Diagnosis, management and new treatments for Spinal Muscular Atrophy Special Focus: SMA Type 1

Transcription

1 Diagnosis, management and new treatments for Spinal Muscular Atrophy Special Focus: SMA Type 1 17 th April 2018 Adnan Manzur Consultant Paediatric Neurologist Dubowitz Neuromuscular Centre, GOSH & ICH, London

2 Conflict on interests NHS clinician On UK advisory board for Biogen (Spinraza manufacturer) Slides with green background in this presentation were provided as a free teaching resource by Biogen

3 Telephone consultation: 8 month old Male infant Feeding difficulties: 2-3 months old 4 months: unable to hold head 5 months: ref to SLT: unsafe swallow 7 months: Severe pneumonia Intubation - Ventilated EMG myopathic unusual breathing diaphragmatic Local hospital wanted to do muscle biopsy

4 8 month old Male infant SMN gene study homozygous SMN1 deletion of exon 7 SMN2 copy number - 2 Extubated to NIV BiPAP dependent (enabled extubation) 8 months: Night and day NIV dependent, with coming off the NIV for 3 breaks or half an hour each. Nasogastric feeding (history of failure to thrive & dysphagia) Gastro-oesophageal reflux Constipation

5 Focus Clinical presentation, severity classification Diagnosis Differential diagnosis Standards of care Changing natural history Nusinersen Implications

6 SMA I. 5q linked AR motor neuron disorder Onset by 6 months, never sit Life limiting to 2 yrs Spectrum of severity: Type IA: (SMA0) presentation at birth, joint contractures, respiratory compromise Type IB: onset of symptoms < age 3 months Type IC: onset after 3 months of age. SMN1 (telomeric) mutations Reduced full length SMN protein SMN2, nearly identical, has exonic splicing enhancer mutation that limits inclusion of exon 7 SMN2 copy number is inversely related to clinical severity

7 SMA I. 5q linked Autosomal Recessive motor neuron disorder SMN1 gene deletions, SMN protein reduction Onset by 6 months, never sit Life limiting

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10 3 newborn siblings generalized weakness respiratory insufficiency, facial diplegia, extraocular muscle involvement. axonal neuropathy. homozygous deletions SMN gene. remained dependent on artificial ventilation died at the ages of 3 weeks, 4 weeks, and 2 days

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13 Outcome measures and treatment of spinal muscular atrophy, 134th ENMC International Workshop. Bertini E, et al. Neuromuscul Disord 2005;15: Type 1a: the severe neonatal variant with joint contractures and a paucity of movement present at birth has a poor prognosis, often needing ventilatory support as a neonate. Type 1b: the typical SMA-1 patient having poor head control and difficulty handling oral secretions upon or shortly after presentation and has an intermediate prognosis. Type 1c: the minority of type 1 patients who achieve head control or who can sit with support and have the best prognosis.

14 Observational study of spinal muscular atrophy type I and implications for clinical trials. Finkel et al. Neurology Aug 26;83(9):810-7 Type IA - (also described in literature as SMA 0) with presentation at birth with joint contractures and respiratory compromise Type IB - onset of symptoms before age 3 months Type IC - onset after 3 months of age.

15 Spinal muscular atrophy. SMN1telomeric & SMN2Centromeric Spinal muscular atrophy. Lunn &Wong Lancet 2008; 371:

16 SMN2 copy number. (centromeric, SMNc) Survival (less than/greater than 24 months)

17 SMN protein Wertz & Sahin 2015

18 Clinical ECG baseline tremor (CK normal to mild elevation) (EMG) (muscle histology) SMN1 gene testing Diagnosis

19 EMG Abnormal spontaneous activity, e.g. Fibrillations, positive sharp waves and fasciculations by EMG. Increased mean duration and amplitude of motor unit action potentials by EMG. Comments: MNCVs may be markedly reduced in SMA type I. There is a rare congenital-onset SMA with death within the first weeks of life in which MNCVs are very long and SNAPs are absent.

20 EMG in SMA diagnosis clinical perspective SMA 1. go straight to SMN gene test (ICU ventilated infant useful to initiate tests, but caution about relying on EMG as the sole diagnostic / prognostic test) Confirmation of neurogenic EMG in affected individuals with one SMN1 copy deleted, before proceeding with point mutation study in the other allele

21 Histopathology of muscle Groups of atrophic Fibers of both types. Hypertrophic fibers of type I. Type grouping (chronic cases). Comment: In early-onset cases of SMA type I these characteristic features may not be present. Instead there are small fibers of both types. In SMA III there may be a concomitant myopathic pattern.

22 Differential Diagnosis of SMA I In the typical case, clinical diagnosis is easy Pompes (severe alpha glucosidase deficiency) Olivopontocerebellar hypolpasia (type 1) with SMA Mitochondrial SMARD 1 key clinical differences Other neurogenic conditions

23 SMA1 Management QOL Survival Customizing care MDT approach Standards of care (Anticipatory care ) Research trials Novel drugs Evolving care Beyond standards of care

24 SMA 1 Survival - changing Natural History Mannaa et al 2009 Thomas et al 1994 Improvement in survival based on General care / nutritional / respiratory support Country / cultural context Implications for treatment trials

25 SMA. Standards of care. SMA1. Anticipatory care. NIV Cough machine

26 SMA1. Genetic therapeutic approaches Wertz and Sahin 2015

27 Anderton & Mastaglia 2015

28 Anderton & Mastaglia 2015

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30 Multicentre randomized, double-blind, shamcontrolled, phase 3 Inclusion criteria: Homozygous deletion or mutation SMN1 2 copies of the SMN2 gene onset of symptoms that were consistent with spinal muscular atrophy before t 6 months age 7 months or younger at screening, did not have low peripheral oxygen saturation

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33 Panel A - probability of event-free survival (the proportion of infants who were alive without the use of permanent assisted ventilation) Panel B -probability of overall survival (proportion of infants who were alive)

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35 Can nusinersen prevent onset of symptoms in genetically diagnosed pre-symptomatic SMA1 infants? in context of positive family history or future newborn screening

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37 Translational timelines. Nusinersen Spinraza TM 1 st Human use 2011, Orphan drug status Apr ISIS (ISIS) Endear Study pre-specified primary endpoint met Aug 16 Biogen announces Extended Access Programme (EAP) Aug 16 FDA approval Dec 2016 NHS commissioners leave EAP uptake to individual trusts UK EAP Sporadic uptake starts Belfast - Apr 2017 CHMP (Committee for Medicinal Products ) +ve recommendation Apr 17 EMA (European Medicine Agency) Marketing authorization June 2017 NICE evaluation pending ( STA? HST?) (NICE Technology Appraisal (TA) or Highly Specialised Technologies Evaluation (HST) NHS England approves EAP supportive funding for SMA1 (2 copies of SMN2 ) Aug 17

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39 15 patients with SMA1 single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. 3 patients received a low dose ( vg per kilogram of body weight) 12 received a high dose ( vg per kilogram). The primary outcome was safety. The secondary outcome was the time until death or the need for permanent ventilator assistance.

40 Data cutoff on August 7, 2017: all 15 patients were alive and event-free at 20 months of age, as compared with a rate of survival of 8% in a historical cohort. In the high-dose cohort: CHOP INTEND scale increase of: 9.8 points at 1 month 15.4 points at 3 months 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Elevated serum ALT levels occurred in 4 patients and were attenuated by prednisolone.