IC29 Alfano SpinalMuscularAtrophy Handout Slides Only … · 2018. 10. 12. · Ventilation in Most Children with Type 1 SMA: Natural History NeuroNext2 PNCR study1 50% survival 10.5

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Spinal Muscular Atrophy:A new era of evaluation and treatment

Linda P Lowes, PhD; Lindsay N Alfano, DPT; Natalie F Miller, DPT; Megan A Iammarino, DPT

Neuromuscular Physical Therapy

Nationwide Children’s Hospital

Center for Gene Therapy & Clinical Therapies

Columbus, OH

FINANCIAL DISCLOSUREAACPDM 72nd Annual MeetingOctober 9-13, 2018

Speaker Name: Linda P Lowes; Lindsay N Alfano; Natalie F Miller; Megan A Iammarino

1. Disclosure of Relevant Financial RelationshipsNationwide Children’s was a site for the initial AVXS-101-CL-101 study, and a site for their ongoing studies. Linda Lowes and Lindsay Alfano serve as PT trainers for the ongoing AveXis studies.

2. Disclosure of Off-Label and/or investigative uses: We will discuss the following investigational products in our presentation: • AVXS-101 – AveXis, Inc• CY 5021 – Cytokinetics, Inc• RG7916 – PTC Therapeutics & Hoffman La Roche

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Diagnosis of SMA• Survival motor neuron protein

(SMN1; SMN2)• 9 exons; Protein with 294 amino

acids

• Degeneration of alpha motor neurons in spinal cord

• Severity associated with number of copies of SMN2

Butchbach MER, Burghes AHM. Perspectives on models of spinal muscular atrophy for drug discovery. Drug Discovery Today: Disease Models. 2004. Vol 1(2):151-156.

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Diagnosis of SMA

https://geneticsupportfoundation.org/archive/genetics-and-you/autosomal-recessive-inheritance

• 96%: homozygous absence of exons 7 and/or 8 • Majority inherited from parents

• 2% de-novo deletions

• 3 – 4% other mutations in SMN1• Typically with an SMN1 deletion

on the other allele

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SMA ClassificationType 0: fetal onsetType 1:

1a: weakness, feeding difficulty, respiratory insufficiency within 2 weeks1b: onset of weakness by 3 months1c: onset of weakness by 6 months

Type 2: onset of weakness between 6 – 18 months Type 3:

3a: onset of weakness between 18 months - 3 years3b: onset of weakness after 3 years

Type 4: Adult onset Zerres K, Rudnik-Schonborn S, Forrest E, et al. J Neurol Sci. 1997;146:67-72.

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Historical Clinical Presentation

Born 1980-1994Born 1995-2006

Children with SMA I are living longer• G-tube• Ventilatory assistance

Oskoui M, Levy G, Garland CJ, et al. The changing natural history of spinal muscular atrophy type 1. Neurology. 2007; 69(20):1931-6.

Survival without ventilatoryassistance

Wang CH et al. J Child Neurol. 2007; 22(8): 1027-1049..

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SMA Clinical CareCurrent care guidelines:

Mercuri E, Finkel RS, Muntoni F, et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28(2):103-115.

Finkel RS, Mercuri E, Meyer OH, et al. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018;28(3):197-207.

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Updated Clinical Classification

• Describes current level of function v. predicted function based on onset of weakness

• Non-sitter

• Sitter

• Ambulant

• Relevant now that there is an approved treatment and others in the pipeline of development

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Spinal Muscular Atrophy:Treatment

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Spinraza®

Spinraza (nusinersen):• First treatment approved by the FDA for treatment of SMA (2016)

• Antisense oligonucleotide that blocks an SMN2 intronic splicing silencer (ISS-N1) element and promotes inclusion of exon 7 to boost SMN2 levels

https://www.spinraza-hcp.com/en_us/home/mechanism-of-action.html Burghes A H , McGovern V L Genes Dev. 2010.Hua Y1, Sahashi K, Hung G, et al. Genes Dev. 2010 Aug 1;24(15):1634-44.

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Spinraza®

• 12-mg (5mL) dose

• Injected into lumbar intrathecal space

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Spinraza®

Finkel RS et al. N Engl J Med 2017;377:1723-1732. E Mercuriet al. N EnglJ Med 2018;378:625-635.

Change over time in the A) HFMS-E and the B) RULM in SMA II & III A) Event-free Survival and B) Overall Survival in SMA I

N = 121Randomized 2:1• 12mg dose• Sham-control

Interim analysis when 80 subjects enrolled at 6 months

• Treated cohort:• 41% (21/51 infants)

improved

• Untreated cohort:• 0% (0/27 infants)

• Prompted early termination

- Due to ethics associated with sham treatment

N = 126Randomized 2:1• 12mg dose• Sham-control

15-month interim analysis:• Between groups

difference of 4.9pts (P<0.001)

Study completion:• Treated cohort:

• 57% improved from baseline

• Untreated cohort: • 26% improved scores

from baseline

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Spinraza® SafetyCoagulation abnormalities & thrombocytopeniaLow platelet level:• 24 of 146 (16%) of treated• 10 of 72 (14%) of sham-control

Renal toxicityElevated urine protein• 71 of 123 (58%) of treated• 22 of 65 (34%) of sham-control

Recommended lab testing & monitoring:• Platelet count; Prothrombin time; activated partial thromboplastin time; quantitative spot

urine protein testing

https://www.spinraza-hcp.com/en_us/home/safety/warnings-and-precautions.html

• Enables rapid onset of effect, which is key in a patient population with rapid deterioration of health

• Rapid onset effectively addresses SMA symptoms very quickly, within days of administration

• Chicken ß-actin promoter activates the transgene to allow for continuous and sustained SMN protein expression

• Eliminates the need for repeat administration, adding convenience and providing lifelong therapeutic benefit for treating SMA

• Full copy of a stable, functioning SMN gene that is introduced into the cell’s nucleus

• Restores production of SMN protein, thereby preventing further loss of motor neurons

Self-Complimentary AAV Inverted Terminal Repeats (scAAV ITR)

Continuous Promoter Human SMN Transgene

Adapted from DiMattia MA, et al. J Virol. 2012;86(21):6947-6958.

• Able to deliver across the blood−brain barrier and into the spinal cord

Recombinant AAV9 Capsid Shell

AVXS-101: An Innovative Treatment Approach for SMA, Utilizing a Highly Efficient Human SMN gene

• Designed not to integrate into genome of the patient

Gene replacement therapy is a logical approach for SMA: monogenic deletion/mutation drives the pathology

Reproduced with permission from AveXis

R e p r o d u c e d w i t h p e r m i s s i o n f r o m A v e X i s

AVXS-101 Phase I Clinical Study Overview

TRIAL OVERVIEWRoute of AdministrationOne-time intravenous infusion through peripheral limb veinPrednisolone 1 mg/kg 1 day Pre-GT

Trial DesignOpen-label, dose-escalation

Principal Investigator Jerry R. Mendell, M.D.

AVXS-101 PHASE 1 TRIAL OVERVIEW – SMA TYPE 1Study Site

OBJECTIVES

Primary• Safety and TolerabilitySecondary• Time from birth until death or time to ≥16-

hour ventilation continuously for ≥2 weeks in the absence of an acute reversible illness or perioperatively

• Video confirmed achievement of ability to sit unassisted*

Additional • CHOP INTEND• Bayley Motor Scales of Infant/Toddler

development – Gross Motor

OBJECTIVESOBJECTIVES

Inclusion• 9 months of age / 6 months of age¹ and younger at day of vector infusion with SMA Type 1 as

defined by the following features: – Bi-allelic SMN1 gene deletion or point mutations

– All enrolled patients carry bi-allelic SMN1 deletions, confirmed by independent laboratory

– 2 copies of SMN2– Onset of disease at birth to 6 months of age– Hypotonia by clinical evaluation with delay in motor skills, poor head control, round

shoulder posture and hypermobility of jointsExclusion• Active viral infection (includes HIV or serology positive for hepatitis B or C)• Use of invasive ventilatory support (tracheotomy)* or pulse oximetry <95% saturation• Patients with Anti-AAV9 antibody titers >1:50 as determined by ELISA binding immunoassay• Abnormal laboratory values considered to be clinically significant • Patients with the c.859G>C mutation in SMN2 exon 7 (predicted mild phenotype)2

KEY ENROLLMENT CRITERIA

Clinicaltrials.gov Identifier = NCT02122952¹ Inclusion criteria was 9 months of age and younger for the first nine patients. 6 months of age and younger for the last six patients.2 Exclusion criteria related to c.859G>C was confirmed for all patients by an independent laboratory.

*Patients may be put on non-invasive ventilatory support (BiPAP) for <16 hours/day at discretion of their physician or study staff.

*key developmental milestone achievements assessed and adjudicated by external independent reviewer

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Age (months)40 8 12 16 20 24 28 32

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Rapid Decline in Event Free Survival Leads to Death Or Permanent Ventilation in Most Children with Type 1 SMA: Natural History

NeuroNext2

PNCR study1

50% survival

10.5 months

25% survival

13.6 months

8% survival

20 months50% survival

8 months

1. Finkel RS, et al. Neurol. 2014;83:810-7. 2. Kolb SJ, et al. Ann Neurol. 2017;82:883-891.

CHOP INTEND, Children’s Hospital of Philadelphia Infant Test of Neuromuscular Dysfunction; PNCR, Pediatric Neuromuscular Clinical Research; SMA, Spinal Muscular Atrophy

SMA Type 1• “Floppy baby” syndrome• Muscle weakness (legs more than

arms)• Poor head control• Belly breathing• Bulbar muscle weakness (weak

cry, difficulty swallowing, aspiration)

• Will never sit unsupported• Loss of motor function:

NeuroNEXT -- CHOP INTEND decrease of 10.5 points/year

PNCR -- CHOP INTEND decrease of 1.27 points/year

*Survival for PNCR1 = no death, or no need for ≥16-hours/day ventilation continuously for ≥2 weeks, in the absence of an acute reversible illness;

n=23 (2 copies of SMN2)

Survival for NeuroNext2 = no death, or no tracheostomy; n=20


Age (months)40 8 12 16 20 24 28 32

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Unambiguous, Dramatic Improvement in Event-Free Survival in Patients Treated with AVXS-101No patients received concomitant nusinersen during 24 month follow-up period

1. Finkel RS, et al. Neurol. 2014;83:810-7. 2. Kolb SJ, et al. Ann Neurol. 2017;82:883-891.

Survival Data Summary

• 15/15 (100%) reached 20 months of age alive and event‐free

• 15/15 (100%) completed 24 months of follow‐up alive

• 12/12 (100%) in cohort 2 completed 24 months of follow‐up alive and event free

Age at Final Study VisitCohort 1*: 30.7 months (median) 30.4 months (mean)Cohort 2*: 27.8 months (median) 27.9 months (mean)

*reflects age at Last Trial Visit or most recent pulmonary assessment, E.02’s age at Pulmonary Event

CL-101 Cohort 1 (n=3)

NeuroNext2

CL-101 Cohort 2 (n=12)PNCR study1


Major Motor Milestone Achievements AssessedCohort 2Proposed

Therapeutic Dose

Age at GT (mos)

Motor Milestone Achievement

Brings hand to mouth Head control Rolla Sitting with

assistanceSitting Unassisted

≥ 5 secondsb ≥ 10 secondsc ≥ 30 secondsd

E.04 6 E.05 4 E.06 2 E.07 4 E.08 8 E.09 5 E.10 1 E.11 2 E.12 3 E.13 1 E.14 4 E.15 2

Total (%) N/A 100 92 75 92 92 92 92

= 24 months of age cut-off

= Long-Term Follow-Up Study(LTFU)

• Two children crawl, pull to a stand, and stand and walk independently• 4 Patients attained new milestones during the LTFU Study*

• Subjects E.04 and E.07 gained the ability to sit for >30 seconds during LTFU Study• Subject E.11 and E.14 gained ability to stand with support during LTFU Study• 3 of the 4 children who achieved new milestones did not receive nusinersen

* Video documentation not assessed and adjudicated by external reviewer Reproduced with permission from AveXis

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Age (months)COHORT 2 (n=12)

Mean CHOP-INTEND Increase: 25.4 points*reflects age at Last Trial Visit or most recent pulmonary assessment

Dashed line denotes missed or partial CHOP-INTEND assessmentsBlack dashed line: According to natural history, SMA1 children do not achieve/maintain CHOP-INTEND scores >40 points (Finkel et al., 2014)

Rapid and Sustained CHOP-INTEND Increase Observed in Patients Treated with AVXS-101 at 1 and 3 Months

COHORT 2 (n=12)

•CHOP-INTEND Increase at

Month 1: 9.8 [mean]

•CHOP-INTEND Increase at

Month 3: 15.4 [mean]

Reproduced with permission from AveXis

Safety Data

SAFETY AND TOLERABILITY OBSERVATIONS• A total 319 AEs (5 treatment-related AEs and 314 non-treatment related AEs) have been reported following

monitoring and source verification

─ 60 SAEs and 259 non-serious AEs

• No new treatment-related SAEs or AEs observed • A total of 5 treatment-related AEs in 4 patients have been reported following monitoring and source verification

─ Treatment-related SAEs and AEs were clinically transient asymptomatic elevated liver function enzymes (LFEs) assessed under CTCAE on the basis of laboratory values and resolved with prednisolone treatmenta

2 were SAEs experienced by 2 patients One patient who experienced an SAE was not pre-treated with prednisolone

3 were AEs experienced by 2 patients

AVXS-101 appears to have a favorable safety profile and to be generally well-tolerated in patients studied to date

aNo drug-induced liver injury (DILI) as defined by Hy’s Law Reproduced with permission from AveXis

• AVXS-101 appears to have a favorable safety profile and to be generally well tolerated• Clinically asymptomatic transient elevated liver enzymes were the only treatment-related SAEs/AEs and were

managed with a prednisolone regimen

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CytokineticsRedelsemtiv:• CK2127107 – fast skeletal troponin activator

• OBJECTIVES: Assess the safety & tolerability and effect on skeletal muscle function in patients with SMA Types II-IV

• 8 week trial: single dose day 1, then BID

• 36 subjects randomized 2:1 at 150mg dose (50% ambulatory)

• 36 subjects randomized 2:1 at 450mg dose (50% ambulatory)

• Age ≥12 years

• Assess effect on pulmonary function, strength, HFMS-E, RULM, TUG, and 6MWT

Hwee DT, Kennedy AR, Hartman JJ, et al. J Pharmacol Exp Ther. 2015;353:159-168.https://cytokinetics.com/clinical-trials/

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Roche, PTC, & SMA Foundation• RG7916 is a SMN2 splicing modifier• SUNFISH

• SMA II & III• Part I: Dose-escalation in 36 patients over 12 weeks: COMPLETED• Part II: Double-blind, randomized study in 150 patients over 24 months

• FIREFISH• SMA Type I• Part I: 8 patient safety study: COMPLETED

• Data presented at cureSMA 2017: • ~400% ↑ in full length SMN2/∆7 mRNA ratio

• Part II: Open-label follow up in 40 infants for 24 months with planned extension

• JEWELFISH• Exploratory study of RG7916 in patients with SMA II & III • Taken part in another SMN2-targeting molecule

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Multidisciplinary Care

• Symmetrical weakness; more proximal than distal.

• Weakness in the legs > arms

• Preserved sensation

• Tendon reflexes are absent or diminished

• Age of symptom onset related to severity of weakness

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RehabilitationAssessment Intervention Care considerations

• Postural control

• Scoliosis

• Hip dislocation

• Sitting tolerance

• Chest deformities

• Contractures (ROM, goniometry)

• Muscle weakness

Positioning and Bracing

Prolonged Bracing & Stretching

Promote function and mobility

• Switch toys, light-weight rattles

• Bath equipment, adapted beds

• Upper extremity assistive devices, hoists (lifts)

• Environmental controls, and eye tracking devices for computers and communication

• Strollers with recline and the ability to lay flat

• Power wheelchairs should have recline/tilt, adapted seating systems

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• Foot and chest deformities

• Scoliosis and pelvic obliquity

• Hip dislocation


• Muscle weakness

Positioning and Bracing



• Night splinting for prolonged stretching, worn nightly if possible

• Supported standing programs recommended

• Recommend swimming, hippotherapy, and wheelchair sports

• Custom seating based on individual needs:

• Power wheelchairs with custom postural support and seating systems

• Tilt and/or recline and a seat elevator may be necessary

• Lightweight manual wheelchairs or power assist wheels

Sit

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• Mobility

• Endurance (6MWT)

• Falls

• Muscle weakness



• Scoliosis

• Hip dislocation



• Aerobic & general conditioning exercise

• Swimming, walking, cycling, yoga, hippotherapy, rowing, elliptical/cross-trainers

• Optimal duration for aerobic exercise: at least 30 minutes

• Balance exercise

• Bracing/stretching based on individual needs

• Night splinting

• Lower limb orthoses – if needed to maximizefunction

• Thoracic bracing may be used to promote posture in sitting

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Rehabilitation – A New Dilemma

• A new phenotype

• With novel effective treatment options, children with SMA can now be expected to make gains in motor skills and function

How do we get sitters to stand??

How do we get standers to walk??

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The Problem• Development is a sequence one skill builds on the development

of the next

Early strength deficits limit the developmental sequence during critical periods of development

• Learning any motor skill requires practiceo Children between 12-19 mos of age take an average of 2,300

steps a day! (Adolph, 2012)

Children with SMA can’t support their own body weight so they can’t practice standing or walking

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A Solution -In-home Body Weight Support Harness System (BWSS)

• Portable Mobility Aid (PUMA) – engineered by Enliten, LLC

• Standing

• Walking

• Changing positions

PRACTICE! PRACTICE! PRACTICE!

Relieves desired amount of body weight to allow practice for:

• Building strength

• Exploring environment

• Interacting with others

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Spinal Muscular Atrophy:Outcome Measures

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Outcomes for SMA• CHOP Intend

• ACTIVE-mini

• Hammersmith Functional Motor Scale – Expanded/Revised

• 6MWT

• Revised Upper Limb Module (RULM)

• ACTIVE

• Bayley-III

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CHOP Intend

• Scale developed specifically for use in SMA I• Items adapted from TIMP, but adapted scoring to

reduce floor effect in SMA I

• 16-item scale; score both right & left sides• Best effort for R & L used to calculated total

score• Maximum score = 64 points

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CHOP Intend

Scores 0 – 4 pts

• 0 = limited/no movement

• 4 = strongest movement

Brazelton state 4 & 5 ideal

for testing

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CHOP Intend

Recent (N=4)Chronic (N=13)

• Mean change = -1.27 pts per year

Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014;83(9):810-7.

• Mean change = -10.71 pts over 12 months• Greatest change in first 12 months of study• Plateau in score beyond 12 months

Kolb SJ, Coffey CS, Yankey JW, et al. Natural history of infantile-onset spinal muscular atrophy. Ann Neurol. 2017;82:883-891.

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CHOP Intend considerations

• Developed to measure decline as a result of natural history in SMA I

• Ceiling effect in treated cohorts

• Implications for use in a chronic adult population

• Development of the CHOP ATEND

• Prolonged use in clinical trials:

• Cooperation as children age

• Reflexive versus voluntary movements

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ACTIVE - mini

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ACTIVE-mini v. VICON

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0-90 days of age

>90 days of age

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Individual subjects

ACTIVE-mini

ControlSMA

Multivariate analysis

0-90 days

91-180 days

Accuracy 98 95

Sensitivity 100 100

Specificity 91 69

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Comparison to CHOP Intend (Extremities Scale)Bag of Words (BoW)• Cluster analysis to identify 100 vectors for each feature• Frequency of each feature

Least Absolute Shrinkage and Selection Operator (LASSO) / Elastic Net Regression• Best fitting regression line (reduces variables & reduces over correlation)

Leave One Out Prediction Modeling

• Predict 1 recording using the remaining dataset• This is repeated until all recordings have generated a predicted score

ACTIVE-mini

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ACTIVE-mini

Actual Score Predicted Score

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ICC: 0.945, p <0.001Wilcoxon p=0.729

Mean = 6.4 ± 5.1Median = 5.0 (0 – 24) Mode = 3

ACTIVE-mini

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ACTIVE-mini considerations

• Requires an infant/child to remain in supine during recording

• Unable to record if a child rolls or crawls out from under camera

• Continued validation of current algorithms in a larger cohort

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Hammersmith• Hammersmith Functional Motor Scales - Expanded• 33 item scale• SMA II & III• Scores 0 – 2 scale

0 = unable1 = compensation2 = able

• Maximum score = 66 pts

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Revised Hammersmith• 36 item scale• SMA II & III• Scores 0 – 2 scale

0 = unable1 = compensation2 = able

• Maximum score = 69 pts• 2 timed items

• Timed to rise• 10 meter walk

Ramsey D, Scoto M, Mayhew A, et al. Revised Hammersmith Scale for spinal muscular atrophy: a SMA specific clinical outcome assessment tool. PLoS One. 2017;12(2):e0172346.

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HFMS-E Revised

Sivo S, Mazzone E, Antonaci L, et al. Upper limb module in non-ambulant patients with spinal muscular atrophy: 12 month changes. Neuromuscul Disord. 2015;25:212-215.

• N = 74• SMA II (+4 patients SMA III who lost ambulation)• Mean change over 12 months = -0.35 points

Ramsey D, Scoto M, Mayhew A, et al. Revised Hammersmith Scale for spinal muscular atrophy: a SMA specific clinical outcome assessment tool. PLoS One. 2017;12(2):e0172346.

• N = 138• SMA II & III• Longitudinal collection ongoing

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Hammersmith considerations• Challenging for some patients with SMA II

• Floor effect in untreated cohorts – difficult measuring small improvements

• Use CHOP ATEND?

• Small change over 12 months – sensitive to change?

• May not be function as a stand alone assessment incertain functional groups

• Difficult to implement in young children – direction following

• Currently used in children >2 years of age

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6 minute walk test (6MWT)

6 minute walk test Developed for adult cardio-thoracic testing; adapted in DMD and SMA

Self-selected walking speed; no running permitted

Designed to measure endurance

McDonald CM, The 6-minute walk test as a new outcome measure in Duchenne muscular dystrophy. Muscle Nerve. 2010;41:500-10.Montes J, McDermott MP, Martens WB, et al. Six-minute walk test demonstrates motor fatigue in spinal muscular atrophy. Neurology. 2010;74:833-838.

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6MWT

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Spinal muscular atrophy

Montes J, McDermott MP, Martens WB, et al. Six-minute walk test demonstrates motor fatigue in spinal muscular atrophy. Neurology. 2010;74:833-838.

9.5m difference between 1st & 6th minute (P=0.0003)

Montes J, McDermott MP, Mirek E, et al. Ambulatory function in spinal muscular atrophy: age-related patterns of progression. PLoS One. 2018;13(6):e0199657.

Overall -7.8m change per yearDifferent trajectories related to age

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6MWT considerations

• Only useful in ambulatory populations

• Data loss if ability to walk is lost

• Motivation/consistency of performance in younger cohorts

• Shorter test of a fixed distance may be useful in young patients

• Order of testing is important if expecting to capture fatigue consistently

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Revised Upper Limb Module

Upper Limb Module (2011)

• 9 items

• Scores 0 – 2 scale

0 = unable

1 = compensation

2 = able


Revised Upper Limb Module (2017)

• 20 items

• Scores 0 – 2 scale

0 = unable

1 = compensation

2 = able


Mazzone ES, Mayhew A, Montes J, et al. Revised upper limb module for spinal muscular atrophy: development of a new module. Muscle Nerve. 2017;55(6):869-874.

Mazzone E, Bianco F, Martinelli D, et al. Assessing upper limb function in nonambulant SMA patients: development of a new module. Neuromuscul Disord. 2011.

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ULM ULM v RULM

Sivo S, Mazzone E, Antonaci L, et al. Upper limb module in non-ambulant patients with spinal muscular atrophy: 12 month changes. Neuromuscul Disord. 2015;25:212-215.

• N = 74• SMA II (+4 patients SMA III who lost ambulation)• Mean change over 12 months = -0.04 points

• N = 42 (3 to 71 years)• SMA II & III• Correlation > 0.90

Mazzone ES, Mayhew A, Montes J, et al. Revised upper limb module for spinal muscular atrophy: development of a new module. Muscle Nerve. 2017;55(6):869-874.

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RULM considerations

• Ceiling effect in stronger patients

• Useful in measuring decline as a result of disease progression

• May have less utility in measuring change in stronger, treated cohorts

• Quick test that can be easily implemented

• Can be part of a battery of testing versus a standalone assessment

ACTIVE

Need for a valid & reliable measure of upper extremity function in DMD for use in both clinical and research environments

• Continuous scale variables

• Minimal training required

• Consistent motivation

• Reduce variability

• Utility across the disease spectrum

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• Quantifies accessible/reachable area

• Relevant across spectrum of function

• Allows compensatory movements used for functional movement

• Trunk lean

• Expected to relate to function as functional tasks require a discrete amount of space • Dressing

• Eating

• Typing

Confidential – not to be reproduced

ACTIVE (Abilities Captured Through Interactive Video Evaluation)

9/19/2018

19

AC

TIV

E s

core

300

200

100

0

Brooke levelP-value <0.001 using Jonckheere-Terpstra test for trend

ACTIVE

1 23 4 5 6

Trunk Movement (cm3 )Brooke Median IQR

0 1399.7 (918, 1943)1 482.7 (255, 675)2 119.6 (54, 216)3 54.4 (0, 129)4 0.8 (0, 3)5 0.2 (0, 0.6)

• Ambulant cohorts have better trunk strength & can lean and reach farther

• Non-ambulant cohorts with the same Brooke level (1 or 2) score lower due to ↓ trunk strength and lesser ability to lean

AC

TIV

Esc

ore

**P<0.001

ACTIVE

• Treated cohort mean change = 33 ± 23 pts• Untreated cohort mean change = -3 ± 8 pts

All treated patients improved beyond the MCID (10.9 pts) whereas no untreated patients surpassed this threshold

Preliminary clinical data suggests ACTIVE can measure change as a result of Spinraza treatment in SMA II & III

Treated patients IMPROVE meaningfully over time while untreated patients decline

Spinal muscular atrophy

ACTIVE

9/19/2018

20

………………..……………………………………………………………………………………………………………………………………..

Confidential – not to be reproduced

ACTIVE

• Highly correlated to other functional measures

• Potential to reduce floor & ceiling

• Useful across the spectrum of function

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ACTIVE considerations

• Useful across the spectrum of function

• Completed reliably from 3 to 4 years of age

• Skeletal tracking algorithm was designed for adolescent proportions

• Can be completed in a wheelchair – not requiring transfer

………………..……………………………………………………………………………………………………………………………………..

Bayley-III

• Clinical trial use

• Unprecedented improvements in gross motor abilities

• Comparison of SMA I to normative peers

• Cognitive & language subtests to predict the potential for quality of life

• Children are continuing to develop & gain milestones

Documents

IC29 Alfano SpinalMuscularAtrophy Handout Slides Only … · 2018. 10. 12. · Ventilation in Most Children with Type 1 SMA: Natural History NeuroNext2 PNCR study1 50% survival 10.5