SMA: REGISTRIES, BIOMARKERS & OUTCOME MEASURES: P.187 Systematic literature review of the economic burden and economic evaluations in spinal muscular atrophy

Abstracts/NeuromuscularDisorders30(2020)S46–S150 S101 impact that caring for someone with SMA has on caregivers. This

understanding is crucialas new therapeutic options become availablethat maychangethestandardofcareandprognosisforindividualsdiagnosedwith SMA.

http://dx.doi.org/10.1016/j.nmd.2020.08.186

P.185

A population-based study examining the epidemiologic burden, healthcare resource utilization and costs of spinal muscular atrophy in Alberta, Canada

G.Chen1_,B.Sharif1_,B.Gerber1_,M.Farris1_{,T. Cowling}1_{,C. Cabalteja}2_,

J.Wu2_,B.Maturi2_{,K.Klein-Panneton}2_,J.Mah3

1_{MedliorHealthOutcome ResLtd, Calgary,Canada;} 2_{Hoffman-LaRoche}

Ltd,Mississauga,ON,Canada;3_{UniversityofCalgary,Calgary,Canada}

Spinalmuscularatrophy(SMA)isarareneurodegenerativediseasethat affects one in 10,000 live births. This study describes the epidemiology, healthcare resource utilization (HRU), and costs for children with SMA in Alberta, Canada. This retrospective study identified pediatric patients with SMA between April 2012 – March 2017by linking several Alberta administrative datasets(healthservices, vital statistics,and pharmacydata) utilizinga published algorithm basedon diagnosticcodes. Ageatthefirst SMA diagnostic codedate was usedas a proxy for SMA typebased on thefollowingcut-offs:typeI(<6months),typeII(6-18months),andtype III(18monthsto<18years).Five-yearincidenceandprevalenceestimates were calculated for SMA cases identified between 2012-2016 divided by the total person-years/persons at risk. All-cause and SMA-specific (SMA as a primary diagnosis) HRUand per-patient costswere examined in the first year post-SMA diagnosis for hospitalizations, length of stay (LOS), physician visits, ambulatory care visits, SMA-related medication expenses andlong-termcare.Allcostswereinflatedto2020Canadiandollars(CAD) usingtheStatisticsCanadahealthand personalcareconsumer priceindex. 49childrenwith SMAwereidentified(median age4.1(interquartile range [IQR] 0.6-8.4) years; type I n=10, type II n=7, type III n=32). The overall five-year incidence and prevalence of SMA in Alberta was 1.0 (confidenceinterval[CI]0.8-1.4)per100,000person-yearsand10.0(CI 9.3-10.6)per100,000persons,respectively.Inthefirstyearpost-SMAdiagnosis, 51.0% of patients had ≥1 hospitalization (SMA-specific: 24.5%) with a meanLOSof29.8(standarddeviation[SD]41.6)days(SMA-specific:14.0 [SD 12.6]); the mean numberof all-cause specialist visits was 48.4 (SD 70.1) (SMA-specific: 12.6 [SD 29.9]), while fewer than five individuals were dispensed medication. The mean all-cause costs were $29,776 (SD 38,405)(SMA-specific:$7,132 [SD12,930]),whereas, amongtypeI, type II,andtypeIIIpatients,all-causecostswere$47,713(SD32,495),$52,209 (SD 34,440),and $19,263(SD37,632), respectively.This studyhighlights the economic burden of SMA. While SMA is rare, the HRU and costs were substantial, particularly among those with type I and II disease in Alberta.

http://dx.doi.org/10.1016/j.nmd.2020.08.187

P.186

“Registre-SMA France”: a national registry of patients with spinal muscular atrophy (SMA)

M. Gomez-GarciadelaBanda1_{, L. Grimaldi}2_{, J. Urtizberea}3_{, A. Behin}4_,

C. Vuillerot5_{, P. Saugier-Veber}6_{, F. Audic}7_{, C. Barnerias}8_{, C. Cances}9_,

E. Campana-Salort7, C. Spil10, P. Laforet1, V. Laugel11, Y. Pereon12, S. Sacconi13, T. Stojkovic4, C. Tard14, B. Chabrol7, I. Desguerre8, S.Quijano-Roy1

1_{RaymondPoincare Hospital, Garches,France;} 2_{Ambroise Pare Hospital,}

Boulogne-Bilancourt,France;3_{MarinHospital,Hendaye, France;}4_Institut

de Myologie, Paris, France; 5_{L’escale Civices Hospital, Lyon, France;}

6_{RouenHospital,Rouen,France;}7_{LaTimoneHospital,Marseille,France;} 8_{Necker Hospital, Paris, France;} 9_{CHU Toulouse, Toulouse, France;} 10_{CHUBordeauxHospital,Bordeaux,France;}11_{CHUStrasbourgHospital,}

Strasbourg,France;12_{CHUNantesHospital,Nantes,France;}13_CHUNice

Hospital,Nice,France;14_{CHULilleHospital,Lille,France}

Changesin standardsofcareand theemergenceof innovativetargeted therapies have changed the natural history of SMA. This new landscape shows the need of real-life registries to answer to clinical, economic and ethical issues. We present the French registry of SMA treated and untreated patients followed in reference centers of the national network (FILNEMUS).TheregistrywillprovideinformationaboutSMApatientsin real-lifeconditionsatthemomentinFrance.Itwillalsobearobustbaseline for a prospective register, as it will longitudinally follow these patients and the newly diagnosed ones over the next 5 years. This observational registrycollectsdataonepidemiology,personalandfamilyhistory,genetics, clinical features, motor and respiratory function, nutrition, rehabilitation, drugtherapies, adverse events,quality of lifeand survival.It will include genetically confirmed SMA types 1, 2, 3 and 4 followed in France from September 2016 with an estimated population of 1000 patients (50% children).EnrolmentstartedinJanuary2020.Asof1April2020,47patients (33children,16adults).havebeenregisteredinfourcenters(9SMA1;21 SMA2;9SMA3).42centerswilltakepartintheproject(26pediatric,13 adults).Preliminary results of theretrospective study from 2016 to 2019 (R-SMA)willbe showed atthemeeting.TheFrench registry is currently operativeandwillspread inthefollowingmonths tocompletethenational territory.CharacterizationoftreatedandnottreatedSMApatientswillallow improvingtheunderstandingofthedisease,anddevelopingbettertherapeutic strategiesandfollow-uptools.

http://dx.doi.org/10.1016/j.nmd.2020.08.188

P.187

Systematic literature review of the economic burden and economic evaluations in spinal muscular atrophy

T.Dangouloff1_,L.Servais2_{,M.Hiligsmann}3

1_{Universityof Liege, Liege, Belgium;}2_{University of Oxford, Oxford, UK;} 3_{MaastrichtUniversity,Maastricht,Netherlands}

Newtreatmentsinspinalmuscularatrophy(SMA)haveledtoacomplete change in thepattern in the use ofhealth care resources in this disease. Through all over theworld, the very high cost of innovative medication hasledtopublicdebateslargelyexpressedinmainstreammedias.Wehave systematically reviewedstudies evaluating thecost ofSMAand economic evaluationsofspinalmuscularatrophy.Thereviewwasconductedaccording to PRISMA guidelines and included original articles published between January1,1998andMarch2020.SevenstudiesreportingthecostofSMA wereidentified.TheaverageannualcostsofuntreatedSMA1(includingearly onsetandSMAbeforeoneyear),wererelativelysimilaracrossthedifferent studies, rangingfrom $106,000 to $140,000per year.On theother hand, thecostsforSMA2,3and4weremainlypresentedtogether(rangingfrom $23,000 to $115,000), despitea high heterogenicity in clinical conditions leadingto very differenthealth careresource consumption.Fiveeconomic evaluationswerepublishedbetween2017and2020andincludedinnovative disease modifying medications. Three assessed the cost-effectiveness of nusinersenagainststandardsofcare,oneofthemtwotreatments(nusinersen andzolgensma)againststandardsofcareandonecomparedNusinersenand Zolgensma. All studiesused a decision-analytic modelto assess the cost-effectivenessandarebasedonsameclinicaltrialsinvolvingalimitednumber of patients. Due to the extremelyhigh cost of treatment, theincremental cost-effectiveness ratio of drugs versus no treatment is generally above $200,000, leading to no cost-effective results. In conclusion, all studies convergeto demonstrate thesignificanteconomic cost ofSMA, especially SMA1,butabetterevaluationofthecostrelatedtootherformsisneeded. Afeweconomicevaluationssuggestthatdrugsdeliveredinpost-symptomatic phaseatcurrentpricesareactuallynotcost-effectiveatcommonlyaccepted

S102 Abstracts/NeuromuscularDisorders30(2020)S46–S150 cost-effectivenessthreshold.Noeconomic evaluation ofnewbornscreening

hasyetbeenconducted.

http://dx.doi.org/10.1016/j.nmd.2020.08.189

P.188

ATEND: Development of a wheelchair based motor assessment T.Duong1,A.Pasternak2,S.DunawayYoung3,L.Nelson4,R.MuniLofra5, T. Carry6, D. Rome-Martin7, E. Kichula8, E. Maczek2, G. Corrati9, A.Glanzman8

1_{StanfordUniversity,PaloAlto, USA;}2_{BostonChildrensHospital,Boston,}

USA;3_{Stanford,PaloAlto,USA;}4_{UnivofTexasSouthwestern,Dallas,USA;} 5_{John Walton Muscular Dystrophy, Newcastle, UK;} 6_{Childrens Hospital}

Colorado,Aurora,USA;7_{ColumbiaUniversity,NewYork,USA;}8_Children’s

HospitalPhiladelph,Philadelphia,USA;9_{CatholicUniversitySacredHeart,}

Rome,Italy

Individuals with chronic SMA have a heterogenous presentation. The onlyscalevalidatedforweakindividualsistheCHOPINTENDdesignedfor SMA1infants.For weakerindividualswhohaveseverecontractures,motor assessmentsareachallengeduetolimitationsintheabilitytotransferorlie prone.WithrecentdevelopmentsintreatmentforSMA,thereisagrowing needfor a wheelchair based scale for non-sitters. Here, we describe the initialdevelopmentofa newscale,AdultTestofNeuromuscularDisorders (ATEND),awheelchair basedassessmentforolderandweaker individuals with SMA. This scale was based on a review of multiple assessments for weaker individuals including: CHOPINTEND, MFM32, RHS, NSAA, PUL2.0,andEK2.InitialreviewoftheHFMSE,RULMandCHOPATEND revealedaflooreffectforboththeHFMSEandRULMinSMAconfirming theneedforamoresensitivescale.CHOPATENDitemswasperformedwith qualitativeitemreviewofexperiencedadministration/scoringchallengesand clinicalreasoningassociatedwithtestingofnon-infantswas interrogatedto determine themes. We reviewed 27 CHOPATEND assessments performed inthewheelchairandfounditemsthatwere notfeasibleincluding rolling, side lyingreaching, suspended hip and knee flexion and headand pelvic extensionin prone suspension. Reviewof itemsthat have beendeveloped andvalidatedinotherscalesemergedas relevanttoassess motorfunction inthewheelchairincludingRHSitemsHooklying,sitting,liftshead,EK2 itemstrunkcontrol,armmovement,joystickcontrols,PUL2.0itemliftsmall weight,andMFM32itemonfingerdiagram.ThefinalATENDhas15items rangingfrom headcontrolto handfunction basedon contracturesand the emergingphenotypefromolder,weakerindividualswithSMAwhohavebeen treatedwithSpinrazaÒ.Testconstructisbasedonatotalscoreof47.The ATENDisacollaborativeeffortbasedonclinicalneedtoassessindividuals withSMAhavingthegreatestlimitations instrength,rangeofmotionand positioning.InitialtrialoftheATENDisfeasibleandmaybemoresensitive todetectmotorfunctioninnon-sitters.Weareactivelycollectingdataonthe ATENDwith futureplans formodernpsychometric analysisto understand reliability,validityanditemfitforindividualswithSMAwhoareunableto sitandtransferoutoftheirwheelchairs.

http://dx.doi.org/10.1016/j.nmd.2020.08.190

P.189

Diverse cohort of spinraza-treated spinal muscular atrophy patients at Mayo Clinic Rochester for theranostic biomarker discovery

S.Cook1_,N.Folch1_,L.Hasadsri1_,D.Oglesbee1_,N.Staff1_,D.Anderson2_,

D.Haile1,D.Selcen1

1_{MayoClinic,Rochester,MN,USA;}2_{MayoClinicHealthSystem,LaCrosse,}

WI,USA

Spinalmuscularatrophy(SMA)isaneurodegenerativediseasecausedby adeletionoftheSMN1gene.TheSMN2genediffersfromtheSMN1gene byaCtoTtransitionthatcausesexonskippingofexon7,whichleadstoa

truncatedSMNproteinthatisrapidlydegraded.Spinrazaworksbybinding downstream of exon7 on SMN2pre-mRNA and promoting theinclusion ofexon 7,therebyincreasingtheamountoffull-length SMNprotein.The discoveryofSMAbiomarkersforthemonitoringofresponsetotherapyis nowaprioritywiththeintroductionofSpinrazaandtherapiddevelopment of other therapeutics. We have currently enrolled a diverse cohort of 17 Spinraza-treatedSMApatientsatMayoClinicRochesterandtheMayoClinic HealthSystemintoourbiomarkerstudy,collectingbloodandCSFfromthese patientsovertimeastheyreceiveSpinraza.Ourpatients include2Type1, 8Type2, and 7Type3SMA patients,ages rangingfrom 6weeksto 53 yearsold.Pathogenicpointmutationsincludedsiblings,a34yearoldman and33yearoldwoman,with amissensemutationinexon 1(c.5C>G)in SMN1aswellasa 10yearold boy,withaframeshiftmutationinexon2 (c.91dupT)inSMN2.Noneofthe17patientshavereportedprogressionof diseasesincereceivingSpinraza.As consistentwith priorreports, younger patientsthatweretreatedearlierinlifehadthehighestrelativeincreasesin motorfunctionscores.Thepatientwiththegreatestincreaseinscores,a26 montholdboywithType1disease,exhibiteda61%increaseinCHOPintend scoreatday373oftreatment.Hisfirstinjectionwasgivenat3monthsofage. Ofnote,2patientswerestillhavingimprovementsinNorthStarAmbulatory Assessmentsatday511,a7yearoldgirland5yearoldboy,bothwithType 3 disease, exhibiting increasesof 15% and 11% respectively. This cohort is diverse and well suitedfor the discovery of theranostic biomarkers of Spinraza-treatedSMAdisease.

http://dx.doi.org/10.1016/j.nmd.2020.08.191

P.190

Investigating temporal changes in percent predicted FVC and RULM score in non-ambulant SMA type III children

A.Wolfe1_,M.Scoto1_,E.Milev2_,R.MuniLofra3_,A.Rohwer1_,R.Wake3_,

A.Mayhew3_{,C.Marini-Bettolo}3_,F.Muntoni2

1_{Great Ormond Street Hospital, London, UK;} 2_{Dubowitz Neuromuscular}

Centre,London,UK;3JohnWalton MuscularDystrophyCentre,Newcastle UponTyne,UK

Spinalmuscularatrophy(SMA)typeIIIisarelativelymildformofSMA, howeverthesepatientsstillgraduallydeteriorate,andasignificantproportion of cases lose ambulation during childhood. There are a lack of studies investigatingchangesinrespiratoryandupperlimbfunctioninthispopulation afterlossofambulation(LOA).Theaimofthisstudyistoinvestigatethe changein thepercentageofpredicted forcedvitalcapacity(FVC) andthe changein therevised upperlimb(RULM) scorein thesepatients acrossa 24-month periodafter LOA. Retrospective analyses were performed on a totalof23non-ambulantSMAIIIpatientsonclinicaldatacollectedaspart ofroutinebiannualappointments attwoUKcentres.Mean ageatbaseline was 10.2 years (range4 to 14). Themean and median FVC percentage predicted score at baseline were both 95.0%. We observed a progressive deteriorationinFVCoverthe24-monthperiod.ThemeandecreaseinFVC percentagepredictedscorewas17.2%withastandarddeviationof15.3.Of these23patients 11had a scoliosis, 1ofthesehad previously had spinal surgeryand5 hadspinalsurgeryduringthestudyperiod.DataonRULM wasavailablein16/23patientswithmeanageatbaselineof11.5years(6.2 to15.7).ThemeanandmedianRULMscoreatbaselinewere30.3and30.0 respectively.Weobservedaprogressivedeteriorationinupperlimbfunction overthe24months.ThemeandecreaseinRULMscorewas3withastandard deviationof 3and arangefrom -8to+1.UsingaWilcoxonsigned rank testbothresultsweresignificant.(p<0.05).ThisstudyhighlightsthatSMA typeIII patients demonstrate progressivedeterioration in their upper limb andrespiratoryfunction afterLOA.Combiningcorrelativedatafromthese assessmentsmayprovideinsightintoclinicalprogressionwithinthispatient populationandultimatelybeusedtogenerateapredictivemodel.