Update on Pulmonary Management in Spinal Muscular Atrophy type 1

Update on Pulmonary Management in Spinal Muscular Atrophy type 1 David Zielinski, MD FRCPC, FCCP Associate Professor McGill University Montreal Children s Hospital

None Disclosures

Objectives Review genetic basis of Spinal Muscular Atrophy Review underlying pulmonary natural history of SMA type 1 Review management options for SMA type 1 Review the impact of disease modifying treatments on disease

Spinal Muscular Atrophy 2 nd most common fatal autosomal recessive disease after Cystic Fibrosis 1 in 6000 10000 births 1/40-1/60 carrier status Degenerative disorder of alpha motor neurons in spinal cord Proximal muscle weakness/paralysis

Spinal Muscular Atrophy Onset Highest Function Life Expectancy Type 1 < 6 months Never sit <2 years of age Type 2 7-18 months Never walk 70% alive at 25 years Type 3 >18 months Stand and walk ~Normal Type 4.>21 years Stand and walk Normal

Natural History Cobben; Neuromuscular Disorders 2008

Clinical subdivisions SMA1 SMA 1A present at birth, joint contractures, respiratory compromise SMA 1B: onset of symptoms before 3 months SMA 1C: onset of symptoms after 3 months

Survival and SMA 1 type Death or 16 hrs/day ventilation Finkel; Neurology 2014

Genetics Buchtbach; Front Mol BioScie 2016

Survival and SMN2 Death or 16 hrs/day ventilation Finkel; Neurology 2014

Options of Care Palliative Care Non-Invasive respiratory support Tracheostomy and ventilation

CTS Pediatric HMV Statement The option of invasive and noninvasive HMV support as well as the differences between therapeutic and palliative NIV should be presented to all parents of children with SMA. (Grade 1C) Children with SMA whose parents would like a respiratory opinion should be referred to an experienced center to discuss the treatment options. (Grade 1C) Amin et al 2017

CTS Pediatric HMV Statement The decision to recommend or not recommend ventilatory support to children with Type 1 and Type 2 SMA by the treating physician should be made on a case-by case basis after discussion with family and other caregivers, and a careful assessment of medical benefit as well as the effect on quality of life. (Grade 1C) Amin et al 2017

HMV and SMA1 in Canada Oskoui; Ped Pulm 2017

Palliative Care Palliative care options needs to be available as a real choice and option for families with new diagnosis of SMA type 1 Canada : 38% at time of diagnosis 15% at time of acute respiratory decompensation 8% based on family request 36% at variable times Oskoui; Ped Pulm 2017

www.fightforford.com Non-Invasive Support

Survival YOB 1995-2005 YOB 1980-1994 Death Death or Ventilation Oskoui; Neurology 2007

CTS Pediatric HMV Statement Assessment for sleep disordered breathing (ideally with a polysomnogram conducted as per the American Academy of Sleep Medicine standards) should be considered for children with SMA if this is in accordance with the child and family s goals of care. (Grade 1C) Amin et al 2017

Natural History

Chest Wall

Natural History

Respiratory Infections

Indications Non-Invasive Ventilation Early prophylactic Hospitalizations with Respiratory Failure Evidence of Sleep Disordered Breathing

Non-Invasive Ventilation 6 mths 18 mths Titrate Bipap for adequate chest wall expansion Usually needs ΔP >12 cm H20 From A. Simonds, Royal Brompton Hospital, UK / M. Schroth Wisonsin

High Span NIV 12 months: IPAP: 10, EPAP: 4 5 years: IPAP 16, EPAP: 4

High Span NIV 24/7 Ventilation; ΔP 17 cm H20 IPAP 20, EPAP 4; 11.4 hrs/day

Mechanical Cough Assist Pressures: +/- 40 cmh2o Ti/Te: 1-2 seconds 3-5 cycles CoughTrak Oscillations Use with percussion/other airway clearance techniques Recommend early initiation Habituation when the child is well

Gastrostomy Allows optimization of nutrition Prevent periods >4 hours of NPO +/- fundoplication

Gastrostomy Fundoplication Prevents aspiration risk, especially as non-invasive respiratory supports increase Extubation risk is minimal Durkin; J Pediatr Surg, 2008 No Fundoplication Can avoid general anesthesia Avoid complications of fundoplication Aspirations are rare

Acute Decompensations Management Principles Volume recruitment with effective ventilation Airway secretion mobilization and clearance Assessments SaO2 <95% is a marker of atelectasis/mucous plugging Resting heart rate >100 may be sign of increased distress Oxygen should not be the primary treatment of a low saturation

CTS Pediatric HMV Statement When and how to augment ventilatory support during acute illnesses should be made on a case-by-case basis for each patient by the treating physician, as there is no validated protocol at present. (Grade 1C) Amin et al 2017

Acute Decompensations Increased respiratory support needs Increased time on BiPAP Increased Pressures Increased airway clearance Cough assist q1-4 hours Increased nutritional demands Bach; Paed Resp Rev; 2008

CTS Pediatric HMV Statement If children are intubated, a protocol-led extubation, including the use of a mechanical in-exsufflation device and NIV, is recommended. (Grade 1C) Amin et al 2017

Bach; Chest 2010 Schroth, FMSA.org Extubation Protocol Extubation Criteria Afebrile SpO2 >94% on FiO2 of 0.21 Alert and Co-operative No atelectasis or collapse on chest radiograph Minimal airway suctioning required Extubation Protocol Do not wean to low pressure CPAP trials Avoid hypercapnia Avoid derecruitment Extubate to high span Bipap Aim for FiO2 of 0.21 with SaO2>94% Aim for normal CO2

SMA type 1 - Intubations 28 episodes of respiratory failure (24 for acute infectious) 48 intubation episodes

SMA type 1 - Intubations Oskoui; Ped Pulm 2017

Malik

MCH SMA 1 Experience At diagnosis families meet with Complex Care Pediatrics, Respirology, Neurology and Palliative Care Families who chose pro-active care Arrangements made to start NIV Cough assist and saturation monitor introduced and teaching done Swallowing assessment and NG tube Once NIV established -> gastrostomy and fundoplication

MCH SMA 1 Experience P7 P6 P5 P4 P3 P2 P1 SMN2 Copies 2 copies 6 (86%) 3 copies 1 (14%) SMA type SMA 1a 1 (14%) SMA 1b 4 (57%) SMA 1c 2 (28%) Onset of: Symptoms: 3 (0-5) months Age (Years) 1 st Resp Failure: 6.5 (2-17) months Disease modifying therapy trial 0 5 10 4 (57%)

MCH SMA 1 Experience P7 P6 P5 P4 P3 P2 P1 Age (Years) 0 5 10 Mean age 5.6 years NIV use (100%) 7 (2-12) months NIV ΔP 12 cm H20 (12-17) NIV hrs/day 13 hrs (11.4-24) Ever Intubated (86%)

MCH SMA 1 Experience 3 2.5 2 1.5 1 0.5 0 Respiratory Failure Admissions per year Year 1 Year 2 Year 3 Year 4 Year 5 Age (years) Admissions/year

MCH SMA 1 Experience 20 LOS days for Respiratory Admissions per year 15 10 5 LOS/year 0 Year 1 Year 2 Year 3 Year 4 Year 5 Age (years)

MCH SMA 1 Experience P7 P6 P5 P4 Mortality or >16 hours/day ventilation 1 (17%) P3 P2 P1 Age (Years) 0 5 10

Tracheostomy Pro No facial interface Easier control of airway Easier suctioning Easier to treat intercurrent illnesses Prolongs survival Improves quality of life CON?loss of speaking Increased secretions locked in syndrome Progression of disease Worsens quality of life Requires Experienced/trained personnel

Tracheostomy n=194 Gregoretti; Pediatrics 2013

Tracheostomy

Nusinersen Anitsense oligonucleotide Modifies pre-mrna slicing of SMN2 to increase functional protein International multicenter RCT with Sham injection as placebo 80 infants in active arm 40 infants in sham arm Inthratecal injections on days 1, 15, 29, 64, 183 and 302 Eligible: 2 SMN2 copies Diagnosed <6 months of age Normal room air gas exchange Nocturnal NIV permitted Singh 2017 Finkel; NEJM 2017

Nusinersen Intern analysis: Motor-milestone response: 41% vs 0% (p<0.001) Study was stopped prematurely Final analysis: Motor-milestone response: 51% vs 0% (p<0.001) 22% full head control 10% roll over 8% sit independently 1% stand Death or >16 hour/day ventilation: 39% vs 68% (P=0.005) Finkel; NEJM 2017

Disease Modification

Single vial: $118,000 Nusinersen Price Year 1: $708,000 Subsequent years: $354,000 CDTAH Common Drug Review December 2017

Nusinersen in Canada CADTH Recognize value for SMA type 1 with: 2 SMN2 copies <7 months of age Not on invasive ventilation Show a clinical response within 6 doses to continue Suggested price too high Ongoing price negotiation and province each will decide Did not recommend for SMA type 2 or 3 INESSS Recognize therapeutic value for SMA type 1 Recommended not to list due to high cost Ministry of Health to decide Did not recommend for SMA type 2 or 3 Ministry agreed with recommendation

Gene Replacement One time IV injection delivery of adenoassociated viral serotype 9 to deliver copy of SMN Crosses blood-brain barrier 1 mg/kg of Prednisone for 30 days Mendell; NEJM 2017

Gene Replacement 11 sat 9 sat >30 sec 9 rolled 2 walked 4 feeding orally (hand to mouth) Mendell; NEJM 2017

Summary SMA type 1 has a varying but severe natural history Treatment options to prolong survival Early high span NIV, airway clearance, nutrition Having an approach to sick management is essential New disease modifying treatments are available for SMA type 1 They are changing the progression of disease Significant resource challenges are awaiting us

Jessika is 3 and a half years old, she has spent approximately 30 days, sick, in hospital care since her diagnosis three years ago. Not a lot considering the bleak outlook that was painted for us of her not living past her second birthday. In our opinion that is due partly to our proactive use of NIV care. We wanted Jessika on the BiPap as soon as we were aware of NIV protocol, to keep her lungs as strong as possible, she uses it everyday during her nap and every night when she sleeps. We wanted to start a chest physio routine right away as well, which included breath-stacking, cough assist, suctioning and chest tapping. We did this everyday since we have had the machines, and now do her chest physio routine 3 times a day when Jessika is healthy and, on the odd occasions when she is sick, at least every 4 hours. Jessika is amazingly happy and intelligent and we appreciate every moment with her as does she. Not only has she surpassed our expectations for longevity but her speech is extremely advanced and clear, something that was not expected from an SMA type 1 child. And Jessika is a world away from being a type 2. She speaks and sings clearly and loudly even when she is wearing her BiPap. Every parent has the right to choose their own path, some choose proactive care, others choose palliative, some are totally lost. These parents should be able to make informed decisions though, based on real world knowledge of this disease and not just the textbook diagnosis. Due to NIV protocols, recent technological advances, and the hospital's approach to treating our children with SMA, we are seeing longer lifespans and greater quality of life. We should also mention that even though taking care of a child with SMA is a monumental task, think full time job with lots of overtime, it is made so much easier knowing that we have a great support network behind us which made up mostly of dedicated, open minded, caring health care professionals, such as the fantastic resp. team from the Mtl Children's. Anyone who wants to know more about Jessika is welcome to visit either her website or her facebook page.