Evolving therapeutic landscape for inherited neurologic disorders

Kathryn Swoboda, MD HMS Child Neurology Course

September 5 2017

Disclosures I’ve received funding as a consultant for Biogen for clinical trial development

I’m the PI recipient for clinical trial contracts:

•  Biogen (NURTURE: phase 2 trial in presymptomatic infants with Spinal Muscular Atrophy at MGH)

I’m the PI recipient of funding from the National Institutes of Child Health and Development, Cure SMA, Biogen

I’m a member of the Scientific Advisory Board for the Alternating Hemiplegia of Childhood Foundation and Cure SMA

Overview Overview of evolving and emerging landscape of therapies for rare inherited neurologic disorders •  Enzyme replacement therapies targeting CNS or systemic

manifestations of disease (Fabry disease, Pompe; Mucopolysaccharidoses types I, II, IVa, VI; late infantile Neuronal Ceroid Lipofuscinosis (CLN2)

•  Adjuvent therapies: gemfibrozal for NCL •  Hematopoetic Stem Cell Transplantation therapies !  X-ALD, Krabbe !  Also increasingly for autoimmune neurologic diseases

including MS •  Antisense oligonucleotide targeted therapy for Spinal

Muscular Atrophy and Spinocerebellar Ataxia type II •  Gene Therapy for Spinal Muscular Atrophy, Neuronal Ceroid

Lipofuscinosis (Batten disease due to CLN6)

New Opportunities for Child Neurologists

To engage synergistically with our clinical genetic colleages

To embrace advances in genomic testing; genetic counselors as collaborative colleagues critical to this process

To become primary or secondary providers in treating and managing patients with rare inherited neurologic disorders

To become engaged in presymptomatic diagnosis and followup of newborns at risk for rare inherited neurologic disorders and to play a major role in enhancing diagnosis and care paradigms (Ataxia-telangiectasia)

SMA Background !  Most common inherited cause of infant mortality

!  Characterized by the progressive degeneration of the anterior horn cells resultant muscle atrophy and weakness

!  Autosomal recessive inheritance !  1 in ~40 carrier frequency (8-57 in various ethnic

and population cohorts) !  1 in ~10,000 live births

!  Affects all racial and ethnic groups !  lower carrier frequency in Africans

Smith et al, Eur J Hum Genet, 2007 15:759. Hendrickson BC et al, J Med Genet. 2009 September; 46(9): 641–644.

Broad Spectrum of Clinical Manifestations

SMA Type

Age of Onset

Typical Life Span

Formerly Called Clinical Characteristics/Milestones

0 Prenatal

<6 months

Congenital arthrogryposis multiplex congenita

No milestones achieved Severe weakness Early respiratory failure

I Birth-6 months

<2 years Werdnig-Hoffman Severe infantile form of SMA Never sits without support Early respiratory failure Accounts for >50 % cases

II 6-12 months

70% alive at 25 years

Dubowitz Independent sitting loss of this ability by mid-teens

III After 12 months

Normal Kugelberg-Welander Ambulation, with loss of this ability as disease progresses

IV Adult-hood

Normal Ambulation, with loss of this ability as disease progresses

Adapted from www.genetests.org: Prior, TW and Russman BS, Spinal Muscular Atrophy, www.geneclinics.org/profiles/sma. 2006.

SMA type I, “Werdnig-Hoffman”

!  Rapid development of geneneralized weakness, respiratory and bulbar insufficiency in early infancy, average ons !  Severe respiratory morbidity or mortality in 70% by age 2 yrs

SMA type II “Dubowitz” type

SMA type III “Kugelberg-Welander”

Incidence and Prevalence of SMA subtypes

Type 1 58%

Type 2 29%

Type 3 13%

Type 4 <1%

Type 1 12%

Type 2 52%

Type 3 36%

Type 4 <1%

Incidence Prevalence

Genetics of SMA !  Caused by mutations in the survival of the motor neuron (SMN1)

gene

!  Full-length (FL) SMN protein is produced normally from SMN1 gene

!  90% of SMN2 gene transcript undergoes alternative splicing leading to truncated, dysfunctional SMN protein that lacks exon 7 (Δ7SMN)

!  Number of SMN2 gene copies affects disease severity

11

Predicting phenotype from genotype

Predicting phenotype from genotype

SMN1=0, SMN2=2

SMN1=0, SMN2=3 SMN1=0, SMN2=3

BIOMARKERS and TREATMENT

Critical need for predictive biomarkers in the neonatal period

!  Most present within first 2 yrs of life !  > 60% by 6 months !  > 85% by 24 months

!  Majority of patients (SMA I and II) with serious denervation and disability by age 5-6 yrs

!  Limited window for therapeutic intervention !  pre-symptomatic or early

symptomatic treatment likely required for best outcomes

Best current predictive biomarkers of outcomes in SMA*

!  SMN genotype !  SMN2 dosage > 2 remains the most potent disease

modifier at the population level

!  Neurophysiologic Outcome Measures !  Ulnar CMAP, measure of distal denervation

!  New data soon to be published from the Neuronext SMA biomarker study - confirms prior markers and identifies new potential candidates from initial SMA-MAP platform

*Relative to ability to distinguish the severe infantile form from intermediate or mild forms, thereby potentially facilitating early intervention

Ulnar CMAP and MUNE in SMA correlate with SMA type and motor function*

!  Surface electrodes MUNE studies via surface multipoint technique (Brown)

•  Ulnar nerve

•  Hypothenar eminence

!  CMAP

•  Supramaximal

•  min 3-6 placements

*Swoboda KJ, Prior TW, Scott CE et al. Ann Neurol 2005;57:704-712

Cohort I vs II: CMAP vs age

Precipitous and progressive denervation 0-6 months in cohort I Markedly slower denervation 0-6 months in cohort II, more variable

Comparison of SMN levels in whoole bloodfrom SMA patients ages 6 years and older in

relation to SMN2 copy number.

2 Copies

3 copies

4 copies0

5000

10000

15000

20000

25000

SMN

(pg/

ml w

hole

bloo

d)

In collaboration with Roche, Pharmoptima and SMA Foundation

Comparison of SMN levels in whole blood from SMA patients ages 6 years and older in relation to

SMN2 copy number

Evolving Treatment Landscape for SMA

!  AAV9-SMN gene therapy (AveXis and others

!  NURTURE STUDY (Biogen) Clinical trial directed at presymptomatic type I or type II infants – must be enrolled < 6 weeks of age, receive antisense oligonucleotide therapy

!  ENDEAR STUDY Sham control trial critical for FDA approval of nusinersen (SPINRAZA)

!  CHERISH STUDY Clinical trial directed at late onset patients with SMA to assess efficacy and safety

"  Antisense oligonucleotide based therapy also known as ISIS-339443, nusinersen approved Dec. 23, 2016 by FDA

Mechanism of Nusinersen

Chiriboga et la., American Academy of Neurology 2016

#  ASO designed to bind to the target hnRNP-A1/A2 dependent splicing silence, in intron 7 of the SMN2 pre-mRNA.

#  It facilitates accurate splicing of SMN2 transcripts and resulting in increased production of full-lenth SMN protein.

Intrathecal ASO Drug Delivery !  Nusinersen is delivered by intrathecal injection as ASOs do not

cross an intact BBB.

!  ASO distribute broadly into spinal cord and specific brain tissues following intrathecal delivery.

!  ASO has a long half-lives (several months) in CNS tissue, with even longer duration of action, so enables infrequent dosing.

IHC against drug in monkey spinal cord following intrathecal delivery of ASO

NURTURE Study Design •  Phase 2, open-label, multicentre, multinational, single-arm study in 10

countries -  Objective: to evaluate the efficacy and safety profile of intrathecal nusinersen in

infants with genetically diagnosed and pre-symptomatic SMA

-  Enrollment completed: 25 infants

CMAP = compound muscle action potential.

Screening period

(≤21 days)

Dosing schedule

D868 post-treatment follow-up visit

4 induction doses with follow-up evaluations

Maintenance dose and follow-up evaluation every 119 days

D1 D15 D29 D64 D183 D302 D421 D540 D659 D778

Nusinersen 12-mg scaled equivalent dose

Key inclusion criteria: •  Age ≤6 weeks at first dose •  Pre-symptomatic •  Genetic diagnosis of 5q SMA gene deletion/

mutation •  Gestational age, 37–42 (34–42 for twins)

weeks •  2 or 3 SMN2 copies •  Ulnar CMAP amplitude ≥1 mV at Baseline

Key exclusion criteria •  Hypoxemia (O2 saturation of <96% awake or

asleep at sea level) •  Infection during Screening period or ongoing

medical condition incompatible with study procedures/ assessments

Study Endpoints !  Primary

!  Time to respiratory intervention (invasive or non-invasive ventilation for ≥6 hours/day continuously for ≥7 days or tracheostomy) or death

!  Secondary

!  Safety, tolerability and pharmacokinetics

!  Effect on development of SMA by assessing clinical milestones

!  Ability to crawl, stand or walk

!  Motor function milestones

!  Assessed using CHOP INTEND,1 HINE2 and WHO3

!  Survival (proportion of patients alive)

!  Growth parameters

CHOP INTEND = Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; HINE = Hammersmith Infant Neurological Examination; WHO = World Health Organization. 1. Haataja L, et al. J Pediatr. 1999;135(2 Pt 1):153-161. 2. WHO Multicentre Growth Reference Study Group. Acta Paediatr Suppl. 2006;450:86-95. 3. Glanzman AM, et al. Neuromuscul Disord. 2010;20(3):155-161.

Interim Analysis: Baseline Characteristics

Characteristic 2 SMN2 copies

n=12a 3 SMN2 copies

n=5 Total n=17

Age at first dose, d, n (%)

≤14 5 (42) 1 (20) 6 (35)

>14 to ≤28 5 (42) 2 (40) 7 (41)

>28 2 (17) 2 (40) 4 (24)

Median (range) 17.0 (8–41) 24.0 (12–42) 19.0 (8–42)

Male, n (%) 8 (67) 3 (60) 11 (65)

Female, n (%) 4 (33) 2 (40) 6 (35)

North America 7 (58) 5 (100) 12 (71)

Europe 3 (25) 0 3 (18)

Asia-Pacific 2 (17) 0 2 (12)

Mean CHOP INTEND total score Median (range; n)b

48.9 45.0 (39.0–60.0; 9)

53.5 57.0 (40.0–60.0; 4)

50.3 55.0 (39.0–60.0; 13)

Mean HINE total motor milestones Median (range; n)b

2.3 3.0 (0–4.0; 9)

4.8 4.5 (3.0–7.0; 4)

3.1 3.0 (0–7.0; 13)

Mean ulnar CMAP amplitude Median (range; n), mVb

2.42 2.3 (1.0–4.2; 9)

3.95 4.1 (2.7–4.9; 4)

2.89 3.0 (1.0–4.9; 13)

Mean peroneal CMAP amplitude Median (range; n), mVb

2.76 2.8 (1.1–4.2; 7)

4.35 4.2 (4.0–5.0; 4)

3.34 3.4 (1.1–5.0; 11)

NURTURE study interim analysis data cutoff date: 8 June 2016. aIncluded 1 set of twins each with 2 copies of SMN2. bBased on efficacy set of patients who completed Day 64 visit or longer (n=13). 7

Primary Endpoint: Time to Death or Respiratory Failurea

!  At the time of the interim analysis, infants had been enrolled for up to ~13 months

!  All infants were still alive !  No infants have required invasive ventilation or

tracheostomy !  No infants have required non-invasive ventilation for ≥6 hours/day continuously for ≥7 days

NURTURE study interim analysis data cutoff date: 8 June 2016. aRespiratory failure was defined as invasive or non-invasive ventilation for ≥6 hours/day continuously for ≥7 days or tracheostomy. 8

HINE Motor Milestones (Max: 26 points)

0 pts 1 pts 2 pts 3 pts 4 pts

3 pts

3 pts

4 pts

3 pts

4 pts

3 pts

4 pts

2 pts

0

2

4

6

8

1 0

1 2

1 4

1 6

1 8

2 0

2 2

2 4

2 6

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

Mean HINE Total Motor Milestone Score Over Time

Mea

n (

SE)

HIN

E t

otal

mot

or

mile

ston

e sc

ore

Study visit day

2 SMN2 copies

3 SMN2 copies

Total

#  In general, all enrolled infants demonstrated increased motor milestone scores from Baseline to last evaluation

-  Milestone gain followed a similar trajectory for infants with 2 and 3 copies of the SMN2 gene

-  Maximal total score on HINE is 26 points by 15 months of age

Maximum total score, 26 points

45

50

55

60

65

1 64 183 302 365

Mean CHOP INTEND Total Score Over Time

Mea

n (

SE)

CH

OP

IN

TEN

D

tota

l sc

ore

Study visit day

2 SMN2 copies

3 SMN2 copies

Total

#  10/13 (77%) infants achieved increases (range, 4–20 points)

#  3/13 (23%) experienced decreases (range, 2–3 points) #  Baseline median (range) CHOP INTEND total score was 55.0 (39–60) points in the

total efficacy population

-  CHOP INTEND total scores in infants with SMA ≤6 months of age from a natural history study ranged from 10–52 points1

Maximum total score, 64 points

1. Kolb SJ, et al; NeuroNEXT Clinical Trial Network and on behalf of the NN101 SMA Biomarker Investigators. Ann Clin Transl Neurol. 2016;3(2):132-145. NURTURE study interim analysis data cutoff date: 8 June 2016.

Mean Ulnar and Peroneal Nerve CMAP Amplitude Over Time

!  Overall, mean CMAP amplitude appears to be increasing

2

4

6

8

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

Mea

n (

SE)

CM

AP

uln

ar

amplit

ude,

mV

Study visit day

2 SMN2 copies 3 SMN2 copies Total

1. Miller RG, Kuntz NL. J Child Neurol. 1986;1(1):19-26. NURTURE study interim analysis data cutoff date: 8 June 2016.

2

4

6

8

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

Mea

n (

SE)

CM

AP

per

onea

l

amplit

ude,

mV

Study visit day

7

4

11

5

2

7

4

2

6

5

5

1

1

9

4

13

8

3

11

7

3

10

5

5

1

1

2 SMN2 copies, n 3 SMN2 copies, n Total, n

Age

CMAP amplitude in healthy infants, mV1

Ulnar nerve Peroneal nerve

Neonate 1.6–7.0 1.8–4.0

1–6 mo 2.5–7.4 1.6–8.0

7–12 mo 3.2–10.0 2.3–6.0

MGH NURTURE EXPERIENCE

!  2 infants enrolled, identified in the context of an older affected sibling

!  Each infant underwent baseline testing and received their first dose of nusinersen before 6 weeks of age

!  1 infant with SMN2=2 (sister with type I SMA, died at 13 months of age)

!  1 infant with SMN2=3 (1 brother age 9 years with SMA type 2, 1 sister age 7 years with SMA type 2, both with SMN2=3)

OB – sitting and reaching at 13 months

AG-knee and hip flexion screening visit

AG – 13 months walking

CHERISH (CS4): Phase 3, randomized, double-blind, sham-procedure–controlled study in later-

onset SMA

Objective

•  To evaluate the clinical efficacy and safety of nusinersen administered intrathecally in patients with later-onset SMA (consistent with Type 2)

Study Participants • M/F, symptom onset at >6 months, 2–12 years of age, medically stable

Treatment groups •  Randomized 2:1 to receive 12 mg intrathecal nusinersen or sham-procedure control

Treatment regimen

•  3 induction doses administered as lumbar puncture bolus injections

• Maintenance dose every 6 months for 15 months

Trial sites •  United States, Canada, Germany, Spain, Italy,

Sweden, France, UK, Hong Kong, South Korea, and Japan

LP, lumbar puncture; SMA, spinal muscular atrophy.

ClinicalTrials.gov NCT02292537; Biogen, data on file

Subject Disposition and Definitions of Datasets

ISIS 396443 ITT Set = 84

Safety Set = 84 IES15 = 35

SHAM ITT Set = 42

Safety Set = 42 IES15 = 19

Withdrawal From Study N=0

126 Subjects Enrolled

Withdrawal From Study N=0

Dataset Definitions: Intention To Treat (ITT) Set: All subjects randomized and received at least one dose of ISIS 396443 or SHAM procedure by randomization assignment. This will be the primary population for the analysis of efficacy endpoints. Safety Set: All subjects randomized and received at least one dose of ISIS 396443 or a SHAM procedure by actual treatment assignment. Interim Efficacy Set (IES): For the WHO milestones only, all subjects who have the opportunity to be assessed for the time point of analysis (e.g. at the Month 15 visit – IES15)

ITT Set

  SHAM (N=42)

ISIS 396443 (N=84)

  Total (N=126) 

Sex Male Female

21 (50%) 21 (50%)

38 (45%) 46 (55%)

59 (47%) 67 (53%)

Age (years) <6 years >=6 years

  36 (86%) 6 (14%)

  70 (83%) 14 (17%)

  106 (84%) 20 (16%)

Age at symptom onset (months) Median

  11.0

10.0

11.0 

Geographic Region North America Europe Asia-Pacific

  23 (55%) 14 (33%) 5 (12%)

  47 (56%) 28 (33%) 9 (11%)

70 (56%) 42 (33%) 14 (11%)

SMN2 Copy Number 2 SMN2 Copies 3 SMN2 Copies 4 SMN2 Copies Unknown Copies

4 (10%) 37 (88%) 4 (2%)

0

6 (7%)

74 (88%) 2 (2%) 2 (2%)

10 (8%)

111 (88%) 3 (2%) 2 (2%)

Number of subjects who ever achieved a milestone Sat without support Stood without support Walked with support Walked independently (at least 15 feet)

42 (100%) 12 (29%) 14 (33%)

0

84 (100%) 11 (13%) 20 (24%)

0

126 (100%) 23 (18%) 34 (27%)

0

HFMSE Median

18.0

20.5

20.0

Interim Analysis: Baseline and Disease Characteristics

39

Primary Endpoint: Significant Greater Improvement in HFMSE Among Treated Subjects over 15 Months

By Study Visit: Observed data By Study Visit: Based on Imputed Data When Missing

MGH Experience with FDA Approved SPINRAZA (sine Dec. 2016)

!  27 patients (9 international; 18 domestic) !  10 started treatments (5 international, 5 domestic)

!  1 SMA type I

!  6 SMA type II

!  3 SMA type III

!  11 pending treatment, !  of which 4 scheduled pts, 4 pending PA, 3 new pts to be

scheduled)

!  6 dose elsewhere, (3 had initial dose here and transferred to their local hospital for dosing)

Ongoing Clinical Trials for SMA

Newborn Screening for SMA and other inherited

neurologic disorders

Challenges associated with implementation of SMA NBS

!  Validation of the assay in the newborn screening lab prior to launching the test

!  Identification of rapid follow up confirmatory diagnostic testing laboratory is needed given NBS is a screening test

!  Patient access to the hospital that provide the SPINRAZA treatment

!  Insurance preauthorization issues associated with the testing and treatment for newborns with SMA

!  Limited efficacy for infants with 2 SMN2 copies, should treatment be available to the severe types of SMA or all types of SMA

!  Counseling supports for the condition, recurrence risk and implication of test results on other family members

Acknowledgements SMA foundation Sergey Paushkin Karen Chen Katherine von Herrmann (Dione Kobayashi) FightSMA Christian Lorson Martha Slay CureSMA Jill Jarecki Kenneth Hobby MDA USA Rodney Howell PharmOptima LLC Phil Zaworski

Ohio State University Tom Prior Ionis Pharmaceuticals Frank Bennet Eugene Schneider Laury Mignon Biogen Jonathan Staripoli Wildon Farwell Sandra Reyna NINDS NeuroNEXT Biomarker Team Members Steven Kolb Project CureSMA Investigator Network NICHD Tiina Urv NBSTRN/ACMG Amy Brower

MGH Ren Zhang Sarah Simeone Elise Townsend Jin Yun (Helen) Chen Flavia Nery Maryam Fatouraei Laura Schwartz Savanah Cosby Northwestern University Kristin Krosschell PharmOptima LLC Phil Zaworski Ohio State University Tom Prior