Nusinersen Use in Spinal Muscular Atrophy

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2 Nusinersen Use in Spinal Muscular Atrophy Report by: Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology Slide 1

3 Evidence in Focus Endorsement and Funding This Evidence in Focus article was endorsed by the American Academy of Pediatrics and the Child Neurology Society. This Evidence in Focus article was funded by the American Academy of Neurology (AAN). Authors who serve as AAN subcommittee members or methodologists (S.A., M.J.A., P.N., M.O.) were reimbursed by the AAN for expenses related to travel to subcommittee meetings where drafts of manuscripts were reviewed.

4 Sharing This Information The American Academy of Neurology develops these presentation slides as educational tools for neurologists and other health care practitioners. You may download and retain a single copy for your personal use. Please contact guidelines@aan.com to learn about options for sharing this content beyond your personal use.

5 Presentation Objectives To present an assessment of the evidence about the use of nusinersen for spinal muscular atrophy.

6 Overview Introduction American Academy of Neurology systematic review process Level of evidence statements table

7 Introduction Evidence in Focus is a pilot product of the American Academy of Neurology (AAN) Guideline Development, Dissemination, and Implementation (GDDI) Subcommittee aiming to provide an evidence-based discussion of focused topics of timely relevance for neurologists and patients. This product is a systematic review that uses an abbreviated version of the AAN guideline methodology 1 to highlight the strength of evidence underlying new therapies, accompanied by a discussion to aid the practicing neurologist, other medical professionals, patients, and families. This first Evidence in Focus examines the use of nusinersen, the first drug approved by the Food and Drug Administration (FDA) for the treatment of spinal muscular atrophy (SMA).

8 Introduction (continued) 5q SMA is an autosomal recessive disorder caused by homozygous deletion or mutation involving exon 7 of survival motor neuron 1 gene (SMN1) and characterized by anterior horn cell degeneration. Nonmotor neuronal cells also may be involved. 2 Without supportive care or treatments, most children with type 1 SMA die before 2 years of age and are never able to sit independently. Children with SMA type 2 achieve the ability to stay seated independently, although some lose this ability and are never able to walk independently; scoliosis is common. With supportive care, individuals with type 2 SMA may live into adulthood. Individuals with types 3 and 4 may have normal lifespans and be able to walk independently, although some may lose this ability.

9 Literature Search/Review Rigorous, Comprehensive, Transparent 15 abstracts A pragmatic literature search for clinical trials of nusinersen use in patients with spinal muscular atrophy (SMA) was performed on September 28, 2017, and updated on November 20, 2017, and February 16, rated articles Exclusion criteria: Conference abstracts

10 AAN Classification of Evidence (2017) Therapeutic Scheme - Class I Randomized controlled clinical trial (RCT) in a representative population Triple-masked studies (i.e. the patient, treating provider, and outcome assessors are unaware of treatment assignment) o Relevant baseline characteristics of treatment groups (or treatment order groups for crossover trials) are presented and substantially equivalent between treatment groups, or there is appropriate statistical adjustment for differences Additional Class I criteria: a. Concealed allocation b. No more than two primary outcomes specified c. Exclusion and inclusion criteria clearly defined d. Adequate accounting of dropouts (with at least 80 percent of participants completing the study) and crossovers e. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*: i. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority ii. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose, and dosage adjustments are similar to those previously shown to be effective) iii. The inclusion and exclusion criteria for participant selection and the outcomes of participants on the standard treatment are comparable with those of previous studies establishing efficacy of the standard treatment iv. The interpretation of the study results is based on a per-protocol analysis that accounts for dropouts or crossovers v. For crossover trials, both period and carryover effects are examined and statistical adjustments performed, if appropriate *Numbers i iii in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

11 AAN Classification of Evidence (2017) Therapeutic Scheme - Class II RCT that lacks one or two Class I criteria a e (see previous slide) Cohort studies employing methods that successfully match treatment groups on relevant baseline characteristics (e.g., propensity score matching) meeting Class I criteria b e (see previous slide) Randomized crossover trial missing one of the following two criteria: a) Period and carryover effects described b) Baseline characteristics of treatment order groups presented All relevant baseline characteristics are presented and substantially equivalent across treatment groups (or treatment order groups for crossover trials), or there is appropriate statistical adjustment for differences Masked or objective* outcome assessment Therapeutic Scheme - Class III Therapeutic Scheme - Class IV Controlled studies (including studies with external controls such as well-defined natural history controls) Crossover trial missing both of the following two criteria: a) Period and carryover effects b) Presentation of baseline characteristics A description of major confounding differences between treatment groups that could affect outcome* Outcome assessment performed by someone who is not a member of the treatment team 1. Studies not meeting Class I, II, or III criteria *Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer s (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data)

12 Study N Population Studied (key inclusion criteria) LOE Explanation LOE Statement Chiriboga, et al (NCT ; NCT , CS1 a ) Finkel, et al (CS3A, a NCT ) Levels of Evidence (LOE) Statement Table 28 Male and female patients aged 2 14 years Symptomatic SMA and documented SMN1 homozygous gene deletion Medically stable, with life expectancy >2 years Able to complete all study procedures 20 Male and female patients aged 3 weeks 7 months Onset of SMA symptoms between 3 weeks and 6 months SMN1 homozygous gene deletion or mutation Body weight >5th percentile, gestational age weeks, gestational body weight 2 kg, receiving adequate nutrition and hydration, not hypoxemic, receiving standard of care, expected to complete all study procedures Class IV due to openlabel design Class III due to openlabel design with comparison to welldefined historical cohort This study provides Class IV evidence that in children with type 2 and type 3 SMA, intrathecal nusinersen is not associated with safety or tolerability concerns. This study provides Class III evidence that in infants with SMN1 homozygous gene deletions or mutations, nusinersen improves the probability of permanent ventilationfree survival at 24 months versus a welldefined historical cohort. Abbreviations: SMA=spinal muscular atrophy, SMN1=survival motor neuron 1 gene a CS labels refer to the FDA review nomenclature identifying different studies Slide 11

13 Study N Population Studied (key inclusion criteria) LOE Explanation LOE Statement Finkel, et al. Younger than 7 months at screening N/A, Class I (CS3B, a NCT , ENDEAR) Levels of Evidence Statement Table (continued) 142 screened, 122 randomized Homozygous deletion or mutation in the SMN1 gene, with two copies of the SMN2 gene Onset of SMA clinical symptoms at 6 months or earlier Body weight >3 rd percentile, gestational age weeks, receiving adequate nutrition and hydration, not hypoxemic, receiving standard of care, able to complete all study procedures, parent/guardian with adequate psychosocial support This study provides Class I evidence that in infants with a gestational age between 37 weeks and 42 weeks with SMA and an SMN2 copy number of 2, treatment with nusinersen results in a better motormilestone response and higher event-free survival than the sham control (after at least 6 months of treatment). Abbreviations: SMA=spinal muscular atrophy, SMN1=survival motor neuron 1 gene; SMN2, survival motor neuron 2 gene a CS labels refer to the FDA review nomenclature identifying different studies Slide 12

14 Study N Population Studied (key inclusion criteria) LOE Explanation LOE Statement Mercuri, et. al CS4, a NCT (CHERISH) Levels of Evidence Statement Table (continued) 126 Male and female patients aged 2 12 years Medically diagnosed with SMA, with sign and symptom onset later than 6 months of age Able to sit independently but never able to walk independently HFMSE 10 and 54 at screening Able to complete all study procedures Estimated life expectancy >2 years No respiratory insufficiency, medically required gastric feeding tube, severe contractures or scoliosis N/A, Class I This study provides Class I evidence that in children aged 2 12 years with SMA symptom onset after 6 months of age, treatment with nusinersen results in greater improvement in motor function at 15 months than the sham control. Abbreviations: HFMSE=Hammersmith Functional Motor Scale Expanded, SMA=spinal muscular atrophy a CS labels refer to the FDA review nomenclature identifying different studies Slide 13

15 Study N Population Studied (key inclusion criteria) LOE Explanation LOE Statement CS2, a NCT : An Open-label Safety, Tolerability and Dose-Range Finding Study of Multiple Doses of Nusinersen (ISIS ) in Participants With Spinal Muscular Atrophy Levels of Evidence Statement Table (continued) 34 Male and female patients aged 2 15 years Genetic documentation of 5q SMA (homozygous gene deletion or mutation) Clinical signs of SMA Able to complete all study procedures No respiratory insufficiency or medically required gastric feeding tube Class IV due to open-label design This study provides Class IV evidence that in children with 5q SMA (homozygous gene deletion or mutation), nusinersen is not associated with safety or tolerability concerns. Abbreviations: SMA=spinal muscular atrophy a CS labels refer to the FDA review nomenclature identifying different studies Slide 14

16 References References cited here can be found in the Evidence in Focus article, which can be found at AAN.com/guidelines. Slide 15

17 Access Article and Summary Tools To access the complete guideline and related summary tools, visit AAN.com/guidelines. Evidence in Focus article Summary for patients/families Q&A for patients/families Slide 16

18 Thank You.

19 Questions?