Therapeutic Update on Neuromuscular Disorders SMA AND DMD Conference Highlights From 2018 Disclaimer

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Conference Highlights from:

• Annual Meeting of the American Academy of – AAN 2018 • 15th International Congress on Neuromuscular Diseases – ICNMD 2018 • 47th Annual Meeting of the Child Neurology Society – CNS 2018 • 23rd Annual Congress of the World Muscle Society – WMS 2018 Faculty

Basil Darras, MD Chief of the Division of Clinical Neurology Director of the Neuromuscular Center Children’s Hospital Boston, MA, USA John Brandsema, MD Neuromuscular Section Head Children's Hospital of Philadelphia, PA, USA Discussion Outline

Therapeutic Update on: Therapeutic Update on: Introduction Duchenne Muscular Dystrophy Introduction

SMA1,2 • Leading genetic cause of infant mortality • Caused by in the SMN1 • Historically classified, based on maximal gross motor function achieved and age of onset, as Type I (onset < 6 months), Type II (onset < 18 months), Type III (onset > 18 months), and Type IV (adult onset)

DMD3 • Lethal X-linked recessive neuromuscular disorder • Caused by mutations in the gene

1. Darras BT, et al. Spinal muscular atrophies. In: Darras BT, et al., editors. Neuromuscular disorders of infancy, DMD, Duchenne muscular dystrophy; childhood, and adolescence: a clinician’s approach. 2nd ed. San Diego, CA, USA: Academic Press; 2015:117-45. SMA, spinal muscular atrophy; 2. Kolb SJ, Kissel JT. Neurol Clin. 2015;33:831-6. SMN, survival of motor neuron. 3. Birnkrant DJ, Lancet Neurol. 2018;17:251-67. Diagnosis and Pathophysiology of SMA and DMD

Symptoms of SMA1 • Weakness • Hypotonia • Respiratory failure • Tongue fasciculations • Paradoxical breathing Symptoms of DMD2 • Motor function delay • Calf pseudohypertrophy • High CPK levels

1. Darras BT, Monani UR, De Vivo DC. Genetic disorders affecting the motor neuron: spinal muscular atrophy. In: Swaiman KF, et al., editors. Swaiman’s pediatric neurology: principles and practice. Elsevier; 2017:1057-64. CPK, creatine phosphokinase. 2. Birnkrant DJ, et al. Lancet Neurol. 2018;17:251-67. Diagnosis and Pathophysiology of SMA and DMD

Confirmation of diagnosis by genetic testing • Homozygous SMN1 deletion in ~ 95% of SMA patients1 • Dystrophin gene deletion (~ 70%), duplications, and micro-mutations/point mutations in DMD patients2 Complications of SMA1 • Respiratory • Feeding problems • Orthopedic complications Complications of DMD2,3,4 • Pulmonary failure • Cardiomyopathy • Orthopedic complications 1. Darras BT, Monani UR, De Vivo DC. Genetic disorders affecting the motor neuron: spinal muscular atrophy. In: Swaiman KF, et al., editors. Swaiman’s pediatric neurology: principles and practice. Elsevier; 2017:1057-64. 2. Birnkrant DJ, Lancet Neurol. 2018;17:251-67. 3. Birnkrant DJ, et al. Lancet Neurol. 2018;17:347-61. 4. Birnkrant DJ, et al. Lancet Neurol. 2018;17:445-55. 2018 Conference Highlights on the Treatment of SMA Mechanistic Strategies to Treat SMA

Splicing modification Gene replacement Muscle activation Modification of SMN2 mRNA Replacement of faulty Improvement of muscle force splicing to increase production SMN1 gene using of functional SMN viral-vector-based gene

Farrar MA, et al. Ann Neurol. 2017;81:355-68. Finkel RS, et al. Lancet. 2016;388:3017-26. mRNA, messenger RNA. Dominguez E, et al. Hum Mol Genet. 2011;20:681-93.

• Antisense SMN2 splicing modifier • First approved treatment for patients with SMA • Approved in the USA, Europe,a and Japan for the treatment of pediatric and adult patients

Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209531s003s004lbl.pdf. Accessed January 2019. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004312/WC500229704.pdf. Accessed January 2019. a All patients with 5q SMA. Available from: https://www.pmda.go.jp/. Accessed January 2019. Nurture: Presymptomatic SMA

• Phase 2, open-label, single-arm study of nusinersen in infants with genetically diagnosed SMA • Patients age ≤ 6 weeks at first dose • Efficacy endpoints: • Time to death or respiratory intervention • Motor function

NCT02386553. Available from: https://clinicaltrials.gov/ct2/show/NCT02386553. Accessed January 2019. Crawford T, et al. Presented at CNS 2018; abstract number 146. Nurture: Interim Resultsa – WMS 2018

• Interim results of the NURTURE study reported that all 25 participating infants were alive • None of the participants required permanent ventilation • All participants were able to sit without support and 22 participants were able to walk • No new safety concerns appeared

Presented at WMS 2018. Available from: http://investors.biogen.com/news-releases/news-release- a Interim Analysis May 2018. details/new-spinrazar-nusinersen-data-presented-annual-congress-world. Accessed December 2018. Newborn Screening

• NURTURE study highlights the importance of early diagnosis1 • SMA is part of the RUSP in the USA2 • Several US states have already implemented newborn screening for SMA1 • Presymptomatic identification of SMA raises the challenge of when to start treatment for the different types of patients classified by SMN2 copy number3

1. Personal communication John Brandsema. 2. RUSP recommendation. Available from: https://www.hrsa.gov/sites/default/files/hrsa/advisory- committees/heritable-disorders/reports-recommendations/final-sign-azar-response-sma.pdf. Accessed July 2018. RUSP, Recommended Uniform Screening Panel. 3. Glascock J, et al. J Neuromuscul Dis. 2018;5:145-58. Considerations and Challenges for Newborn Screening

• Patients with < 4 SMN2 copies should be treated immediately • Unclear risk:benefit ratio for patients with ≥ 4 copies • Lack of biomarkers makes detection of motor neuron damage challenging • Early treatment for patients with ≥ 4 copies may be advisable to avoid irreversible damage • Patients with point mutations will not be detected by newborn screening

Personal communication Basil Darras and John Brandsema. Nusinersen Open-Label Extension Studies

• SHINE: patients who previously participated in investigational studies with nusinersen • Accumulating data regarding long-term treatment effects in patients with SMA Types I–III

Castro D, et al. Presented at WMS 2018; abstract number P.170. NCT02594124. Available from: https://clinicaltrials.gov/ct2/show/NCT02594124. Accessed January 2019. Ambulatory Function and Fatigue in Nusinersen-Treated Children With SMA

• 14 patients from CS2/CS12 open label studies: • Ambulatory, • Nusinersen-treated, • Mean age at screening 8.6 years • Efficacy endpoints: • 6MWT • Fatigue

Results • Median distance walked increased by 17 m at Day 253 and by 99 m at Day 1,050 (baseline 250.5 m) • Median fatigue decreased by 0.1% at Day 253 and by 3.8% at Day 1,050 (baseline 14.8%)

6MWT, 6-minute walk test. Montes J. et al. Presented at AAN 2018; abstract number P2.322. Nusinersen Experience in Individuals With SMA Type III: A Case Series

• 11 patients: • SMA Type III • 3 or 4 copies of SMN2 • Median age at data cut-off: 14.1 years

Results • Stabilization or improvement in 6MWT over a long follow-up period • Higher-functioning patients also benefit • AEs were consistent with previous experience

Chiriboga C, et al. Presented at CNS 2018; abstract number 60. AE, adverse event. Kirschner JC, et al. Presented at ICNMD 2018; abstract number 640. Nusinersen Efficacy in Adults With SMA

• Evidence of efficacy in teenage and adult patients with SMA is emerging1,2,3 • Original study population: no adults • Presentation of single-center experience in adults treated with nusinersen at Stanford University1 • Comparison with PNCR’s natural history study

1. Day J, et al. Presented at WMS 2018; abstract number P.176. 2. Elsheikh B, et al. Presented at AAN 2018; abstract number S46.001. PNCR, Pediatric Neuromuscular Clinical Research Network. 3. Stauber AJ, et al. Presented at ICNMD 2018; abstract number 009. Nusinersen Efficacy in Adults With SMA

Single-center experience: Stanford University • Patients age 18–65 years

Results • Stabilization or improvement in HFMSE and RULM compared with a decline in natural history study • Most improvements in respiratory measures (MIP, FVC) • More data collection required

FVC, forced vital capacity; HFSME, Hammersmith Functional Motor Scale-Expanded; MIP, maximal inspiratory pressure; RULM, Revised Upper Limb Module. Day JW, et al. Presented at WMS 2018; abstract number P.176. Importance of Real-World Data and Experience

• Patients with very low motor function or severe comorbidities are often excluded from SMA clinical trials • Functional scales may be challenging to use outside the trial setting • Improved patient experience may not be reflected in scores on functional scales • Listening to patient experience is key

Personal communication Basil Darras and John Brandsema. Challenges for the Treatment of Adult Patients

• Comorbidities may make intrathecal delivery challenging • Slow functional change may make patients reluctant to take treatment • Lack of clinical data on treatment of adults made clinical expectations challenging

Personal communication Basil Darras and John Brandsema. AVXS-101: SMN1 Gene Replacement Therapy

• AAV9-based gene-replacement therapy containing a copy of the human SMN1 gene • AVXS-101 received Breakthrough Therapy designation and is currently under by the FDA • SAKIGAKE (Japan) and PRIME designations (Europe)

Available from: https://clinicaltrials.gov/. Accessed April 2018. FDA, US Food and Drug Administration. Available from: http://investors.avexis.com/phoenix.zhtml?c=254285&p=irol-newsArticle&ID=2378942. Accessed January 2019. AVXS-101: Phase 1 Data – 24-Month Follow-Up

• Open-label dose-escalation, one-time IV dose • Minimally effective dose (cohort 1) or proposed therapeutic dose (cohort 2) • Symptomatic SMA Type I; two SMN2 copies • Outcome measures: • Safety • Death or permanent ventilation • Ability to sit unassisted • Motor function

IV, intravenous. Mendell JR, et al. Presented at CNS 2018; abstract number 136. AVXS-101: Phase 1 Data – 24-Month Follow-Up

• All 15 patients in the study were alive without requiring permanent ventilation 24 months after gene transfer • Cohort 2: median age 27.8 months at last follow-up • 11 of 12 patients were able to sit unassisted and could feed orally • AVXS-101 safety profile of appeared to be favorable

Mendell JR, et al. Presented at CNS 2018; abstract number 136. AVXS-101: Phase 1 Data – 24-Month Follow-Up

60 High-dose cohort 2 50 Patient 4 • CHOP INTEND mean increase Patient 5 at Month 1: 9.8 Patient 6 40 Patient 7 • CHOP INTEND mean increase Patient 8 at Month 3: 15.4 30 Patient 9 Patient 10 20 Patient 11

CHOP INTENDscore CHOP Patient 12 Patient 13 10 Patient 14 Patient 15 0 0 5 10 15 20 25 30 Age (months) Mendell JR, et al. Poster presented at CNS 2018; abstract number 136. CHOP INTEND, Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders. Mendell JR, et al. N Engl J Med. 2017;377:1713-22. RG7916/: SMN2 Splicing Modifier

• Risdiplam is an orally bioavailable small molecule that distributes centrally and peripherally

Trial name Patients Phase FIREFISH1 SMA Type I; age 1–7 months 2/3 SUNFISH2 SMA Type ll, lll; age 2–25 years 2/3 SMA Type ll, lll; age 6 months–60 years; JEWELFISH3 2 previously treated with an SMN2-targeting therapy

1. NCT02913482. Available from: https://clinicaltrials.gov/ct2/show/NCT02913482. Accessed April 2018. 2. NCT02908685. Available from: https://clinicaltrials.gov/ct2/show/NCT02908685. Accessed April 2018. 3. NCT03032172. Available from: https://clinicaltrials.gov/ct2/show/NCT03032172. Accessed April 2018. FIREFISH Interim Data: Infantile-Onset SMA

• Multicenter, open-label study, • Symptomatic SMA Type I

• Results after 8 months of treatment: • 90% of infants were alive and event-free • 43% were able to sit with or without support and achieved head control • 57% achieved a CHOP INTEND score of ≥ 40 • 93% achieved ≥ 4-point CHOP INTEND increase (clinically meaningful)

The safety profile appeared favorable. The three most common AEs were (52.4%), (26.8%) and upper respiratory tract infections (19%).

Baranello G, et al. Abstract presented at AAN 2018; abstract number 004. Available from: https://www.roche.com/media/releases/med-cor-2018-10-03.htm. Accessed January 2019. Data cutoff: September 2018 Available from: http://ir.ptcbio.com/news-releases/news-release-details/risdiplam-demonstrates-preliminary-evidence-clinical-benefit. Accessed January 2019. SUNFISH Interim Data: SMA Type II and III

• Double-blind, two-part, -controlled trial; SMA Type II and III • Part 2: safety and efficacy in non-ambulant patients Endpoint (at 12 months of treatment)  12 months of treatment All patients Age 2–11 years Age 12–24 years MFM (N = 30)a (n = 17) (n = 13) Mean total MFM change from baseline 2.47 (4.17) 3.31 (4.5) 1.36 (3.57) (SD) Median total MFM change from baseline 3.13 (−7.3 to 11.5) 4.17 (−6.3 to 11.5) 2.08 (−7.3 to 5.2) (range) Proportion of patients who achieved improvement (i.e. a change from 63.3 (19/30) 76.5 (13/17) 46.2 (6/13) baseline in MFM score ≥ 3), % (n) a Excludes 4 patients who performed the MFM20 assessment (only patients who performed the full MFM32 assessment are included in the analysis) and 1 patient who had dropped out of the study prior to the Month 12 visit. Data cut-off July 6, 2018. Available from: https://www.roche.com/media/releases/med-cor-2018-10-03.htm. Accessed January 2019. MFM, motor function measure. Available from: http://ir.ptcbio.com/news-releases/news-release-details/risdiplam-demonstrates-preliminary-evidence-clinical-benefit. Accessed January 2019. Current and Emerging SMA Treatments

• New era in terms of SMA treatment • There is a disease-modifying therapy • There are more options on the horizon • The optimal time to treat must be determined • Combination treatments • Phenotype modulators + SMN-targeted therapy may be optimal • The feasibility of combination therapy has yet to be determined

Personal communication Basil Darras and John Brandsema. Treatment Initiation: Further Considerations

• Determining the optimal treatment strategy might depend on the individuals genetic background and predicted phenotype1 • Presymptomatic treatment is likely to be optimal • Biomarkers may help optimize treatment timing1 • pNF-H is a potential disease-activity and treatment-responsive biomarker • pNF-H levels are highest in patients with SMA Type I • Treatment with nusinersen appears to decrease pNF-H levels2

1. Personal communication Basil Darras and John Brandsema. pNF-H, phosphorylated neurofilament heavy chain. 2. Darras B, et al. Presented at CNS 2018; abstract number O5. 2018 Conference Highlights on the Treatment of DMD Mechanistic Strategies to Treat DMD

• Corticosteroids to decrease inflammation (e.g. prednisone, deflazacort) • skipping with ASOs to increase dystrophin expression (, ) • Targeting RNA translation to increase dystrophin levels () • Gene-replacement therapy (micro-dystrophin) • Other strategies

ASO, anti-sense oligonucleotide. Personal communication Basil Darras. Current DMD Treatment Landscape

USA: • Deflazacort for patients age ≥ 5 years1 • Eteplirsen for patients with of the dystrophin gene amenable to exon 51 skipping2 • Conditional approval based on increased dystrophin production

Europe: • Ataluren for ambulatory patients age ≥ 2 years with nonsense-mutation DMD3

1. Available from: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm540945.htm. Accessed January 2019. 2. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206488lbl.pdf. Accessed January 2019. 3. Available from: https://www.ema.europa.eu/documents/product-information/translarna-epar-product-information_en.pdf. Accessed January 2019. Meta-Analysis of Deflazacort vs Prednisone/Prednisolone

• Post-hoc analysis of the ACT DMD trial: • Randomized, double-blind, placebo-controlled 48-week trial • Patients with DMD, age 7–16 years • Post-hoc analysis of patients in placebo arm who received corticosteroid therapy for ≥ 6 months at study entry and throughout the study • Deflazacort (n = 53) • Prednisone/prednisolone (n = 61) • Endpoints included: • 6MWD • TFT

Darras B, et al. Presented at AAN 2018; abstract number P2.325. TFT, timed function test. Shieh PB, et al. Muscle Nerve. 2018;58:639-45. Meta-Analysis of Deflazacort vs Prednisone/Prednisolone

LS mean change (95% CL) from baseline to Week 48 Standardized t-statistic Prednisone/ Endpoint Δ (SE) Deflazacort prednisolone (95% CL) (n = 53) Deflazacort (n = 53) LS mean difference (n = 61) In favor of deflazacort −70.59 (13.40) −39.01 (15.05) Prednisone/ prednisolone (n = 61) (95% CI) 6MWD, meters (−97.16 to (−68.85 to −9.17) −44.02) TFTs, seconds 6MWD, meters 31.6 (0.2 to 62.9) 3.79 (1.13) 6.67 (1.0) 4-stair climb 10-m run/walk, seconds 0.1 (−1.9 to 2.1) (1.54 to 6.03) (4.69 to 8.64) 3.89 (1.29) 5.66 (1.12) 4-stair climb, seconds 2.9 (0.5 to 5.23) 4-stair descent (1.33 to 6.45) (3.43 to 7.89) 4-stair descend, seconds 1.8 (−1.0 to 4.5) 4.50 (1.24) 7.10 (1.13) Rise from supine (2.05 to 6.95) (4.86 to 9.34) Rise from supine, seconds 2.6 (−0.0 to 5.2) 3.16 (0.93) 3.25 (0.85) 10-m walk/run (1.32 to 500) (1.56 to 4.94) NSAA (total) 1.1 (−0.4 to 42.6) NSAA total score −3.39 (0.70) −4.53 (0.66) PODCI (mobility) 1.7 (−3.9 to 7.2) (−4.78 to −2.01) (−5.83 to −3.23) PODCI PODCI (sports) 6.0 (0.7 to 11.3) −4.80 (2.49) −10.76 (2.25) Sport/physical functioning (−9.73 to 0.13) (−15.21 to −6.31) LoA,  3.84 (−2.43 to 10.11) −7.53 (2.62) −9.20 (2.34) Transfers/basic/mobility (−12.72 to −2.35) (−13.84 to −4.57) −4 −3 −2 −1 0 1 2 3 4 5 6

CI, confidence interval; CL, confidence limit; LoA, loss of ambulation; LS, least squares; NSAA, North Star Ambulatory Assessment; PODCI, Pediatric Outcomes Data Collection Instrument. Shieh PB, et al. Muscle Nerve. 2018;58:639-45. Role of Corticosteroids in the DMD Treatment Landscape

• Corticosteroids remain the standard of care • Data on prednisone vs deflazacort are emerging via post-hoc analysis • FOR-DMD, a double-blind, randomized, prospective study on the comparison of prednisone vs deflazacort, is ongoing

Personal communication Basil Darras. NCT01603407. Available from: https://clinicaltrials.gov/ct2/show/NCT01603407. Accessed January 2019. Considerations for the Comparison of Corticosteroids

• Access to the two corticosteroids was different in the USA before the approval of deflazacort • Post-hoc analysis also included international patients, with wider access to deflazacort • Dosing and schedules vary between patients, posing a challenge when comparing different corticosteroids

Personal communication Basil Darras and John Brandsema. Eteplirsen: Antisense Oligonucleotide

• Targets patients amenable to exon 51 skipping • Additional data presented on respiratory function

Khan N, et al. Presented at WMS 2018; abstract number P2.125. Kinane TB, et al. J Neuromuscul Dis. 2018;5:47-58. Available from: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm521263.htm. Accessed January 2019. Eteplirsen: Respiratory Function

• Patients in eteplirsen clinical trials (amenable to exon 51 skipping, on glucocorticoids) compared with natural history control

Annual change in FVC % predicted (assessed between age 10 years and 18 years) Natural history Study Eteplirsen-treated control (n = 20) 201/202 (ambulatory) −6.00% −2.19% (n = 12) 204 (mainly non-ambulatory) −6.00% −3.66% (n = 20) 301 (ambulatory, interim analysis) −6.00% −3.79% (n = 46)

Khan N, et al. Presented at WMS 2018; abstract number P2.125. Golodirsen: Antisense Oligonucleotide

• Targets patients amenable to exon 53 skipping • Interim analysis data were presented • Dystrophin production quantified in muscle biopsies of 25 patients treated with golodirsen

Results: • Mean percent of normal dystrophin protein increased from 0.095% at baseline to 1.019% at Week 48 • Exon 53 skipping had increased significantly

Muntoni F, et al. Presented at AAN 2018; abstract number S22.001. Antisense Oligonucleotide Therapies

• Eteplirsen has been approved in the USA, with golodirsen still under investigation • Patients amenable to skipping of exon 51 (eteplirsen) and 53 (golodirsen) are candidates • More efficacy data are required for golodirsen; clinical studies are ongoing • Further eteplirsen studies are also ongoing

Personal communication Basil Darras. Ataluren

• Ataluren has been approved by the EMA in Europe for ambulatory patients age ≥ 2 years with nonsense-mutation DMD • Label extension for patients ≥ 2 to < 5 years approved May 2018 • Safety profile was shown to be comparable in younger patients

Available from: https://www.ema.europa.eu/documents/variation-report/translarna-h-c-2720-ii-0037-epar-assessment-report-variation_en.pdf. EMA, European Medicines Agency. Tian C et al. Presented at ICNMD; abstract number 807. Ataluren in Patients Age ≥ 2 to < 5 Years

Study 030: • Observational, phase 2 study to evaluate safety and in patients age ≥ 2 to < 5 years Study goal: • Assess ataluren therapy for dystrophin restoration at a younger age before substantive muscle loss Safety results: • The safety profile was similar to that in older patients • The most common TEAEs were: • Pyrexia • Ear • Nasopharyngitis

Tian C et al. Presented at ICNMD; abstract number 807. TEAE, treatment-emergent adverse event. Available from: https://www.ema.europa.eu/documents/variation-report/translarna-h-c-2720-ii-0037-epar-assessment-report-variation_en.pdf. Ataluren in Patients Age ≥ 2 to < 5 Years

Study 030 (n = 12): TFT at baseline and Week 281 TFT change from baseline to Week 282 8 CINRG 7 Study 030 natural history 6 Time to run/walk 10 m, n = 31 n = 12 5 seconds −0.32 −0.6 4 Time to climb n = 28 n = 12 3 4 stairs, seconds −1.3 −2.1 Time (seconds) Time 2 Time to stand from n = 25 n = 12 1 a supine position, seconds −0.65 −3.3 0 Time to run/walk Time to climb 4 Time to stand from 10 m stairs a supine position Baseline Week 28 1. Based on: Tian C et al. Presented at ICNMD; abstract number 807. 2. Available from: https://www.ema.europa.eu/documents/variation-report/translarna-h-c-2720-ii-0037-epar- CINRG, Cooperative International Neuromuscular Research Group. assessment-report-variation_en.pdf. Ataluren in Patients Age ≥ 2 to < 5 Years

Study 030 (n = 12): NSAA at baseline and NSAA change from baseline to Week 282 Week 281

14 Change from baseline CINRG Study 030 12 to Week 28 natural history 10 n = 11 n = 12 NSAA 8-item score 8 0.00 1.5 n = 11 n = 12 6 NSAA 3-item score 0.09 0.5 4 2 0 NSAA 8-item score NSAA 3-item score Baseline Week 28 1. Based on: Tian C et al. Presented at ICNMD; abstract number 807. 2. Available from: https://www.ema.europa.eu/documents/variation-report/translarna-h-c-2720-ii-0037-epar- assessment-report-variation_en.pdf. Treatment of Younger Patients

• Initial trials focused on active motor decline phase (age 4–6 years) • Studies are expanding into older, non-ambulatory, and younger patients • Earlier treatment appears to be more efficacious Considerations for Long-Term Treatment

• Studies to evaluate the long-term efficacy and safety of ataluren are ongoing • Safety results are encouraging • We need to understand the safety implications of long-term therapy Micro-Dystrophin

• Micro-dystrophin gene therapy is challenging due to gene size • Micro-gene therapy targets key functional protein areas • Aims to create a semi-functional protein • Several studies under way in the USA • Initial results are encouraging • CRISPR-Cas9 for gene editing may have a role in the future

CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats. Key Messages

• There is now an approved treatment for SMA, 125 years after the first description of the disease by Werdnig and Hoffman • Nusinersen is an effective and safe treatment for patients with SMA; results have been best in presymptomatic patients treated early • Gene therapy with AVXS-101 and splicing modification with risdiplam seem promising, and may be approved in the future • Steroids continue to be the standard of care in DMD • Eteplirsen and ataluren have been approved in the USA and Europe, respectively, for the treatment of specific mutations; there are other treatments on the horizon Therapeutic Update on Neuromuscular Disorders SMA AND DMD Conference Highlights From 2018