Evolving therapeutic landscape for inherited neurologic disorders. Kathryn Swoboda, MD HMS Child Neurology Course September

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1 Evolving therapeutic landscape for inherited neurologic disorders Kathryn Swoboda, MD HMS Child Neurology Course September

2 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

3 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)

4 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)

5 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, :759. Hendrickson BC et al, J Med Genet September; 46(9):

6 Broad Spectrum of Clinical Manifestations SMA Type Age of Onset 0 Prenata l I Birth-6 months II 6-12 months III After 12 months IV Adulthood Typical Life Span <6 months Formerly Called Congenital arthrogryposis multiplex congenita Clinical Characteristics/ Milestones No milestones achieved Severe weakness Early respiratory failure <2 years Werdnig-Hoffman Severe infantile form of SMA Never sits without support Early respiratory failure Accounts for >50 % cases 70% alive at 25 years Dubowitz Independent sitting loss of this ability by mid-teens Normal Kugelberg-Welander Ambulation, with loss of this ability as disease progresses Normal Ambulation, with loss of this ability as disease progresses Adapted from Prior, TW and Russman BS, Spinal Muscular Atrophy,

7 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

8 SMA type II Dubowitz type

9 SMA type III Kugelberg-Welander

10 Incidence and Prevalence of SMA subtypes Type 3 13% Type 2 29% Type 4 <1% Type 1 58% Type 3 36% Type 4 <1% Type 1 12% Type 2 52% Incidence Prevalence

11 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

12 Predicting phenotype from genotype

13 Predicting phenotype from genotype SMN1=0, SMN2=2 SMN1=0, SMN2=3 SMN1=0, SMN2=3

14 BIOMARKERS and TREATMENT

15 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

16 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

17 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:

18 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

19 Comparison of SMN levels in whole blood from SMA patients ages 6 years and older in relation to SMN2 copy number SMN (pg/ml whole blood) Copies 3 copies 4 copies In collaboration with Roche, Pharmoptima and SMA Foundation

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

21 Mechanism of Nusinersen # 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 fulllenth SMN protein. Chiriboga et la., American Academy of Neurology 2016

22 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

23 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 Key inclusion criteria: Age 6 weeks at first dose Pre-symptomatic Genetic diagnosis of 5q SMA gene deletion/ mutation Gestational age, (34 42 for twins) weeks 2 or 3 SMN2 copies Ulnar CMAP amplitude 1 mv at Baseline Key exclusion criteria Hypoxemia (O 2 saturation of <96% awake or asleep at sea level) Infection during Screening period or ongoing medical condition incompatible with study procedures/ assessments Screening period ( 21 days) Nusinersen 12-mg scaled equivalent dose Dosing schedule D1 D15 D29 D64 D183 D302 D421 D540 D659 D778 4 induction doses with follow-up evaluations CMAP = compound muscle action potential. Maintenance dose and follow-up evaluation every 119 days D868 post-treatment follow-up visit

24 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 HINE 2 and WHO 3! 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): WHO Multicentre Growth Reference Study Group. Acta Paediatr Suppl. 2006;450: Glanzman AM, et al. Neuromuscul Disord. 2010;20(3):

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26 Characteristic Age at first dose, d, n (%) Interim Analysis: Baseline Characteristics 2 SMN2 copies n=12 a 3 SMN2 copies n=5 Total n= (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 ( ; 9) ( ; 4) ( ; 13) Mean HINE total motor milestones Median (range; n) b (0 4.0; 9) Mean ulnar CMAP amplitude Median (range; n), mv b ( ; 9) Mean peroneal CMAP amplitude Median (range; n), mv b ( ; 7) ( ; 4) ( ; 4) ( ; 4) (0 7.0; 13) ( ; 13) ( ; 11) NURTURE study interim analysis data cutoff date: 8 June a Included 1 set of twins each with 2 copies of SMN2. b Based on efficacy set of patients who completed Day 64 visit or longer (n=13). 7

27 Primary Endpoint: Time to Death or Respiratory Failure a! 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 a Respiratory failure was defined as invasive or non-invasive ventilation for 6 hours/day continuously for 7 days or tracheostomy. 8

28 HINE Motor Milestones (Max: 26 points) 2 pts 4 pts 3 pts 4 pts 3 pts 4 pts 3 pts 3 pts 0 pts 1 pts 2 pts 3 pts 4 pts

29 Mean HINE Total Motor Milestone Score Over Time # 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 Mean (SE) HINE total motor milestone score Study visit day 2 SMN2 copies 3 SMN2 copies Total

30 Mean CHOP INTEND Total Score Over Time # 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 points 1 Mean (SE) CHOP INTEND total score SMN2 copies 3 SMN2 copies Total Maximum total score, 64 points Study visit day 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): NURTURE study interim analysis data cutoff date: 8 June 2016.

31 Mean Ulnar and Peroneal Nerve CMAP Amplitude Over Time! Overall, mean CMAP amplitude appears to be increasing 2 SMN2 copies 3 SMN2 copies Total 8 8 Mean (SE) CMAP ulnar amplitude, mv 6 4 Mean (SE) CMAP peroneal amplitude, mv SMN2 copies, n 3 SMN2 copies, n Total, n Study visit day Study visit day CMAP amplitude in healthy infants, mv 1 Age Ulnar nerve Peroneal nerve Neonate mo mo Miller RG, Kuntz NL. J Child Neurol. 1986;1(1): NURTURE study interim analysis data cutoff date: 8 June 2016.

32 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)

33 OB sitting and reaching at 13 months

34 AG-knee and hip flexion screening visit

35 AG 13 months walking

36 CHERISH (CS4): Phase 3, randomized, doubleblind, sham-procedure controlled study in lateronset SMA Objective Study Participants Treatment groups Treatment regimen To evaluate the clinical efficacy and safety of nusinersen administered intrathecally in patients with later-onset SMA (consistent with Type 2) M/F, symptom onset at >6 months, 2 12 years of age, medically stable Randomized 2:1 to receive 12 mg intrathecal nusinersen or sham-procedure control 3 induction doses administered as lumbar puncture bolus injections Maintenance dose every 6 months for 15 months Trial sites LP, lumbar puncture; SMA, spinal muscular atrophy. United States, Canada, Germany, Spain, Italy, Sweden, France, UK, Hong Kong, South Korea, and Japan ClinicalTrials.gov NCT ; Biogen, data on file

37 Subject Disposition and Definitions of Datasets 126 Subjects Enrolled Dataset Definitions: SHAM ITT Set = 42 Safety Set = 42 IES15 = 19 Withdrawal From Study N=0 ISIS ITT Set = 84 Safety Set = 84 IES15 = 35 Withdrawal From Study N=0 Intention To Treat (ITT) Set: All subjects randomized and received at least one dose of ISIS 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 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)

38 Interim Analysis: Baseline and Disease Characteristics Sex Male Female Age (years) <6 years ITT Set SHAM (N=42) ISIS (N=84) Total (N=126) 21 (50%) 21 (50%) 36 (86%) 6 (14%) 38 (45%) 46 (55%) 70 (83%) 14 (17%) 59 (47%) 67 (53%) 106 (84%) 20 (16%) >=6 years Age at symptom onset (months) Median Geographic Region North America Europe Asia-Pacific SMN2 Copy Number 2 SMN2 Copies 3 SMN2 Copies 4 SMN2 Copies Unknown Copies Number of subjects who ever achieved a milestone Sat without support Stood without support Walked with support Walked independently (at least 15 feet) 23 (55%) 14 (33%) 5 (12%) 4 (10%) 37 (88%) 4 (2%) 0 42 (100%) 12 (29%) 14 (33%) 0 47 (56%) 28 (33%) 9 (11%) 6 (7%) 74 (88%) 2 (2%) 2 (2%) 84 (100%) 11 (13%) 20 (24%) 0 70 (56%) 42 (33%) 14 (11%) 10 (8%) 111 (88%) 3 (2%) 2 (2%) 126 (100%) 23 (18%) 34 (27%) 0 HFMSE Median

39 Primary Endpoint: Significant Greater Improvement in HFMSE Among Treated Subjects over 15 Months 39 By Study Visit: Based on Imputed Data When Missing By Study Visit: Observed data

40 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)

41 Ongoing Clinical Trials for SMA

42 Newborn Screening for SMA and other inherited neurologic disorders

43 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

44 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 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 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