Spinal Muscular Atrophy (SMA): Possible Addition …...• “Iowa should add Spinal Muscular Atrophy (SMA) caused by homozygous deletion of exon 7 of the SMN1 gene to the panel of

Spinal Muscular Atrophy (SMA):Possible Addition to Iowa NBSCIDAC Quarterly Meeting7/20/18

SMA - ClinicalGenetic condition that leads to loss of motor neurons

Key symptom: proximal weakness & muscle atrophy

Most common genetic cause of death in early childhood

SMA - Genetics

• Autosomal recessive inheritance- SMN1 gene▫ Pan-ethnic carrier rate in U.S. is 1/54▫ 2% of mutations in diagnosed cases are de novo

• Incidence estimated around 1/12,000• 95% of cases are homozygous for a common

deletion mutation (exon 7 +/- exon 8)• 2-5% have one common deletion mutation and a

point mutation in SMN1 (compound heterozygote)

Presenter

Presentation Notes

1/54 carrier rate from Sugarman et al. 2012 (also referenced in GeneReviews)

SMA - Genetics• SMN2 gene ▫ modifier of clinical severity▫ Located downstream of SMN1▫ Functionally different than SMN1 because of a

variant that leads to altered splicing of the protein product

▫ Only about 10% of proteins produced are full length (functional)

▫ Humans can have 0 to 5 copies of SMN2 (usually 0-3)

SMA Genetics

Presenter

Presentation Notes

Sumner & Crawford 2018 figure 1A

SMA – Clinical & Genetic Variability

Severity of Clinical Presentation correlates with SMN2 copy number

All types of SMA are caused by deletion/disruption of both SMN1 genes

Presenter

Presentation Notes

Classification table from Russman 2007 ; SMN2 copy number table from Mailman et al. 2002

SMA – Clinical & Genetic Variability

Type 0: RareType 1: 60% of casesType 2: 30-40%Type 3: 10%Type 4: Rare (possibly undetected or underdiagnosed)

Presenter

Presentation Notes

Classification table from Russman 2007

SMA - Treatment• Historically only multidisciplinary supportive

care• FDA approved Nusinersen in December 2016▫ Antisense oligonucleotide▫ Designed to increase % of full length protein

produced by SMN2 genes▫ Delivered by lumbar puncture▫ 4 Loading doses in the first 2 months▫ Maintenance treatment: 1 dose every 4 months▫ Price per dose: $125,000

SMA – Treatment: Nusinersen• Phase II dose escalation study (Finkel et al. 2016)▫ 20 patients with type 1 SMA▫ Significant improvements in motor function

SMA - Treatment

• Other therapies in clinical trials

SMA Treatment

Presenter

Presentation Notes

Sumner & Crawford 2018 figure 1C

SMA TreatmentFDA ApprovedClinical trials

Clinical trials

Presenter

Presentation Notes

Sumner & Crawford 2018 figure 1C

SMA - ACHDNC• SMA Timeline▫ 2008 initial nomination resulted in the committee

declining to hold a formal evidence review and recommended prospective pilot studies to evaluate the testing method proposed

▫ [Nusinersen approved by FDA in December 2016]▫ 2017 Committee accepted proposal and started the

evidence review process ▫ February 8th, 2018 – voted to recommend the HHS

Secretary add SMA to the RUSP ▫ July 2nd, 2018 – HHS Secretary Azar accepts ACHDNC

recommendation to add SMA to RUSP

SMA – ACHDNC Evidence Review

• Systematic Evidence Review 2000- June 2017, update through January 12, 2018▫ 4 of 7 key treatment and screening articles were

published during the review▫ 5 of 8 key background articles published after

November 2017▫ Also included 4 grey literature/conference

presentation/posters (not peer reviewed sources)


• Single dose gene-replacement study (Mendell et al. 2017)- NOT FDA approved…

•


• Nusinersen – Manufacturer-funded studies▫ CHERISH: Phase III, later-onset SMA▫ ENDEAR: Phase III, infantile-onset SMA▫ NURTURE: Phase II open-label, pre-symptomatic

SMA▫ EMBRACE: Phase II open-label, not eligible for

other studies▫ SHINE: Open-label extension study

SMA – Treatment: Nusinersen

• Phase III blinded treatment/control study ▫ ENDEAR study▫ Enrolled infants with Type 1 SMA, 7 months or

younger – NOT pre-symptomatic▫ halted after 13 months when the unblinded

monitor identified significant differences between the two groups

SMA – Treatment: Nusinersen

• Phase III blinded treatment/control study

Event-free survival = alive without use of permanent ventilation


• Phase II open-label, pre-symptomatic SMA ▫ NURTURE study▫ Not completed (or published) before review time-

frame▫ References several poster presentations of the

data from this study subjects (siblings, NBS, prenatal screening)- 20 in 1

poster, 9 in another Suggest motor milestone development better in

those treated pre-symptomatically


• Treatment Guidelines▫ At time of the review, a 13 voting member

workgroup was developing guidelines▫ In February, a manuscript had been submitted for

publication and was under review. ▫ [Prepublished on-line in March, then published

online in May- Glascock et al. article] Expert consensus on whom to treat at diagnosis

(with 2 or 3 copies of SMN2) and how/how often to monitor those with 4+ copies of SMN2

SMA - ACHDNC

• Secretary Azar’s letter excerpt:

SMA - ACHDNC

• Secretary Azar’s letter excerpt:

Previously, HHS secretary has not asked for additional information, updates…

CIDAC Panel Management Subcommittee Discussion• Wilson & Junger Criteria▫ Important health problem? YES▫ Accepted treatment? Discussion about the amount of data available on

presymptomatic patients and regarding the cost of treatment

▫ Facilities for dx and treatment? YES▫ Recognizable latent/early symptomatic stage?

YES, for types 1, 2, 3, & 4▫ Suitable test? YES

CIDAC Subcommittee Discussion• Wilson & Junger Criteria▫ Acceptable to the population? YES▫ Natural hx of condition understood? YES, for

types 1, 2, & 3▫ Agreed Policy on whom to treat? YES▫ Cost of case finding (including dx and treatment)

economically balanced? Discussion regarding the cost of nusinersen and the

long-term possible effects of treatment via lumbar puncture

▫ Case finding a continuing process? YES

CIDAC Subcommittee Discussion• Iowa’s capacity to provide a suitable test▫ CDC-developed combination SCID/SMA assay▫ Targets only exon 7 deletions- no carrier detection▫ Approximately 5% false negative rate▫ Does not detect SMN2 copy number▫ 2nd tier SMN2 testing would not be cost effective and would

delay results by several days (similar to CF screening)• Facilities/expertise for dx & treatment▫ UIHC has the only Neuromuscular clinic in IA – general

pediatric neurology not recommended (Glascock et al.)▫ Centers in surrounding states: Omaha, NE; Gillette in MN;

Wash U & Mercy Kansas City in MO. IL currently limited (maybe Lurie Children’s in Chicago)

Panel Management Subcommittee Discussion• Potential impact on existing NBS system▫ SHL- feasible with existing lab space and minimal

need for additional staffing. Would require additional $ for testing and IT

▫ STFU- feasible with expected staffing of 5 staff▫ LTFU- UIHC neuromuscular team has capacity to see

NBS cases; Lack of formal LTFU system in state for late-onset types

▫ IDPH- would need to update NBS brochure and lead to request for legislative change to increase the NBS fee

▫ Program wide- education/marketing for changes to NBS for PCPs, birthing facilities, general public

Panel Management Subcommittee Discussion• Financial Feasibility▫ SHL would request to use developmental funding for a pilot

study▫ Uncertainty of how another request to increase the NBS fee

(new fee of $150 –increase of $28- goes into effect 7/1/19)▫ Per clinical members, insurance has been covering cost of

Nusinersen▫ What is the overall cost to insurance/state/society?

Extremely hard to calculate▫ Treatment cost is high, but it lowers other medical costs for

patients & potentially allows for parent(s) and patient to remain/become productive members of society

Panel Management Subcommittee Discussion• Position Statements from local/national

organizations▫ Support from CureSMA, Child Neurology

Foundation, MDA, and SMA Foundation▫ No known groups opposed to NBS for SMA

• Public Forum Needed?▫ Subcommittee consensus that a public forum is

not needed▫ Request was voiced to have a consented pilot (not

previously done in IA)

Panel Management Subcommittee Discussion• Summary of Primary Support▫ Low false positive rate (0% in published NBS trials)▫ Ability to screen for SMA without detecting carriers

(estimated at approximately 700 per year)▫ Majority of cases are earlier onset▫ INSP currently has capacity for adding SMA to NBS

without major staffing or infrastructure changes▫ Vigorous enthusiasm from clinical staff regarding

effectiveness of treatment with nusinersen ▫ Treatment is currently being covered by insurance,

including Iowa Medicaid

Panel Management Subcommittee Discussion• Summary of Main Areas of Concern

▫ Cost of treatment/insurance coverage/healthcare equity Looked into possible options for cost/benefit analysis tools, but nothing

was readily useable▫ Limited data on pre symptomatic treatment with Nusinersen (9 cases

followed for 1 year)▫ Lack of Long-Term Follow Up system in INSP- how to track late-onset

cases over time to determine when to start/offer treatment?▫ It is unknown if our current funding process (developmental funds for

pilot studies) will be sufficient for adding all new RUSP disorders▫ Lack of consent process in the pilot process for new conditions in Iowa

NBS▫ Unknown false negative rate (estimated at 5-7%)▫ Would be the first time the primary screening method is by genomic

molecular analysis (not brought up during subcommittee discussion)

Panel Management Subcommittee Vote

• “Iowa should add Spinal Muscular Atrophy (SMA) caused by homozygous deletion of exon 7 of the SMN1 gene to the panel of conditions on Newborn Screening.”

• Sent via email to all subcommittee members with Yes, No, and Maybe options for voting


• Results▫ Yes: 9▫ No: 2▫ Maybe: 0▫ Three members chose to abstain from voting

• Most votes were submitted without additional comments


• Questions/Concerns submitted▫ “Certainty of benefit is lacking”▫ Does pre-symptomatic detection provide improved

outcomes over clinical detection? Does it vary by SMN2 (2 vs 3)copy number? Possible plateau of motor milestones in cases with 2

SMN2 copies- from poster presentation▫ Risks associated with treatment? Renal toxicity noted

in medication package insert▫ Recommendation to reconvene the subcommittee

when additional data is published from the NURTURE trial


• Additional supportive information submitted▫ Link to the Spring 2018 CureSMA newsletter that

highlights SMA’s addition to RUSP and need for advocacy on the state level http://www.curesma.org/documents/compass-publications/compass-spring-2018.pdf

http://www.curesma.org/documents/compass-publications/compass-spring-2018.pdf

References – Peer Reviewed Articles• Burgart et al. Ethical Challenges Confronted When Providing Nusinersen Treatment for Spinal

Muscular Atrophy. JAMA Pediatrics (2018)172 (2), 188-192.• Finkel et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2,

open-label, dose escalation study. Lancet (2016) 388: 3017-26.• Finkel et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. NEJM

(2017) 377: 1723-32.• Glascock et al. Treatment Algorithm for Infants Diagnosed with Spinal Muscular Atrophy through

Newborn Screening. Journal of Neuromuscular Diseases (2018) 5, 145-158.• Phan et al. Newborn screening for spinal muscular atrophy: Anticipating an imminent need.

Seminars in Perinatology (2015) 39; 217-229.• Mailman et al. Molecular analysis of spinal muscular atrophy and modification of the phenotype

by SMN2. Genetics in Medicine (2002) 4 (1), 20-6.• Mendell et al. Single-Dose Gene-Replacement Therapy for SMA. NEJM. 2017; 377: 1713-1722. • Russman. Spinal Muscular Atrophy: Clinical Classification and Disease Heterogeneity. Journal of

Child Neurology (2007) 22(8), 946-951.• Sugarman et al. Pan-Ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy:

clinical laboratory analysis of >72 400 specimens. European Journal of Human Genetics (2012) 20, 27–32

• Sumner and Crawford. Two breakthrough gene-targeted treatments for spinal muscular atrophy: challenges remain. J Clin Invest (July 9, 2018) https://doi.org/10.1172/JCI121658.

https://doi.org/10.1172/JCI121658

References - Other• ACHDNC home: https://www.hrsa.gov/advisory-

committees/heritable-disorders/index.html• ACHDNC – Evidence Review of SMA

https://www.hrsa.gov/sites/default/files/hrsa/advisory-committees/heritable-disorders/meetings/20180208/kemper-smae-evidence-review.pdf

• Clinicaltrials.org• CureSMA.org• GeneReviews for Spinal Muscular Atrophy

https://www.ncbi.nlm.nih.gov/books/NBK1352/

https://www.hrsa.gov/advisory-committees/heritable-disorders/index.html

https://www.hrsa.gov/sites/default/files/hrsa/advisory-committees/heritable-disorders/meetings/20180208/kemper-smae-evidence-review.pdf

https://www.ncbi.nlm.nih.gov/books/NBK1352/

Summary of the UIHC clinical opinion re: SMA newborn screening • Type 1 SMA is uniformly fatal in infancy or requires fulltime

ventilation and significant medical support for life

• The clinical diagnosis cannot be made until there is obvious weakness that might not be recovered.

• Newborn screening is inexpensive, sensitive and specific while the economic and psychological costs of early childhood death or longterm profound disability are quite high.

• Treatment is highly effective when started before there is disease progression for all types of SMA • The cost of current or evolving treatments is not pertinent to the discussion

of newborn screening

• Early diagnosis will prevent morbidity and potentially mortality

FDA Review Summary of Nusinersen (note that the FDA has access to data not yet published and is experienced at interpreting this data)

• Please refer to the Table titled “Evidence and Uncertainties” • Benefit: “This application has established that nusinersen is effective in early

onset patients, with information supporting a beneficial effect in later onset patients. “

• FDA did not create an advisory committee to assist in review because there were “no controversial issues that would benefit from advisory committee discussion”.

RUSP Chairman letter to the Secretary re: SMA • “The Committee believes that screening for SMA will lead to

significant benefits for infants born with this rare condition and respectfully requests that you accept the recommendation to add SMA to the RUSP.” • Joseph A. Bocchini, Jr., M.D. Chairperson

Secretary’s Letter to the RUSP on ALD

• ”I also want to clarify that the addition of X-ALD to the RUSP does not constitute a requirement for the states to implement screening and is only a recommendation.” • Sylvia M Burwell, Feb 2016

• This language is not specific to SMA and does not imply a lack of enthusiasm for adding the disease on the part of HHS.

Long term follow-up

• There are national efforts in place through advocacy groups and clinicians to formalize long term follow-up of patients with SMA • CureSMA

• MDA

• Regional groups

• Individual clinic’s databases.

• There is no need for the state of Iowa to duplicate these activities and doing so is outside the scope of newborn screening.

Wilson and Jungner Criteria applied to SMA

• 1. The condition sought should be an important health problem. YES 2. There should be an accepted treatment for patients with recognized disease. YES 3. Facilities for diagnosis and treatment should be available. YES 4. There should be a recognizable latent or early symptomatic stage. YES 5. There should be a suitable test or examination. YES 6. The test should be acceptable to the population. YES 7. The natural history of the condition, including development from latent to declared disease, should be adequately understood. YES 8. There should be an agreed policy on whom to treat as patients. YES 9. The cost of case-finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole. YES 10. Case-finding should be a continuing process and not a “once and for all” project. YES

Evolving criteria for newborn screening

• Wilson and Jungner criteria were developed in 1968

• Medicine and science have evolved since then and new criteria or systems for discussing newborn screening are under discussion • There is no nationally agreed-upon new set of criteria.

• We feel that SMA easily fulfills the Wilson and Jungner criteria

• As more genetic treatments come to the clinic, perhaps a subcommittee needs to consider how Iowa will consider new conditions for newborn screening. Currently we don’t have these new criteria.

Newborn Screening for SMA in Iowa

Paper/Source (Au, Yr) Title Summary Travis x2 slide shows Focuses ONLY on nusinersen, ignores other

interventions that could affect disease course Example: survival significantly impacted by

respiratory interventions Ignores ENDEAR results (below), which showed

earlier=better treatment with nusinersen Swoboda et al, 2015 Natural History of Denervation in

SMA: Relation to Age, SMN2 Copy Number, and Function

The irreversible loss of motor neurons in humans with SMA type 1 begins early in the perinatal period, with severe denervation in the first three months and loss of more than 90% of motor units within six months of age

Lin, 2015 Delay in Diagnosis of Spinal Muscular Atrophy: A Systematic Literature Review

21 reports included mean ages of symptom onset were 2.5, 8.3, and 39.0 months for SMA types 1, 2, and 3 respectively, whereas the weighted mean ages of confirmed SMA diagnosis were 6.3, 20.7, and 50.3 months for types 1, 2, and 3, respectively

Nearly 4 month delay in Dx for SMA type 1 Glascock, 2018 Treatment Algorithm for Infants

Diagnosed with Spinal Muscular Atrophy through Newborn Screening

Consensus statement to guide action “Preclinical studies looking at the timing of drug

delivery in severe mouse models of SMA consistently show that the best results occur when drugs are given as early as possible,before significant motor weakness or loss is present”

Statements re: ENDEAR study (published in Finkel below):

o only 32% of infants with a disease duration of more than 12 weeks responded positively

o 75% of infants with disease duration of 12 weeks or less responded positively

Finkel, 2017 Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy

ENDEAR phase 3 data infants with a shorter disease duration at screening

were more likely than those with a longer disease duration to benefit from nusinersen

the likelihood of event-free survival was higher among infants who had a shorter disease duration at screening (≤13.1 weeks) than among those who had a longer disease duration

Case Examples

Baby boy: 1st NM clinic visit @ 7 mos

o Born prematurely @ 32 wks, needed O2 x2 wks. NBS neg for CF, HgbSS Cough noted at 1 mo old, gone by 6 wks old At 2 mos: noted to have retractions with head bobbing w/ breathing At 2½ mos: admitted for respiratory distress, worsening despite antibiotics.

After discharge: sent for swallow study (normal) At 4½ mos: admitted after bronchoscopy (done to work up persistent resp

concerns & abnormalities on CXR) o Motor concerns: at 3-4 mos old: reached with arms, rolled “halfway”

Stopped lifting UEs/LEs against gravity by 4-5 mos old No head control

o In clinic (7 mos old): sent SMA gene test, arranged Pulm appt (NM expert) for 10 days later

6 days later: result came back w/ 0 SMN1, 2 SMN2 = SMA. Plan to discuss face-to-face at upcoming clinic visit (in 4 days).

2 days later: brought to urgent care for resp distress. Gene test result not known by family or urgent care, sent home after a breathing treatment.

2 days later (day of planned clinic visit w/ pulmonary): found not breathing and pulseless at home by mom. After long course of CPR, pulse returned but died in UIHC PICU a couple days later. Mom informed of SMA test result while in PICU

Baby boy: 1st NM clinical eval @ 2 ½ mos old o Born at 36 weeks but did fine, home after 3 days o At 2 mo checkup:

Noted to have 2 tight fingers on R hand Subsequently came to involve bilat hands & all fingers Saw non-NM pediatric neurologist, noted abnormal finger posture but

otherwise felt to be normal o 2 wks later: admitted for resp distress, noted to have bilat finger and wrist & toe

contractures Neuro consulted, had EMGmotor denervating disorder Large workup undertaken, incl SMA gene test

o Within the next wk: 0 SMN1, 2 SMN2 = SMA o 6 days later: got 1st dose of nusinersen o 7 mos later: signif improvement on HINE and CHOP-INTEND motor scales, rolls over,

good head control, no further hospitalizations BUT: still with bilat finger/hand deformities despite PT, bracing, stretching

(didn’t start until deformities already were present)

Summary

The 2 concrete, exemplary cases above illustrate that, while nusinersen is an exciting and novel therapy that changes the course of disease and impacts morbidity and mortality, there remain other interventions (respiratory, orthopedic, etc) that can only be appropriately mobilized if the diagnostic delay is eliminated. In addition, data and publications that abound in the literature demonstrate that there is an early and irreversible loss of motor neurons in SMA before clinically apparent weakness may manifest. This loss of motor neurons cannot be reversed and dead cells cannot be regenerated. In both animal and human (NURTURE, ENDEAR) treatment trials, there is evidence that earlier treatment of SMA (whether presymptomatic or after weakness develops) produces better results. It is clear that there is a several month delay in diagnosis in the most severe form (type 1) of SMA, with even longer delays in types 2 and 3. During the months (or longer) of delay, there is ongoing and rapid death of motor neurons. Newborn screening for SMA would eliminate the delay in diagnosis and allow early initiation of nusinersen and other interventions to improve health outcomes.

9/17/2018 State of Iowa Mail - Newborn screening for SMA

https://mail.google.com/mail/ca/u/0/?ui=2&ik=51b1a3557c&jsver=K8SpjNhSmRc.en.&cbl=gmail_fe_180909.14_p3&view=pt&cat=CIDAC%2FSMA%2… 1/1

Piper, Kimberly <[email protected]>

Newborn screening for SMA 1 message

[email protected] <[email protected]> Fri, Jul 20, 2018 at 12:14 AMTo: [email protected]

Hello! I wanted to share my experience as parent to an older child who has Type I SMA and how newborn screening is soimportant in my opinion. Feel free to share at your meeting today. Thank you, Sarah Turnbull Hello! I am writing on behalf of my daughter Stella who was born with Type I SMA. Born a perfectly healthy baby girl, wehad no reason to fear she would be any different than our first child health-wise. Suddenly at just one month of age, ourhealthy baby girl suddenly became severely floppy. Her primary care doctor even commented that he had seen her justone week before and had no indication of something being terribly wrong. After extensive testing, we were told there wasnothing we could do and that we should simply “take her home and love her “. Since she was the most severe case the hospital had diagnosed, we were given weeks or months as a prognosis. At two months of age, she quit breathing in her car seat because she couldn’t manage her secretions while sitting up. After performing CPR for a half hour, she came back to us, thankfully unscathed over the whole situation, only for it tohappen again the following month. To be honest, I can’t accurately count how many times we were lucky not to lose herbecause she choked on secretions or had a trach plug that nearly took her life. Our home gradually became a medicalarsenal, first with a suction machine, oxygen, bipap and a pulse oximeter and then a feeding tube, a tracheostomy, coughassist and various other machines and supplies. She has endured various surgeries and hospital stays. As a family, wehave come to rely on my husband’s job as I have to be available for the various doctor appointments, therapies,unexpected illnesses and medical emergencies that happen and therefore could never be a reliable employee for anemployer. With all of this said, I am happy to report that our Stella is now 11 years old and will start 6th grade this fall. The past 11years has been incredibly trying, not only from the touch-and-go situations but also the stress it puts on a marriage andthe siblings and extended family members. However, all of that stress means that our Stella is still with us and I wouldn’ttrade it for the world. With that said, I have sent far too many cards and memorials to other SMA families who had to say goodbye to their littlewarriors far too soon. Before 2017, we understood why newborn screening did little to help the disease course and therefore not worth the cost.However, with the advancements of Spinraza and gene therapy, there is incredible hope for these children. We personallyknow a family that has three children with Type I SMA. Their first child is very weak like my daughter. Their second Type Ichild was treated with Spinraza shortly after birth and is now a walking, talking toddler. Their third child was recently bornand treated with gene therapy after birth and is making typical gains as an infant. Future generations of SMA familieshave so much hope and they deserve the opportunity to treat their children as early as possible. We know what happensif you wait too long for the disease progression to take place ... you risk losing your child or losing muscle mass that couldhave allowed the child to be strong. While I hate to bring money into it, we all know how much it costs to raise a medicallycomplex child. Getting help to the child as early as possible gives them the best possible outcome. The majority of SMAchildren end up being Type I which is even more reason to find out as early as possible. As the leading genetic killer ofinfants, it is simply a moral obligation to give these families the opportunity to help their child as early as possible whenwe know what happens if we don’t help them as early as possible. Thank you for your time and consideration. Sincerely, Sarah Turnbull Pella, IA 641 780 1701 Sent from my iPhone

Spinal Muscular Atrophy:What is the Benefit Associated with

Presymptomatic Treatment with Nusinersen?

Travis Henry PhDNewborn Screening Scientist

State Hygienic Laboratory at the University of Iowa

Nusinersen benefit

• Nusinersen clinical trial data has been collected for postsymptomatic/clinical treatment of SMA as well as presymptomatictreatment

• Does presymptomatic treatment result in improved outcomes as compared to postsymptomatic treatment?

Nusinersen benefit• Nusinersen clinical trial: CS3A• 24 months of data• n=20 patients enrolled• Symptoms before 6 months of age• Nusinersen loading doses:

– n=4; 6 mg first 3 doses then 12 mg afterwards• All 4 have 2 SMN2 copies

– n=16; 12 mg for all doses• 13 have 2 SMN2 copies• 2 have 3 SMN2• 1 unknown

• Overall, 17 of 20 subjects with 2 SMN2 copies• Those with 3 SMN2 copies appeared to achieve greater

motor milestones

Nusinersen benefit• Nusinersen clinical trial: CS3B• Randomized trial (2:1, Nusinersen:sham treatment)• Outcome measures:

– Motor milestones– Ventilator-free survival

• >/= 6 months of data following first dose• n=73 (37 sham treatment)• Symptoms before 6 months• ALL subjects with 2 SMN2 copies• Trial terminated early due to statistically significant increase

in event free survival for Nusinersen group• FDA approval based on this data

Nusinersen benefit

• Improvement in motor milestones based on Hammersmith Infant Neurological Examination (HINE) Section 2

• HINE2 provides a grading system for achieving developmental milestones such as grasping, sitting unsupported, standing, etc

Nusinersen benefit

CS3A: 17/20 with 2 SMN2 copies

CS3B: 2 SMN2 copies

Nusinersen benefit

• NURTURE trial– Presymptomatic treatment– Infantile onset SMA– Primary endpoint measure:

• Ventilator-free survival• Secondary outcome: motor milestones

– Enrollment </= 1 month of age– 12/17 with 2 copies of SMN2

Nusinersen benefit

Source: ACHDNC SMA Evidence Review Summary

Nusinersen benefit• NURTURE trial; subjects with 1 year of data

and 2 SMN2 copies

Nusinersen benefit• NURTURE trial; subjects with 1 year of data

and 3 SMN2 copies

Nusinersen benefit

• SMN2 copy number impacts motor milestones

Source: ACHDNC SMA Evidence Review Summary

SUMMARY• Does presymptomatic treatment (newborn

screening) provide improved outcomes as compared to postsymptomatic treatment (clinical detection)?– CS3A trial (postsymptomatic, n=20): sitting without

support at 2 years– Nurture trial (presymptomatic, n=9): sitting without

support at 1 year• Motor milestones for presymptomatic treatment

is not known past 1 year and data is mixed on improved motor milestones as compared to clinical detection

SUMMARY

SUMMARY• Is there sufficient data available for

presymptomatic treatment to determine benefit as compared to clinical detection?

• Is sufficient data available to determine benefit in a proposal for possible mandated screening for SMA?

• How can we get more data?– Nurture interim analysis data to be released

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2018-06-18 SMA Condition Review Travis Henry PhD Questions of benefit Does pre-symptomatic detection provide improved outcomes over clinical detection? What is the impact of SMN2 copy number on motor milestones achieved?

Figure 1. Poster presented by Nurture clinical trial group Using the above poster data (from the group leading the Nurture trial/presymptomatic treatment; Figure 1), I assigned HINE2 scores and plotted on the same graph as the ACHDNC Evidence Review data (Figures 2 and 3). Ultimately, the strength of the data published is decreased when considering SMN2 copy numbers. 3 of 9 patients do not achieve the same motor milestones and it is these 3 patients that have only 2 SMN2 copies. Achievements in motor milestones are split in the 2 SMN2 copy number group: 3 achieve standing or walking and 3 achieve sitting without support. All 3 patients with 3 SMN2 copies achieve standing or walking. However, compared to clinical detection, even the worst outcome for presymptomatic detection results in improved outcomes: HINE score of 7 versus 12 which equates to not being able to sit versus sitting with support. This is comparison of data at 1 year; the data for clinical detection at 2 years indicates patients treated with Nusinersen are achieving a HINE2 score of 12. So, it’s possible motor milestones

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associated with clinical detection may be the same at 2 years (HINE score of 11 versus 12). However, without additional data, the opposite could be true: presymptomatic detection may result in continued achievement of motor milestones versus clinical detection. Patient outcomes when treated with Nusinersen appear to equate with the number of SMN2 copies; the greater the number of SMN2 copies, the greater the motor milestones achieved. The CS3A and CS3B trials, which were nearly exclusively patients with 2 copies of SMN2 (86 of 88 patients; only 2 in the combined trial data had 3 copies) were able to achieve HINE2 scores of 12 by 2 years of treatment. Patients enrolled in the Nurture/presymptomatic trial with only 2 copies of SMN2 (n=3) achieve HINE2 scores of 12 by 1 year of age, but at this time, the data suggests that may be where development plateaus. Due to limited data, conclusions cannot be drawn, but this data suggests presymptomatic treatment of patients with 2 copies of SMN2 will result in the same motor milestone achievements as current clinical detection. Similarly, the data is not clear on the significant improvement in milestones achieved by 3 patients with 2 SMN2 copies in the Nurture trial. With only 3 patients it is difficult to assess the impact of unknown variables. CureSMA.org has announced a grant to study impact of SMA on organ systems other than SMA, so perhaps the 3 patients with 2 SMN2 copies with near normal milestones may have attenuated impact to other organ systems as compared to patients in the same trial that don’t achieve near normal milestones. Perhaps there are unknown genetic modifiers for SMN2. Again, data is extremely limited. There is the added unknown of renal toxicity associated with continuous treatment with Nusinersen. Published FDA data as well as the Nusinersen package insert identified “potentially fatal acute inflammation of the kidney” (proteinuria) in 33% of subjects treated for 1 year, with an increase to 69% of subjects experiencing proteinuria if treated for 2 years (Nusinersen Risk Assessment and Risk Mitigation Review(s), Section 5.4 Laboratory Abnormalities). The cost of possible renal treatment would need to be considered in the cost/benefit analysis.

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Figure 2. Data from ACHDNC collated trial data with addition of normal controls and Nurture poster data with motor milestones achieved based on SMN2 copy number.

2 copies SMN

2 n=3

2 and 3 copies SMN

2 n=6 (3 w

ith 2 copies and 3 w

ith 3)

2 copies SMN

2 n=73

Nurture trial

(presymptom

atic); n=9

2 copies SMN

2 n=13 of 15

4

Figure 3. ACHDNC graph for clinical trial data.

5

Figure 4. ACHDNC Evidence review for mean age of onset, diagnosis and delay for SMA. Figure 4 presents data from collated studies for mean age of onset, diagnosis and delay for SMA. The mean age of confirmed diagnosis for SMA Type I is 6.3 months, which would be equivalent to the patients enrolled in the CS3A and CS3B Nusinersen trials which required symptom onset before 6 months. Thus, the data from the CS3A and CS3B trials should be indicative of response to Nusinersen in the clinical setting. Summary and recommendation At this time, the data on which to recommend SMA review by CIDAC for possible addition to Iowa’s newborn screening panel is based on 9 patients with 1 year of treatment data. Unfortunately, due to the small number of patients for which data has been reported and the limited window of time over which the data has been captured, it is difficult to determine if additional benefit is associated with Nusinersen treatment in presymptomatic infants versus current clinical detection and treatment. Patient outcomes when treated with Nusinersen appear to equate with the number of SMN2 copies. When stratifying patients enrolled in the Nurture/presymptomatic trial based on SMN2 copy number, the data is split on the benefit of presymptomatic treatment versus clinical detection for those patients with 2 copies of SMN2. Data collated from worldwide studies of SMA reports only 20% of the global population will have 3 or more copies of SMN2. Due to limited data, conclusions cannot be drawn, but

6

this data suggests presymptomatic treatment of patients with 2 copies of SMN2 will result in the same motor milestone achievements as current clinical detection. When I assess Wilson and Jungner criteria and the impact of a state mandate for screening, there should be unquestionable benefit associated with screening in the newborn period. At this time, due to the limited data available on presymptomatic treatment with Nusinersen and the benefit associated with presymptomatic treatment for patients with 2 copies of SMN2, there is uncertainty associated with the benefit of newborn screening for SMA. As reported by CureSMA.org on March 12, 2018, Biogen announced interim results have been announced for the Nurture trial with a maximum follow up length of 25.6 months. CureSMA.org reported that all patients in the trial have achieved sitting without support. However, it is unclear from this announcement if this is the maximum motor milestone achieved for some patients as well as the duration of treatment associated with this achievement. The data from the interim analysis has not yet been released at this time. Additionally, large scale data release at 2018 Cure SMA Annual meeting June 14-17, 2018 http://investors.biogen.com/news-releases/news-release-details/biogen-enhances-commitment-sma-research-data-presented-annual It is my recommendation not to forward SMA to CIDAC for a full review at this time. However, this subcommittee should be re-convened when either additional data from the Nurture trial has been published or pertinent data has been made available.

http://investors.biogen.com/news-releases/news-release-details/biogen-enhances-commitment-sma-research-data-presented-annual

http://investors.biogen.com/news-releases/news-release-details/biogen-enhances-commitment-sma-research-data-presented-annual

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

209531Orig1s000

RISK ASSESSMENT and RISK MITIGATION REVIEW(S)

1

Division of Risk Management (DRISK) Office of Medication Error Prevention and Risk Management (OMEPRM)

Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER)

Application Type NDA

Application Number 209531

PDUFA Goal Date December 23, 2016

OSE RCM # 2016-2353

Reviewer Name(s) Bob Pratt, Pharm.D.

Acting Team Leader Donella Fitzgerald, Pharm.D.

Deputy Division Director Jamie Wilkins Parker, Pharm.D.

Review Completion Date December 13, 2016

Subject Evaluation of Need for a REMS

Established Name Nusinersen

Trade Name Spinraza™

Name of Applicant Biogen, Inc.

Therapeutic Class

Formulation(s)

Antisense oligonucleotide

12 mg in 5 mL solution

Dosing Regimen 12 mg intrathecal administration. Loading doses on Days followed by maintenance doses every 4 months.

Reference ID: 4026954

(b) (4)

2

Table of Contents

EXECUTIVE SUMMARY ............................................................................................................................................................3

1 Introduction........................................................................................................................................................................3

2 Background .........................................................................................................................................................................3

2.1 Product Information..............................................................................................................................................3

2.2 Regulatory History .................................................................................................................................................4

3 Therapeutic Context and Treatment Options ......................................................................................................4

3.1 Description of the Medical Condition.............................................................................................................4

3.2 Description of Current Treatment Options .................................................................................................5

4 Benefit Assessment .........................................................................................................................................................5

5 Risk Assessment & Safe-Use Conditions ...............................................................................................................6

5.1 Serious Adverse Events........................................................................................................................................6

5.2 Post Lumbar Puncture Associated Adverse Events.................................................................................7

5.3 Neurologic Toxicity................................................................................................................................................7

5.4 Laboratory Abnormalities .................................................................................................................................7

6 Expected Postmarket Use .............................................................................................................................................8

7 Risk Management Activities Proposed by the Applicant.................................................................................8

8 Discussion of Need for a REMS...................................................................................................................................8

9 Conclusion & Recommendations...............................................................................................................................9

10 Materials Reviewed ....................................................................................................................................................9

11 Appendices ..................................................................................................................................................................10

11.1 References...............................................................................................................................................................10


3

EXECUTIVE SUMMARYThis review by the Division of Risk Management (DRISK) evaluates whether a risk evaluation and mitigation strategy (REMS) for the new molecular entity Spinraza™ (nusinersen) is necessary to ensure the benefits of this product outweigh its risks. Biogen submitted a rolling New Drug Application (NDA 209531) on August 9 and September 23, 2016, for nusinersen with the proposed indication of treatment of spinal muscular atrophy. The risks associated with the use of nusinersen for which a REMS is being evaluated include post-lumbar puncture events and potential neurologic toxicity. The Applicant did not submit a REMS with this application but proposed risk management activities that include long-term data collection in ongoing open label studies as well as post-marketing surveillance to assess the potential for rare adverse reactions.

Spinal muscular atrophy is a rare, serious, debilitating, and life-threatening genetic disease of children with no treatment other than supportive care. Nusinersen showed significant clinical benefit and fulfills an unmet medical need. The primary risk associated with nusinersen is related to the intrathecal method of administration; potential neurologic toxicity is an additional risk. Therefore, DRISK and the Division of Neurologic Products (DNP) agree that a REMS is not needed to ensure the benefits of nusinersen outweigh its risks.

1 IntroductionThis review by the Division of Risk Management (DRISK) evaluates whether a risk evaluation and mitigation strategy (REMS) for the new molecular entity (NME) Spinraza™ (nusinersen) is necessary to ensure the benefits of this product outweigh its risks. Biogen submitted a rolling New Drug Application (NDA 209531) on August 9 and September 23, 2016, for nusinersen with the proposed indication of treatment of spinal muscular atrophy. This application is under review in the Division of Neurology Products. The Applicant did not submit a REMS with the application but proposed risk management activities that include long-term data collection in ongoing open label studies, as well as post-marketing surveillance to assess the potential for rare adverse reactions.

2 Background2.1 PRODUCT INFORMATION

Spinraza™ (nusinersen), a new molecular entitya, is an antisense oligonucleotide proposed for the treatment of spinal muscular atrophy, an autosomal recessive disease that involves the survival motor neuron gene. Antisense oligonucleotides are synthetic single-stranded nucleic acids that bind to RNA and modify gene expression. Nusinersen is designed to bind to and modulate splicing of the survival motor neuron 2 (SMN2) gene pre-mRNA, which intends to promote inclusion of exon 7 in SMN2 and increase the production of a functional SMN protein.

Nusinersen is supplied as a 12 mg/5 mL solution and administered by intrathecal injection using a 12 mg dose given on Days followed by a maintenance dose every 4 months.b The drug will

a FDAAA factor (F): Whether the drug is a new molecular entity.b FDAAA factor (D): The expected or actual duration of treatment with the drug.


(b) (4)

4

likely be administered in various settings that include hospital-affiliated outpatient clinics, interventional radiology departments, and the operating room, as anesthesia/sedation and fluoroscopy or ultrasound will be required for drug administration in some patients. Nusinersen received orphan product designation in April 2011 and was granted Fast Track designation in November 2011. Nusinersen is not currently approved in any other country.

2.2 REGULATORY HISTORY

The following is a summary of the regulatory history for NDA 209531 relevant to this review:

04/18/2011: Orphan product designation granted for the treatment of spinal muscular atrophy

11/29/2011: Fast track designation granted

08/09/2016: NDA 209531, Rolling Submission Part 1 of 2, for the treatment of spinal muscular atrophy received

09/23/2016: NDA 209531, Rolling Submission Part 2 of 2, for the treatment of spinal muscular atrophy received

10/31/2016: A post mid-cycle meeting was held between the Agency and the Applicant via teleconference. The Agency informed the Applicant that there is currently no need for a REMS.

3 Therapeutic Context and Treatment Options

3.1 DESCRIPTION OF THE MEDICAL CONDITION 1,2,3

Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by deletions or mutations in the survival motor neuron 1 (SMN1) gene. The most common mutation is a deletion of exon 7. Humans have a paralogousc SMN2 gene that differs from SMN1 by 11 nucleotides, including a single nucleotide difference that causes skipping of exon 7. The skipping of exon 7 results in only low levels of SMN2 protein, which are insufficient on a functional level. Modulation of splicing of the SMN2 pre-mRNA to include exon 7 intends to increase the production of a functional compensatory SMN protein.

The incidence of SMA ranges from 4 – 10 per 100,000 live births, and the U.S. prevalence is estimated to be around 25,000 patients.d

SMA is characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem, resulting in muscular atrophy and weakness. Patients with SMA have symmetric proximal muscle weakness that is greater in the lower than upper limbs. The disease is also associated with a restrictive, progressive respiratory insufficiency that leads to respiratory failure. SMA is classified as type 1 through 4 depending upon the age of onset and disease course. SMA type 1, also known as infantile spinal muscular atrophy, is the most common (approximately 60% of patients) and severe type

c Paralogous genes originate by duplication wherein one copy of the gene receives a mutation that gives rise to a new gene with a new function, though that function is often related to the role of the ancestral gene.d FDAAA factor (A): The estimated size of the population likely to use the drug involved.


5

of SMA. It typically presents in the neonatal period and progresses rapidly. Infants with SMA-1 have a severe symmetric flaccid paralysis, are unable to sit unsupported, and usually die within the first two years of life from respiratory failure and infection.e SMA-2 (intermediate form) and SMA-3 (mild form) have a later onset and a less severe course. SMA-2 presents between 3 and 15 months of age; patients can sit but cannot walk independently, and death from respiratory complications typically occurs after two years of age. SMA-3 is less severe and typically presents with signs of weakness at or after one year of age and progresses to a chronic course; patients are able to walk but with difficulty. Adult onset of SMA (type 4) usually presents in the second or third decade of life and is the mildest variant.

3.2 DESCRIPTION OF CURRENT TREATMENT OPTIONS

Current treatment for SMA is supportive and directed at providing nutrition and respiratory assistance as needed, and treating or preventing complications. Physical therapy may be helpful.

4 Benefit Assessment f,g

The pivotal clinical study (Study CS3B) supporting this application is a multicenter, randomized, double-blind, multiple-dose, sham-controlled study of intrathecal nusinersen in 121 subjects with infantile-onset SMA. The study examined 12 mg doses of nusinersen. In infants less than 24 months of age, the dose was adjusted for the estimated cerebrospinal fluid (CSF) volume at that age to deliver an equivalent dose volume. Subjects received loading doses of nusinersen by intrathecal injection on Days 1, 15, 29, and 64, and then received maintenance doses once every 4 months. The primary efficacy endpoint was a responder analysis for the development of motor milestones using the Hammersmith Infant Neurological Examination (HINE). A responder was defined as a subject who improved in more motor milestone categories than worsened. Survival and additional measures of motor function, such as the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), served as secondary endpoints. Survival analyses were performed on the intent-to-treat population.

Analysis of the interim efficacy population, which was comprised of 82 subjects, found a statistically significantly greater percentage of subjects achieved a HINE motor milestone response in the nusinersen group (40%; n=20 of 52) compared to the control group (0%; n=0 of 30) (p<0.0001). Of note, five subjects achieved independent sitting and one subject achieved standing (which SMA-1 patients typically never achieve) whereas no subjects in the control group achieved these milestones. Although not statistically significant, neuromuscular function as measured by the CHOP INTEND score also improved in the infants who received nusinersen. 65% of infants who received nusinersen had at least a 4-point improvement in CHOP INTEND score compared to 4% of infants in the control group. An analysis of overall survival found a lower percentage of subjects in the nusinersen group (15%) died compared with the control group (32%), though this was not statistically significant.

e FDAAA factor (B): The seriousness of the disease or condition that is to be treated with the drug.f Paine, R. Draft Clinical Review for Spinraza (nusinersen), NDA 209531, dated December 1, 2016.g Massie T. Statistical Review for Spinraza (nusinersen), NDA 209531, November 30, 2016.


6

As a result of the positive interim analysis, the Applicant decided to terminate the study early on the grounds that continuing a controlled study was no longer ethical.h

5 Risk Assessment & Safe-Use Conditions i

The safety population is comprised of 173 nusinersen-treated subjects in controlled and uncontrolled studies. 83 and 54 subjects had at least one and two years of exposure, respectively.

5.1 SERIOUS ADVERSE EVENTS j,k

In the controlled pivotal study, 12 of 80 subjects (15%) in the nusinersen group and 13 of 41 subjects (32%) in the control group died. 17 of the 25 deaths were due to respiratory disorders (nusinersen 7; control 10) including respiratory failure and respiratory arrest. Two subjects in each group died of cardio-respiratory arrest. Two subjects in the nusinersen group died of nervous system disorders, including one due to hypoxic brain injury after cardiorespiratory arrest, and one due to hypoxic-ischemic encephalopathy after aspiration. One subject in the nusinersen group had an unclear cause of death, and one subject in the control group expired after the patient had initiated palliative care. The clinical safety reviewer stated that the deaths were related to complications of the underlying SMA disease (with the exception of the case with an unclear cause of death).

Serious adverse events (SAEs) were reported in 56 subjects (70%) in the nusinersen group and 33 subjects (80%) in the control group. The clinical safety reviewer stated most of the SAEs were manifestations of SMA. The most common SAEs were respiratory distress (nusinersen versus control: 24% versus 24%), respiratory failure (21% versus 34%), pneumonia (18% versus 10%), acute respiratory failure (14% versus 17%), atelectasis (14% versus 5%), pneumonia aspiration (8% versus 10%), rhinovirus infection (8% versus 5%), pneumonia viral (6% versus 2%), and cardio-respiratory arrest (6% versus 7%). The clinical safety reviewer considered that obstructive atelectasis related to infection and mucus plugging may have contributed to the increased frequency of serious atelectasis, and that use of sedation with nitrous oxide may have contributed to at least one of these cases. In addition, cases of cardio-respiratory arrest were assessed by the safety reviewer as likely related to advanced disease.

h FDAAA factor (C): The expected benefit of the drug with respect to such disease or condition. i Mentari E. Draft Clinical Safety Review for Spinraza (nusinersen), NDA 209531, December 3, 2016.j Any adverse drug experience occurring at any dose that results in any of the following outcomes: Death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or patient and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.k FDAAA factor (E): The seriousness of any known or potential adverse events that may be related to the drug and the background incidence of such events in the population likely to use the drug.


7

5.2 POST LUMBAR PUNCTURE ASSOCIATED ADVERSE EVENTS

Post lumbar puncture adverse events reported in the safety population included back pain (17%), post lumbar puncture syndrome (12%), headache (12%), vomiting (9%), nausea (5%), and other symptoms. Most of these events were reported in subjects with later-onset SMA (it's noted that subjects with infantile-onset SMA as infants are not yet able to verbally communicate symptoms). Two of the 21 post lumbar puncture syndrome events were categorized as SAEs.

Information regarding failed lumbar punctures was not systematically collected across the clinical development program. However, adverse events related to failed lumbar puncture attempts in infants with presymptomatic SMA included spinal cord hematoma, epidural hemorrhage and spinal subarachnoid hemorrhage, extradural hematoma, and subdural hematoma. These events were managed with the standard of care, and all events resolved.

5.3 NEUROLOGIC TOXICITY

In the controlled study, a higher percentage of nusinersen-treated subjects experienced events within the MedDRA SOC nervous system disorders compared with the control group (10% versus 5%). No single event contributed to the higher incidence; nine events with different preferred terms were reported in 8 nusinersen-treated subjects, including nystagmus (2 reports), muscle contractions involuntary, seizure, drooling, brain injury, clonus, hypoxic-ischemic encephalopathy, and somnolence. Two of these events were SAEs; one subject experienced seizure in the setting of a brain injury event that was categorized as serious. A second subject experienced an SAE of cardiac arrest after aspiration of a tube feeding and hypoxic-ischemic encephalopathy. The clinical safety reviewer was of the opinion that these SAEs were unlikely related to nusinersen.

Evidence of neurotoxicity was reported in nonclinical studies of nusinersen in juvenile cynomolgus monkeys. Some animals showed dose-dependent hippocampal vacuolization, with necrotic cells identified in some monkeys who received a nusinersen dose equivalent of 130 to 520 mg total first year doses in humans (the adult human total first year dose is 72 mg). No cell necrosis or vacuolization was observed in animals that received a nusinersen first year total dose equivalent of 39 mg.l

5.4 LABORATORY ABNORMALITIES m

Six of 56 (11%) nusinersen-treated subjects had a platelet level below the lower limit of normal, compared to 0 of 28 control subjects in Study CS3B. No patient had a platelet count less than 50,000 cells/µL in that study.

Proteinuria occurred in 17 of 51 (33%) nusinersen subjects with infantile onset SMA, compared to 5/25 (20%) control subjects. Proteinuria occurred in 26 of 52 (69%) later-onset SMA subjects with a longer duration of treatment. Treatment-emergent low serum bicarbonate occurred in 32 of 48 (67%) of

l The 39 mg dose equivalent in monkeys is half the human first-year dose (72 mg) but similar to the yearly human chronic maintenance dose (36mg). m Laboratory abnormalities were nonserious adverse events (except when stated otherwise) or were not coded as adverse events.


8

nusinersen subjects in whom it was measured; measurements from a control group were not performed.

In Study CS3B, 1 of 59 (2%) nusinersen subjects had treatment-emergent low serum sodium, compared to 0 of 28 control subjects. Of all treated nusinersen subjects, 6 of 151 (4%) had at least one low serum sodium measurement. Three subjects had hyponatremia below 130 mmol/L. One of these events was a severe and serious adverse event that the clinical safety reviewer considered possibly related to nusinersen. The patient required sodium supplementation during the time of subsequent nusinersen doses.

In Study CS3B, 2 of 55 (4%) nusinersen-treated subjects had an alanine aminotransferase (ALT) level greater than 3 times the upper limit of normal, compared to 0 of 25 control subjects. There were no cases of Hy’s law drug-induced liver injury.

6 Expected Postmarket UseNusinersen is likely to be prescribed by pediatric neurologists, and perhaps by other members of the multidisciplinary clinical teams that manage SMA patients. The use of imaging or sedation will limit the practice setting for drug administration, and lumbar puncture is routinely performed for diagnostic and therapeutic purposes in children and infants and is generally a safe procedure. Therefore, it is expected that the drug will be administered by neurologists, radiologists, and pediatric anesthesiologists in various hospital settings that include interventional radiology departments, affiliated outpatient clinics, and the operating room.4

7 Risk Management Activities Proposed by the ApplicantThe Applicant did not submit a REMS with this application but proposed risk management activities that include long-term data collection in ongoing open label studies, as well as post-marketing surveillance to assess the potential for rare adverse reactions.

8 Discussion of Need for a REMSSpinal muscular atrophy is a rare, serious, life-threatening genetic disease of children that is usually lethal in infants. There are no approved treatments for SMA at this time, and current clinical management is limited to supportive care. The pivotal trial's interim efficacy analysis found a substantially greater percentage of subjects achieved a HINE motor milestone response in the nusinersen group compared to the control group. Five subjects achieved independent sitting and one subject achieved standing, whereas no subjects in the control group achieved these milestones.

The potential serious adverse reactions of nusinersen include post lumbar puncture events, hyponatremia, and potential neurotoxicity. The clinical safety reviewer recommends describing several additional issues, including thrombocytopenia, renal effects, and hepatic effects as well as monitoring


9

recommendations, in the warnings and precautions section of the label based on their being class effects observed with other oligonucleotide treatments.

Lumbar puncture can be technically difficult in SMA patients with scoliosis, spinal rods, or other hardware, however, the risks of lumbar puncture and the management of associated adverse events are well-known in the medical community. Ultrasound guidance was frequently used in the clinical studies, and is preferred to fluoroscopy to minimize repeated radiation exposure. The Applicant's proposed prescribing information states that sedation should be considered as indicated by the clinical condition of the patient, and that ultrasound or other imaging techniques should also be considered to guide intrathecal administration of nusinersen, particularly in younger patients.

Neurotoxicity is another potential safety concern based primarily on animal data at this time, and the risk is likely to require a warning and precaution in the professional labeling. Pediatric neurologists who specialize in the treatment of SMA and perhaps other members of the multidisciplinary clinical teams that manage SMA patients are the likely prescribers of nusinersen. The use of imaging or sedation will limit the practice setting where nusinersen will be administered. At this time, this reviewer is not recommending a REMS for the management of the potential risks of nusinersen therapy.

9 Conclusion & RecommendationsBased on the available data a REMS is not necessary to ensure the benefits of nusinersen outweigh the risks. Spinal muscular atrophy is mainly treated in specialty centers by healthcare providers with detailed knowledge of the disease and the risks of treatment, who are familiar with the importance of patient monitoring.

Should DNP have any concerns or questions or if new safety information becomes available, please send a consult to DRISK.

10Materials ReviewedThe following is a list of materials informing this review:

1. Biogen. Draft labeling for nusinersen, October 19, 2016.

2. Biogen. Clinical Overview for nusinersen, September 23, 2016.

3. Biogen. Nonclinical Overview for nusinersen, September 23, 2016,

4. Biogen. Summary of Clinical Safety for nusinersen, September 23, 2016.

5. Paine R. Division of Neurologic Products. Draft Clinical Review for nusinersen NDA 209531, December 1, 2016.

6. Mentari E. Division of Neurologic Products. Draft Clinical Safety Review for nusinersen NDA 209531, December 3, 2016.


10

7. Massie T. Division of Biometrics. Statistical Review for nusinersen NDA 209531, November 30, 2016.

11Appendices

11.1 REFERENCES

1 Bodamer OA. Spinal muscular atrophy. In:UpToDate, Nordli DR, Firth HV, Martin R (Eds), UpToDate, Waltham, MA 2016.2 Chiriboga CA, et al. Results from a phase 1 study of nusinersen (ISIS-SMNRx) in children with spinal muscular atrophy. Neurology 2016;86:890-897.3 Rodichok L and Farkas R. Breakthrough Therapy Designation Review for ISIS 396443, IND 110011, August 22, 2014.4 Haché M, et al. Intrathecal injections in children with spinal muscular atrophy: nusinersen clinical trial experience. J Child Neurol 2016;31:899-906.


---------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.---------------------------------------------------------------------------------------------------------/s/----------------------------------------------------

ROBERT G PRATT12/13/2016

JAMIE C WILKINS PARKER12/13/2016


CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

209531Orig1s000

SUMMARY REVIEW

2

Controlled Substance Staff Martin Rusinowitz, Michael Klein Cardiac Safety Christine Garnett, Norman Stockbridge Rare Diseases Althea Cuff Associate Director for Labeling Tracy Peters Cross-Discipline Team Leader Nicholas Kozauer


3

1. Benefit-Risk Assessment


APPEARS THIS WAY ON ORIGINAL

4

Benefit-Risk Summary and Assessment

Spinal muscular atrophy (SMA) is a rare genetic disorder characterized by atrophy of the voluntary muscles of the limbs and trunk. It is the most common genetic cause of death in infants. SMA is caused by a deletion or mutation of the survival motor neuron 1 (SMN1) gene located on chromosome 5q coding for the survival motor neuron (SMN) protein, which helps to maintain motor neurons. A small amount of SMN protein is produced from a similar gene known as SMN2. However, most SMN2 mRNA transcripts lack exon 7, which leads to the production of a truncated protein that is easily degraded. Nusinersen (ISIS 396443) is a 2’‐O‐(2‐methoxyethyl) antisense oligonucleotide (ASO) that is designed to bind to the SMN2 pre‐mRNA and promote the inclusion of exon 7 in the mRNA transcript, with the goal of increasing the production of functional SMN protein. The number of copies of the SMN2 gene that a patient has is the best predictor of clinical phenotype. Patients with infantile‐onset SMA, consistent with having 2 copies of the SMN2 gene, uniformly fail to reach developmental motor milestones such as the ability to sit unassisted, and rarely survive beyond 24 months of age in the absence of life‐sustaining interventions. Patients with 3 copies of the SMN2 gene are generally unable to walk without assistance, and approximately 70% are alive at 25 years of age. Patients with 4 or more copies of the SMN2 gene may have normal life expectancies, and tend to experience a more varied clinical course ranging from mild weakness to the loss of previously attained motor milestones in adulthood (although some can still be more severely affected). There is no FDA‐approved treatment for SMA. This application includes data from an interim analysis of a double‐blind, sham‐procedure controlled trial in infantile‐onset SMA patients who have 2 copies of the SMN2 gene (Study CS3B). This trial demonstrated a clear and important benefit of nusinersen, with 21/52 (40%) of nusinersen‐treated patients who met a motor milestone development responder definition, vs. 0/30 (0%) of sham‐procedure controls (p<0.0001). Secondary endpoints, although only presented descriptively according to the analysis plan, consistently support a treatment benefit. During the review cycle, the applicant provided the topline results of a double‐blind, sham‐procedure controlled trial in patients with later‐onset SMA Study (Study CS4), with the majority having 3 copies of the SMN2 gene [range: 2‐4]). The study was stopped based on a highly statistically significant (p=0.000002) treatment effect on the Hammersmith Functional Motor Scale – Expanded (HFMSE). The applicant reports that all sensitivity analyses for the primary endpoint consistently supported this result. The findings of this study, although not yet independently reviewed by FDA, are supportive of efficacy in later‐onset SMA patients. The applicant has also conducted several open‐label studies with nusinersen, covering a broad range of age groups, from presymptomatic infantile‐onset (genetically diagnosed) SMA to later‐onset SMA. Findings from these studies are generally supportive of efficacy, with patients achieving milestones not expected for the study population, maintaining milestones to ages at which they would be expected to be lost, and surviving to ages unexpected considering


10

This application includes data from the results of an interim analysis of a study in patients with infantile-onset SMA (Study CS3B), which was double-blind and sham-procedure controlled, and is proposed as primary support for the efficacy of nusinersen. Data from several completed or ongoing open-label trials were also provided, including the topline results of Study CS4, a 15-month, double-blind, sham-procedure controlled trial in patients with later-onset SMA, which was ongoing at the time of the original NDA submission.

3. Product Quality I concur with the conclusions reached by the chemistry reviewer regarding the acceptability of the manufacturing of the drug product and drug substance. Manufacturing site inspections were acceptable. OPQ will grant a month re-test period for the drug substance when stored

, and a 30-month drug product expiration period when stored refrigerated in commercial packaging. Several post-approval quality agreements have been reached between the applicant and OPQ. There are no outstanding CMC issues.

4. Nonclinical Pharmacology/Toxicology I concur with the conclusions reached by the pharmacology/toxicology reviewer that there are no outstanding pharm/tox issues that preclude approval. A noteworthy finding in nonclinical studies is neuronal vacuolation in the inferior region of the hippocampus. In some animals, this vacuolation was associated with neuronal and glial cell necrosis and cellular debris. Vacuolation and necrotic cells/cellular debris were still present following 24 weeks of recovery. The no-observed adverse effect level (NOAEL) for neurohistopathology in monkeys (39 mg/year) is similar to the proposed human maintenance dose (36 mg/year), and was associated with tissue levels similar to those measured in patient tissue samples at autopsy. In addition, possible long-term effects on performance in a learning and memory test, which could be related to drug-related hippocampal neurohistopathology, were observed in juvenile monkeys in a 1-year study. The nonclinical reviewer also describes histopathologic findings attributed to the expected effects of local and systemic accumulations of oligonucleotide and/or their pro-inflammatory effects, including basophilic granules in the kidney, liver Kupffer cell hypertrophy, and vacuolated macrophages at the injection site and in the lymph node and multiple other tissues. No clear evidence of reproductive or developmental toxicity was seen in mice and rabbit studies, and testing for genotoxicity was negative in a standard battery of in vitro and in vivo assays. Carcinogenicity studies were not conducted. The applicant has requested a waiver based on the infeasibility of conducting lifetime studies in rodents by the IT route, but given the significant systemic exposure documented in clinical studies, the nonclinical reviewer recommends a parenteral study in one species be conducted postmarketing. I support requesting that study.


(b) (4)

(b) (4)

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Study CS3B in patients with infantile-onset SMA, which used a double-blind, sham-control design, provides the primary source of efficacy data for this application. The additional trials, which all used an open-label design, were intended to provide supportive efficacy information across a broad age range of patients with SMA. Study CS3B in Infantile-Onset SMA Study CS3B was a 13-month, multicenter, randomized, double-blind, sham-procedure controlled trial in patients with infantile-onset SMA. Approximately 111 subjects were to be randomized in a 2:1 ratio to receive either a scaled-equivalent 12 mg dose of nusinersen, administered intrathecally by lumbar puncture, or a sham-procedure control. Subjects received loading doses on Day 1, 15, 29, and 64, followed by maintenance doses on Day 183 and 302 (i.e., every 4 months). Randomization was stratified based on disease duration at screening (≤12 weeks versus >12 weeks). Subjects were required to have 2 copies of the SMN2 gene, consistent primarily with a clinical diagnosis of Type I SMA, but also in a small proportion of patients with type II. An interim analysis was to include all subjects that had a Day 183 visit at the time of the cut-off date of June 15, 2016. The interim analysis conducted by the applicant included 78 subjects (nusinersen n=51; sham controls n=27). The primary endpoint for the interim analysis was the between-group difference in the proportion of patients who achieve an improvement in motor milestones, based on a definition using Section 2 of the Hammersmith Infant Neurological Examination (HINE). That scale is comprised of eight tests: head control, sitting, voluntary


13

grasp, ability to kick in supine position, rolling, crawling, standing, and walking. A responder had to satisfy the following two criteria: (1) The subject demonstrated at least a 2-point increase in the motor milestones category of ability to kick, or achievement of a maximal score on that category (i.e., touching toes), or a 1-point increase in the motor milestones of head control, rolling, sitting, crawling, standing, or walking, AND (2) among the 7 motor milestone categories (with the exclusion of voluntary grasp), the subject demonstrated improvement in more categories than worsening. That endpoint is very relevant and interpretable clinically, and the separation between the milestones allows a clear assessment of meaningful functional differences. Time to death or permanent ventilation, determined in a blinded fashion by a central, independent Event Adjudication Committee, was the second primary efficacy endpoint. The next endpoint to be tested was the proportion of CHOP INTEND responders, defined as a change from baseline of at least 4 points. CHOP-INTEND is a 64-point motor development scale for SMA, with higher scores being better. These endpoints were descriptively reported, as per the analysis plan. The responder definition for the HINE was met by 41% of nusinersen-treated patients, vs. 0% of patients in the control group (p<0.0001). A sensitivity analysis that includes all patients who died or withdrew after baseline showed similar results (40% responders on nusinersen vs. 0% in the control group; p<0.0001). This analysis is recommended by the team for description in labeling. Other sensitivity analyses conducted by the statistical reviewer were supportive of the primary efficacy results. Five patients in the nusinersen group were able to sit unassisted, vs. no patient in the sham- control group. As discussed by the review team, the achievement of this milestone would be extremely rare in patients historically diagnosed with Type I SMA, and is also supportive of efficacy of the product, although some of the patients who achieved that milestone could have had type II SMA. A descriptive analysis of secondary endpoints was consistent with efficacy of nusinersen. In the overall study population, 15% of patients in the nusinersen-treated group died, vs. 32% in the control group (HR = 0.44); 34% of patients in the nusinersen-treated group died or required permanent ventilation, vs. 49% of patients in the control group (HR = 0.71). In the interim analysis data set, 65% of nusinersen-treated subjects met the pre-specified responder definition for the CHOP-INTEND, as compared to 4% of patients in the control group. A worsening in CHOP-INTEND score of at least 4 points was observed in 4% of nusinersen-treated patients, vs. 48% in the control group. Findings on various electrophysiologic studies were also supportive of the efficacy. Following the highly positive results of the interim analysis, Study CS3B was stopped, with all subjects switched over to receive active treatment with nusinersen. Study CS4 in Later-Onset SMA During the review cycle, the applicant provided the topline results of Study CS4, which was ongoing at the time of the NDA submission. Study CS4 was a 15-month, double-blind, sham-procedure controlled trial in patients with later-onset SMA. Patients in Study CS4 mostly


14

would have had a clinical diagnosis of Type 2 SMA, with the majority having 3 copies of the SMN2 gene [range: 2-4]). The nusinersen dosing regimen was the same as in Study CS3B. The applicant conducted an interim analysis based on a data cut-off of August 31, 2016. The analysis included 126 patients (84 on nusinersen and 42 controls). The study was stopped based on a highly statistically significant treatment effect. The applicant describes that Hammersmith Functional Motor Scale – Expanded (HFMSE) scores were significantly higher in the nusinersen group (4.0) as compared to the control group (-1.9), p=0.000002. The applicant reports that all sensitivity analyses for the primary endpoint consistently supported this result. A total of 57% of subjects in the nusinersen group achieved a 3-point or greater increase in HFMSE scores over baseline at 15 months, vs. 21% of controls. The findings of this study, although not yet independently reviewed by FDA, appear supportive of efficacy in later-onset SMA patients. Other studies The applicant has conducted several additional open-label studies with nusinersen, covering a broad range of age groups, from presymptomatic infantile-onset (genetically diagnosed) SMA to later-onset SMA. These studies are discussed in Dr. Paine’s review and Dr. Kozauer’s memorandum. Findings from these studies were generally supportive of efficacy, with patients achieving milestones not expected for the study population, maintening milestones to ages at which they would be expected to be lost, and surviving to ages unexpected considering their number of SMN2 gene copies. Efficacy Conclusions I am in full agreement with Dr. Kozauer that the current application provides substantial evidence of effectiveness based on the “single study plus confirmatory evidence” standard. As discussed by Dr. Kozauer, Study CS3B, conducted in infantile-onset SMA, demonstrated a clinically important and highly statistically significant effect on motor milestone development that was consistently supported by multiple secondary endpoints. The results of Study CS3B are supported by the topline results of Study CS4, and by the results of open-label studies conducted by the applicant. These studies cover a broad range of ages of disease onset. I also agree with the argument presented by Dr. Kozauer that the efficacy findings can be generalized to the full range of SMA subtypes. As discussed by Dr. Kozauer, the mechanism of action of nusinersen, i.e., increase in transcription of full-length SMN2 mRNA, is expected to result in clinical efficacy across the whole disease spectrum. Also, the available evidence already covers a wide range of SMA age of onset, from early to late onset of the disease. Therefore, I support an indication without restriction of age of onset. I also agree with Dr. Kozauer that the 12mg/5mL dose of nusinersen is appropriate across age groups, as the average CSF volume shows largely overlaps between children and adults.


15

8. Safety I agree with the review team that the size of the safety database is acceptable for this indication. Out of 173 patients in the database, 82 were exposed for ≥ 12 months, mostly at the 12 mg dose proposed for marketing. As discussed above, there were fewer deaths in nusinersen-treated patients (15%) than in sham-procedure controls (32%) in Study CS3B. The review team identified a few significant safety issues with nusinersen. These issues do not outweigh the clear treatment benefit, but justify description in labeling with appropriate risk mitigation recommendations for prescribers. These issues include the following: Bleeding Risk: Thrombocytopenia was seen 11% of nusinersen-treated patients in Study

CS3B, compared with 0% of sham-control patients. In the safety database, 2% of nusinersen-treated patients had platelet counts < 100,000 cells per microliter, but no patient had a count below 50,000 cells per microliter. Patients with thrombocytopenia may be at increased risk of bleeding complications after lumbar puncture for intrathecal administration. This risk should be described in the “Warnings and Precautions” section of labeling, with a recommendation for coagulation laboratory testing at baseline and prior to each maintenance administration of nusinersen.

Renal Toxicity: Nusinersen accumulates in the kidney, which is a target organ for

nusinersen, as has also been observed for other antisense oligonucleotides. In Study CS3B, 33% of nusinersen-treated patients had elevated urine protein, compared with 20% of sham-controls. In a group of later-onset SMA patients (mean treatment exposure 34 months), 36 of 52 (69%) had elevated urine protein. Potentially fatal glomerulonephritis has been associated with other oligonucleotides, but was not seen with nusinersen. This risk should be described in the “Warnings and Precautions” section of labeling, with a recommendation for quantitative urine protein testing at baseline and prior to each dose of nusinersen.

Hyponatremia: prolonged severe hyponatremia was observed in a patient treated with

nusinersen; this required salt supplementation for 14 months. There was no obvious cause other than nusinersen treatment, but potential confounders were present. As this is a single case, and the treatment causality is not entirely clear, I recommend description of this event in the “Adverse Reactions” section of labeling, and postmarketing monitoring for serious cases of hyponatremia.

Effect on growth: In Study CS3B, nusinersen-treated subjects had reduced growth

compared with sham-procedure controls. This observation is somewhat surprising, considering the robust effect of nusinersen on spinal muscular atrophy, which would be expected to improve growth in treated patients. Although the causes of these effects are speculative, they should be described in the “Adverse Reactions” section of labeling.

Rash and Possible Vasculitis: There were 3 cases of possible vasculitis with nusinersen.

One patient, 8 months after starting nusinersen treatment, developed painless red macular lesions on the forearm, leg, and foot over an 8-week period. The lesions ulcerated and


16

scabbed over within 4 weeks, and resolved without treatment over several months. A second patient developed red macular skin lesions on the cheek and hand ten months after the start of nusinersen treatment; these lesions resolved over 3 months. Importantly, treatment with nusinersen was continued in both of these patients, with resolution of the reash. In addition, one patient had a cerebral infarction, described by the team as possibly related to vasculitis. While vasculitis is in the differential diagnosis for this event, this remains very speculative. The review team notes that the pro-inflammatory effects of antisense nucleotides have been described in the published literature and may have been involved in these suspected cases of vasculitis. Considering the resolution of the skin rash and continued treatment with nusinersen, I believe that description of the events in the “Adverse Reactions” section of labeling is adequate.

Neurologic Toxicity: As described above, neurotoxicity including hippocampal vacuolization and necrotic cells was observed in monkeys administered nusinersen. Clinical correlates have not been observed, but would not have been easily identified in the SMA population. This information should be described in the “Nonclinical Toxicology” section of labeling.

Hepatic Effects: Nusinersen is deposited in the liver and therefore has the potential for

hepatic toxicity. In Study CS3B, small increases alanine aminotransferase (ALT) were observed in 4% of nusinersen-treated patients, compared to none in control patients. As increases of ALT and AST could also be of skeletal muscle origin, and considering the limited increase and small number of patients, and the absence of hepatic adverse reactions, I do not believe that this observation deserves a description in labeling, as drug causality is not established. I recommend postmarketing monitoring for serious cases of hepatotoxicity.

Immunogenicity Plasma samples from all clinical studies were analyzed for anti-drug antibody (ADA) presence. Across the safety database, five patients had positive ADA samples. There was no adverse events associated with the presence of ADA in these patients. The ability of ADA to cross-react with nucleic acids was not evaluated. The team recommends a post-marketing requirement to conduct a study to assess for the presence of antibodies that bind native double-stranded (ds) DNA among patients treated with nusinersen. I agree. QT effects In Study CS3B, 4 of 80 (5%) of nusinersen patients had a QTc value above 500 milliseconds (ms), and an increase of >60 ms from baseline, compared to 0 of 41 control patients. The QT review team comments that they are not aware of other small therapeutic proteins that directly inhibit the hERG channel and cause QTc interval prolongation. However, they note that the applicant has not conducted in vitro safety pharmacology studies to rule out such a mechanism. They observe that it is difficult to determine from the clinical data whether nusinersen affects cardiac repolarization, as measured by QTc prolongation. They note that prolonged QTc interval in individual patients could have also occurred for reasons related to concomitant medications, the underlying disease or associated adverse events related to the disease. They suggest evaluating the potential for nusinersen to delay cardiac repolarization in


17

ongoing clinical trials, acknowledging that a thorough QT study is not feasible for this product. The QT review team recommends a description of the findings in Section 12 of labeling. I agree.

9. Advisory Committee Meeting This application was not referred for review to an advisory committee, because outside expertise was not necessary. There were no controversial issues that would benefit from advisory committee discussion.

10. Other Relevant Regulatory Issues There are no unresolved regulatory issues.

The Office of Scientific Investigations (OSI) has inspected three clinical investigator sites. Data submitted by the applicant in support of the pending application for these sites were found acceptable and the studies appear to have been conducted adequately. The Controlled Substance Staff concludes that there are no data indicating that nusinersen has abuse potential or induces physical dependence. Nusinersen should not bind to receptors known to be involved in drug abuse, and the intrathecal route of administration is unlikely to have a potential for abuse.

11. Labeling There are no outstanding labeling issues. As discussed by the review team, the label will include WARNINGS AND PRECAUTIONS for thrombocytopenia and coagulation abnormalities and renal toxicity..

12. Postmarketing I agree with the review team that a risk evaluation and mitigation strategy (REMS) is not needed for nusinersen, considering the highly specialized setting under which nusinersen will be administered, with regular visits required for drug administration. I agree that risk management of nusinersen can be accomplished through appropriate labeling and enhanced pharmacovigilance for thrombocytopenia, glomerulonephritis, nephrotic syndrome or nephrotic range proteinuria. The following are the recommended post-marketing requirements:


18

A study to assess for the presence of antibodies that bind native double-stranded (ds) DNA among patients treated with nusinersen. The study may be conducted with plasma samples from patients treated with nusinersen in the clinical development program, including ongoing studies, but should include samples from patients who test negative as well as patients who test positive for antibodies to nusinersen. Among patients who develop anti-drug antibodies, samples should be included from patients shortly after seroconversion as well as from sustained responders. A sensitive assay should be used to assess presence of antibodies to double-stranded (ds) DNA in patient samples.

A two-year carcinogenicity study in one rodent species (CD-1mice) with subcutaneous administration of nusinersen.

A pre-and postnatal development (including maternal function) study of nusinersen in rodent.


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ERIC P BASTINGS12/23/2016


Ethical Challenges Confronted When Providing NusinersenTreatment for Spinal Muscular AtrophyAlyssa M. Burgart, MD, MA; David Magnus, PhD; Holly K. Tabor, PhD; Erin Daksha-Talati Paquette, MD, JD;Joel Frader, MD; Jaqueline J. Glover, PhD; Brian M. Jackson, MD, MA; Charlotte H. Harrison, PhD, JD, MPH;David K. Urion, MD; Robert J. Graham, MD; John F. Brandsema, MD; Chris Feudtner, MD, PhD, MPH

T he US Food and Drug Administration’s December 2016approval of nusinersen for the treatment of patients withall subtypes of spinal muscular atrophy (SMA) ushered in a

new era for patients with SMA, their families, and all those involvedin their care.1-5 For tertiary care centers that have chosen to makenusinersen available to patients, the extreme cost of the medica-tion and the complicated logistical requirements for administeringnusinersen via lumbar puncture have created practical challengesthat raise important ethical considerations.6

The effect of these challenges at the level of individual patientcare, hospital management, health care economics, and nationalhealth care distribution suggests broader challenges for health caresystems,7 and illuminates issues likely to be encountered on futureapproval of novel and expensive treatment options. We discuss 6challenges faced at the institutional level in the United States. Thesechallenges must be understood to ensure that patients with SMAbenefit from treatment, are protected from harm, and are treatedfairly. In addition, health care systems must assess and manage theirability to provide effective care for all their patients in a sustainablemanner. Spinal muscular atrophy is a rare, hereditary neuromuscu-lar disease caused by a mutation in the SMN1 gene (OMIM 600354)affecting 1 in 10 000 live births. The mutation causes abnormalexpression of the SMN protein, leading to progressive muscle weak-ness and motor neuron death. Although patients are ultimately pro-foundly physically disabled, intellectual development and functionare not affected. Disease presentation is variable, with clinical sever-ity inversely associated with the number of copies of the SMN2gene (OMIM 601627) (which produces a less stable SMN proteinthan does SMN1).8 Spinal muscular atrophy subtypes 0 through 4represent the age of onset and functional status. Spinal muscularatrophy subtype 0 results in prenatal onset of weakness and deathbefore or shortly after birth; in recent classifications, this subtype is

often included in type 1. The onset of SMA1 is usually before 6 monthsof age and is the most common genetic cause of infant death.Patients with SMA1 are never able to sit, and without invasive or non-invasive respiratory support, most die by 2 years of age. Spinal mus-cular atrophy subtype 2 presents in early childhood. These patientsare never able to stand, and often live significantly longer than pa-tients with SMA1. Spinal muscular atrophy subtype 3 presents in child-hood or adolescence, while the onset of SMA4 is in adulthood. Be-fore the approval of nusinersen, no disease-modifying treatmentswere available and care was primarily supportive or palliative.

Nusinersen is an antisense oligonucleotide therapy that in-creases expression of the SMN protein. The medication is adminis-tered intrathecally via repeated lumber punctures, with 4 loadingdoses administered during the first 2 months, then maintenanceadministration every 4 months thereafter, presumably for life.9 There-fore, patients require 6 doses in the first year, and 3 doses annually insubsequent years. Advocacy groups, such as CureSMA, contributedearly funding to the drug developers, Ionis Pharmaceuticals andBiogen, and the relationships remain strong.10 The US Food and DrugAdministration granted fast-track designation and priority review forthe treatment for this rare and often fatal disease, leading to a rapidtransition from research study to approved medication.11

CostThe first challenge is nusinersen’s remarkably expensive cost.12,13

Although reported prices vary, a single dose currently costs $125 000,amounting to $750 000 in the first year and $375 000 annually insubsequent years. This price does not include costs associated withadministration, which vary based on individual patient needs and site-specific charges. As of August 2017, Ionis Pharmaceuticals reports

The US Food and Drug Administration’s December 2016 approval of nusinersen for thetreatment of patients with all subtypes of spinal muscular atrophy ushered in a new era forpatients with spinal muscular atrophy, their families, and all those involved in their care. Theextreme cost of the medication and the complicated logistical requirements for administeringnusinersen via lumbar puncture have created practical challenges that raise important ethicalconsiderations. We discuss 6 challenges faced at the institutional level in the United States:cost, limited evidence, informed consent, treatment allocation, fair distribution ofresponsibilities, and transparency with stakeholders. These challenges must be understoodto ensure that patients with spinal muscular atrophy benefit from treatment, are protectedfrom harm, and are treated fairly.

JAMA Pediatr. doi:10.1001/jamapediatrics.2017.4409Published online December 11, 2017.

Editorial

Author Audio Interview

Author Affiliations: Authoraffiliations are listed at the end of thisarticle.

Corresponding Author: Alyssa M.Burgart, MD, MA, Center forBiomedical Ethics, StanfordUniversity, 1215 Welch Rd, Modular A,Stanford, CA 94305([email protected]).

Clinical Review & Education

JAMA Pediatrics | Special Communication

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earnings from Biogen associated with nusinersen exceeding $435million.14 Nusinersen is currently without competition and until newerdrugs are approved, this price is unlikely to diminish. The price raisesmultiple institutional challenges, including how payers will ap-proach issuing approvals for treatment and how hospitals will re-spond to bearing the cost of either partial or complete nonpaymentfor the medication.15-19 For hospitals, this cost may be the primaryreason to not offer nusinersen treatment. For many patients, insur-ance denial or delay may be the primary impediment to initiation oftreatment.20 Volatility in US public and private reimbursementscomplicate this matter, as hospital administrators worry that they willnot be able to meet the most basic obligations to patients.

This situation will likely produce at least 2 bedside ethical chal-lenges. First, clinically similar patients will receive different ordelayed treatment owing to payer financing, generating concernsfor the just distribution of health care.21,22 Lack of uniformity inpayers’ approaches to authorization of treatment is alreadyevident.23,24 Anecdotally, families report that their children’s pro-jected coverage has changed multiple times since initiation ofnusinersen treatment. Second, unless the price is reduced, sus-tained high and lifelong costs of nusinersen treatment could resultin families feeling forced to forgo disease-modifying treatment orbecoming financially strained or outright impoverished.25,26

Limitation of the EvidenceSecond, uncertainty remains about the sustained benefit and safetyof nusinersen, and how to best assess patients’ responses to it. Theclinical trials on which the US Food and Drug Administration basedtheir broad approval have not been fully published and may not en-tirely clarify the magnitude of potential benefits of treatment acrossSMA subtypes and disease stages.27 In a small and relatively shortphase 2 dose-escalation study of nusinersen, while all patients in thehigh-dose group demonstrated some measurable electrophysiologi-cal improvement, only 65% had clinically relevant improvements infunction.28 Given the eligibility criteria for previous clinical trials, andthat such trials were conducted in only a few hundred patients, studyfindings may not be generalizable to the rest of the population withSMA.29 This unselected group may have more severe disability atbaseline or more severe comorbidities. Given the rarity of SMA andthe short-term nature of the trials, many years may pass before aclear understanding of the long-term effects of nusinersen emerges.As the only current alternative is supportive care for untreated SMA(or entry into a clinical trial), patients may be willing to assume suchundefined risks. Institutions hold the responsibility for tracking andmonitoring drug delivery and outcomes to ensure that the pro-gram is achieving effective results for its patients and to facilitatequality improvement efforts.

Now that nusinersen may be administered to patients with mini-mal residual strength, new questions emerge regarding bench-marks for effective treatment. Maintaining the most marginal func-tion may be the key quality of life indicator for a patient seekingnusinersen treatment. The measurements used during the trials,while sufficient for patients who met study criteria, may not be sen-sitive enough to detect minute differences in strength maintainedor gained. Some insurers, while willing to initiate treatment, mayrequire patients to demonstrate arbitrarily determined end points

(eg, CHOP-INTEND [Children’s Hospital of Philadelphia Infant Testof Neuromuscular Disorders] or Hammersmith Infant NeurologicalExamination scores) within a certain time frame, or subsequent drugcoverage will be stopped. All centers may not conduct such special-ized testing routinely, which may further disadvantage patientswho are in conflict with insurers. Without good evidence regardinghow to approach and measure success for these severely affectedpatients, the association between evidence and cost may be espe-cially perilous, and patients may lose coverage before they are ableto demonstrate measurable benefit from nusinersen treatment.

Informed ConsentThese uncertainties have implications for informed consent.30,31

Given the paucity of available results, patients, parents, and clini-cians who consent to start nusinersen treatment should expectthose discussions to be periodically updated as new data emerge.In addition, if the benefits of ongoing treatment for a patient donot appear to outweigh the hazards encountered, challenges indecision making about stopping treatment will emerge. Exactlywhat constitutes an important beneficial difference in function oran unexpected intolerable toxic effect will be difficult to defineand keenly tied to the patient’s values. In anticipation of such diffi-cult decisions, before nusinersen therapy is initiated clinicians andparents should discuss expectations of therapy and clarify whatcriteria might lead to a decision to stop therapy.32 Alternativepotential therapies through clinical trial enrollment adds furthercomplexity. Helping a family to understand the various options,risks, and potential benefits associated with each will be an ongo-ing challenge for institutions treating patients with SMA. Families’values and clinical recommendations may evolve during treatmentand should be readdressed as appropriate. Although these com-plex discussions occur at the bedside, institutions should ensurethat clinicians and patients have the support they need whilefacing prognostic uncertainty.

Treatment AllocationThe fourth challenge posed by nusinersen is the difficulty of initiat-ing and then sustaining repeated treatment for all patients whocould benefit, potentially requiring that patients be placed inqueues.33 If many patients present for treatment at once, thislogistical bottleneck could cause a delay in drug administration.34

Although performing the lumbar puncture for some patients foradministration of nusinersen is relatively straightforward, for otherpatients—owing to weakness, bulbar dysfunction, respiratoryinsufficiency, scoliosis, spinal fusion, or other sequelae of SMA—performing a lumbar puncture safely may require advanced airwaymanagement, fluoroscopy or ultrasonography, sedation or anes-thesia, or overnight hospitalization. Thus, potentially rate-limitingfactors in treating patients include not only the availability ofnusinersen (which depends on payment arrangements, discussedbelow) but also the local resources required to administer thetreatment. Providing the treatment safely will require high-leveloperational planning and coordination and perhaps increasedinstitutional resources, including staff and treatment facilities.

Clinical Review & Education Special Communication Ethical Challenges When Providing Nusinersen Treatment for Spinal Muscular Atrophy

E2 JAMA Pediatrics Published online December 11, 2017 (Reprinted) jamapediatrics.com




As SMA is a progressive disease and nusinersen is thought towork primarily by slowing or stopping its progression, any delay ininitiation of treatment risks a reduction in maximum effectiveness.One goal, then, is to minimize wait times. The wait time at any siteis likely to depend on approval of payment for treatment and the re-sources for clinical workflows. The wait times will likely be longestas programs initiate nusinersen treatment for existing patients withSMA, while simultaneously determining when to treat any newlydiagnosed patients. As this current population completes the inten-sive loading dose phase and shifts into the maintenance phase, cli-nicians can more easily accommodate future patients who are di-agnosed with SMA. The task of administering the medication consistsof at least 3 clinical workflows: the first involves patients for whomlumbar puncture administration is relatively straightforward and canbe performed in an outpatient clinic visit, the second involves pa-tients who require a higher level of supportive care to safelyundergo the procedure and fully recover to return home, and thethird involves patients who are already hospitalized or thosewhose clinical condition requires recovery in the hospital. Theseworkflows do not necessarily compete with each other for re-sources, so that patients queued in one workflow are not necessar-ily ahead of or behind patients queued in another workflow.

Methods to decide the ordering of patients into queuesinclude lottery, case by case consideration, and establishment ofallocation criteria.35 A lottery appeals to one notion of fairness,namely, giving every participant equal chance to be treated first.This method reduces the influence of bias. A lottery, however, can-not account for other notions of fairness, such as rescuing the mosttenuous patients first, treating patients who would benefit themost from earlier treatment, or attempting to maximize the utilityof treatment initiation. Some proponents of a lottery to allocatetreatment, believing that all patients with SMA are likely to benefitto a meaningful degree from nusinersen treatment, hold that a lot-tery may be the fairest approach; otherwise, they worry that newlydiagnosed patients with SMA1 could repeatedly bump otherpatients further down the queue. Different workflow tracks,whereby newly diagnosed infants receive treatment via a relativelylow-resource workflow while older patients with symptoms ofmore advanced SMA receive treatment using more resource-intensive workflows, may alleviate this concern.

A case-by-case process would allow for patient-specific nu-ances to be taken into consideration, attending to concerns for res-cue, maximal benefit, or fairness. For example, older patients withadvanced SMA may be clinically stable in terms of vital physiologi-cal functions but on the verge of losing a key functional ability, suchas communicating by computer or operating adaptive equipment.A committee charged with case-by-case determinations couldweigh these circumstances when making decisions about nusin-ersen treatment. Downsides of this approach include the possibil-ity of biases, either explicit or implicit, shaping the decision makingprocess. Furthermore, a committee would have to meet frequentlyenough to keep the queue updated as new patients enter the sys-tem or patients’ clinical statuses change. If used, such committeesshould incorporate appropriate stakeholders, including patient ad-vocates, clinicians, community members, ethicists, and others.36,37

A criteria-based approach enables a process of systematicqueuing based on general principles (eg, elements of fairness andutility) and their clinical equivalents for this patient population,

while reducing the effects of potentially biased case-by-casejudgments.38,39 For example, on the basis of rescue and maximiz-ing benefit (or minimizing loss), the criteria could prioritize patientsfor whom waiting a few weeks or months would likely be most det-rimental, such as patients newly diagnosed with SMA1, who havethe fastest decline and the most function to lose when subjectedto a longer wait time. Alternatively, criteria could prioritize patientswho have been waiting longer for treatment initiation. Thisapproach, if adhered to strictly, would not readily allow for patients’personal circumstances to factor into the queuing order, unlessthere were a companion process to accommodate reasonableexceptions. Such a system may work best in centers in which waittimes are expected to be long, leading to an increased number ofpatients who cannot receive treatment. A committee of some typewould be needed to develop appropriate criteria using the diverserepresentation already mentioned.

Combinations of these 3 approaches are possible, and mightserve to offset the disadvantages of each. For example, a criteria-based process could provide the initial queuing order, withpatients who meet the same criteria ordered via a lottery, and adedicated committee could handle appeals for earlier treatmentinitiation and modify criteria as patient safety and outcomes databecome available. In facilities with shorter wait times, principles ofrescue and utility may put patients in the same place on any givenlist. In a facility in which wait times are particularly long, however,balancing these concerns becomes far more problematic and acombined approach may best satisfy the range of values in ourpluralistic society.40,41

Fair Distribution of Roles and ResponsibilityA fifth challenge posed by nusinersen treatment involves the geo-graphic distribution of treatment centers.42 Across the nation, thou-sands of patients eligible for nusinersen treatment could be distrib-uted to many medical centers or to only a few. Clearly, one of themost effective ways to reduce wait times is to expand the numberof qualified treatment centers. Not all centers would have to pro-vide all the levels of care described above, but the more centers thatparticipate, the faster patients could initiate nusinersen treatment.43

At a minimum, 1 or more centers per geographic region wouldfacilitate the distribution of care.

Although the mission and purpose of health care centerswith neuromuscular services should align with offering nusinersenand its follow-up care, the financial consequences may beuntenable.44 Almost certainly, some organizations will either optout of offering nusinersen treatment or be unable or unwilling tofully develop their operational capacity to treat more patients.Compounding this situation, if 1 or 2 centers in a region providetreatment, other centers may argue that they do not need to par-ticipate. Such a system may increase overall wait times and strainthe participating centers in an unsustainable and unfair fashion.Patients who live far from a participating center may not have theresources or clinical stability to travel, creating further disequilib-rium of justice.45 Local patients, with an established relationshipwith the health care team, may have to wait longer owing to theincreased population being served. Entrepreneurial practicescould arrange to treat well-insured children or those from wealthy

Ethical Challenges When Providing Nusinersen Treatment for Spinal Muscular Atrophy Special Communication Clinical Review & Education





families, leaving safety-net facilities to bear the cost of uninsuredor underinsured children without offsetting income from thosewhose care will be reimbursed. International treatment optionsremain limited, and worldwide demand for nusinersen treatmentin the United States may further complicate this situation. Evenwith the best institutional intentions, broad distributional goalscannot be achieved without attention to structural factors beyondthe control of individual hospitals.

Transparency and Stakeholder EngagementWhen addressing all the challenges mentioned so far, a final criticalelement is transparent communication with individual patients andparents, and more broadly with members of SMA communities.46

Stakeholders need to be engaged in the allocation process and givefeedback as the situation evolves.47 To make informed decisionsabout whether and where to pursue nusinersen treatment, pa-tients and parents need to have access to key information about amedical center’s process of care. The queuing procedure(s) used ateach treatment center should be shared openly, along with clear andfrequently updated anticipated wait times. If a center prioritizestreatment of patients who have an established relationship with thecenter or who reside within a geographic region, this fact should also

be disclosed. Such transparency is essential to the relationship amongthe patient, family, and physician, serving patients’ interests andassisting front-line clinicians tasked with discussing treatmentavailability and timing of initiation.48 Patients and families may usethis information to relocate, self-refer, or travel to obtain nusin-ersen treatment from centers that have procedures most advanta-geous to their particular circumstances.

ConclusionsIf treatment teams decide to provide nusinersen, management ofthe institutional challenges posed by the medication requires forti-tude and flexibility, pressing forward to maximize treatment capac-ity even as the landscape of therapy shifts owing to high cost andemerging data on clinical effectiveness. Nusinersen has been re-cently approved in the European Union, Japan, Canada, and Brazilat comparable cost, with applications under review in multiple otherworldwide sites. As we pass through the initiation phase of nusin-ersen treatment among prevalent and newly diagnosed patients,pressure must be applied to reduce the cost and its effect onaccess, learn more details of medication benefit and safety, andexamine different ways to initiate treatment and manage clinicalworkflows for this therapy.

ARTICLE INFORMATION

Accepted for Publication: September 26, 2017.

Published Online: December 11, 2017.doi:10.1001/jamapediatrics.2017.4409

Author Affiliations: Stanford Center for BiomedicalEthics, Stanford University, Stanford, California(Burgart, Magnus, Tabor); Center for BiomedicalEthics and Humanities, Northwestern University,Chicago, Illinois (Paquette, Frader); Center forBioethics and Humanities, University of ColoradoAnschutz Medical Campus, Aurora (Glover,Jackson); Center for Bioethics, Harvard MedicalSchool, Boston, Massachusetts (Harrison); Office ofEthics, Boston Children’s Hospital, Boston,Massachusetts (Harrison, Urion); Department ofNeurology, Harvard Medical School, Boston,Massachusetts (Urion); Department of Critical CareMedicine, Boston Children’s Hospital, Boston,Massachusetts (Graham); Division of Neurology,The Children’s Hospital of Philadelphia,Philadelphia, Pennsylvania (Brandsema);Department of Medical Ethics, The Children’sHospital of Philadelphia, Philadelphia, Pennsylvania(Feudtner).

Author Contributions: Drs Burgart and Feudtnerhad full access to all the data in the study and takeresponsibility for the integrity of the data and theaccuracy of the data analysis.Study concept and design: All authors.Acquisition, analysis, or interpretation of data: Allauthors.Drafting of the manuscript: Burgart, Feudtner.Critical revision of the manuscript for importantintellectual content: All authors.Administrative, technical, or material support:Harrison, Urion.

Conflict of Interest Disclosures: Dr Brandsemareported serving as a paid consultant to Biogen onadvisory boards and educational panels to Biogen

staff regarding spinal muscular atrophy and servingas an expert on demand for Biogen’s nusinersenprogram; and participating as a paid consultant onadvisory boards for Sarepta, Marathon, PTCTherapeutics, Alexion, and AveXis. Dr Grahamreported serving as a paid consultant to Ionis andserving on an advisory panel; when Biogensubsequently purchased nusinersen from Ionis, DrGraham served a paid consultant to Biogenregarding recommendations for the safe provisionof nusinersen and provided education to Biogenstaff. No further conflicts were reported.

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12. Thomas K. Costly drug for fatal musculardisease wins FDA approval. New York Times.December 30, 2016. https://www.nytimes.com/2016/12/30/business/spinraza-price.html.Accessed March 22, 2017.

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14. Ionis Pharmaceuticals. Ionis earns $40 millionSPINRAZA regulatory milestone payment fromBiogen. http://www.prnewswire.com/news-releases/ionis-earns-40-million-spinraza-regulatory-milestone-payment-from-biogen-300511251.html. Published August 30, 2017.Accessed September 13, 2017.

15. Goozner M. Why Sovaldi shouldn’t cost$84,000. Mod Healthc. 2014;44(18):26.

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17. Paulden M, Stafinski T, Menon D, McCabe C.Value-based reimbursement decisions for orphan

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24. Weisman R. Hope for devastating child diseasecomes at a cost: $750,000 a year. The BostonGlobe. March 28, 2017. https://www.bostonglobe.com/business/2017/03/27/spinraza/QnBmQrcmLLfUwvJunn0P8K/story.html.Accessed March 27, 2017.

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35. Unguru Y, Fernandez CV, Bernhardt B, et al. Anethical framework for allocating scarce life-savingchemotherapy and supportive care drugs forchildhood cancer. J Natl Cancer Inst. 2016;108(6):djv392.

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42. Axelrod DA, Lentine KL, Xiao H, et al.Accountability for end-stage organ care:implications of geographic variation in access tokidney transplantation. Surgery. 2014;155(5):734-742.

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Ethical Challenges When Providing Nusinersen Treatment for Spinal Muscular Atrophy Special Communication Clinical Review & Education








https://smanewstoday.com/2017/05/05/cure-sma-chief-urges-families-seeking-spinraza-insurance-coverage-not-to-get-discouraged/







http://thefastmovement.org/insurance-companies-must-not-be-a-roadblock-to-sma-patients-accessing-lifesaving-treatments/




https://www.bostonglobe.com/business/2017/03/27/spinraza/QnBmQrcmLLfUwvJunn0P8K/story.html













































Nusinersen for Spinal Muscular AtrophyAre We Paying Too Much for Too Little?Vinay Prasad, MD, MPH

Nusinersen, one of several recently approved drugs intendedfor use in a rare disease, boasts an eye-popping price tag.Biogen Pharmaceuticals announced that nusinersen will

cost $750 000 for the firstyear of treatment and$375 000 each year thereaf-ter (prescribed indefinitely)for patients with spinal mus-cular atrophy (SMA).1 Other

recently approved costly therapies for rare diseases includeivacaftor, costing $311 000 per year, for responsive patients withcystic fibrosis2; combination lumacaftor-ivacaftor, costing$272 000 per year, for patients with cystic fibrosis2; eteplirsen,costing $300 000 per year, for a 25-kg child with Duchennemuscular dystrophy3; and asfotase alfa, costing $285 000per year, for patients with infantile and juvenile-onsethypophosphatasia.4 Many more such drugs are poised toenter the market, particularly in fields such as cancermedicine.5

In most cases, these therapies are noncurative, and mustbe taken for life. Some have been studied in randomizedtrials, but others have not. Some have shown improvementin clinical end points—survival or quality of life—but othershave not. Many of these therapies are for conditions wherethere is heterogeneity in the disease’s age of onset or clinicalcourse, and the data for approval come from some, but per-haps not all, subgroups or clinical presentations. All thesedrugs carry lofty price tags. In these cases, an inevitable clashis coming. Will insurers cover the drug widely or placerestrictions on its use? The article by Burgart and colleagues6

in this issue of JAMA Pediatrics tries to anticipate this clash,and outlines ethical issues to navigate. As such, it representsan important contribution to a debate that is only justbeginning.

To understand the specific case of nusinersen, one has tocontrast the price tag with the benefit provided. Nusinersenis an antisense oligonucleotide drug that is administeredintrathecally for patients with SMA. There are 5 subtypes ofSMA, subtypes 0 to 4, ranging in severity and age of onset.Nusinersen was approved for all subtypes based on 1 random-ized trial conducted in patients with subtype 1 and uncon-trolled data in patients with subtypes 1, 2, and 3.7

In the randomized trial submitted to the US Food andDrug Administration (FDA), nusinersen demonstrated a mar-ginal improvement in motor function. Although the FDAlabel emphasizes that the drug improves “motor milestoneresponders” from 0% (0 of 30), as seen with sham injection,

to 40% (21 of 52) seen with nusinersen, “responder” is anarbitrarily dichotomized end point that does not capture themean treatment effect.7 The FDA Office Director’s summarycontrasts the benefit of nusinersen with the development ofa healthy child without SMA subtype 1. Specifically, a healthychild by 12 months of age will score approximately 22 pointson the Hammersmith Infant Neurological Examination, themeasure of motor milestones used in the study.8 In the ran-domized trial used for approval, nusinersen was started ininfants at approximately 6 months of age and the interimanalysis was performed at approximately 12 months of age.The summary states that “the mean motor milestone score innusinersen-treated patients increased from approximately1 point (prior to treatment) to approximately 4 points at 12months—a difference of ~3 points over 6 months.”9(p3) Thus,nusinersen appears to be a very marginal drug with a tinyeffect (4 points at 12 months) on a motor milestone end pointthat is far below what a healthy child would achieve (22points at 12 months). For this reason, the FDA summary cor-rectly states that nusinersen “does not represent a cure.”9(p16)

Although some have touted the drug’s potential toimprove mortality or reduce the need for mechanical venti-lation, these were not shown in data submitted to the FDA.The FDA notes that time to death or disability was 34%among patients receiving nusinersen and 49% amongthose receiving sham treatment, but this analysis wasdescriptive and not significant (hazard ratio, 0.71).9(p14)

Moreover, FDA documents note that if motor milestoneresponders excluded patients who were receiving mechani-cal ventilation, the response rate would fall to 17 of 52patients (33%).10(p28) Like so many new, costly drugs, whenit comes to nusinersen, we are paying so much for so little.

The accompanying article by Burgart and colleagues6

focuses on several important ethical challenges faced bynusinersen. The authors address the following questions:how can treatment be equitably distributed? How canpatients with a heterogeneous clinical condition be fairlyprioritized for therapy? And how can these decisions beopenly communicated to patients and other stakeholders?I wish to focus on the most provocative question raised inthe article by Burgart and colleagues6: Can payers say no?

The high cost of prescription drugs has led to desperateefforts by payers to limit spending. Recently, the state ofMassachusetts petitioned the federal government for per-mission to exclude drugs from its Medicaid formulary, par-ticularly drugs that come to market with marked clinicaluncertainty, such as those based on improvement in surro-

Author Audio Interview

Related article

Opinion

EDITORIAL







gate end points.11 This action is likely a last resort. In Massa-chusetts, for instance, spending on prescription drugs byMassHealth increased from $917 million to $1.94 billionannually between 2010 and 2016.11

Under what circumstances can payers decline to covernusinersen? Burgart and colleagues6 outline one scenariowhereby reimbursement ceases based on the use of “arbi-trarily determined end points.” In other words, if patients donot improve by a certain threshold of motor function at acertain time point, payment might be stopped. Burgart et al6

are right to question this scenario as arbitrary, although onecan sympathize with the decision to stop a therapy that hasyielded absolutely no improvement in motor milestones.However, there is a rational basis by which nusinersen maybe denied.

The randomized data submitted to the FDA supportingthe benefit of nusinersen is, to date, for only one particularsubgroup of the disease (SMA subtype 1). The broader FDAapproval was made for all subtypes based on uncontrolleddata. Uncontrolled or historically controlled data arenotorious for inflated and even spurious conclusionsregarding the efficacy of a therapy. In a famous analysis ofquestions with both randomized and historically controlleddata, 44 of 56 historically controlled trials (79%) found atreatment beneficial, but only 10 of 50 randomized trials(20%) agreed.12

Irrespective of cost, a fundamental principle of evidence-based medicine—caution in extrapolating benefits shown insevere disease settings to more indolent settings—may formthe basis for denial of coverage in SMA subtypes that lackrandomized data. This decision may frustrate many stake-holders, but the blame should not be placed on payers, but thedrug’s sponsor, which designed and set the clinical trialsagenda, and has set a lofty price for a medication with mar-ginal results. As always, the easiest way to improve the valueof any medication—whose benefits are fixed by biology—is tolower the price, which is modifiable by the sponsors.

We need transformative drugs for rare diseases, and thesedrugs need to be priced fairly so that patients can accessthem. Although some may view drugs with marginal resultsas a path of incremental progress, the approval of these agentsoften directly competes against ongoing clinical trials, andmay paradoxically slow progress if they are used instead ofaccrual toward trials.9 Although many will debate whetherdrugs with marginal results should be pursued and approved,what is less debatable is that the price of these drugs shouldbe commensurate with the benefit provided. This clearly isnot the case for nusinersen, nor is it the case with many newcancer drugs for rare diseases.5,13 The article by Burgart et al6

is particularly timely, as the ethical challenges faced by nusin-ersen are emblematic of broader challenges as we enter theera of high-cost therapies for rare diseases.

ARTICLE INFORMATION

Author Affiliations: Division of HematologyOncology, Knight Cancer Institute, Oregon Health &Science University, Portland; Department of PublicHealth and Preventive Medicine, Oregon Health &Science University, Portland; Center for Health CareEthics, Oregon Health & Science University,Portland.

Corresponding Author: Vinay Prasad, MD, MPH,Division of Hematology Oncology, Knight CancerInstitute, Oregon Health & Science University, 3181SW Sam Jackson Park Rd, Portland, OR 97239([email protected]).

Published Online: December 11, 2017.doi:10.1001/jamapediatrics.2017.4360

Conflict of Interest Disclosures: Dr Prasadreported receiving royalties from his book EndingMedical Reversal. No other conflicts were reported.

REFERENCES

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2. Herper M. For Vertex Pharmaceuticals, can onebillion-dollar breakthrough beget another? Forbes.

August 8, 2017. https://www.forbes.com/sites/matthewherper/2017/08/08/vertex-pharmaceuticals-and-the-price-of-inspiration.Accessed September 27, 2017.

3. Tirrell M. New price for muscular dystrophy drugdraws criticism. https://www.cnbc.com/2017/05/08/new-price-for-muscular-dystrophy-drug-draws-criticism.html. Updated May 8, 2017.Accessed September 27, 2017.

4. Carroll J. UPDATED: Alexion wins FDA OK onStrensiq, but startles analysts on price. http://www.fiercebiotech.com/regulatory/updated-alexion-wins-fda-ok-on-strensiq-but-startles-analysts-on-price. Published October 23, 2015.Accessed September 27, 2017.

5. Mailankody S, Prasad V. Five years of cancer drugapprovals: innovation, efficacy, and costs. JAMAOncol. 2015;1(4):539-540.

6. Burgart AM, Magnus D, Tabor HK, et al. Ethicalchallenges confronted when providing nusinersentreatment for spinal muscular atrophy [publishedonline December 11, 2017]. JAMA Pediatr. doi:10.1001/jamapediatrics.2017.4409

7. SPINRAZA [package insert]. Cambridge, MA:Biogen Pharmaceuticals; 2016.

8. Center for Drug Evaluation and Research, USDepartment of Health and Human Services.Application number: 209531Orig1s000: Office

Director memo. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209531Orig1s000ODMemo.pdf. AccessedOctober 26, 2017.

9. Bates SE, Fojo T. Clinical trials: new drug forpancreatic cancer highlights the dual effect ofregulatory approvals. Nat Rev Clin Oncol. 2016;13(4):205-206.

10. Center for Drug Evaluation and Research, USDepartment of Health and Human Services.Application number: 209531Orig1s000: statisticalreview(s). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209531Orig1s000StatR.pdf. AccessedOctober 26, 2017.

11. Silverman E. To lower costs, Massachusettsseeks to limit Medicaid drug coverage. Stat.September 28, 2017. https://www.statnews.com/pharmalot/2017/09/28/massachusetts-medicaid-drug-prices/. Accessed October 26, 2017.

12. Sacks H, Chalmers TC, Smith H Jr. Randomizedversus historical controls for clinical trials. Am J Med.1982;72(2):233-240.

13. Prasad V, De Jesús K, Mailankody S. The highprice of anticancer drugs: origins, implications,barriers, solutions. Nat Rev Clin Oncol. 2017;14(6):381-390.

Opinion Editorial




mailto:[email protected]


http://www.xconomy.com/boston/2016/12/28/biogen-sets-750000-initial-price-for-first-ever-spinal-atrophy-drug/




https://www.forbes.com/sites/matthewherper/2017/08/08/vertex-pharmaceuticals-and-the-price-of-inspiration



https://www.cnbc.com/2017/05/08/new-price-for-muscular-dystrophy-drug-draws-criticism.html



http://www.fiercebiotech.com/regulatory/updated-alexion-wins-fda-ok-on-strensiq-but-startles-analysts-on-price








https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209531Orig1s000ODMemo.pdf





https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209531Orig1s000StatR.pdf



https://www.statnews.com/pharmalot/2017/09/28/massachusetts-medicaid-drug-prices/








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