10/15/2018 - aacpdm€¦ · prednisolone 1 mg/kg 1 day pre-gt trial design open -label, dose...

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Spinal Muscular Atrophy:A new era of evaluation and treatment

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

Neuromuscular Physical Therapy

Nationwide Children’s Hospital

Center for Gene Therapy & Clinical Therapies

Columbus, OH

FINANCIAL DISCLOSURE

AACPDM 72nd Annual Meeting

October 9-13, 2018

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

1. Disclosure of Relevant Financial Relationships

Nationwide 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 SMN2Butchbach MER, Burghes AHM. Perspectives on models of spinal

muscular atrophy for drug discovery. Drug Discovery Today: Disease

Models. 2004. Vol 1(2):151-156. ………………..……………………………………………………………………………………………………………………………………..

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 Classification

Type 0: fetal onset

Type 1:

1a: weakness, feeding difficulty, respiratory insufficiency within 2 weeks

1b: onset of weakness by 3 months

1c: 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 years

3b: 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. ………………..……………………………………………………………………………………………………………………………………..

Clinical Features

• 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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Clinical Features

Type I(generally 2 copies SMN2)

Type II(generally 3 copies SMN2)

Type III(generally 4 or more copies SMN2)

Videos courtesy of Wendy King

• Minimal to no anti-gravity movement

• No milestone achievement

• Bell-shaped chest

• Paradoxical breathing pattern

• Achieve ability to sit

• May lose this ability with growth and

decreased strength

• Achieve independent walking

• May lose this ability with growth and

decreased strength

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Historical Clinical Presentation

Born 1980-1994

Born 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 ventilatory

assistance

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

.

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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

https://www.spinraza-hcp.com/en_us/home/dosing.html………………..……………………………………………………………………………………………………………………………………..

Spinraza®

Finkel RS et al. N Engl J Med 2017;377:1723-1732. E Mercuri et 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 = 121

Randomized 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 = 126

Randomized 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® experience in our clinic

MCID – distribution-based method

• 1/3 standard deviation = 10.9 points

• SEM=[baseline SD*√(1-r)] = 4.2 points

Change in our cohort (N=50):

• Treated median change = 15.9 pts

Range: 13-66 pts

• Untreated median change = -6.4 pts

Range: -11– 6 pts

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Spinraza® Safety

Coagulation 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

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https://www.spinraza.com/en_us/home/resources/video-library.html

Spinraza treatment centers: https://www.spinraza.com/en_us/home/resources/treatment-locator.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 cordRecombinant 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

https://www.spinraza.com/en_us/home/resources/treatment-locator.html

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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 Administration

One-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 1

Study Site

OBJECTIVES

Primary• Safety and Tolerability

Secondary

• 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 joints

Exclusion• 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 discret ion of their physician or study staff.

*key developmental milestone

achievements assessed and adjudicated by external independent reviewer

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 il lness; 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 Visit

Cohort 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 RollaSitting with assistance

Sitting Unassisted

≥ 5 secondsb ≥ 10 secondsc ≥ 30 secondsd

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

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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0

10

20

30

40

50

60

0 5 10 15 20 25 30

CH

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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 assessments

Black 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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Ongoing clinical trials

Type I:

• STR1VE: NCT03306277 (no longer enrolling)

• STR1VE-EU: NCT03461289

Type II:

• STRONG: NCT03381729

All types: presymptomatic

• SPR1NT: NCT03505099

https://clinicaltrials.gov

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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/

https://clinicaltrials.gov/

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Roche, PTC, & SMA Foundation• Risdiplam (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/Δ7 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………………..……………………………………………………………………………………………………………………………………..

Spinal Muscular Atrophy:Clinical Care Considerations

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Newborn Screening

SMA added to Recommended Uniform Screening Panel (RUSP) in United States

Decision of which diseases are included in newborn panel lies with each state

Adopted by 7 states: Ohio, Illinois, Indiana, Minnesota, Missouri, New York, and Utah

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Facilitating Access to SMA Therapies (FAST) at Nationwide Children’s Hospital

SpinrazaFDA

Approval

• Nationwide Children’s Hospital was not a trial location for Spinraza, therefore the program had be to built from the ground up

• P&T approval with requirement for buy and bill 2/2/2017

• Multidisciplinary teams in finance and clinical departments were formed to created, develop, implement, and monitor drug administration

Requestsfor

Medication

Appointments Made

Decision to Treat with Spinraza

• Decision to treat with Spinraza made together with family and SMA team

• Physical Therapy motor evaluation to take place during regular clinic appointments

• Each patient and their treatment plan is looked at individually

Therapy Plan

Placed

TreatmentStarted

• First Spinraza injection at Nationwide Children’s Hospital 2/28/2017• 8 patients started by the end of March 2017• Treatment provided to 50 patients; Types 1- 3, ages <1 to 23, at three separate settings within the hospital

• Decision to add an additional SMA clinic was made to accommodate the increased need, therefore allowing clinic capacity to be doubled• Additional staffing needed to accommodate patient load and Spinraza therapy demands

• Initiation of therapy plans to aid staff in the monitoring of all aspects of Spinraza

• One time order set to account for multiple order placed at specific intervals to release orders

• Decreased time spent ordering, decreased need for spreadsheets to track prior authorizations and appointments

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FAST

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Initial authorization varies based on provider but typically

includes:

• Confirmatory genetic diagnosis using SMN1 copy

number or molecular genetic testing of 5q SMA

• Documentation of baseline levels of function

Different payers have different policies for coverage

Payer Reimbursement

NOT ALWAYS STATED BUT NECESSARY

FOR CONTINUATION OF THERAPY

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Reimbursement Policies

Continued authorization of Spinraza® therapy based on

variable language based on provider

General

Improvement

Specific

Quantified

Improvement

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SMA Clinical Care

Current 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

• No longer expected natural history

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Multidisciplinary Care

• Recommended approach for

treated and untreated

individuals.

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Treatment ≠ Cure

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Pulmonary considerations:

Treated cohorts:

Nusinersen

• 39% reached endpoint of death or permanent assisted ventilation (risk 47% lower in treated cohort compared to control)

AVXS-101

• 10 of 12 patients required at least 1 hospitalization for respiratory distress infections (mean = 2.1)

• 7 of 10 patients not requiring BiPap at enrollment continue without BiPap support

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Pulmonary

Assessment Intervention Care considerations

• Physical Exam

• Hypoventilation

• Sleep study or pneumogram

• Gastroesophageal reflex

• Support airway clearance

• Oral suctioning

• Manual chest therapy

• Cough Assist

• Support ventilation with BiPAP

• Nebulized bronchodilators

• Customary immunizations,

• Palivizumab through 24

months

• Influenza annually after 6

months of age

• Assessments every 3-6 months

• Use of suctioning, physiotherapy and cough assist

is critical to all non-sitters

• Ventilation started in all symptomatic patients-

even before respiratory failure

• BiPAP masks fitted by skilled therapists and select

2 interfaces with different skin contact points

• Mucolytics should not be used long-term

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Pulmonary


• Physical Exam

• Spirometry

• Sleep study or pneumogram

• Gastroesophageal reflex

• Support airway clearance

• Physio/respiratory therapy

• Manual chest physiotherapy

• Cough Assist

• Support ventilation with BiPAP as

needed

• Nebulized bronchodilators

• Customary immunizations

• Influenza

• Pneumococcal

• Assessments every 6 months

• Airway clearance is critical to those with ineffective

cough

• Ventilation started in all symptomatic patients-

even before respiratory failure

• BiPAP fitted by skilled therapists and select 2

interfaces with different skin contact points

• Mucolytics should not be used long-term

Sit

ters

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Pulmonary


• Clinical exam with review of

cough effectiveness

• Detailed search for signs of

nocturnal hypoventilation

• Supportive care when needed

• Customary immunizations

• Influenza

• Pneumococcal

• Evidence of weak cough or recurrent infections or

suspicion of nocturnal hypoventilation should

prompt referral to pneumologist

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Pulmonary Toolkit

Cough Assist

www.phillips.ca

Suction

www.medline.com

BiPAP

www.medline.com

Chest Physiotherapy

www.mountnittany.org

The Vest

www.medafore.com

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Passenger Safety

Cure SMA recommends a car bed for all babies with type I

Limited resources on use in SMA May not always be most appropriate or safest option

Car bed may be indicated when• Cardiorespiratory safety at risk in semi-reclined position (apnea,

O2 desaturation)

• Poor head control airway occlusion

Certified Passenger Safety Technician with

specialized training in Safe Travel for All Children………………..……………………………………………………………………………………………………………………………………..

Nutrition considerations

Treated cohorts:

Nusinersen

• Some needed continued feeding support

AVXS-101

• 11 of 12 patients feeding orally, 6 exclusively fed by mouth

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Orthopedic considerations

Both SMA III

Difference in function occurred post-spinal fusion

Videos courtesy of Wendy King

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Rehabilitation


• 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

• Use of TLSO (with abdominal cutout) may be

helpful for sitting activities – not intended to

reduce scoliosis progression

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Rehabilitation



• 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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Rehabilitation


• 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 maximize

function

• Thoracic bracing may be used to promote

posture in sitting

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Maximizing Therapeutic Benefit

• 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 practice

o 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………………..……………………………………………………………………………………………………………………………………..

Facilitating Access to SMA Therapies (FAST) at Nationwide Children’s Hospital

SpinrazaFDA

Approval

• Nationwide Children’s Hospital was not a trial location for Spinraza, therefore the program had be to built from the ground up

• P&T approval with requirement for buy and bill 2/2/2017

• Multidisciplinary teams in finance and clinical departments were formed to created, develop, implement, and monitor drug administration

Requestsfor

Medication

Appointments Made

Decision to Treat with Spinraza

• Decision to treat with Spinraza made together with family and SMA team

• Physical Therapy motor evaluation to take place during regular clinic appointments

• Each patient and their treatment plan is looked at individually

Therapy Plan

Placed

TreatmentStarted

• First Spinraza injection at Nationwide Children’s Hospital 2/28/2017• 8 patients started by the end of March 2017• Treatment provided to 50 patients; Types 1- 3, ages <1 to 23, at three separate settings within the hospital

• Decision to add an additional SMA clinic was made to accommodate the increased need, therefore allowing clinic capacity to be doubled• Additional staffing needed to accommodate patient load and Spinraza therapy demands

• Initiation of therapy plans to aid staff in the monitoring of all aspects of Spinraza

• One time order set to account for multiple order placed at specific intervals to release orders

• Decreased time spent ordering, decreased need for spreadsheets to track prior authorizations and appointments

REMINDER:

• Documentation of baseline function & maintained/improved function is

not always stated in payer policies but is necessary for continuation of

therapy

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

Spinal Muscular Atrophy:Outcome Measures

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

Accessing outcomes for SMA

• CHOP-Intend http://columbiasma.org/edu.html

• Neuromuscular GRO [email protected]

• ACTIVE-mini [email protected]

• ACTIVE [email protected]

• Hammersmith Functional Motor Scale – Expanded/Revised

http://columbiasma.org/edu.html

• 6MWT

• Revised Upper Limb Module (RULM) http://columbiasma.org/edu.html

• Bayley-III – Pearson Clinical website


mailto:[email protected]





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14

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

What are the best tires?One size does not fit all:

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

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

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

CHOP Intend

Scores 0 – 4 pts

• 0 = limited/no movement

• 4 = strongest movement

Brazelton state 4 & 5 ideal

for testing

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

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

• Prolonged use in clinical trials:

• Cooperation as children age

• Reflexive versus voluntary movements

• Implications for use in a chronic adult population

• Development of the CHOP ATEND

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

Ceiling effect in treated cohorts

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

Same score, clearly improved function

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

Cooperation/reflexive

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

CHOP ATEND

Consistent evaluations of feeding

Young kids treated later may need tube feeding

to get them over the hurdle and gain the weight

needed

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

Hammersmith http://columbiasma.org/edu.html

• Hammersmith Functional Motor Scales - Expanded

• 33 item scale

• SMA II & III

• Scores 0 – 2 scale

0 = unable

1 = compensation

2 = able

• Maximum score = 66 pts

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

Revised Hammersmith

• 36 item scale

• SMA II & III


0 = unable

1 = compensation

2 = able


• 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.

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

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 useful as a stand alone assessment in

certain functional groups

• Difficult to implement in young children – direction following

• Currently used in children >2 years of age………………..……………………………………………………………………………………………………………………………………..

Hammersmith exampleChallenges implementing in younger children:

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

Hammersmith exampleChallenges implementing in younger children:

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

Neuromuscular GRO- In Progress

Intended for use from birth to adult

46 items scored• 0 = unable

• 1 = partially achieved

• 2 = achieved

Items listed in developmental order

from supine to standing activities

Potential to serve as a continuous scale across functional abilities

Confidential – not to be reproduced

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

Neuromuscular GRO:Initial Validation

Type I: mean = 17 points

Type II: mean = 31 points

Type III: mean = 54 points

Nonsitter: mean = 13 points

Sitter: mean = 39 points

Ambulant: mean = 75 points

SMA type Function

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

Mock scoring #1CHOP Intend

Neuromuscular GRO

HFMSE/RHS

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

Mock scoring #2

CHOP Intend

HFMSE/RHS

• No available items to score - floor

Neuromuscular GRO

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

Mock scoring #3CHOP Intend

• No available items to score - ceiling

Neuromuscular GRO

HFMSE/RHS

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

ACTIVE - mini

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

ACTIVE-mini v. VICON

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

0-90 days of age

>90 days of age

Cert

ain

ty o

f g

roup

assig

nm

ent

Individual subjects

ACTIVE-mini

Control

SMA

Multivariate analysis

0-90

days

91-180

days

Accuracy 98 95

Sensitivity 100 100

Specificity 91 69

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

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

ICC: 0.945, p <0.001

Wilcoxon p=0.729

Mean = 6.4 ± 5.1

Median = 5.0 (0 – 24)

Mode = 3

ACTIVE-mini

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

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

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

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

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

6MWT

Minutes

Perc

ent

change

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

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

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

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

Revised Upper Limb Module

Upper Limb Module (2011)

• 9 items


0 = unable

1 = compensation

2 = able


Revised Upper Limb Module (2017)

• 20 items


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.

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

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

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

• 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


ACTIVE (Abilities Captured Through Interactive Video Evaluation)

10/15/2018

23

AC

TIV

E s

co

re

300

200

100

0

Brooke level

P-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)

1 2 3 4 5

0

1 0 0

2 0 0

3 0 0

4 0 0

5 0 0

6 0 0

7 0 0

8 0 0

9 0 0

B ro o k e L e v e l

Tru

nk

Mo

ve

me

nt

(cu

bic

cm

)

• 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

Escore

**P<0.001

ACTIVE

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


ACTIVE • Highly correlated to other

functional measures

• Reduces floor & ceiling

• Useful across the spectrum of

function

• Responsive to change

3 4 5 6 7 8 9 1 0 1 1 1 2

-1 0

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

S u b je c t

Ch

an

ge

in

sc

ore

A C T IV E

H F M S E

R U LM

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

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

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

In case you missed it……

Accessing outcomes information:

Email: [email protected]

• ACTIVE

• ACTIVE-mini


• CHOP Intend

• HFMS-E or revised

• RULM

Bayley-III – Pearson Clinical website

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

Questions

[email protected]

[email protected]

[email protected]

[email protected]

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

Nationwide Children’s Hospital

Neuromuscular Team:Jerry Mendell, Kevin Flanigan, Garey Noritz, John Kissell, Megan Waldrop, Albert Tsao,

Rachel Schrader, Jeannie Toops

Participants: Children and families from Nationwide Children’s Hospital

AcknowledgementsOutcome Measures Research Team

Linda Lowes, Lindsay Alfano,

Natalie Miller, Megan Iammarino

Maggie Dugan







10/15/2018 - aacpdm€¦ · prednisolone 1 mg/kg 1 day pre-gt trial design open -label, dose...

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