NCT02193074, years 2014–
2016) assessed safety and clinical efficacy of nusinersen in 121 infants
with infantile-onset SMA and younger than seven months.

16. • In the interim analysis, infants treated with nusinersen had higher
improvement in the motor milestone categories of the Hammersmith
Infant Neurological Examination (HINE) than controls (41% vs. 0%, p <
0.001).
• Moreover, the nusinersen group demonstrated a prolonged time to death
(hard ratio for death 0.37; p = 0.004) or need for permanent ventilation
compared to controls and six out of 73 treated patients achieved
independent sitting over a one year treatment period.

17. • CHERISH (ClinicalTrials.gov identifier: NCT02292537, years 2014–
2017) involved 126 children with later-onset SMA.
• The median age at baseline was four years (two to nine years) in the
treated group and three years (two to seven years) in the controls.
• The ad interim results of the NURTURE open-label study
(ClinicalTrials.gov identifier: NCT02386553, started in 2017 and
ongoing).

18. 2.Onasemnogene Abeparovec-xioi:
• It is indicated for gene replacement therapy in children aged 2 years or
younger with spinal muscular atrophy (SMA) type 1 (also called
Werdnig-Hoffman disease) who have biallelic mutation in the survival
motor neuron 1 (SNM1) gene.

19. Pharmacology of Onasemnogene Abeparovec
Mechanism of Action
• Recombinant AAV9(adeno-associated virus)-based gene therapy
designed to deliver a copy of the gene encoding the human survival
motor neuron (SMN) protein.
Dosing(Pediatric)
• Suspension for IV infusion
• Provided in a kit containing 2 to 9 vials, as a combination of 2 vial fill
volumes (either 5.5 mL or 8.3 mL)
• All vials have a nominal concentration of 2 x 10^13 vector genomes
(vg) per mL
• Each vial contains an extractable volume of not less than either 5.5
mL or 8.3 mL

20. • ≥2 years: Safety and efficacy not established
• Administered as a one-time, single IV infusion through a venous catheter
• 1.1 x 10^14 vector genomes per kilogram (vg/kg) of body weight
Adverse Reactions:
• In >10% cases,Elevated aminotransferases (>ULN) (27.3%)
• In 1-10% case,Vomiting (6.8%)

21. Clinical Trials:-
• Approval was based on the ongoing phase 3 STR1VE trial and the
completed phase 1 START trial.
• Fifteen patients with SMA1 received a single dose of intravenous
adeno-associated virus serotype 9 carrying SMN complementary DNA
encoding the missing SMN protein.
• Out of the 12 patients who had received the high dose, 11 sat
unassisted, 9 rolled over, 11 fed orally, could speak and 2 walked
independently.
• Elevated serum aminotransferase levels occurred in 4 patients and
were attenuated by prednisolone.

22. • Interim data analysis from the ongoing phase 3 STR1VE trial described
21 of 22 (95%) patients were alive and event-free.
• The median age was 9.5 months, with 6 of 7 (86%) patients aged 0.5
months or older surviving event-free.
• Interim results also showed ongoing improvement of motor milestones
(eq. holding head erect, rolling over, sitting without support).

23. II.Small molecule
1.Risdiplem:
• It is indicated for spinal muscular atrophy, including types 1, 2, and 3,
in adults and children aged 2 months or older.
• It is a first drug which are given by orally.
• The drug was developed by Genentech, a member of the Roche
Group, in partnership with SMA Foundation and PTC Therapeutics.
• Evrysdi (risdiplam) is available as an oral solution with a maximum
dose of 5mg administered once daily, directly distributed to patients’
homes in the US by Accredo Health Group, a speciality pharmacy.

24. • The FDA approved Evrysdi (risdiplam) for the treatment of SMA in adults
and children aged two months and older in 7 August 2020.
Pharmacology of Risdiplam
Mechanism of Action:
• Survival of motor neuron 2 (SMN2) mRNA splicing modifier designed treat
mutations in chromosome 5q that lead to SMN protein deficiency
Absorption:
• Peak plasma time: 1-4 hr
• Steady-state reached: 7-14 days
Distribution:
• Protein bound: Predominantly bound to serum albumin, without any binding
to alpha-1 acid glycoprotein, with a free fraction of 11%
• Vd: 6.3 L/kg

25. Metabolism:
• Primarily metabolized by flavin monooxygenase 1 and 3 (FMO1 and
FMO3) and also by CYPs 1A1, 2J2, 3A4, and 3A7
• Parent drug was the major component found in plasma, accounting for
83% of drug-related material in circulation
Elimination:
• Half-life: ~50 hr
• Clearance: 2.1 L/h (14.9 kg patient)
Excretion: Feces 53% (14% unchanged); urine 28% (8% unchanged)

26. Dosing:
• Powder for oral solution-60mg/bottle
• In Spinal Muscular Atrophy-5 mg orally once a day for one year in
Adult.
• In Child ≥2 months:
1.Age ≥2 months to <2 years: 0.2 mg/kg PO qDay
2.Age ≥2 years and weight <20 kg: 0.25 mg/kg PO qDay
3.Age ≥2 years and weight ≥20 kg: 5 mg PO qDay
• Administer at approximately the same time each day after a meal
Adverse Effects:
• Mostly fever,diarrhea,Rashes but sometimes mouth and aphthous
ulcers,arthralgia & urinary tract infection.

27. Clinical Trials:
• Approval was supported by results from several phase 3 trials
(FIREFISH, SUNFISH, JEWELFISH, RAINBOWFISH).
• FIREFISH is an open-label, two-part pivotal clinical trial in infants
aged 2–7 months with Type 1 SMA. Results showed 41% (7/17) of
infants achieved ability to sit without support for at least 5 seconds and
90% (19/21) were alive without permanent ventilation at 12 months.
• After a minimum of 23 months of treatment and reaching an age of 28
months or older, 81% (17/21) of all patients were alive without
permanent ventilation.
• The SUNFISH study was a two-part, double-blind, placebo-controlled
pivotal clinical trial in children and young adults (aged 2–25 years) with
Type 2 or 3 SMA.

28. • A clinically meaningful and statistically significant improvement in
motor function among children and adults was observed as measured
by a change from baseline in the MFM-32 total score.
• Improved upper limb motor function compared to baseline, as
measured by the Revised Upper Limb Module (RULM), a secondary
independent motor function endpoint of the study, also showed
statistically significant improvement.

29. • JEWELFISH is an open-label exploratory trial in people with SMA
Type 1, 2 or 3, aged 6 months to 60 years who have been previously
treated with SMA therapy, gene therapy, or olesoxime.
• Recruitment is complete with 174 people enrolled.
• RAINBOWFISH is an open-label, single-arm, multicenter study,
investigating the efficacy, safety, pharmacokinetics, and
pharmacodynamics of risdiplam in babies (~n=25), from birth to 6
weeks of age (at first dose) with genetically diagnosed SMA who are
not yet presenting with symptoms.
• The study is currently recruiting.

30. III.Muscle enchancing therapy
1.Reldesemtiv:-
• It is a selective small-molecule troponin activator in fast skeletal
muscles.
• The rationale for its use in SMA stands on several lines of evidence.
• This molecule increases the affinity of troponin C to calcium, sensitizes
the sarcomere to calcium effects and reinforces contraction.

31. • Following a phase I study confirming its safety, a phase II, double-
blind, randomized, placebo-controlled trial (ClinicalTrials.gov
identifier: NCT02644668, years 2015–2018) on 70 patients with SMA
type II to IV examined its effect on functional and respiratory
performance.
• The results showed, in the higher dosage group, a trend towards an
increase from baseline in the six-minute walk test (6MWT) and of the
maximal expiratory pressure (MEP).

32. • Adverse events were similar between treated and placebo groups SRK-
015 is a monoclonal antibody, which selectively inhibits myostatin,
promoting muscle cells growth and differentiation and improving
muscle force in SMA mice .
• A phase I trial (ClinicalTrials.gov identifier: NCT02644777, years
2017–2018) confirmed its safety and tolerability.
• A phase II study (TOPAZ, ClinicalTrials.gov identifier: NCT03921528,
started in 2019 and ongoing), involved 58 SMA type II and SMA III
patients, aged two to 21 years. Patients have received treatment by
intravenous infusion every four weeks for one year. The six-month
interim results will be available by the end of 2020.

33. IV.Other therapy:-
• Medications such as valproic acid, phenylbutyrate, hydroxyurea, and
albuterol have been shown to increase SMN transcription in laboratory
studies, but clinical trials have not demonstrated significant
improvement in disease progression.
• The SMA CARNIVAL trials (parts 1 and 2) found valproic acid and L-
carnitine ineffective with regard to strength or functional improvement
at 6 months and 12 months in both ambulatory and non-ambulatory
children.
• Adverse effects were reported in 85% of patients.

34. • Gabapentin, riluzole, and olesoxime have been studied for their
suspected neuroprotective properties, without significant clinical
benefit noted.
• Treatment with creatine, phenylbutyrate, gabapentin, thyrotropin-
releasing hormone, and hydroxyurea have also proved ineffective.

35. References
• Werdnig G: Zwei frühinfantile hereditäre Fälle von progressive Muskelatrophie unter dem Bilde der Dystrophie, aber auf neurotischer
Grundlage [Two early infantile hereditary cases of progressive muscular atrophy simulating dystrophy, but on a neural basis; in
German]. Arch Psychiatr Nervenkr 1891, 22:437-480.
• Hoffmann J: U” ber chronische spinale Muskelatrophie im Kindesalter, auf familiärer Basis [On chronic spinal muscular atrophy in
childhood, with a familial basis; in German]. Dtsch Z Nervenheilkd 1893, 3:427-470
• Brzustowicz LM, Lehner T, Castilla LH, Penchaszadeh GK, Wilhelmsen KC, Daniels R, Davies KE, Leppert M, Ziter F, Wood D,
Dubowitz V, Zerres K, Hausmanowa-Petrusewicz I, Ott J, Munsat TL, Gilliam TC: Genetic mapping of chronic childhood-onset spinal
muscular atrophy to chromosome 5q11.2-13.3. Nature 1990, 344:540-41.
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• Chiriboga, C.A.; Swoboda, K.J.; Darras, B.T.; Iannaccone, S.T.; Montes, J.; De Vivo, D.C.; Norris, D.A.; Bennett, C.F.; Bishop, K.M.
Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology 2016, 86, 890–897.
• Finkel, R.S.; Chiriboga, C.A.; Vajsar, J.; Day, J.W.; Montes, J.; De Vivo, D.C.; Yamashita, M.; Rigo, F.; Hung, G.; Schneider, E.; et al.
Treatment of infantile-onset spinal muscular atrophy with nusinersen: A phase 2, open-label, dose-escalation study. Lancet Lond. Engl.
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• Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, et al. Single-Dose Gene-Replacement Therapy for Spinal
Muscular Atrophy. N Engl J Med. 2017 Nov 2. 377 (18):1713-1722.
• Al-Zaidy S, Pickard AS, Kotha K, Alfano LN, Lowes L, Paul G, et al. Health outcomes in spinal muscular atrophy type 1 following
AVXS-101 gene replacement therapy. Pediatr Pulmonol. 2019 Feb. 54 (2):179-185.
• Novartis. AveXis data reinforce effectiveness of Zolgensma in treating spinal muscular atrophy (SMA) Type 1. 2019 Apr 16.

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• Evrysdi (risdiplam) [package insert]. South San Francisco, CA: Genentech. August 2020.
• Hwee, D.T.; Kennedy, A.; Ryans, J.; Russell, A.J.; Jia, Z.; Hinken, A.C.; Morgans, D.J.; Malik, F.I.;
Jasper, J.R. Fast skeletal muscle troponin activator tirasemtiv increases muscle function and
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37. Thank You