Collaborative Care in SMA

Evolving Roles for Neurologists,

Ob‐Gyns, PCPs, and Counselors

Presented by:

Julie A. Parsons, MD
Haberfeld Family Endowed Chair in Pediatric Neuromuscular Disorders
Professor of Clinical Pediatrics and Neurology
University of Colorado School of Medicine
Children’s Hospital Colorado

Lizbeth McCarthy, MD
Director of Genetics and Ultrasound
Denver Health

Melissa Gibbons, MS, CGC

Certified Genetic Counselor
Assistant Professor
University of Colorado School of Medicine
Children's Hospital Colorado

This activity is supported by educational grants from Biogen, 1

MRC Holland, and Novartis Gene Therapies, Inc.
Faculty Disclosures

▪ Julie A. Parsons, MD
− Consulting Fees: Biogen, Genentech Roche, Novartis,
Scholar Rock
− Contracted Research: Biogen, Novartis, PTC
Therapeutics, Scholar Rock
 Lizbeth McCarthy, MD
− Nothing to disclose
▪ Melissa Gibbons, MS, CGC
− Consulting Fees: Novartis Advisory Board, Speaker at
Biogen Medical Forum
− Other: Cure SME Medical Advisory Board
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Learning Objectives

▪ Discuss how DMTs are expected to change the course

of SMA disease and result in new phenotypes across
the spectrum of patients
▪ Explain how new SMA phenotypes will lead to
expansion of the roles of PCPs and Ob-Gyns in the
management of SMA, from genetic carrier identification
to early diagnosis and adult-care transitions
▪ Describe issues that may arise in patients with SMA
who transition from pediatric to adult care and develop
strategies on how those issues can effectively be
addressed, with a focus on reproductive care
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The Evolving
SMA Phenotypes
Spinal Muscular Atrophy

▪ Autosomal recessive neuromuscular

disease
▪ Carrier frequency 1:40 to 1:60
▪ Incidence about 1:11000 live births
▪ Most common genetic cause of death in
children under 2 years old prior to disease-
modifying therapies

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SMA Clinical Patient Groups Based on
Maximal Achieved Motor Function
Clinical Age of Motor
Prognosis*
Group Onset Milestones
Most common form (~50% of
Non- 2 weeks to None; unable cases); Severe hypotonia; death or
sitters 6 months to sit or roll need for permanent ventilation
assistance by 2 years
Sitting; unable
6 to 18 Proximal weakness; survival into
Sitters to walk
months adulthood
independently
Range of motor impairment from
Walkers >18 months Walking mild to moderate; some may lose
ability to walk; normal life span

*Prognosis varies with phenotype and supportive care interventions.

1. Farrar MA et al. Ann Neurol. 2017;81(3):355-368. 6

2. Mercuri E et al. Neuromuscul Disord. 2018;28(2):103-115
SMN Expression in a Healthy Individual

Normal SMN protein levels Low SMN protein levels

Burghes AH, Beattie CE. Nat Rev Neurosci. 2009;10(8):597-609.

7
SMN Expression in a Healthy Individual

Normal SMN protein levels Low SMN protein levels

Burghes AH, Beattie CE. Nat Rev Neurosci. 2009;10(8):597-609.

8
SMN2 Is a Modifying Gene

▪ In humans, SMA disease severity

correlates with SMN2 gene copy
number and SMN protein levels

▪ SMA type I: 1-2 copies of SMN2

▪ SMA type II: 2-3 copies of SMN2
▪ SMA type III: 4 copies of SMN2

▪ Individuals with more than 5 copies

of SMN2 are clinically unaffected

Charlotte J et al. Spinal Muscular Atrophy. In: Gilman S. Neurobiology of Disease. Elsevier; 2007:501-511.
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SMA: Progressive Loss of
Motor Function

Sumner CJ, Crawford TO. J Clin Invest. 2018;128(8):3219-3227.

10
Natural History of SMA Type 1

1. Survival = no death and no need for ≥16-hr/day ventilation continuously for ≥2 weeks, in the absence of an acute reversible illness;
n = 23 (2 copies of SMN2). Finkel RS et al. Neurology. 2014;83(9):810-817.
11
2. Survival = no death and no tracheostomy; n = 20. Kolb SJ et al. Ann Neurol. 2017;82(6):883-891.
 Summary of Clinical Trials in SMA
Key registration trials Studies in
Agent Trials Study design and patients pre-symptomatic children
⮚ Phase III, randomized, double-blind, NURTURE3
placebo-controlled
ENDEAR1 ⮚ Phase II, open-label,
⮚ Infantile-onset
SMA Type 1, n=121, age ≤7 months
single-arm
Nusinersen ⮚ Infants genetically
⮚ Phase III, randomized, double-blind, diagnosed as likely to
placebo-controlled develop SMA Type 1/2
CHERISH2 ⮚ Late-onset ⮚ n=25, age ≤6 weeks
SMA Type 2/3, n=126, age=2-9 years

⮚ Phase I, open-label, dose-finding SPR1NT6

START4 SMA Type 1, n=15 ⮚ Phase III, open-label, single-
Onasemnogene
arm, multicentre SMA type
abeparvovec ⮚ Phase III, open-label, single-arm
STR1VE5 SMA Type 1, n=22 1, n=30, age ≤6 weeks

⮚ Phase II/III. open-label, two-part pivotal trial RAINBOWFISH

FIREFISH7 SMA Type 1, n=62 (recruiting)9
Risdiplam ⮚ Open-label, single-arm,
⮚ Phase II/III, two-part, double-blind, placebo- multicentre
SUNFISH8 controlled pivotal trial
⮚ SMA Type 1, age ≤6 weeks
SMA Type 2/3, n=231, age=2-25 years old

1. Finkel RS et al. N Engl J Med. 2017;377(18):1723-1732. 2. Mercuri E et al. N Engl J Med. 2018;378(7):625-635.
3. De Vivo DC et al. Neuromuscul Disord. 2019;29(11):842-856. 4. Mendell JR, et al. N Engl J Med. 2017;377:1713-1722.
5. NCT03306277. 6. NCT03505099. 7. NCT02913482. 8. NCT02908685. 9. NCT03779334. 12
Clinical trials listed by their identifiers at: ClinicalTrials.gov; accessed November 25, 2020.
Strategies for Therapies

▪ Replacement or correction of the faulty SMN1

gene

▪ Modulation of the low-functioning SMN2

“back-up gene.”

▪ Neuroprotection of the motor neurons affected

by loss of SMN protein

▪ Muscle protection to prevent or restore the

loss of muscle function in SMA
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Current and Emerging Therapies for SMA
Gene Therapy
(Onasemnogene abeparvovec-xioi)*
• AAV9 vector with DNA coding for SMN
protein
• IV, single dose

� (Risdiplam)* *

*FDA-approved

Schorling CD et al. J Neuromusc Dis. 2020;7(1):1-13. 14

Available Treatments in SMA and Their
Mechanisms of Action
Nusinersen and risdiplam Onasemnogene abeparvovec

Modify SMN2 pre-mRNA splicing SMN1 gene replacement using

increasing full-length SMN2 protein adenovirus vector AAV9-SMN

Pre-mRNA 6 7 8
↑Exon 7 inclusion
mRNA
6 8 6 7 8
SMN1
cDNA
Protein (exons
only)
Unstable incomplete ↑ Complete SMN2
SMN Functional SMN protein

AAV = adeno-associated virus; cDNA = complementary deoxyribonucleic acid; mRNA = micro-ribonucleic acid; SMN = survival motor neuron.

Messina S, Sframeli M. J Clin Med. 2020;9(7):2222 15

 SMA Treatments: Approvals and
Indications
Agent Approval date and indication
FDA EMA
Nusinersen 2016 2017
SMA in pediatric and adult Patients with 5q SMA2
patients1
Onasemnogene 2019 2020
abeparvovec Patients <2 years with SMA with Patients with 5q SMA with a bi-allelic
bi-allelic mutations in the SMN1 mutation in the SMN1 gene and:
gene3 • A clinical diagnosis of SMA Type 1
or
• ≤3 copies of the SMN2 gene4

Risdiplam 20205 20207

SMA in patients ≥2 months of Marketing authorization application
age6 accepted
EMA = European Medicines Agency; FDA = Food and Drug Administration.
1. Nusinersen. Prescribing Information. Revised 6/20. 2. Nusinersen Summary of Product Characteristics. Updated 1/31/20.
3. Onasemnogene abeparvovec. Prescribing Information. Revised: 5/19.
4. Onasemnogene abeparvovec. Summary of Product Characteristics. Updated 11/6/20.
5. FDA Press release. Available at: www.fda.gov/news-events/press-announcements/fda-approves-oral-treatment-spinal-muscular-atrophy. Accessed 11/25/20. 16
6. Risdiplam Prescribing Information. Revised August 2020. 7. PTC announcement. Available at: https://ir.ptcbio.com/node/13116/pdf. Accessed 11/25/20.
Nusinersen

▪ Injected intrathecally
▪ Dosing schedule: Day 1, 15, 30, 60 and
quarterly for life
▪ Increases SMN protein in motor neuron cells
▪ Favorable safety profile
▪ FDA approved December 2016 for all 5q SMA types

Nusinersen. Prescribing Information. Revised June 2020.

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Nusinersen Treatment

▪ Intrathecal drug
administration – Lumbar
puncture bolus injection
▪ ASOs have long half-lives
(several months) in CNS
tissue
▪ Loading doses – to saturate
motor neurons as the
primary target
▪ Maintenance doses – to
maintain effective drug levels
▪ Favorable safety profile
Image adapted from: www.cancer.gov.

Grayev A et al. AJNR Am J Neuroradiol. 2021;42(5):980-985. 18

Gene Transfer Therapy

▪ Delivery of a fully
functional human SMN
gene into target motor
neuron cells

▪ Production of sufficient
levels of SMN protein
required to improve
motor neuron function

▪ Rapid onset of effect,

in addition to sustained
SMN protein
Risingtidebio.com expression

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Onasemnogene Abeparvovec
Gene Therapy
▪ Delivery of a fully functional human SMN gene into target
motor neuron cells

▪ Single peripheral IV infusion over 60 minutes

▪ Production of sufficient levels of SMN protein required to

improve motor neuron function

▪ Rapid onset of effect in addition to sustained SMN protein

expression

▪ FDA approved in May 2019 for treatment of SMA in

patients <2 years old

Al-Zaidy SA et al. Pediatric Neurology,. 2019;100:3-11.

Onasemnogene abeparvovec. Prescribing Information. Revised: May 2019 20
SMN2 Splicing Modifier Risdiplam
(RG7916)
▪ Given orally
▪ Centrally and peripherally distributed SMN2
pre-mRNA splicing modifier that increases
levels of functional SMN protein
▪ FDA approved August 2020 for patients
>2 months old

Singh RN et al. Neurosci Insights. 2020;15:2633105520973985.

Risdiplam Prescribing information. Revised 2021. 21
The Needs of the Patients are Evolving

Mercuri E et al. Neuromuscul Disord. 2018;28:103-115.

Finkel RS et al. Neuromuscul Disord. 2018;28:197-207. 22
Caregiver Story
24
What Will the Future Look Like?

▪ Treated SMA patients may transition into less

severe phenotypes
▪ Need for continued or ongoing interventions?
▪ Will expanded lifespans and abilities result in
development of new comorbidities?

Chen TH. Int J Mol Sci. 2020;21(9):3297.

25
The Evolving Roles of
Ob-Gyns and PCPs
Early Diagnosis
The Genetics of SMA

27
 The Genetics of SMA (cont)

SMA Care Series: The Genetics of Spinal Muscular Atrophy. Cure SMA.
Available at: www.curesma.org/wp-content/uploads/2020/09/09172020_Genetics-of-SMA_vWeb.pdf. Published 2009. Accessed September 11, 2017. 28
 Inheritance of SMA

Unaffected: 25% Carrier: 50% Affected: 25%

SMA Care Series: The Genetics of Spinal Muscular Atrophy. Cure SMA. 29
Available at: www.curesma.org/wp-content/uploads/2020/09/09172020_Genetics-of-SMA_vWeb.pdf. Published 2009. Accessed September 11, 2017.
Why Test for SMA?

1:54 individuals
are a carrier of
SMA

Early diagnosis
leads to earlier
treatment

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Patient Story
Audience Polling Question

Which is a recommendation
from ACOG regarding SMA
testing?

A. Carrier screening
B. Prenatal testing
C. Newborn screening
D. I am not sure

32
ACOG Recommendations for
Carrier Screening

33
 Interpreting the Results
Carrier Frequencies – It’s All in the Fine Print

Ethnicity Detection a priori riska a priori risk Reduced risk for 2- Reduced risk
rate (%) (95% CI) (95% CI) copy result for 2 copy
(2012 study) (2009 study) (2012 study) result
(2009 study)
Pan-ethnic 91.2 1:54 (1:51–1:57) NA 1:527 NA
Caucasian 94.8 1:47 (1:43–1:51) 1:35 1:834 1:632
Ashkenazi 90.5 1:67 (1:54–1:83) 1:41 1:611 1:350
Jewish
Asian 93.3 1:59 (1:47–1:74) 1:53 1:806 1:628
Hispanic 90.0 1:68 (1:57–1:83) 1:117 1:579 1:1061
Asian 90.2 1:52 (1:33–1:82) NA 1:443 NA
Indian
African 70.5 1:72 (1:54–1:94) 1:66 1:130 1:121
American
Not 91.3 1:54 (1:48–1:161) NA 1:536 NA
provided

Sugarman EA et al. Eur J Hum Genet. 2012;20(1):27-32.

34
Interpreting the Results
Different “Types of Carriers”

“1 + 0” 5q SMN1
5q

5q SMN1 SMN1
“2 + 0”
5q

5q SMN1 *
“1 + 1*”
5q SMN1
*Point mutation or microdeletion.

Adapted from Sugarman EA et al. Eur J Hum Genet. 2012;20(1):27-32.

35
Interpreting the Results
Carrier Frequencies – It’s All in the Fine Print

Natera. Available at: www.natera.com. Accessed July 20, 2021.

36
Free Testing Program for SMA

Genetic testing options for SMA at no charge to your patients

The genetic test may be helpful if you are:
- Suspected of having SMA
- Diagnosed with SMA but do not know your SMN2 copy number
- Undiagnosed but have a family history of SMA
- A first-degree relative of an individual diagnosed via SMA genetic testing
- Considering getting pregnant, or are already pregnant, and want to determine
your SMA carrier status

SMA Identified. Invitae. Available at: www.invitae.com/en/sma-identified. Accessed July 20, 2021. 37
Prenatal Screening When Mother is
Identified as a Carrier of SMA

Mother is identified
as a carrier of SMA

Father is negative
Father is identified on carrier screening
as a carrier of SMA (deletion and
sequencing)

Refer to local Consider prenatal Lower likelihood

neuromuscular diagnostic testing that fetus has SMA
clinic for prenatal or confirmation (2+0 carrier is not
consult testing at birth excluded)

38
Prenatal Screening When Mother
Has SMA

Don’t assume that the

affected individual is
aware of their risk

Take the time to ensure

their partner is
educated about SMA
and the recurrence risk

Health Centre for Genetics Education. Available at: www.genetics.edu.au. Accessed July 19, 2021.
39
Prenatal Screening When Mother
Has SMA

Images: Health Centre for Genetics Education. Available at: www.genetics.edu.au. Accessed July 19, 2021.
40
Newborn Screening

Approved by the RUSP (Recommended Uniform

Screening Panel) committee on February 9, 2018
Signed by HHS Secretary, Alex Azar on July 3, 2018

Detects >95% of SMA patients

Quantitative (q)PCR to screen for a homozygous
deletion of exon 7 of the survival of motor neuron 1
gene (SMN1)

Screening does not identify what type of SMA a baby

has or when a baby with SMA will develop symptoms

41
Newborn Screening as of June 28, 2021

Information Courtesy of Cure SMA. 42

Methods of Confirmation Testing

▪ Traditional Sanger sequencing and Next

Generation Sequencing (NGS) detect small
mutations
▪ MLPA quantifies SMN1 to distinguish patients
[0 copies], carriers [1 copy], and non-affected
individuals [≥2 copies])
▪ Can also distinguish single nucleotide differences
to discriminate SMN1 copy numbers from SMN2
(for prognosis and management decisions)
▪ Available in Europe
Strunk A et al. Int J Neonatal Screen. 2019;5(2):21. 43
MRC Holland. Available at: https://support.mrcholland.com/downloads/files/brochure-newborn-screening-spinal-muscular-atrophy-sma.
How Can Genetic Counselors and
Ob-Gyns Work Together
▪ Collaboration between prenatal providers
and neuromuscular specialist
− Allows for detailed conversations with the
family prenatally
− Provides time to learn about SMA and
treatment options so they can make an
informed decision
− Can accelerate access to treatment

44
The Evolving Roles of
Ob-Gyns and PCPs
PCPs and Ob-Gyns as New Entities
in Multidisciplinary Care
Audience Polling Question

Which is correct regarding

fertility and pregnancy for
women with SMA?

A. Higher rate of infertility

B. Higher risk of miscarriage
C. Higher risk of pneumonia
D. Pregnancy is contraindicated

46
Birth-Control
Options
▪ There would be no
contraindication to
any of the birth-
control options

▪ Some may be
preferred over
others given
patient’s wishes,
mobility, pelvic
structure, and
safety for a
surgical procedure

Adapted from: www.acog.org/womens-health/infographics/effectiveness-of-birth-control-methods. 47

Patient Story
Pregnancy

▪ Historically SMA has been thought to be a

contraindication to pregnancy

49
Pregnancy
Outcomes in
Women with Spinal
Muscular Atrophy:
A Review

Abati E, Corti S. J Neurol Sci. 2018;388:50-60.

50
Pregnancy Outcomes

▪ No published evidence that SMA interferes with

fertility
▪ Miscarriage does not appear to be greater than in
the general population
▪ Fetal complications:
− Polyhydramnios
− Intrauterine growth restriction
− Macrosomia
− Not different than in the general population

51
Pregnancy Outcomes (cont)

▪ Maternal complications
− These were increased over the general
population
• Recurrent urinary tract infections

• Chronic low back pain

• Costochondritis

• Pneumonia

52
Restrictive Lung Disease (RLD)

▪ Many patients with SMA have varying degrees

of RLD
− Lungs are restricted from fully expanding
− Stiff chest wall
− Muscle weakness
− Nerve damage
− Decreased FEV1, FVC, and total lung capacity
▪ Pregnancy results in reduced lung capacity

53
Labor and Delivery Complications

▪ Increased preterm delivery rates

▪ Increased C-section rates but vaginal
delivery is not contraindicated
▪ Difficulties with anesthesia both general
and spinal/epidural

54
Conclusions

▪ Treated SMA patients may transition into

less severe phenotypes
▪ Needs of SMA patients are evolving
▪ Anticipated larger roles of PCP and
Ob-Gyn as part of the SMA care team

55
Q&A
Live Q&A with the experts

56
Be sure to watch the companion patient session!
Treatment and Post‐treatment Decisions in
SMA: What it Looks Like for Patients,
Caregivers, and Families

Today from 5:00pm – 6:00pm ET

www.rarediseaselive.com
and
www.neurocarelive.com
Speakers
Julie A. Parsons, MD Melissa Gibbons, MS, CGC Lizbeth McCarthy, MD
Haberfeld Family Endowed Chair in Certified Genetic Counselor Director of Genetics and Ultrasound
Pediatric Neuromuscular Disorders Assistant Professor, Certified Denver Health
Professor of Clinical Pediatrics University of Colorado School of
and Neurology Medicine Mary Schroth, MD
University of Colorado School of Medicine Children's Hospital Colorado Chief Medical Officer
Children's Hospital Colorado Cure SMA
Annie Heathcote
Adult with SMA Type II 57
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