MONITORING INTERNATIONALTRENDS

Prepared February 2012

TheNBA monitors international developmentsthat may influencethemanagement ofblood andbloodproducts inAustralia.Ourfocusison:

•Information that mayhaveanimpact onglobal supply,demandandpricing,suchas changes incompanystructure,capacity,organisationandownership

•Potential newproduct developmentsandapplications

•Global regulatoryandbloodpracticetrends,and

•Otheremerging risksthatcouldpotentiallyput financial orother pressuresonthe

Australiansector.

A summaryofcurrent mattersofinterestappearsbelow. Commentsondirect implications for Australiahavealsobeenincluded. Highlightsinclude:

•Baxterisproceeding toasecondPhaseIII trial of its IVIg,GammagardinAlzheimer’s disease.

•Inspirationisseekingapprovalsfor itshaemophiliaB treatment.

•CSLhasinitiateditsPhaseII/III trial ofits longer-acting rFIX.

•Baxteristriallingits longer- acting rFVIII.

•Researchershavefoundawayto reverseanaemiain mice.

•A small studyhassuggestedasingletreatmentof genetherapy might substantially improvesymptomsandqualityoflifeinpatientswith withhaemophiliaB.

•Scientistshavecreatedbloodplateletcellsbyreprogrammingstem cellsderivedfromadult cells.

•ThenewCollaborativeBiosecurity ResearchFacility in Geelongwill,amongstother things,investigatetheoriginandtreatmentofdiseases that canbetransmittedbetween humansandanimals.

1. RegulatoryMatters:

a. .TheUS FoodandDrugAdministration(FDA) approvedBaxter’sAdvateforroutine prophylaxis toprevent or reducethefrequencyof bleedingepisodesinpatientswith haemophiliaA. Advateis theonlyanti-haemophilicfactor approvedintheUSfor prophylacticuseinbothadultsandchildren.Theapproval isbasedonaPhase IV prophylaxisstudysponsoredby Baxterdemonstrating thatAdvatefor routine prophylaxissignificantlyreduced medianannual bleedratesfrom44toone comparedwithanon-demandregimen. Forty-twopercentof studypatients experiencedzerobleedsduringone yearonprophylaxis.

b. InspirationBiopharmaceuticalsappliedinOctober for approval ofitsdrugfor haemophiliaB inEuropeand plans filinganapplicationwith theFDAin thefirsthalfof

2012. Itisalsodevelopingadrug totreatpatientswitheither congenital oracquired haemophiliaA whohavedevelopedinhibitors. FrenchcompanyIpsenowns40%of Inspirationandhasoptions tobuymoreifInspiration meetsaseriesofmilestones.

  1. Abbott receivedapprovalfrom theFDAfor anewChagas invitrodiagnostic test. TheABBOTTESA ChagasisthefirstFDA-approvedsupplementaltest thatdetects antibodies toTrypanosomacruzi,aparasitecommonlyacquiredthroughcontact with theblood-sucking triatomine, alsoknownasa"kissingbug."Thetest will be usedasanadditional, morespecifictest onhumanserumorplasmaspecimens foundrepeatedlyreactiveusingalicensedscreening test. Amidconcernsabout the transmissionofChagasdisease throughblood, theFDA mandateddonor screening in2007.TheAmericanAssociationofBloodBanks(AABB) ChagasBiovigilance Network reportsthatnearly1,500donorswithChagasdiseasehavebeenidentified in thefour yearssince mandatorydonor screeningwasimplemented.
  2. ProMetic'sproprietaryprioncaptureresin, PrioClear, isincorporatedinto Octapharma'smanufacturingprocessfor itssolvent/detergent treated, prion-reduced, plasmaproduct, OctaplasLG.OctaplasLG, previouslyapprovedfor

1

A study publishedOnlineFirstbytheArchives of InternalMedicinonJanuary 9, 2012said dabigatran isassociatedwithan

increasedriskof myocardialinfarction (heartattack)or acutecoronary syndromeinabroad spectrumofpatients when tested against someothermedicines. Authors KenUchinoandAdrianV. Hernandez,oftheClevelandClinicinOhio, searchedthe medicalliterature for randomizedcontrolled trialsofdabigatran that reportedonMIor acutecoronary syndrome(ACS) as secondary outcomes.Seven trials were selected,involving30,514participants, for theirmeta-analysis. Thetrials they includedwere:two studies of stroke prophylaxisinatrialfibrillation, one in acute venous thromboembolism,onein ACSand three trialsorshort-termprophylaxisofdeepvenous thrombosisinjointreplacement. Thecontrolgroupsincluded administrationofwarfarin,enoxaparin or placebo.

marketingin4countries(Germany, Switzerland,Portugal andAustralia),received regulatoryapproval inNovember for marketinginseveral moreEuropeanUnion countries,namelytheUnitedKingdom, Ireland, Belgium, Netherlands, Luxemburg, SwedenandFinland. ProMeticnoted thatit recentlyreceivedapurchaseorder and bindingforecast from Octapharmafor approximately$US 3 millionofPrioClearresin tobemanufacturedbetweenDecember2011andJune2012withfurther binding forecastsanticipatedfor thesecondhalf2012.

g. IntheUK, JonathanMason,National Clinical DirectorforPrimary Careand Community Pharmacyat theDepartmentofHealth,saidinNovember thattheNHS needs to start thinkingabout theuseof medicinesasaninvestment rather thanasa spendingissue. HetoldthethirdannualnationalQuality,Innovation, Productivity andPrevention(QIPP)symposiuminLiverpool:Value-basedpricing(VBP)is coming, andweneedtothinkaboutwhether wearewilling tospendmoreonanew drugwhichwill providebetteroutcomesorkeepongoingwiththecheaper

options…..If youfocuspurelyondrivingdownspending,costswill ultimatelyincrease andqualitydecreases.Butafocus onquality, oncontinuous improvement, will improvequalityandalsodrivedowncosts.

h. Octapharmareportedinmid-November that global sales totalled1.7milliongramsof

Octagam®5%andOctagam®10% in thefirst ten monthsof 2011, anestimated

60,000treatments,duringwhich therewerenoreportsofthromboembolicevents. AlsoinNovember, theFDA clearedthewayfor theUS market returnof Octagam®

5%.ThiswasbasedonchangesOctapharmahas madeinthemanufacturing

processandthecompany'sdecision toimplement aqualitycontroltest onevery batchofproduct released tothemarketplacefor theabsenceofthrombogenic potential. Additionally,Octapharmawill implementpost-marketingstudiestoensure product safety. Earlierin2010, multipleinternational regulatoryagenciesauthorized thereturnof Octagam®5%andOctagam®10%inimportant worldwide markets. Octagam®10%isnot approvedfor marketingin theUS.

•Octagam wasreintroduced withTGA approval inAustraliainOctober2011.The

NBA and theBloodServiceworkedcollaboratively toensure smoothtransition to revisedsupplyarrangementswiththereintroductionof Octagam.

i.TheAmericanRedCross must paysubstantialfinesafter federal inspectorsdiscovered bloodsafetyviolationsat theRedCrossDonor

andClientSupportCenterinPhiladelphia. That centrecoordinatesblooddonor

informationfrom morethan30collectionpointsaround thecountry.Theviolations includedineffectivedonorscreeningandfailuretoaddnewdonorswithinfected

blood tothenational list ofdeferreddonors.TheFDA says theseareserious

violations,but thenation'sbloodsupplywasnotcompromised.

j.Thefirst cordbloodstorageandresearchfacilityinWesternAustraliawasopenedin

December tostoredonationsfrom newmothersatKingEdwardMemorial Hospital.

k. CSLBehringannouncedinJanuarythat theFDAhadapprovedalabel expansionfor self-administrationof Berinert,C1EsteraseInhibitor(Human), apasteurized, nanofilteredtherapy indicatedfor thetreatmentofacuteattacksof

hereditaryangioedema(HAE),arareandpotentiallyfatalgeneticdisorder. TheFDA

hasstatedthatwithappropriatetraining, patientscannowself-administerBerinert by

intravenousinfusion. Also,aspartof their label expansion,Berinertisnowalso indicated totreat life-threateninglaryngeal HAE attacks,aswell asfacial and abdominal attacks.

•CSLBioplasmahassubmittedBerinertasaSchedule4application. Berinert has beenapprovedbytheTGAfor thetreatment ofacuteattacksinpatientswith hereditaryangioedema.

l.BaxterinJanuarysubmittedasupplemental biologics licenseapplication(sBLA)to theFDAfor approval of GammagardLiquid10%[ImmuneGlobulin Infusion (Human)]

for thetreatment of multifocal motor neuropathy(MMN). Theproduct, marketedas

Kiovigoutside theUnitedStatesandCanada, wasapprovedfor the MMNindication inEuropein2011.ThefilingisbasedonaPhaseIII, randomized,double-blind,

placebo-controlled,cross-over, multi-center studyoftheefficacy, safety,and

tolerabilityof GammagardLiquid10%inatotal of 44MMN patients.Thestudy evaluatedwhetherGammagardLiquidwassuperior toplaceboadministrationin the primaryandsecondaryendpoints,includinggripstrength.

•Kiovig wasselectedunder therecent IVIgtenders. ItisregisteredinAustralia for useasasub-cutaneousproduct but isnotapprovedunder thesupply

arrangementsforuseinthis manner.

2. Products

a. BaxterannouncedinJanuarythat it wouldproceed tothesecondphase III trial using IVIG totreatAlzheimer’safterpreliminaryresultsofthefirst phaseIII trialshowed morethan20%chanceofimprovement. Enrolmentinthefirst trial wascompletedin June2011.

•TheDataSafetyMonitoringBoard(DSMB) for thefirstphaseIII trialtookaninitial readof120patientsat18 months(from390)andshowed that thetrial hada greater than20%chanceofreachingstatistical significanceintheprimary combinedendpoints. However,thisinitial readwasconductedonlyasa “futility analysis’’ toseeif thetrial wasworthcontinuing, and thefull datareleaseisnot expected till thefirst quarter of2013.

•Baxterwill nowstartitssecond400-patient phaseIII trial.Thisisexpectedto takethree yearstocompleteandisrequiredforFDA approval so thiscould

happenin2016. ThesecondPhaseIII trial is identical indesigntothefirstPhase

III trial.It isaglobal, multi-centretrialthat will enrol approximately400patients. Approximately80centresinNorthAmerica,Europe,JapanandAustraliawill

participatein the study. Theprimaryendpointof thestudy istoevaluatethe

effectivenessofGammagardLiquid10%onpreservingcognitiveperformance andfunctional activitiesinpatientswithmild tomoderateAlzheimer'sdisease,as comparedwithstandardofcare, overan18-monthperiod.

•Thissecond, confirmatorytrialfollowsaseparate, ongoingPhaseIII GammaglobulinAlzheimer's Partnership (GAP) trial sponsoredby Baxterin

collaborationwith theAlzheimer's DiseaseCooperativeStudy(ADCS), aclinical trial consortium supportedbytheUSNational InstitutesofHealth.

b. Researchersat King's CollegeLondonhavedevelopeda test thatusesmass spectrometrytodetect variousdiseasesfrom asinglespotof driedblood.Thetest

wasdevelopedfor thediagnosisofsicklecell diseaseandinheritedmetabolic

diseaseinnewborns,but hasbeenimproved todetect diabetes, kidneydiseaseand heart diseaseaswell. Driedurinespotscanalsobeusedfor the veryearlydetection

of kidneydisease,particularly inpatientswithahighriskofdeveloping renal

complications,forexamplepatientswith type1ortype2diabetes.Themethodfor sicklecell diseaseandhaemoglobinopathyscreeningusing massspectrometrywas grantedanEU patent in2010.

c. InNovember, theNewEnglandJournal ofMedicinepublished resultsofan evaluationofwhetherprophylaxiswithFEIBA candecreasebleedingeventsinpatientswithseverehaemophiliaA andinhibitors, comparedwithon-demandtherapy.Thestudy reportedthat patientstreatedprophylacticallyoversixmonthsexperienceda62%reductioninall bleedsintheprophylaxisperiod,anaverageof5bleedingevents comparedwithanaverageof13.1duringon-demandtreatment.

d. BaxterannouncedinJanuarythedosingofthefirstpatients inaPhaseIclinical trial

ofBAX855,alonger-acting (pegylated) form ofafull-lengthrecombinant factor VIII (rFVIII)protein. Intermsofmanufacturingprocess,BAX855isbasedonBaxter's Advate. ThePhaseI trial isaprospective,open-label studythatwill assess the safety, tolerabilityandpharmacokineticsofBAX855inpreviously-treatedpatients aged12yearsor olderwithseverehaemophiliaA.Whenusedfor prophylaxis, Baxter'sAdvaterequirespatientstoinfuseevery twoto threedays toreduce the occurrenceofbleedingepisodes.ThisPhaseI trial is thefirst stepinassessing whetherBAX855canbeinfusedlessfrequently.

e. Amgenwrotetwonewlong-term supplycontractswith majordialysisproviders DaVitaandFresenius, asitpreparesfor potential competitionfor its Epogen.The supplydealscomeasUS Medicareischangingitsreimbursement for dialysis toaflat

rate.ThechangehasbeenexpectedtocutintoEpogensales, becausethedialysis providerswon'tbepaidany morefor higher dosesofthedrug thantheyareforlower

doses. Safetyquestionsabout higherdosesofEpogencontinuetomount. Anaemia drugAffymaxcouldbelaunchedin2012,Roche'sMircerain2014andbiosimilarsas soonas2015.

f.Atthe4thAsiaPacificCongressonControversiesinObstetrics, Gynaecologyand

Infertility inBangkokinNovemberthereweretwooral presentationsontheclinical valueoftheOrSenseLtdNBM200non-invasivehaemoglobin monitor formaternal

healthandanaemia- monitoringprior, duringandpostdelivery.

g. DatafromBaxter’snewphaseIII clinical trial ofHyQ,itscombinationimmunoglobulin productforuseinpatientswithprimary immunodeficiencies, waspresentedat the AmericanCollegeofAllergy, AsthmaandImmunologyannual meeting. HyQhad alreadybeensubmittedforapproval in theUS andEurope.

h. AMAGPharmaceuticalsinNovemberannouncedpositivenewdatafrom thefirst head-to-headtrial comparingFeraheme (ferumoxytol)Injectionfor intravenoususeto

ironsucroseinpatientswithirondeficiencyanaemiaandchronickidneydisease. Thedatawerepresentedinaclinical trialsposter sessionat theAmericanSociety

ofNephrology KidneyWeek meetinginPhiladelphia.

i.CytoSorbentsCorporationisaNewJerseycompanyusingbloodpurification totreat life-threateningillnesses.Itstechnology isbasedonbiocompatible,highlyporous polymerbeadstoremove toxicsubstancesfrombloodandotherbodilyfluidsbypore captureandadsorption.

•In2011,CytoSorbachievedEU CE Markapproval asanextracorporeal cytokine filter2.ItsEuropeansepsistrial showedstatisticallysignificant mortalitybenefitsin patientstreatedwithCytoSorbintwosubgroupsathighriskofdeath–thosewith veryhighcytokinelevelsandpatientsabove theageof65. CytoSorb reimbursementwasestablishedin Germany,addressingamajor barrier tosales for mostnewproducts.Thetechnologywasintroducedat medicalconferences suchastheGermanSepsisSociety Conferenceand theInternational Societyof IntensiveCareMedicine. ThecompanywasawardeditsfirstPhaseI Small Business InnovationResearchgrantfromtheUSArmytodevelopitstechnology tohelptreat traumapatientswith rhabdomyolysis. Rhabdomyolysisis the breakdownofmusclefibres thatleadstothereleaseofmyoglobinintothe bloodstream, whichcanbedamaging tokidneys.TheUS DefenseAdvanced ResearchProjects Agency(DARPA)notifiedthecompanythatit hadselectedits technologyproposalforfundingaspart ofits"Dialysis-LikeTherapeutics"

program todevelopabloodpurificationdevice totreat sepsis, pendingsuccessful contractnegotiations. ThecompanyreleaseditsnewHemoDefendtechnology

platform, whichwasintroducedforout-licensingopportunitiesat theAABB

conference.ThecompanyclaimsHemoDefendhas thepotential toremove contaminantsfrom thebloodsupplythat cancausetransfusionreactionsinthe morethan30millionbloodproductsadministeredannually in theUS alone. It saysHemodefendremovesantibodies,freehaemoglobinandinflammatory mediators.

j.Atthe53rdAnnualMeetingoftheAmericanSocietyofHematology(ASH) inSan Diego, Symphogenpresentedfinal PhaseII datademonstrating thatitsrecombinant polyclonal antibodydrugcandidate rozrolimupabexhibitedafavourablesafetyprofile

andinducedarapidincreaseinbloodplateletsinpatientswithImmune

ThrombocytopeniaPurpura(ITP). ProductscurrentlyusedinITPinclude

immunoglobulin,PromactaandNPlate.

k. CSLBehringannouncedthat thefirstsite(Vienna)hasbeeninitiatedinitsglobal phaseII/III,multi-centrestudytoevaluate thesafety,efficacyandpharmacokinetics ofrecombinant fusionproteinlinkingcoagulationfactor IXwith recombinantalbumin

(rIX-FP).Theprospective,open-label studywill enrol patientsaged12-65yearswho havehaemophiliaB. CSLBehring, incollaborationwithitsparent company,CSL

Limited, isdevelopingrIX-FPfor theprophylaxisandtreatment ofbleedingepisodes inpatientswithcongenital Factor IX (FIX) deficiencyaspartof thePROLONG-9FP clinical studyprogram.Todate, thePROLONG-9FP program hasestablishedstudy

sitesinAustria, Bulgaria, France, Germany, Italy, Spainand Israel.Incoming monthsadditional trial siteswill beestablishedintheUnitedStates,Japanand

Russia.

•ThisstudyfollowsaPhaseI pharmacokinetic trial which thecompanysays showed "verypromising" half-lifeextension results. CSLBehringandCSLhave

2The company saysthatthe overproductionof cytokinesor "cytokinestorm"iswidelyacknowledgedtoplaya causalroleinthedevelopmentof organfailure,immunesuppression,andsecondaryinfections,theleading causesofdeathintheICU fromlife-threateningillnessessuchasinfection and sepsis,burn injury,trauma,acute respiratorydistresssyndrome,pancreatitisand others.Itsaysthat physicianscontinuetoaffirmthatthereareno effective "active"therapiesavailabletotreattheseconditionsandthattheycontinuetorelyonsupportivecare therapiessuchasmechanical ventilation,vasopressors, anddialysisto helpkeep patientsalive.Thevoluntary worldwidewithdrawal ofXigrisbyEli LillyinlateOctober,previouslythe onlyapprovedtherapyintheUS and Europetotreatsepsis, hashighlightedthelackoftherapiesavailable.

engineered rIX-FPtoextend thehalf- lifeofFactor IX while minimizingany tolerability issues. Intheprocess, recombinantalbumin--aproteinwithan inherently longhalf-life--isusedasafusionpartner. Aspecificallydesignedlinker connectstherecombinant factor IXandrecombinantalbuminasa meansof optimizingtheefficacyofrIX-FP.

•ThePhaseII/III studyconsistsofascreeningperiod,apharmacokinetic evaluationperiod, followedbyanapproximately12-monthsafetyandefficacy

evaluationperiodwith rIX-FP. A surgical prophylaxissub-trial isincluded.

3. Market structureandcompanynews:

a. InNovember ProMeticLifeSciencesannouncedthatitsexpandedpartnershipwith WuhanInstituteofBiologicProductsanditsparentcompany ChinaNational Biotech Grouphadresultedin thesuccessful completionofthefirstmilestonesassociated with thescalingupof thePlasmaProteinPurificationSystem (PPPS)3in theWuhan facility. Thishadcreatedcriticalknowledgewhichwill lead tofurther cost reduction for ProMetic'sownfacility inLaval,Canada.

b. NovoNordiskwill nolongeruseliveanimals totestproductionbatchesofits biological products.It will usecellsfromhamstersandother animalstotestits productionbatchesforbiological activity. NovoNordisksaysthesemethodsproduce anarrowerrangeof resultswith moreprecisionand reliability. Thetransitionhas involvedamending thousandsofregistrationdossierstosatisfyhealthauthorities worldwide. Theuseofliveorganismsintheproductionofbiologicsraisesconcerns aboutbatch-to-batch variabilityand thepotentialforcontamination. Asa result, potencyandsafetytestingaretypicallyrequiredforeachindividual batchofa biological tomaintainqualitycontrol.Thisofteninvolvesanimal testsrather thanin vitroassaysusedforqualitycontrol ofsmall-moleculedrugs.Thenumber ofanimals neededforbiologicalcontroltests, aswell as thetypesoftestsrequired, are determinedbytheregulatoryrequirementsof thecountries inwhichNovoNordisk sellsitsproducts.

c. AlnylamPharmaceutical(headquarteredinCambridge,Massachusetts) iscontinuing its "Alnylam5x15"program, whichwaslaunched inJanuary2011tohavefiveRNAi therapeuticprogramsinclinical developmentby theendof2015.Thecompany explains that RNAi isanatural processof genesilencing that couldleadtoanew classofmedicines,RNAi therapeutics.Among thecompany’splansareprograms in haemophiliaand refractoryanaemia.

d. Canadiancompany CangeneannouncedinJanuarythat itiscutting120jobs,or about17per cent ofits total workforce. It has, however,signedacollaborative

researchagreementwith theUniversityofBritishColumbia todevelopimmune-based

therapiesfor Alzheimer'sdisease.

4. Overseasevents

a. TheScottishNational BloodTransfusionServiceis tobuilditsnewnational headquartersinEdinburgh,at theHeriot-WattUniversity ResearchPark.

b. DebatecontinuesoverCanadianBloodServices’ decision tocloseitsproduction facility inStJohn,infavourofaconsolidatedoperationin theMaritimeProvinces.

3PrometicsaysthatthePlasmaProteinPurificationSystemallowsforthetargetingandremovalof multiplehigh- value proteinsfromasingleplasmasampleat unprecedented activitylevelsusingProMetic'sMimeticLigand adsorbenttechnology.Thissystemalso providesfortherecoveryof newbiotherapeuticsastheyare discovered andidentified.The effect ofthisprocessistoreducethesignificantlossesincurredwhenusingthemore conventionalCohn precipitation process.

Somesupport continuesfor thenotionofanindependentbloodagency inNew

Brunswick. Suggestionshavealsobeenmadeof partneringwithHéma-Québec. c. MichaelMosleyfilmedforaBBC series,FrontlineMedicine,in themainhospital in

CampBastion, theheadquartersof theBritishforcesinAfghanistan.Inanarticlefor

theMail OnlineinNovember hewrote “Thesurvival rateamongst woundedtroopsin Afghanistanisupto90percent, which makesit thehighestinthehistoryof warfare…..For mynewseriesIwantedtofindoutwhattheyweredoingon the frontline that was making thedifferenceandhowwhatwasbeinglearnt couldbe used toimprovephysical-injurycareinBritain”.Theseincluded:

•thesingle- handedtourniquet, issuedtoallthetroopsontheground.

•soldiersbeing taught to stuffawoundwithCelox-bandagesimpregnatedwith chitosan, asubstancefoundinshrimpshells.

•theintraosseousneedle:TheMedical Emergency ResponseTeamonan evacuationhelicoptercandrill intobone(usually thehumeral head) sobloodis

transfusedintothebone’ssoft marrowinterior.This is easierinamovinghelicopter than searching for aveincollapsed throughbloodloss.

•transfusingwithaunit of plasmafor everyunitofredcells4

d. Europe'shealthissuffering,witharound80,000 casesoftuberculosisinfectionayear andseriousproblemswith measles,HIV andthreatsfrom "superbug" infections,an annual health reportonthe regionsaidinNovember.

e. 15,000newbornbabiesat twoofBahrain'smainhospitalswill bescreenedfor geneticandmetabolicdisorderswithin thenext twoyears.It will takeplaceaspart of

a major studybeinglaunchedinJanuarybythenon-profitAl JawharaCentrefor Genetic DiagnosisandResearch. Diagnosticservices managingdirector,DrJamal Golbahar saiditwasimperativesuchascreeningprogrammewasintroduced

because theriskofbabieswithgeneticdisorders increases inconsanguineous marriage (marriagebetween relatives), whicharebetween60%centand70%inthe

region. Ingeneralthereisaonein2,000chanceofachildbeingbornwitha metabolicdisorder,butit isonlyonein50,000to60,000intheUSandEurope, said DrGolbahar.Thepilotstudyscreeningwill beconductedbytakingabloodspotfrom

thebaby'sheel bypricktestwhenitistwodaysold. Itwill be testedfor50genetic disorders, includingblooddisorderssuchassicklecell anaemiaandthalassaemia.

Thosefoundtohaveadisorder will befollowedupbya team ofexperts whowill treat theircondition.

5. SafetyIssues:

a. A study intheTownsvilleregionhasconfirmedseropositivityofthecausativeagent ofQ fever, Coxiellaburnetii,inover20%ofdomesticdogs.Thismayhavepublic healthimplicationsfor bothdogownersandveterinarians.

b. Newmothersat Bathurst BaseHospital in2009 receivedblood transfusionsat arate ofmorethanfour times thestateaverage,newfiguresshow.

c. Manyprematureinfantssufferalife-threateningdestructionofintestinal tissuecalled necrotizingenterocolitis(NEC). NowaLoyolaUniversityMedical Centerstudy5has identifiedamajor risk factorforNEC. Prematurenewbornswith theAB blood type whodevelopNEC arenearlythreetimesas likelytodiefromitasthosewithother

blood types.TheauthorssayneonatalICUstypicallygiveTypeOintransfusion, the

4A studyinvolving22centresinEnglandandWalesisassessinghowchangingthemixof bloodcomponents givencanaffect outcomes.

5The studywaspublished online aheadof printintheJournal ofPerinatology.Senior author isJonathan

Muraskas,MD, co-medicaldirectorofLoyola'sneonatalICU.

universal donortype.Thispracticemay inadvertentlycauseanenhancedimmune reaction.

6. Research:

a. Once-monthlypeginesatide,aninvestigational peptide-basederythropoiesis stimulatingagent (ESA), issimilar toepoetinadministratedonetothreetimesweekly in maintainingmeanhaemoglobinlevelsin the10-12g/dLrangeinhaemodialysis patientswithanaemia,accordingtostudyfindingspresentedinPhiladelphiain NovemberatKidneyWeek2011.

b. Researchersat Children’sHospital Bostonhavefoundawayto reverseanaemiain lab mice.Theydiscovered that geneticallyengineeredbloodvesselswere successfulinsecretingdrugsintothebloodstream.Ifthemethodsucceedsin deliveringother therapeuticproteinsondemand, itcouldbeusedforpatientswith haemophilia todeliverFactor VIII andFactorIX proteins; withhepatitisCtodeliver

alphainterferon; andwith multiplesclerosistodeliverinterferonbeta,all accordingto JuanMelero-Martin,thestudy’sprincipal investigatorfrom theDepartmentofCardiac Surgeryat Children’sHospital,Boston.6

c. A novel immunoglobulin replacement therapythat useshyaluronidasetofacilitate dosingwithgammaglobulinhasshowngoodefficacy inpreventinginfectionsin peoplewithprimary immunodeficiencydisease (PIDD), according toastudy presentedinapostersessionat theAmericanCollegeofAllergy,AsthmaImmunology2011Annual ScientificMeetinginNovember. Itmayalsoenable reducing thefrequencyofdosing from monthlytoweekly.

d. Medical researchersinCanadaandtheUSrecentlypublished theirjointfindingsthat fatal priondiseases,whichincludeBSE or "madcowdisease,"haveahidden

signature.InthejournalPublicLibraryofScience(PLoS) Pathogens, they

demonstratethat uptoseven monthsbeforeananimal showedphysical signsof havingaprioninfection, aparticularprionproteinin thebrainwasbeingeradicated. Thisisknownasshadooprotein.Theresearcherssuggestedthat thebraincellsare infact trying toget ridof thefatal prionproteinandasaconsequence, thisbystander shadooproteinisbeingdestroyedunintentionally.

e. InDecember,Chinalaunchedaresearchprogramonthetreatmentofbeta thalassemia, apredominant typeofMediterraneananaemia, inGuangzhou, the capital cityofsouthChina'sGuangdongprovince.

f.Erythropoietin, considereda"performanceenhancing" substancefor athletes, may increase riskofvascular problemsinthebrain, Swiss researcherssaid.Thestudy,

publishedbytheJournalof theFederationof theAmericanSocieties for ExperimentalBiology, found thatprolongedEPOadministrationincreased haematocrit –theconcentrationofredbloodcellsinblood– whileacute

administrationdidnot.Thestudyfoundbothgroupshadincreasesinbloodvessel constrictionandhigherbloodpressure.

g. Preoperativeautologousblooddonationduringposterior lumbarspinal surgery is associatedwithpreoperativeanaemia,andalower transfusionthresholdthan

allogeneicblooduse,according toastudy inSpine(15December2011).

h. Newresearchshows that transfusionsdidnot speed recoveryor reducethe riskof dyingamong morethan2,000elderlypeoplewhohadhipsurgery.Thestudy

appearsonlineintheNewEnglandJournal ofMedicine(15December 2011). i.Theannual meetingof theAmericanSocietyofHematology inSanDiegoin

December was told thathydroxyurea,approvedforuseinadultswithseveresickle cell anaemia, canalsohelpyoungchildrenwiththedisease.

j.SixhaemophiliaB patientsgivenasingletreatmentof genetherapyenjoyed

substantially improvedsymptomsandqualityoflife.Their liverswereinfusedwitha

6November17issueofBlood

correctversionof thegene that makesFactor IX. Fourwereabletostop receiving FIX uptothetimeof thereportandtheother twoincreasedthetimeperiodbetween receivingFIX. Thepatientsrangedinagefrom27to64.7 Thefirst patientwho received thegenehasmaintainedsteady levelsof theFIXproteinfor morethan

18 months.

•Altering thediseasefrom severe tomild maybeharderforhaemophiliaAbecause themissingproteinis muchlargerandthereforemoredifficultfor a vectorvirus todelivertotheliver. HemophiliaA isalso thought morelikelytogenerateanimmuneresponse.TwoofthegenetherapypatientswithhemophiliaB sufferedmildimmuneresponsesthat requiredsteroidtreatment.

7. / O
a. / nthehorizon
MITresearchershavedescribedthekeyroleofplateletsinspreadingcancer through
secondarytumours. Cancer researchprofessor RichardHynesandhis team
publishedinCancerCell, pointing tochemical signalsfrom theplatelets leading
tumourcellstospreadintoother locations. Plateletswerefoundtocontributeto
metastaticcellsafter comingincontact with tumourcells. Metastasismaybe
responsibleforupto90%ofcancerdeaths.

•This may inthelonger termchangecancer treatmentprocessesgiventhat alargeproportionof platelettransfusionsaregivento peopleundergoingchemotherapyor bonemarrow transplantation.

b. Inahigh-stakesexperiment fundedbytheUS DefenseDepartment, theUniversityof PittsburghMedical Centeristotestahypothermiastrategyonahandful of trauma victimswhoarebleedingsobadlyfromgunshots, stabwoundsor similarinjuriesthat

theirheartsstopbeating.Get coldenoughand"youdoOK withnobloodfora while,"sayslead researcherDr.SamuelTisherman. Hecallstherescueattempt

"emergencypreservationandresuscitation", EPRinsteadofCPR. Histeamplansto begintestingitearlythisyear.

•Beforethefirst candidatesarechilled,thescientistsfaceahurdle: Thelaw

requiresthat patientsconsent tobepartof medical experimentsafter they'retold theprosandcons.That'simpossiblewhen thepersonisbleeding todeath.

Therewon'tevenbetime toseekarelative'spermission. SothePittsburghteam isbeginningacampaignrequiredbytheFDAtoeducatearearesidentsabout the study instead—withsignsoncitybuses, videoonYouTube, awebsiteand two

town-hall meetings. Residentsworriedabout possible risks, suchasbrain damage, couldsignalist saying they'dopt out iftheyeverwereseverely injured.

c. Scientistshavecreatedbloodplateletcellsbyreprogrammingstem cellsderivedfromadult cells,offering thepotentialforarenewablesupply. Researchersat theCentrefor iPS Cell ResearchandApplicationat KyotoUniversitypresenteddataat ameetingof theAmericanSocietyofHematology inDecember showingtheywereabletocreatethecellsin thelaboratoryandconfirm theyhad thesamelifespanasnormalhumanplateletswheninfusedinmice.Inducedpluripotent stem cells, or iPS cells,areproducedbymanipulatingordinaryhumanskinor bloodcellsbacktoastateinwhich theyareable todifferentiateintoanumber ofdifferent cell types.

7The studywaspresentedinDecemberatthe annualmeeting oftheAmericanSocietyofHematologyinSan

Diego,andwaspublishedconcurrentlyintheNew England JournalofMedici

8. Infectiousdiseases:

a. Mosquito- bornediseases

•InvirageninNovemberannounced the startofPhase2trialsofDENVax,its investigational denguevaccine.Thetrialswill test thesafetyandimmunogenicityof thevaccineinmultipleagegroups incountries wheredenguefeverisendemic– PuertoRico,Colombia,SingaporeandThailand.Thetesting follows thesuccessful completionofPhaseI trialsofthe vaccine,conductedinColombia.

•A groupof researchersledby Novartishasdiscoverednovel malariacompounds that mayprove tobemoreefficientthancurrentlyavailable treatmentsandcouldbeused asaprophylactic.Thisnewclassofantimalariatreatmentstargets infectionsbothin thebloodandintheliver, thusreducing theriskofadiseaserelapse.

b.Influenza/Avian Influenza

•InovioPharmaceuticalsannouncedinNovember thatasingleintradermal (ID) electroporationboostofitsSynConavianinfluenzavaccinegenerated hemagglutinationinhibition (HAI) titresagainst sixdifferent, unmatchedstrainsof H5N1–adistinctnewclinical achievementontheglobal researchcommunity'spath todevelopuniversal influenzavaccines. Thissinglesyntheticvaccinegenerateda four-foldor greater riseinHAI titresin50per centofboostedsubjects initsPhaseI clinical study. Theseresultswerepresentedat the5thWHO Meetingon Influenza Vaccines that InduceBroadSpectrum andLong-LastingImmuneResponses.

•According toresearchpublishedin theNovemberJournal of Virology, vaccinating childrenannuallyagainst influenzaviruscouldinterferewith their development of cross-reactivekiller Tcells tofluviruses. Leadauthor RogierBodewesof Erasmus Medical Center, Rotterdam, andhiscollaboratorswarnofpotentiallyconflicting outcomesfromannualflushots. "Annualflu vaccinesareeffectiveagainstseasonal flu,butcouldleavepeople morevulnerable tonovel pandemics", saidBodewes. "Inductionofvirus-specifickiller Tcellscausedbychildhoodfluinfectionmayreduce morbidityandmortalityratesfrompandemicinfluenzaviruses."

•Sustainedcommunitytransmissionofoseltamivir-resistantA(H1N1) 2009pandemic viruseshavebeenidentifiedinAustralia. Relevantsampleswereobtainedin the HunterNewEnglandregionofNSWbetweenMayandAugust20118.

•A reviewofoseltamivir(Tamiflu) raisedquestionsabout boththeefficacyofthe medicationandthecommitment ofitsmaker to supplyenoughdatafor claimsabout thedrug tobeevaluatedby independentexperts9.

•ScienceandNaturejointlypublishedaletter on20Januarydeclaringa voluntarytwo- monthsuspensionofresearchintotransmissionofH5N1highlypathogenicavian influenza.Theletter, signedby39influenzaresearchersaroundtheworld, acknowledgesthatbefore researchcontinues, thereshouldbeinformed, global discussions regardingitsregulationandpublication.Themovecameafterthenews that H5N1,whichsofarhasnot evolved transmissibilitybetweenhumans, hadbeen

8N.Engl.J.Med., 2011;365:2541-2542

9 JeffersonT, etal "Neuraminidaseinhibitorsforpreventingand treating influenza inhealthyadultsandchildren"CochraneDatabase ofSystematicReviews2011;12.Art.No.:CD008965.

transformedinlabexperiments intoavirusthat isaerosolizedandeasilytransmitted betweenferrets, theanimal modelthatbest mimicshumaninfluenzainfection. On

20December, theUSNational ScienceAdvisoryBoardfor Biosecurity(NSABB)

recommendedthatdetailsofthe mutationswhichevolved thisnewtransmissibilitybe redactedbeforepublication,sparkingaheateddebateamong thescientific

communityregardinghowtosharetheresultsof suchpotentiallydangerous

research,andwhetheror not todoitinthefirstplace.

•InDecember, thefirstUSfacilityfor makinginfluenzavaccineincell culturewas openedinNorthCarolina.TheNovartisplanthad49%ofits constructionfundedbytheUSHealthandHumanServicesDepartment. Cell cultureisseenassomewhatfaster thanconventional,egg-basedproductionof flu vaccine. Thereissomesuggestionthatchicken-basedeggproductionmightbe vulnerable toanavianflupandemic.Thefacilityusesculturedcaninekidneycells to growinfluenzavaccine.

c.vCJD

•Aninternational teamof researchers identifiedtwoSwisscowswithanewform of“mad- cowdisease”. Previously,scientistshaduncovered threeprionvariants, butwhen the current team examinedtheprionsof thetwocows, theyfoundafourthvariant10.

d. Other

•InNovember,Senator KimCarropenedthenewAustralianAnimal HealthLaboratory (AAHL)CollaborativeBiosecurity ResearchFacility(ACBRF)in Geelong.Thefacility, whichisapart oftheCSIRO’sAAHL,will researchviruses that threatenpeople,livestock andwildlife.It will beused toinvestigatetheoriginandtreatmentof‘zoonotic’ diseases

– thatis, diseasesthat canbetransmittedbetweenhumansandanimals.

•A recentstudy11publishedin theMedical Journal ofAustraliaexaminedwhether premigrationscreeningfor tuberculosisisworthundertakingin visaapplicants, and

whetherscreening resourcesarebeingappropriatelydirected towardsintending migrantsathighest riskof tuberculosis.Theauthorsreport that theoverseasscreening

programisdetectingsubstantial numbersofpeoplewithactive tuberculosiswho otherwisewouldhave travelled toAustralia. Premigrationscreeningdetected519

peoplewho requiredtreatment for active tuberculosisin the2009–10financial year. It is

uncertainif thisistypical,althoughatMay2011nearly400caseshadbeenidentifiedin the2010–11program year.Theprevalenceoftuberculosisfound(137per100000 population)compareswith that foundinpeopleinAustralianimmigrationreceptionand processingcentres(157per100000).12 Theseratesarehighcomparedwiththe estimatedprevalenceoftuberculosisinAustraliaof7.9per100000populationin2009.13

•Almost4000casesofwhoopingcoughwere reportedlast year totheWAHealth

Department,comparedwith1458casesfor the wholeof2010.

•Britishtroopsarereturningfrom Afghanistanwith thedesertboilsdiseaseleishmaniasis.

Theydevelopcrater-likeskinboils thaterupt andareveryslowtoheal.Thetreatment is

10inthe journalEmergingInfectiousDiseases,published bytheU.S.Centersfor DiseaseControland

Prevention,January2012.

11AuthordetailsKathleenKingBSc(Hons),MB ChB,FRCPath,formerlySenior MedicalAdviser ,GlobalHealth Branch,DeptofImmigrationandCitizenship,Sydney. PaulJDouglasMB BS,MHA,FRACMA,ChiefMedical OfficerandGlobalManager Health,Immigration. KenBeathBE,MAppStat,PhD, Lecturer,Dept ofStatistics, MacquarieUniversity.

12KingK,VodickaP.Screeningfor conditionsofpublichealthimportance inpeoplearrivinginAustralia byboat without authority.MedJAust2001;175:600-602.

13WorldHealthOrganization.Globaltuberculosiscontrol.WHOreport2010.Geneva:WHO,2010:183.

intravenousdosingwith sodiumstibogluconate.Cutaneousleishmaniasis, thecommon formamongsoldiers, isadiseasespreadbythebiteofthefemalesandfly. Itcan eventuallycausepartsof thenoseandlips towearaway ifleftuntreated.