Spinal Muscular Atrophy Newborn Screening

Transcription

1 Spinal Muscular Atrophy Newborn Screening Melissa Gibbons, MS, CGC Erica Wright, MS, CGC Clinical Genetics and Metabolism Department of Pediatrics Children s Hospital Colorado/ University of Colorado

2 Disclosures Melissa Gibbons is on the Medical Advisory Committee for Cure SMA and has served on an Advisory Board for Sarepta Therapeutics 2

3 Objectives Review evidence based process for inclusion of disorders on the national Recommended Uniform Screening Panel (RUSP) Review natural history and diagnosis of Spinal Muscular Atrophy (SMA) Describe current and emerging treatment options for SMA and anticipated outcomes Provide regional and national update of newborn screening for SMA

4 Background The Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) was formed in 2003 following the Newborn Screening Saves Lives Act Chartered to advise the Secretary (Health and Human Services) regarding the most appropriate application of universal newborn screening tests, technologies, policies, guidelines and standards for effectively reducing morbidity and mortality in newborns and children having, or at risk for, heritable disorders. develop a model decision-matrix for newborn screening expansion, including an evaluation of the potential public health impact of such expansion, and periodically update the recommended uniform screening panel, as appropriate, based on such decision-matrix. Amended in 2014 by the Newborn Screening Saves Lives Reauthorization Act 4

5 .Background ACHDNC Recommended Uniform Screening Panel (RUSP) Based on American College of Medical Genetics report Newborn Screening: Towards a Uniform Screening Panel and System Initially, 29 core disorders and 25 secondary disorders ACHDNC Nomination Process Lengthy evidence-based process for inclusion on the RUSP. Recommendations are sent to Secretary of Health and Human Services Thus far, severe combined immune deficiency (SCID), critical congenital heart defect (CCHD), Pompe disease, mucopolysaccharidosis type 1, X-linked adrenoleukodystrophy, and spinal muscular atrophy have been approved by the secretary for addition to the RUSP. 5

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9 Mechanisms for Adding a Disorder LEGISTLATIVE ACTION RULE MAKING/ BOARD OF HEALTH Often driven by parent advocates Law may be named after an affected child (i.e. Aiden s Law for XALD) Timeline of implementation can be quick and difficult Health Departments may have input Pricey (Lobbyists) Health Department initiates addition of disorder Change in rules and regulations Key stakeholders need to be on board May need to be formally recommended by state NBS advisory committee Collaborative approach Timeline can seem long and frustrating to parent advocates 9

10 RUSP Laws Some states now have laws that require the state to add a condition once included on the RUSP. California 2016 legislation (SB 1095) allows a period of 2 years to start testing. The department shall expand statewide screening of newborns to disease that is detectable in blood samples as soon as practicable, but no later than two years after the disease is adopted by the federal Recommended Uniform Screening Panel (RUSP), or enrollment of the act amending this subdivision, whichever is later. * Texas Health and Safety Code Section as funding is available (a-1) Except as provided by this subsection and to the extent funding is available for the screening, the department shall require newborn screening tests to screen for disorders listed as core and secondary conditions in the Recommended Uniform Screening Panel of the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children or another report determined by the department to provide more stringent newborn screening guidelines to protect the health and welfare of this state's newborns. 10

11 RUSP Laws North Carolina Appropriations Act of 2018 (S99) Override of Governor s veto of state budget Massive bill The Commission shall amend the rules as necessary to ensure that each condition listed on the Recommended Uniform Screening Panel developed by the Secretary of the United States Department of Health and Human Services and the Advisory Committee on Heritable Disorders of Newborns and Children (the RUSP) is included in the Newborn Screening Program, except that the Commission is exempt from rule making with respect to adding screening tests for Pompe disease, Mucopolysaccharidosis Type I (MPS I), and X-Linked Adrenoleukodystrophy (X-ALD). 11

12 Spinal Muscular Atrophy Spinal muscular atrophy (SMA): A clinically and genetically heterogeneous group of diseases in which there is a loss of anterior horn cells and progressive muscle atrophy and weakness

13 5q Related SMA The most common SMA - accounting for over 95% of cases Incidence: 1 in 10,000 live births Pan-Ethnic Autosomal Recessive Disease Caused by Homozygous Deletion or Pathogenic Variant in the Survival of Motor Neuron (SMN1) gene 13

14 A Tale of 2 Genes

15 SMN1 Cure SMA. SMA Care Series: The Genetics of Spinal Muscular Atrophy Available at Accessed September 11, 2017.

16 Inheritance of SMA

17 SMA Carrier Frequencies

18 Classification System For Spinal Muscular Atrophy Type Age of Onset Highest Motor Activity Natural Age of Death 0 Prenatal Respiratory Support <1 month months Never Sits < 2 years 2 < 18 months Sits, does not stand alone Adult 3 >18 months Stands Alone, walks unassisted Adult 4 >21 years Walk during adulthood-unassisted Adult

19 SMA, type 0 Onset: Prenatal Distinctive Features: Congenital Hypotonia Severe joint contractures (Arthrogryposis multiplex congenita) Digital contractures Facial diplegia Respiratory failure Fractures possible Minimum/No milestones met Natural Life expectancy: < 6 months 19

20 SMA type 1 Onset: 0-6 months Distinctive Features: Poor Muscle Tone Muscle Weakness Fasciculations of tongue Postural tremor of the fingers Contractures No sensory loss Natural Life expectancy: 50% by 7 months; 95% by 17 months

21 SMA, type 2 Onset: 6-18 months Distinctive Features: Hypotonia, weakness (proximal/symmetric) Decreased/Absent DTRs Normal cognition Poor roll & crawl Weak sitting (Tripods) Tremor May stand, does not walk without assistance Natural Life expectancy: 70% alive at 25 years

22 Distinctive Features: Able to stand and walk Progressive proximal weakness of the legs more than the arms. Cognition is normal Natural life expectancy: Normal SMA, type 3/4

23 Emerging Therapies in SMA

24 SMA Pipeline Gene Localized to 5q SMN1 gene identified First Clinical Trial in SMA December 23 rd -FDA Approves first drug for SMA

25 Spinraza On December 23, 2016 Spinraza was approved by the FDA as the first and only treatment for SMA in pediatric and adult patients.

26 Nusinersen/ Spinraza Neurology 2016 Mar 8; 86:

27 Event-free Survival and Overall Survival Finkel RS et al. N Engl J Med 2017;377:

28 Change Over Time in the Hammersmith Functional Motor Scale Expanded Score and the Revised Upper Limb Module Score (Final Analysis). E Mercuri et al. N Engl J Med 2018;378:

29 Gene Therapy Delivery of a fully functional human SMN gene into target motor neuron cells Production of sufficient levels of SMN protein required to improve motor neuron function Rapid onset of effect in addition to sustained SMN protein expression

30 Single-Dose Gene-replacement therapy for spinal muscular atrophy Published in the New England Journal of Medicine MENDELL JR ET AL. N ENGL J MED 2017;377:

31 Motor Function after Gene Therapy. Mendell JR et al. N Engl J Med 2017;377:

32 Event-free Survival and Motor and Other Milestones among the 12 Patients in Cohort 2. Mendell JR et al. N Engl J Med 2017;377:

33 Survival Free from Permanent Ventilation in the 15 Study Patients. Mendell JR et al. N Engl J Med 2017;377:

34 Current State of SMA Gene Therapy trials in the United States The U.S. Food and Drug Administration (FDA) has granted AVXS-101 Orphan Drug Designation for the treatment of all types of SMA and Breakthrough Therapy Designation, as well as Fast Track Designation, for the treatment of SMA Type 1. SMA Type 1 Pivotal Trial (STRIVE) The open-label, single-arm, single-dose, multi-center trial is designed to evaluate the efficacy and safety of a one-time IV infusion of AVXS-101 in patients with SMA Type 1 SMA Type 2 Phase 1 Trial (STRONG) The open-label, dose-comparison, multi-center Phase 1 trial is designed to evaluate the safety, optimal dosing, and proof of concept for efficacy of AVXS-101 in two distinct age groups of patients with SMA Type 2, utilizing a one-time IT route of administration. Pre-Symptomatic SMA Types 1, 2, 3 (SPRINT) A multi-national study that will evaluate AVXS-101 in approximately 44 patients less than 6 weeks old with SMA Types 1, 2 or 3 who have 2, 3 or 4 copies of SMN2 often called the SMA back-up gene and have not yet shown symptoms of the disease, also referred to as being pre-symptomatic.

35 Carrier Screening and Prenatal Diagnosis in the Era of Treatment Allows for earlier access to FDA approved treatments Allows for consideration of involvement in age-restricted research trials Shifts the diagnosis conversation to the OB/GYN and prenatal genetic counselors

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37 Newborn Screening In July of 2017 Missouri passed legislation adding SMA and MPS II to their screening panel. They will begin screening for both conditions by January 1, 2019 Approved by the RUSP (Recommended Uniform Screening Panel) committee on February 9, 2018 and signed by HHS Secretary, Alex Azar on July 3, Utah became the first state to implement permanent SMA newborn screening on January 29, 2018 Additional states have started to screen or have legislation in the works to add SMA to the Newborn Screen

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39 Resources Update-May-2018.pdf 39

40 References ACMG Newborn Screening Expert Group. Newborn screening: Toward a uniform screening panel and system- Executive Summary. Pediatrics 2006; 117: Calonge, N., et al., Committee report: Method for evaluating conditions nominated for population-based screening of newborns and children. Genet Med, (3): p Cure SMA. SMA Care Series: The Genetics of Spinal Muscular Atrophy Available at Accessed September 11, Farrar MA, et al. Ann Neurol. 2017;81: Kemper, A.R., et al., Decision-making process for conditions nominated to the recommended uniform screening panel: statement of the US Department of Health and Human Services Secretary's Advisory Committee on Heritable Disorders in Newborns and Children. Genet Med, (2): p Sugarman, E et al European journal of human genetics., 2012, Vol.20(1), p Wilson, J. and G. Junger, Principles and Practice of Screening for Disease. Public Health Papers, Additional references listed on slides as appropriate 40