Landscape analysis of Amyotrophic Lateral S2ContentsIntroduction3Methodology3Global ALS drug distribution analysis4Phase wise distribution analysis(2009-2023)4Marketed drugs5Approved drugs6Drugs in preregistration phase6Drugs under late-stage clinical development7Drugs under early-stage clinical development9Major players in the clinical development of ALS drugs16Drug development landscape for ALS16Diagnostic Agents for ALS17Upcoming treatments for ALS17Major players in the overall market25Target trend analysis for overall drug profiles26Drug classes in focus for ALS therapeutics27Agreements for ALS drugs27Conclusion30References31Landscape analysis of Amyotrophic Lateral Sclerosis IntroductionAmyotrophic lateral sclerosis(ALS),also known as Lou Gehrigs Disease,is a rare neurological disease that affects motor neuronsthose nerve cells in the brain and spinal cord that control voluntary muscle movement.As motor neurons degenerate and die,they stop sending messages to the muscles,which causes the muscles to weaken,start to twitch(fasciculations),and waste away(atrophy).Eventually,the brain loses its ability to initiate and control voluntary movements.Some of the symptoms involved with the disease include muscle twitching and cramps,tight and stiff muscles(spasticity)with weakness affecting an arm,a leg,the neck,or diaphragm and slurred/nasal speech.The patients may also develop problems with language or decision-making along with dementia over time.Stages of ALSThere are 4 stages in ALS:Stage 1-The Beginning-The muscles will become softer,appear to be weaker,or sometimes,they become tight and spastic.Stage 2-The Middle-The muscles of the affected areas will become paralyzed,and other muscles will seem stiff as if they were about to become paralyzed as well.Stage 3-The Late Stage-All the voluntary muscles or at least 90%of them will be paralyzed.Stage 4-The Ending-The elderly patient may expire due to the lack of air and the disability to use lung muscles.Types of ALSSporadic-This is the most common form of ALS in the U.S.,making up 90%to 95%of all cases.These cases occur randomly,without any known cause,and there is no family history of ALS.Familial-This form of ALS affects a small amount of people and is thought to be inherited.TreatmentTreatments cant reverse the damage of amyotrophic lateral sclerosis,but they can slow the progression of symptoms,prevent complications,and make a person more comfortable and independent.In this report,we will explore the available treatment options and the ALS landscape.MethodologyIn this report,we conducted a comprehensive analysis of the ALS drug landscape using the AdisInsight database.We identified all ALS drugs currently catalogued in the AdisInsight database which included drugs that are available on the market,approved by regulatory authorities,under regulatory review,or in various stages of clinical and early development.The ALS drug landscape was analyzed along with the key pharmaceutical companies involved in the development of ALS drugs and the trends in research focus,particularly regarding the mechanisms of action and properties of the drugs.Finally,we analyzed the agreements and partnerships formed in the development of ALS drugs to uncover key industry trends in collaboration and partnership strategies among pharmaceutical giants in the ALS drug development Landscape analysis of Amyotrophic Lateral Sclerosis4Global ALS drug distribution analysisAs per the 2017 CDC data,over 31,000 people are living with ALS in the United States.Approximately 5,000 individuals are diagnosed with ALS annually in America.This may explain why the USA are leading the market when it comes to the number of ALS drug development programmes over the years.Distribution analysis by phase(2009-2023)With the increase in the prevalence of patients with ALS,drug profiles for ALS treatment have gradually increased from 2009 to 2023.There was a major spike in 2023 which marks a remarkable year with the highest number of ALS drugs development programmes.In total,147 drugs are in the Clinical stage of drug development,and 7 drugs are Registered and Marketed respectively.0501001502002503003504004505002009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023UnspecifiedResearch/PreclinicalClinicalRegulatoryMarketedGeographical distribution of all ALS drugsDistribution analysis by phase(2009-2023)Fig.1:Distribution by country of ALS drugsFig.2:Yearly trend of ALS drugs across various development stagesLandscape analysis of Amyotrophic Lateral Sclerosis 5Marketed drugsThere are currently seven drugs marketed to treat ALS and its symptoms:Exservan,Radicut,RELYVRIO,Teglutik,Rilutek,NEURONATA-R,Qalsody.The following table provides further details on these medicines along with the locations of availability:Drug TypeBrand NameOrganisationLocation(s)RiluzoleSMExservanMonoSol Rx Aquestive TherapeuticsUSAEdaravone SMRadicutMitsubishi Pharma CorporationJapan,USA and CanadaSodiumSMRELYVRIOAmylyx PharmaceuticalsUSA,CanadaRiluzole oral suspensionSMTeglutikITF PharmaUSA,United Kingdom,Italy,Spain,GreeceRiluzoleSMRiluteksanofi aventisArgentina,China,Colombia,Japan,Norway,Peru,Switzerland,Uruguay,USA,New Zealand,Saudi Arabia,Zimbabwe,Brazil,Croatia,Hong Kong,Israel,Lebanon,Mexico,Singapore,South Korea,Syria,Taiwan,Canada,Turkey,Australia,Chile,Thailand,Venezuela,European UnionLenzumestrocel MSCNEURONATA-RCORESTEMSouth KoreaTofersen ASOQalsodyIonis Pharmaceutical USALegends:SM-Small molecules,MSC-Mesenchymal stem cell therapies,ASO-Antisense oligonucleotidesFrom the data,it is evident that the USA has the highest number of marketed drugs for treating ALS,which is further followed by Canada,Japan,and South Korea respectively.Number of drugsGlobally marketed drugsFig.3:Distribution of marketed drugs by countryTable 1:Marketed drugs for ALS Landscape analysis of Amyotrophic Lateral Sclerosis6Approved drugsThe following are the drugs currently approved by various worldwide regulatory agencies:Riluzole(Exservan),an oral soluble film formulation,for the treatment of ALS has been approved in the European Union in 2022.Riluzole can slow the progression of ALS,extend survival,and delay the time to tracheostomy.Edaravone(Radicut)is a small molecule,free radical scavenger,which blocks the action of the lipoperoxide 15-HPETE,which normally increases with age and may be associated with neurodegeneration.Edaravone has been approved in South Korea,Switzerland,China,Indonesia,Thailand,Malaysia,Australia,and Japan.Sodium phenylbutyrate/ursodoxicoltaurine(RELYVRIO)is an oral proprietary fixed-dose combination of sodium phenylbutyrate and ursodoxicoltaurine,designated as AMX 0035,developed for the treatment of ALS.Sodium phenylbutyrate reversibly inhibits class I and II histone deacetylases(HDACs),which may result in a global increase in gene expression,decreased cellular proliferation,increased cell differentiation,and the induction of apoptosis in susceptible tumour cell populations,and the induction of apoptosis in susceptible tumor cell populations.The candidate is designed to reduce nerve cell death by blocking key cellular death pathways that originate in cellular compartments called the mitochondria and endoplasmic reticulum,both of which result in nerve cell death.The drug is available in Canada and the US and is approved in Puerto Rico(2022)for the treatment of ALS in adults.The drug candidate is under regulatory review in the EU.Drug Synonym/Brand nameMechanism of actionOrganisationLocation(s)RiluzoleAQST117,Exservan,Riluzole oral soluble film,Riluzole OSFExcitatory amino acid antagonists,Glutamate release inhibitors,Voltage-gated sodium channel inhibitorsMonoSol RxAquestive TherapeuticsEuropean Union(2022)Edaravone RADICAVA,ORS,RADICUT,Radicut,Radicut BagAntioxidants,Free radical scavengersMitsubishi Pharma CorporationSouth Korea(2015)Switzerland,China,Indonesia(2019)Thailand,Malaysia(2021)Australia(2023)Japan(2022)Sodium phenylbutyrate/ursodoxicoltaurineALBRIOZA,AMX0035,PB/TURSO,RELYVRIOAmmonia scavengers,Histone deacetylase inhibitors,Phosphotransferase inhibitorsAmylyx PharmaceuticalsPuerto Rico(2022)Drugs in preregistration phaseThere are four drugs in the pre-registration phase for the treatment of ALS that are expected to be launched in the future:all of these have been awarded an Orphan Drug Designation(ODD)in the USA.Table 2:Approved drugs for ALSLandscape analysis of Amyotrophic Lateral Sclerosis 7Neurotrophic factor-producing mesenchymal stem cell therapy,developed by Tel Aviv University and licensed by Brainstorm Cell Therapeutics,was earlier in the preregistration phase but was later withdrawn in the US.From the above data we can see that among the current pre-registered drugs,the USA has awarded the highest ODDs followed by the EU.Number of ODD designations Fig.4:Pre-registered drugs with country-wise highest ODD01234USAEuropean UnionCount of ODD designa?onsCountriesDrugs in late-stage clinical developmentAmong the thirteen drugs that are in late-stage clinical development,six drugs are in Phase III development,whereas the other seven drugs are in Phase II/III stage.DrugDev PhaseLocationMechanism of ActionOrganisationRegulatory DesignationSmall moleculesABBV CLS 7262 II/IIICalicoEukaryotic-initiation-factor-2b-stimulantsAbbVie-Masitinib IIIUnited Kingdom,USA,NorwayColony stimulating factor inhibitors,Coronavirus-3C-like-proteinase inhibitors,Endopeptidase Clp inhibitors,Focal adhesion protein-tyrosine kinase inhibitors,Lyn protein-tyrosine kinase inhibitors,Macrophage colony-stimulating factor receptor modulators,Mast cell inhibitors,Platelet-derived growth factor receptor antagonists,Protein tyrosine kinase inhibitors,Proto oncogene protein c-kit inhibitors,Proto-oncogene protein c-fyn modulators,Type 3 fibroblast growth factor receptor antagonistsAB ScienceUSA(ODD),European Union(ODD),Switzerland(ODD)Table 4:Drugs for ALS undergoing late stage clinical developmentDrug TypeOrganisationLocation(s)ODD territoriesMasitinib SMAB ScienceCanada,European UnionUSA,European Union(2022)Tofersen ASOIonis PharmaceuticalsEuropean UnionUSA(2022)Riluzole sublingualSMBiohaven PharmaceuticalsUSAUSA(2018)Legends:SM-Small molecules,ASO-Antisense oligonucleotides,ODD-Orphan drug designationTable 3:Preregistered drugs for ALS Landscape analysis of Amyotrophic Lateral SclerosisDrugDev PhaseLocationMechanism of ActionOrganisationRegulatory DesignationSmall moleculesPridopidineII/IIIUSADopamine D2 receptor antagonists,Glutamate modulators,Sigma-1 receptor agonistsNeuroSearch Sweden AB,Prilenia TherapeuticsUSA(ODD),Europe(ODD)LevosimendanIIIAustria,USA,Sweden,Spain,Belgium,Finland,Australia,Canada,Italy,Germany,United Kingdom,Ireland,Netherlands,FranceCalcium-sensitising phosphodiesterase inhibitors,Potassium channel agonists,Calcium-binding protein modulators,Type 3 cyclic nucleotide phosphodiesterase inhibitorsOrion,AbbVie/Tenax TherapeuticsUSA(ODD),Europe(ODD)TrehaloseII/IIIUSAProtein aggregation inhibitors,Transcription factor stimulantsBioblast Pharma,Seelos TherapeuticsEuropean Union(ODD),USA(ODD)IbudilastII/IIIUSA,Canada,HungaryLeukotriene receptor antagonists,Macrophage migration inhibitory factor inhibitors,Phosphodiesterase 10A inhibitors,Type 4 cyclic nucleotide phosphodiesterase inhibitors,Nitric oxide synthase inhibitors,Phosphodiesterase 11A inhibitors,Toll-like receptor 4 antagonists,Type 3 cyclic nucleotide phosphodiesterase inhibitorsKyorin Pharmaceutical,MediciNovaEuropean Union(ODD),USA(ODD)Edaravone oralIIIBelgium,Germany,Italy,Netherlands,Poland,SpainFree radical scavengersTreewayEuropean Union(ODD),USA(ODD)VerdiperstatII/IIIUSAPeroxidase inhibitorsAstraZeneca,Biohaven PharmaceuticalsDNL 343II/IIIUSAEukaryotic-initiation-factor-2b-stimulantsDenali Therapeutics IncAntisense OligonucleotidesUlefnersenIIIUSARNA interference,RNA-binding protein FUS inhibitorsIonis PharmaceuticalsHeavy MetalsCNM Au 8IIIUSAEnergy metabolism stimulantsClene NanomedicineEuropean Union(ODD)AntibodiesLatozinemabIIIUSA,CanadaSortilin inhibitorsAlectorPeptidesZilucoplanII/IIIUSAComplement C5 inhibitorsRa Pharmaceuticals,UCBLegend:ODD-Orphan drug designation8Landscape analysis of Amyotrophic Lateral Sclerosis Landscape analysis of Amyotrophic Lateral SclerosisGeographical distribution of drugs in late-stage clinical developmentA detailed geographical distribution analysis of the thirteen drugs in late-stage clinical development revealed that the USA has the highest number of drugs in late-stage clinical development followed by Canada.Geographical distribution of late-stage clinical development drugsFig.5:Geographical distribution of late stage clinical development drugsDiscontinued drug:Reldesemtiv(CK-107;CK-2127107),developed by Astellas Pharma,was discontinued in phase III development based on the results of its trial.Drugs in early-stage clinical developmentSeventy-six drugs are currently in early-stage clinical development globally.Further details on these medicines,alongside with primary developer organisations and drug properties can be found in the table below:DrugDev PhaseLocation(s)OrganisationMechanism of ActionRegulatory DesignationHeavy MetalsCNM Au 8IIAustraliaClene NanomedicineEnergy metabolism stimulantsEuropean Union(ODD),USA(ODD)Small moleculesAcamprosate/baclofenIFranceBioSystems International,INSERM,Pharnext,University of BordeauxGABA B receptor agonists,GABA receptor agonists,Glutamate receptor antagonists-Table 5.Early-stage clinical development drugs for ALS10Landscape analysis of Amyotrophic Lateral Sclerosis DrugDev PhaseLocation(s)OrganisationMechanism of ActionRegulatory DesignationCelecoxib/ciprofloxacinIIUSA,Israel,ItalyNeuroSense TherapeuticsCyclo-oxygenase 2 inhibitors,DNA gyrase inhibitorsEuropean Union(ODD),USA(ODD)DNL 343IUSA,NetherlandsDenali Therapeutics IncEukaryotic-initiation-factor-2b-stimulants-BosutinibI/IIJapanPfizerBcr-abl tyrosine kinase inhibitors,Src-Family kinase inhibitors-SPG 302IAustralia SpinogenixSynaptic transmission modulatorsUSA(ODD)Trehalose IIAustraliaSeelos TherapeuticsProtein aggregation inhibitors,Transcription factor stimulantsUSA(ODD),European Union(ODD)DeferiproneIIFranceApotexChelating agents-ABBV CLS 7262IUSA,CanadaAbbVieEukaryotic-initiation-factor-2b-stimulants-NP 001IIUSANeuvivoMacrophage modulatorsUSA(ODD)VRG 50635INetherlandsVerge GenomicsPIKFYVE protein inhibitors-Censavudine IIUSA,Belgium,France,Germany,SpainOncolys BioPharmaNucleoside reverse transcriptase inhibitors-IbudilastIIUSAMediciNovaMacrophage migration inhibitory factor inhibitors,Phosphodiesterase 10A inhibitors,Type 4 cyclic nucleotide phosphodiesterase inhibitors,Astrocyte inhibitors,Nitric oxide synthase inhibitors,Phosphodiesterase 11A inhibitors,Toll-like receptor 4 antagonists,Type 3 cyclic nucleotide phosphodiesterase inhibitorsUSA(FD)ION 541IIUSA,Canada,Netherland,ItalyIonis PharmaceuticalsAtaxin-2 expression inhibitors-Utreloxastat IIUSA,FrancePTC Therapeutics15-lipoxygenase inhibitors-FB 101ISouth Korea1St BiotherapeuticsBcr-abl tyrosine kinase inhibitors-SBT 272IUSAStealth BioTherapeuticsAdenosine triphosphatase stimulants,Cardiolipin modulators,ROS inhibitorsUSA(ODD) Landscape analysis of Amyotrophic Lateral SclerosisDrugDev PhaseLocation(s)OrganisationMechanism of ActionRegulatory DesignationDazucorilantIINetherlands,Germany,Poland,Spain,United KingdomCorcept TherapeuticsGlucocorticoid receptor antagonists-DexpramipexoleIIUSAAreteia TherapeuticsDopamine receptor agonists,Free radical scavengersUSA(ODD,FD)Sodium cromoglicateIIUSAAZTherapiesGlial cell modulators,Mast cell stabilisers-Cu(II)ATSMIIAustraliaCollaborative Medicinal Development,Procypra TherapeuticsNeuron modulators-CrisdesalazineISouth KoreaGNT PharmaAmyloid beta-protein inhibitors,Dinoprostone antagonists,Prostaglandin-E synthase inhibitors-DNL 788IIUSA,Spain,Belgium,United Kingdom,Netherlands,Germany,France,Canada,USA,China,Italy,SwedenDenali TherapeuticsRIPK1 protein inhibitorsUSA(FD)IcerguastatIIItaly,FranceInFlectis BioSciencePPP1R15A protein inhibitorsUSA(ODD)TriheptanoinI/IIUSAUltragenyx PharmaceuticalTriglyceride replacements-Ropinirole extended-releaseI/IIJapanGlaxoSmithKlineDopamine D2 receptor agonists-QRL 201ICanadaQurAlis CorporationStathmin modulators-QRA 244INetherlandsEli Lilly and CompanyKCNQ2 potassium channel stimulants,KCNQ3 potassium channel stimulants-RNS 60IIUSA,ItalyRevalesioG protein-coupled receptor modulators,HSP90 heat-shock protein modulatorsUSA(ODD,FD)PleconarilIISwedenApodemusVirus replication inhibitors-RT 001IIEstonia,Latvia,Netherlands,SwedenRetrotopeLipid peroxidation inhibitors-12Landscape analysis of Amyotrophic Lateral Sclerosis DrugDev PhaseLocation(s)OrganisationMechanism of ActionRegulatory DesignationDextran sulfate-low molecular weightIISweden,United KingdomTikoMedBlood coagulation factor inhibitors,Complement system protein inhibitors,Intracellular signalling peptide and protein stimulants,Tumour necrosis factor alpha inhibitors,Virus internalisation inhibitors-FasudilIIUSAAsahi Kasei,Woolsey PharmaceuticalsRho-associated kinase inhibitors,Calcium channel antagonists,Protein kinase C inhibitors-Monepantel IAustraliaPharmAustCyclin-dependent kinase 2 modulators,Cyclin-dependent kinase 4 modulators-ProsetinIUSAProJenXMitogen-activated protein kinase inhibitorsUSA(ODD)EPI 589IIUSA,JapanEdison PharmaceuticalsNAD(P)H dehydrogenase(quinone)modulators-Z-Butylidenephthalide polymer wafer implantITaiwanEverfront BiotechAxl receptor tyrosine kinase modulators,Nuclear receptor subfamily 4 group A member 1 modulators-AGX 201IUSAAgoneX BiopharmaceuticalsHistamine receptor modulators-ZYIL 1IIIndia Zydus CadilaNLRP3 protein inhibitors-TQS 168IUnited KingdomTranquis TherapeuticsPeroxisome proliferator-activated receptor modulatorsUSA(ODD)TrametinibI/IISouth KoreaGENUVMAP kinase kinase 1 inhibitors,MAP kinase kinase 2 inhibitors-SotuletinibIIUSA,Finland,SwedenNovartisMacrophage colony stimulating factor receptor antagonists-Ranolazine extended releaseIIUSAGilead SciencesPartial fatty acid oxidation inhibitors,Pyruvate dehydrogenase stimulants,Sodium channel antagonists-Tetramethylpyrazine NitroneIIChinaGuangzhou Magpie PharmaceuticalsBrain derived neurotrophic factor agonists,Calcium channel antagonists,Cyclic AMP response element-binding protein stimulants,MTOR protein inhibitors,Proto oncogene protein c akt modulators- Landscape analysis of Amyotrophic Lateral SclerosisDrugDev PhaseLocation(s)OrganisationMechanism of ActionRegulatory DesignationPeptidesAlirinetide IIUSAGenervon Biopharmaceuticals1 Phosphatidylinositol 3 kinase modulators,Bcl-X protein inhibitors,Proto oncogene protein c akt modulatorsUSA(ODD,FD)NX 210cIFranceAxoltis PharmaSynaptic transmission modulators,Thrombospondin replacements-IPL 344IIIsraelImmunity Pharma1 Phosphatidylinositol 3 kinase modulators,Proto oncogene protein c akt modulatorsUSA(ODD),European Union(ODD)T-lymphocyte cell therapiesCOYA 101IIUSACoya TherapeuticsRegulatory T-lymphocyte replacementsUSA(ODD)CK 0803IUSACellenkosRegulatory T-lymphocyte replacements-TocilizumabII USAChugai PharmaceuticalInterleukin 6 receptor antagonists-TegoprubartIIUSA and CanadaEledon PharmaceuticalsCD40 ligand inhibitorsUSA(ODD)RAPA 501I/IIUSARapa TherapeuticsT-lymphocyte-replacements-AntibodiesANX 005IIUSA,CanadaAnnexonComplement C1 inhibitors-AP 101IICanadaAL-S PharmaSuperoxide dismutase inhibitors-Goat serum-derived polyclonal antibodiesIIAustralia,United KingdomDaval InternationalCorticotropin-releasing hormone stimulants,Sodium channel modulatorsAustralia(ODD),USA(ODD)ProteinsRPI MNIUSAReceptoPharmNicotinic receptor antagonists-AldesleukinIIFrance,United KingdomNovartisInterleukin-2 receptor beta subunit agonistsUSA(ODD)Oremepermin alfa IIJapanKringle PharmaProto-oncogene protein c-met modulators,Angiogenesis inducing agents-AldesleukinIIFranceILTOO PharmaInterleukin-2 receptor beta subunit agonists-CorticotropinIIUSA,Peru,Mexico,Colombia,Chile,CanadaMallinckrodtCorticotropin receptor agonists,Steroid receptor agonistsUSA(ODD,FD)3K3A-APCIIAustraliaSocratechActivated protein C receptor modulators,Factor V inhibitors,Factor VIII inhibitors,PAR 1 receptor modulators,PAR-3 receptor modulators-14Landscape analysis of Amyotrophic Lateral Sclerosis DrugDev PhaseLocation(s)OrganisationMechanism of ActionRegulatory DesignationBacteriasBL 0020USABloom ScienceGastrointestinal microbiome modulators-MaaT 033IIFranceMaaT PharmaGastrointestinal microbiome modulators,-Gene therapiesDonaperminogene seltoplasmid IIUSAHelixmithHepatocyte growth factor expression stimulantsUSA(ODD,FD)mEphA 4 FcIAustraliaNuNerveGene transference-Stem cell therapiesAutologous neuroregenerative stem cell therapyINetherlandsNeuroplastCell replacements-Astrocyte cell therapyI/IIIsraelKadimastemGlial cell replacementsUSA(ODD)NSI 566IIUSANeuralstemCell replacementsUSA(ODD)Umbilical cord-derived allogeneic mesenchymal stem cell therapyIAntigua,BarbudaVitro BiopharmaCell replacements-Neurotrophic factor producing mesenchymal stem cell therapyIINetherlands,Israel,USABrainStorm Cell TherapeuticsCell replacementsUSA(ODD,FD),European Union(ODD)FlavonoidsIsoquercetinIIUSAQuercis PharmaBlood coagulation factor inhibitors,P selectin inhibitors,Platelet activating factor inhibitors,Platelet aggregation inhibitors-siRNAARO SOD1IUSA,AustraliaArrowhead PharmaceuticalsSuperoxide dismutase 1 expression inhibitors-UnspecifiedFB 1071IChina4B TechnologiesUndefined-RDC 5IUnited KingdomChronos TherapeuticsReactive oxygen species modulators,Synuclein inhibitors,Tau protein inhibitors-Legend:ODD-Orphan drug designation,FD-Fast track designation15Geographical distribution of early-stage ALS drugsAmong the seventy-six drugs in early-stage clinical development,45 drugs are in phase II development,with the USA having the highest number of drugs in early-stage clinical development suggesting a serious global trend among pharma companies to actively work and develop therapeutics for ALS,an orphan disease.Geographical distribution of early-stage clinical drugsFig.6:Distribution by country of early stage clinical development drugsGeographical distribution of early-stage clinical drugsFig.7:Distribution by phase of ALS drugs in early clinical development45266105101520253035404550Phase IIPhase IPhase I/IIPhase 0Number of drugsPhasesAmongst the drugs which were discontinued during the early stages of clinical development we find:Pegcetacoplan(Aspaveli):This drug was discontinued following top-line results from the phase II MERIDIAN study Ketamine(KETALS):This drug was discontinued,since the Company has decided to pause allocating funds for its product and clinical programs.WVE 004:This drug was discontinued as reductions in poly(GP)did not correlate with improvements in amyotrophic lateral sclerosis and frontotemporal dementia.BIIB 100:This drug was discontinued based on the decision by management as part of its strategic review Landscape analysis of Amyotrophic Lateral Sclerosis16Major players in the clinical development of ALS drugsFig.8 provides a snapshot of key pharmaceutical companies involved in the clinical development of drugs for ALS.Roche leads with four drugs in clinical development,indicative of its significant investment and commitment to tackling this challenging medical condition followed by Biogen,Ionis Pharmaceuticals,Isis Pharmaceuticals,and Novartis demonstrating a strong and competitive field of research and development.Landscape analysis of Amyotrophic Lateral Sclerosis Key players in clinical developmentFig.8:Major key players in clinical development4333300.511.522.533.544.5RocheBiogenIonisPharmaceu?calsIsisPharmaceu?calsNovar?sNumber of drugsCompaniesDrug development landscape for ALSThe following is a snapshot of all the ALS drugs in each phase of development(Fig.6)including medicines currently available,approved,and under review as well as drugs under clinical development around the world.Landscape analysis of Amyotrophic Lateral Sclerosis Pictorial representation of ALS drugsFig.9:Overview landscape of ALS drugsVRG 50635CNM Au 8camprosate/baclofenTegoprubartDeferiproneABBV CLS 7262NP 001Neurotrophic factor-producing mesenchymal stem cell therapyARO SOD1COYA 101TrehaloseNX 210cCelecoxib/ciprofloxacinDNL 343ZYIL 1AlirinetideANX 005CensavudineIbudilast ION 541 UtreloxastatFB 101SBT 272DazucorilantDexpramipexole TocilizumabRPI MNCrisdesalazineMaaT 033Bosutinib-PfizerDNL 788IcerguastatSPG 302BL 002TriheptanoinDonaperminogene seltoplasmidRopinirole extended-releaseQRL 201QRA 244MonepantelFingolimodAutologous neuroregenerative stem cell therapyOremepermin alfaSotuletinib IPL 344PleconarilAldesleukin-Assistance Publique Hopitaux de Paris/ILTOO PharmaRT 001Dextran sulfate3K3A-APCUmbilical cord-derived allogeneic mesenchymal stem cell therapyVRG 50635Sodium cromoglicate Cu(II)ATSMCK 0803TQS 168RDC 5Astrocyte cell therapyTrametinibTetramethylpyrazine NitroneCorticotropinFasudilEPI 589ProsetinAP 101FB 1071IsoquercetinRAPA 501Z-Butylidenephthalide polymer wafer implantAGX 201mEphA 4 FcRanolazine extended releaseNSI 566Goat serum-derived polyclonal antibodiesCNM Au 8MasitinibPridopidineLevosimendanTrehaloseUlefnersenIbudilastEdaravone oralVerdiperstatZilucoplanExservanRadicutRELYVRIOTeglutikNEURONATA-RRilutekRegistered&launchedPreregistration Late-stage clinical development Early-stage clinical development MasitinibNeurotrophic factor-producing mesenchymal stem cell therapyTofersenRiluzole sublingualLatozinemabDNL 343Qalsody1718Diagnostic agents for ALSThere is no single test that can diagnose ALS.A neurologic examination will test reflexes,muscle strength,and other responses and will be held at regular intervals to assess whether symptoms such as muscle weakness,muscle wasting,and spasticity are progressively getting worse.Most of the diagnostic agents being developed for ALS are imaging enhancers,with PMI 04,OP 801,Fluorine-18 Bavarostat,and Fluorine-18 PBR 06 being positron emission tomography enhancers.PMI 04 and Fluorine-18 Bavarostat act at the same time as single proton emission computer tomography enhancers and radionuclide enhancers.Some of the diagnostic agents in early-stage development are listed below:DRUGDEV PHASELOCATION(S)ORGANISATIONAMDX 2011PIUSAAmydisPMI 04IUSAPrecision MolecularOP 801 I/IIUSAOrpherisFluorine-18 BavarostatIBelgiumEikonizo TherapeuticsFluorine-18 PBR 06 IUSAMolecular NeuroImagingUpcoming treatments for ALSThere are other drugs which are in early development(preclinical/research)for the treatment of ALS.Many biotechnology and pharmaceutical companies(Alexion AstraZeneca Rare Disease,Abbisko Therapeutics,AstraZeneca amongst others)are actively working on the orphan indication suggesting healthy competition and good participation among the big players in the pharma market.Some of the ALS drugs under the early development cycle have been listed below:DrugSynonymsDev PhaseOrganisationLocation(s)Research programme:zinc finger DNA binding protein transcription factorsZFtranscription factorsPreclinicalAlexion AstraZeneca Rare Disease,Sangamo TherapeuticsUSAPimicotinibABSK021PreclinicalAbbisko TherapeuticsChinaThera 101NFx101Theratome Bio,T101Theratome Bio,Thera101PreclinicalTheratome BioUSATetramethylpyrazine NitroneNitoxazine Guangzhou Magpie Pharmaceutical,Nitrazine Guangzhou Magpie Pharmaceutical,TBNPreclinicalGuangzhou Magpie PharmaceuticalsUSAResearch programme:neurodegenerative disease therapeuticsPMN 267 ALS therapeutic,PMN 300,PMN 320,PMN 330,PMN 340,PMN 350,TDP 43 targeting therapeuticsPreclinicalProMIS NeurosciencesCanadaASHA 091ASHA091PreclinicalAsha TherapeuticsUSAASHA 624ASHA624PreclinicalAsha TherapeuticsUSACB 03CB 04,CB003 Zhimeng Biopharma,CB03,CB03154,CB04 Zhimeng BiopharmaPreclinicalZhimeng BiopharmaChinaTable 6.Diagnostic agents for ALSTable 7.Upcoming treatments for ALS Landscape analysis of Amyotrophic Lateral Sclerosis19Landscape analysis of Amyotrophic Lateral Sclerosis DrugSynonymsDev PhaseOrganisationLocation(s)NVG 300NVG300ResearchNervGen PharmaUSAVTx 002VTx002 VectorY TherapeuticsPreclinicalVectorYNetherlandsAMX 0114AMX0114PreclinicalAmylyx PharmaceuticalsUSANG 201NG 201ALS,NG201AD,NG201NPPreclinicalNeuracle GeneticsSouth KoreaNibrozetoneRRx001PreclinicalRadioRx,EpicentRxUSAXT 150IL10 transgene plasmid DNA,XT 101,XT101R,XT150PreclinicalXalud TherapeuticsUSAZafirlukastAccolate,Accolate SR,Accoleit,Aeronix,Azimax,ICI 204219,Olmoran,Respix,Vanticon,ZafirstPreclinicalAstraZenecaUSA,SwitzerlandResearch programme:neurodegenerative disorders therapyTDP43 stress granulesPreclinicalAquinnah PharmaceuticalsUSAForalumabNI0401,NI0401/aCD3,NI0401/alfaCD3,NI0401/alphaCD3,NI0401/CD3,TZLS401PreclinicalTiziana Life SciencesUnited KingdomJK 07JK07,SAL007Phase ISalubrisBioUSAResearch programme:neurodegenerative diseases targeting therapeuticsResearch programmeneurodegenerative diseases targeting therapiesLibra TherapeuticsResearchLibra TherapeuticsUSAAmyotrophic lateral sclerosis gene therapy-ResearchHuidaGene TherapeuticsChinaNVG 291NVG291,NVG291RResearchNervGen PharmaUSAS- -ApomorphineApomorphine-Aclipse Therapeutics,M 102PreclinicalUniversity of Sheffield,Aclipse TherapeuticsUnited KIngdomATH 1105ATH1105PreclinicalAthira PharmaUSASOL 257SOL257PreclinicalSOLA BiosciencesUSAAS 202AS202PreclinicalAcuraStemUSAALPHA 0602Alpha 602,ALPHA0602,ND602,Progranulin gene therapy Alpha cognitionPreclinicalNeurodynCanadaBEN 34712BEN34712PreclinicalBenevolentAIUnited KingdomKFRX 03KFRX03PreclinicalKeifeRxUSAResearch programme:superoxide dismutase 1 targeting therapeuticsRNA interferencebased therapeutics Thera Neuropharma,sdrxRNA based therapeutics Thera Neuropharma,SOD1 targeting sdrxRNA therapeutics Thera Neuropharma,THN 1PreclinicalThera NeuropharmaUSAResearch programme:transmembrane protein 175 agonistsTMEM175 activators AbbVie/Caraway Therapeutics,TMEM175 agonists AbbVie/Caraway TherapeuticsPreclinicalCaraway Therapeutics,AbbVieUSA20DrugSynonymsDev PhaseOrganisationLocation(s)Research programme:CD14/TLR4 antagonistsIAXO small molecules Innaxon,IAXO101 Innaxon,IAXO102 InnaxonPreclinicalInnaxonUnited KingdomAB 126AB126,Neural exosome ArunA BiomedicalPreclinicalArunA BiomedicalUSAS-oxprenolol-ACM002PreclinicalActimed TherapeuticsUnited KingdomResearch programme:UNC13A-targeting antisense oligonucleotide therapeutics-PreclinicalQurAlis CorporationUSAResearch programme:AAV based gene therapies-ResearchNeuShen TherapeuticsChinaAutologous stem cell therapyAutologous adiposederived stem cells Regeneration Biomedical,RBADSCResearchRegeneration BiomedicalUSANB 001NB001 NysnoBioPreclinicalNysnoBioUSAAKV 9AKV9,NU 9PreclinicalAKAVA TherapeuticsUSABL 001BL001PreclinicalBloom ScienceUSAIBC Ab002IBCAb002PreclinicalImmunoBrain CheckpointIsraelPAS 003Alpha5-Pasithea Therapeutics,PAS003PreclinicalPasithea TherapeuticsUSAATLX 1282ATLX1282PreclinicalAlchemabUnited KingdomMacimorelinAEZS130,ARD07,D87575,EP01572,EP1572,Ghryvelin,JMARD07,JMV1843,Macimorelin acetate,Macrilen,SolorelPreclinicalAEterna Zentaris AustraliaResearch programme:mitochondrial permeability transition pore inhibitorsMitochondria targeted therapies NRG TherapeuticsPreclinicalNRG TherapeuticsUnited KingdomResearch programme:neurological disorder therapeutics-PreclinicalNido BiosciencesUSAResearch programme:amyotrophic lateral sclerosis therapeutics-ResearchreMYNDBelgiumResearch programme:neurodegenerative disorder therapeuticsBMSxxxPreclinicalEvotec,Bristol-Myers SquibbGermanyBSC 3301BSC3301PreclinicalBiSiChemSouth KoreaENT 03ENT03,Enterin03ResearchEnterinUSABLX 0209BLX0209PreclinicalBiolexis TherapeuticsUSAAPB 104APB104ResearchApic BioUSAAPB 105APB105ResearchApic BioUSA Landscape analysis of Amyotrophic Lateral SclerosisDrugSynonymsDev PhaseOrganisationLocation(s)Research programme:amyotrophic lateral sclerosis gene therapies-PreclinicalBeacon TherapeuticsUSAAGTC 801AGTC801PreclinicalApplied Genetic Technologies CorporationUSAResearch programme:microRNA therapeuticsantimiR10b,antimiR122,antimiR132,miR122,miR296,miR34,miR34a,miRK1211(viral oncomir),miRNA therapeutics Regulus Therapeutics,miRX,RGLS 5579,RGLS 6650,Viral microRNAs Regulus TherapeuticsPreclinicalRegulus TherapeuticsUSAORY 4001ORY4001PreclinicalOryzonSpainSLS 009SLS009PreclinicalSeelos TherapeuticsUSAANEW 202ANEW202PreclinicalANEW MEDICALUSABMD 001BMD001PreclinicalBIORCHESTRASouth KoreaPMN 267PMN267,TDP43 targeting antibody ProMIS NeurosciencesPreclinicalProMIS NeurosciencesUSAResearch programme:neurodegenerative diseases gene therapiesCORRECTx RNAtargeting gene therapyPreclinicalLocanabioUSAOC 514OC514PreclinicalOncocrossSouth KoreaResearch programme:degenerative disorders therapeuticsFECD GeneTAC molecules Design Therapeutics,FECD GeneTAC small molecules Design Therapeutics,SynTEF1,SynTEF2,SynTEFs,Synthetic transcription elongation factors Design TherapeuticsPreclinicalDesign TherapeuticsUSATrans-resveratrol oralJNS 101,JNS 102,JNS 107,JNS 108,JNS 109,JNS 110,JNS 120,JOT101,JOTROLPreclinicalJupiter Orphan TherapeuticsUSAIcapamespibPUAD,PUHZ151PreclinicalSamus TherapeuticsUSAResearch programme:receptor for activated protein kinase C 1 antagonistsRACK1 antagonists ProMIS NeurosciencesPreclinicalProMIS NeurosciencesCanadaPRX 019PRX019PreclinicalBristol-Myers SquibbIrelandINF 11INF11PreclinicalBeijing Joekai BiotechnologyChinaResearch programme:histone deacetylase-6 inhibitors-PreclinicalEikonizo TherapeuticsUSASNP 210SNP210PreclinicalSciNeuro PharmaceuticalsChinaResearch programme:antibody therapeuticsAntibody therapeutics Alchemab,Huntington#8217#s disease therapeutics Alchemab,Huntingtons disease therapeutics AlchemabPreclinicalAlchemabUnited KingdomSYF2 targeting antisense oligonuclotide therapeutic-PreclinicalAcuraStemUSA21Landscape analysis of Amyotrophic Lateral Sclerosis DrugSynonymsDev PhaseOrganisationLocation(s)Research programme:neurodegenerative disorder therapeutics-PreclinicalSelonterraUSAResearch programme:small molecule therapeuticsAS3PreclinicalAcuraStemUSAUdonitrectag methyl esterMT2,NegerminmethylesterPreclinicalMimeTechItalyMimeTechDC645,NVG0645PreclinicalNevrargenicsUnited KingdomResearch programme:geranylgeranylacetone trans-isomerCNS 101,CNS 102,CP102,DDS103,Geranylgeranylacetone transisomer,GGA transisomerPreclinicalCoyote PharmaceuticalsUSAUNC13A targeting small molecule therapeutic-PreclinicalMaze TherapeuticsUSAUNC13A targeting antisense oligonuclotide therapeutic-PreclinicalAcuraStemUSAResearch programme:AAV-based gene therapies-PreclinicalAviadoBioUnited KingdomTFM 023TFM023ResearchCuramysSouth KoreaMIRX 1802MIRX1802ResearchCuramysSouth KoreaUNC13A targeting antisense oligonuclotide therapeutic-PreclinicalMaze TherapeuticsUSACTx TFEBxCTxTFEBxResearchCoave TherapeuticsFranceFB 418FB418Preclinical1St BiotherapeuticsSouth KoreaResearch programme:histone deacetylase 6 protein inhibitorsHDAC6 inhibitors Augustine therapeutics,HDAC6i Augustine therapeuticsResearchAugustine TherapeuticsBelgiumGNK 301AntiHERVK mab GeNeuro Pharma,GNK01,GNK301,pHERVK Env antibody GeNeuro PharmaPreclinicalGeNeuroUSAPP 007PP007PreclinicalPrimary PeptidesCanada1ST 1031ST 103Research1St BiotherapeuticsSouth Korea4P 0194P019Research4P-PharmaFranceResearch programme:neurodegenerative therapeutics-ResearchKineta,MerckUSANI 308NI308PreclinicalNeurimmune TherapeuticsSwitzerlandCOYA 201COYA201PreclinicalCoya TherapeuticsUSAResearch programme:neurodegenerative disorder therapeutics-ResearchExpansion TherapeuticsUSAAMA 007AMA007ResearchAmarna TherapeuticsN Landscape analysis of Amyotrophic Lateral SclerosisDrugSynonymsDev PhaseOrganisationLocation(s)NM 301NM301PreclinicalHelixmithSouth KoreaResearch programme:amyotrophic lateral sclerosis therapeutics-PreclinicalNeuron23USAFB 1006FB1006Preclinical4B TechnologiesChinaFB 1006FB1006Preclinical4B TechnologiesChinaResearch programme:neurological disorders therapeuticsPreclinicalAthira PharmaUSABEN 9160BEN 9160PreclinicalBenevolentAIUnited KingdomResearch Programme:TDP-43 protenopathies therapueticsPreclinicalBiohaven PharmaceuticalsUSAHuman glial restricted progenitor cells based therapeuticsGlial cellbased therapeutics Q Therapeutics,hGRPs Q Therapeutics,QCellsPreclinicalQ TherapeuticsUSAResearch programme:amyotrophic lateral sclerosis gene therapyNXL003PreclinicalNeuExcell TherapeuticsUSAND BT3814NDBT3814ResearchBioArcticSwedenResearch programme:protein modulator therapies-ResearchOrigami TherapeuticsUSAResearch programme:BAX/BAK inhibitorsBAX/BAK inhibitors Amylyx Pharmaceuticals/Sunnybrook Research InstituteResearchSunnybrook Research Institute,Amylyx PharmaceuticalsCanadaBMD 002BMD002PreclinicalBIORCHESTRASouth KoreaB 2069B2069PreclinicalTasly BiopharmaceuticalsChinaVTx 001VTx001PreclinicalVectorYNetherlandsResearch programme:potassium channel activatorsKCNQ2 potassium channel activators Knopp Biosciences,Kv7 channel activators,Kv7 modulator,Kv7.2/7.3 channel activatorsResearchKnopp BiosciencesUSAResearch programme:in vivo gene editing therapies-ResearchCapsida Biotherapeutics,CRISPR TherapeuticsUSALP 143AN143,LP143PreclinicalLongboard PharmaceuticalsUSAResearch programme:central nervous system disorder therapies-PreclinicalMabylonSwitzerlandResearch programme:oligonucleotides-ResearchCeptur TherapeuticsUSAResearch programme:ataxin2 tageting antibodiesAtaxin2 ProMIS NeurosciencesResearchProMIS NeurosciencesCanadaALN SODALNSODPreclinicalAlnylam PharmaceuticalsUSAAMT 161AMT161PreclinicaluniQureNetherlands23Landscape analysis of Amyotrophic Lateral Sclerosis DrugSynonymsDev PhaseOrganisationLocation(s)VRN 04VRN04PreclinicalVoronoiSouth KoreaResearch programme:TAR DNA binding protein-43 targeting therapeutics-PreclinicalMabylon,SciNeuro PharmaceuticalsSwitzerlandResearch programme:apolipoprotein E targeting therapeutics-PreclinicalMabylonSwitzerlandResearch programme:apolipoprotein E targeting therapeutics-PreclinicalMabylonSwitzerlandResearch programme:casein kinase 2 inhibitorsCK2 inhibitors Chaperone TherapeuticsPreclinicalChaperone TherapeuticsUSAResearch programme:amyotrophic lateral sclerosis therapeutics-PreclinicalQ-State BiosciencesUSAFB 1002FB1002Research4B TechnologiesChinaGB 1GB1ResearchDenali Therapeutics IncUSAResearch programme:amyotrophic lateral sclerosis therapeuticsALS(Target 2)Verge GenomicsResearchVerge GenomicsUSAResearch programme:next generation amyotrophic lateral sclerosis therapeuticsNext Generation ALS(Target 1)Verge GenomicsResearchVerge GenomicsUSAResearch programme:small molecule therapies-Research4B TechnologiesChinaResearch programme:antisense oligonucleotide therapeutics-PreclinicalVanqua BioUSAResearch programme:intrabodiesTDP43 targeting intrabodies ProMIS NeurosciencesResearchProMIS NeurosciencesCanadahNPC 02hNPC02,Human motor neural progenitor cellResearchHopstem BiotechnologyChinaCTx FUSCTxFUSPreclinicalCoave TherapeuticsFranceResearch programme:amlyotropic lateral sclerosis therapeutics-ResearchEli Lilly and CompanyUSAGO 102GO102PreclinicalGeneroathSouth KoreaEXO 001EXO001PreclinicalCoya TherapeuticsUSAAGT 110AGT110PreclinicalArmaGen TechnologiesUSAOTL 205OTL205PreclinicalOrchard TherapeuticsUnited KingdomSOL 258SOL258PreclinicalSOLA BiosciencesUSANI 205NI205ResearchNeurimmune TherapeuticsS Landscape analysis of Amyotrophic Lateral SclerosisDrugSynonymsDev PhaseOrganisationLocation(s)Research programme:dipeptide repeat inhibitor vaccineDRP inhibitor vaccine VaxxinityPreclinicalVaxxinityUSAResearch programme:Ataxin 2 inhibitorsAtaxin 2 inhibitors Maze Therapeutics,ATXN2 programme Maze TherapeuticsPreclinicalMaze TherapeuticsUSATEJ 1704J2H1704PreclinicalJ2H BiotechSouth KoreaResearch programme:CNS disorder therapeutics-ResearchBristol-Myers SquibbUSAResearch programme:small molecule therapeutics-PreclinicalFaze MedicinesUSABREN 02BREN 01,BREN02,Recombinant human homeoprotein Engrailed 1(rhEN1)Brain Ever TherapeuticsPreclinicalBrainEverFrancePBAL 05PBAL05PreclinicalPassage BioUSAResearch programme:neurodegenerative disorder therapeuticsNPT 1220 312,Tolllike receptor modulators Neuropore therapiesPreclinicalNeuropore TherapiesUSAResearch programme:CNS disorder therapeutics-ResearchAcuraStemUSAResearch programme:CRISPR-based therapeutics-ResearchScribe Therapeutics,BiogenUSAAS 203AS203ResearchAcuraStemUSAAS 201AS201PreclinicalAcuraStemUSA1ST 1041ST104Research1St BiotherapeuticsSouth KoreaResearch programme:muscle wasting disease therapies-PreclinicalImmusoftUSAZinc finger protein-based gene therapyC9ORF72 ZFPTF,ZFP TF gene therapy,ZFPbased therapeutics Sangamo/Pfizer,ZFPTF gene therapies,Zinc finger protein gene therapy Pfizer/Sangamo,Zinc finger protein gene therapy Sangamo/Pfizer,Zinc finger protein transcription factors Sangamo/PfizerPreclinicalSangamo Therapeutics,PfizerUSAEXP 200EXP200PreclinicalExpesicorUSAResearch programme:amytotrophic lateral sclerosis therapeutics-PreclinicalQurAlis CorporationUSAND 3014ND3014ResearchBioArcticSwedenCALS 01CALS01PreclinicalCuratisSwitzerland25Landscape analysis of Amyotrophic Lateral Sclerosis Major players in the overall market As per fig.10,Pfizer and AcuraStem are leading the efforts with seven drugs each,potentially reflecting a strong commitment to discover effective treatments for ALS.Biogen and Roche are also prominent contributors with six and five drugs in development respectively,with Sanofi,ProMIS Neurosciences,QurAlis Corporation,Denali Therapeutics,GSK,and Merck,with five drugs each,highlighting a competitive and dedicated landscape of companies working toward advancements in ALS treatment.Sangamo Therapeutics,Novartis,Bristol-Myers Squibb,and AbbVie,each with four drugs in development,round out the list of key players.This diversity in companies and their sizable investments in ALS drug development illustrate the industrys collective endeavor to address the unmet medical needs of ALSKey Market PlayersFig.10:Key pharma companies working on ALS drugs012345678Number of drugsCompanies26Target trend analysis for overall drug profilesAfter reviewing all the ALS drug profiles found in AdisInsight,there are in total 376 targets in the ALS drug development cycle.Among these targets,we selected and highlight here a group of 15 which have shown a steady increase in the number of drug profiles across the yearsMajor targets for ALS drugsFig.11:Targets in focus for ALS drugs16117666655444444024681012141618Number of drugsT Landscape analysis of Amyotrophic Lateral Sclerosis27Detailed analysis revealed that some selected targets are slowly emerging in the market with good efficacy results.These are Cytokine and Dopamine D2 receptor targets.The following sections will provide further details on these two targets in relation to ALS:CytokinesThese are small soluble polypeptide proteins secreted by immune cells and histiocytes that regulate cell growth,differentiation,and immune responses by binding to their receptors.In neurodegenerative diseases,during the early course of the disease,cytokines are released by some resident cells of the CNS which neutralizes the inflammatory damage by limiting inflammation or promoting tissue remodeling.While the disease progresses,cytokines released by invasive immune cells and some glial cells target the CNS and play a neurotoxic role.It was also reported that patients with ALS have abnormal changes in cytokines.Therefore,cytokines play a potential target for ALS drug development.An example of medicine in this category is Ibudilast(Originated by Kyorin Pharmaceutical),which seems to be a potential drug for treating ALS and has shown good results in a phase Ib/II trial and showed that from baseline to six months,the rate of decline in the ALS functional rating score for the ibudilast and placebo subjects combined,was below the rates observed in other ALS studies.This drug has also in combination with temozolomide showed that treatment was safe and well-tolerated,and no unexpected adverse effects were reported in a phase II trial.Dopamine D2 receptorThis is a two G-protein-coupled receptor that can form dimers and negatively regulate their partners.These receptors role in motor neuron hyperexcitability had not previously been recognized.Moreover,some DRD2 agonists(bromocriptine,sumanirole)are commercially available,opening the possibility of testing them in patients with ALS.An example of drug in this group is offered by Pridopidine(Originated by NeuroSearch Sweden AB),which seems to be a potential drug for treating ALS and has shown good results from a phase II/III HEALEY ALS platform trial showing that the quantitative speech measures with significant improvement in speaking rate and articulation rates.Drug classes in focus for ALS therapeutics Based on the number of drug profiles present in the AdisInsight database,we identified 15 drug classes that showed the highest number of records.Major drug class contributors were small-molecules(174)which were followed by gene therapies(59)and biological proteins(56).While analyzing late-stage drug development,it could be confirmed that small molecules seem to be the most established drug class for ALS drug development with most of the marketed ALS drugs belonging to the drug class viz.RELYVRIO,RADICAVA,AQST-117,TEGLUTIK and Rilutek.Top 15 drug classesFig.12:Major drug classes for ALS drugs in development020406080100120140160180200Number of drugsDrug classesLandscape analysis of Amyotrophic Lateral Sclerosis 28Agreements for ALS drugsAmyotrophic Lateral Sclerosis(ALS)is an orphan disease with a high unmet need for therapeutic options.Developing drugs tailored to such niche orphan diseases requires significant upfront investment,along with a collaborative approach to fully complete a drugs development cycle.Therefore,collaborations across all fronts are crucial.Some of the major deals signed for ALS drugs have been added below for:Table 8:Tabular representation of deals signed for ALS drugsActiveCompletedTerminatedIndex:Licensing AgreementsCompanies involvedProduct/TechnologyInitiation date/Completed dateCountriesLicensing InLicensing OutDr Reddys LaboratoriesCoya TherapeuticsProduct6-Dec-23Canada,European Union,Japan,Mexico,North America,South America,United Kingdom,USASpecialised Therapeutics AsiaTreewayProduct28-Aug-23Australia,New ZealandSanofiDenali Therapeutics IncProduct1-Nov-18WorldANEW MEDICALUniversity of BarcelonaTechnology7-Dec-22-Sperogenix TherapeuticsAbbisko TherapeuticsProduct5-Jul-21China,Hong Kong,MacauBloom ScienceYeda Research and Development Company LtdTechnology4-Jan-23WorldMerck&CoKinetaProduct24-Jun-20-TreewayuniQureProduct14-Jan-15-Voyager TherapeuticsREGENXBIOTechnology2-Jun-14-Huadong MedicineAshvattha TherapeuticsProduct27-Apr-22China,Malaysia,SingaporeEikonoklastes TherapeuticsUniversity of California,San DiegoProduct19-Jan-22-InFlectis BioScienceUniversity of ChicagoProduct22-Jun-21-MeiraGTxBrandeis UniversityProduct31-Dec-15-Orchard TherapeuticsUniversity of PaduaProduct12-Nov-20-Quercis PharmaWestern New England UniversityProduct19-May-21WorldEledon PharmaceuticalsALS Therapy Development InstituteProduct1-Jan-15-PfizerSangamo TherapeuticsProduct3-Jan-18-Novartis Gene TherapiesREGENXBIOProduct7-Jun-17W Landscape analysis of Amyotrophic Lateral Sclerosis29Licensing AgreementsCompanies involvedProduct/TechnologyInitiation date/Completed dateCountriesLicensing InLicensing OutDaiichi Sankyo CompanyMitsubishi Tanabe Pharma GmbHProduct17-Sep-19Brazil,Central America,South AmericaApic BioUniversity of Massachusetts Medical SchoolProduct7-Jan-19USACavoGene LifeSciencesUniversity of California,San DiegoProduct23-Oct-18-Biogen IdecNeurimmune TherapeuticsProduct20-Nov-07WorldContext TherapeuticsChemDivProduct15-Nov-17-Amsterdam Molecular TherapeuticsAmgenProduct18-Sep-08-Knopp NeurosciencesUniversity of PittsburghTechnology7-Sep-05-ALS BiopharmaVybionTechnology27-Sep-10-Amorfix Life SciencesNonindustrial sourceProduct2-Feb-06WorldBiogen IdecAmorfix Life SciencesProduct14-Jul-10WorldAmorfix Life SciencesPan-Provincial Vaccine EnterpriseProduct3-Jun-10WorldNeuralstemUniversity of California,San DiegoTechnology20-Nov-07WorldTikvah TherapeuticsNavintaProduct7-Aug-07WorldNeuro-HitechGeorgetown UniversityTechnology31-May-07-CeregeneSalk InstituteTechnology7-Aug-03-Purchase AgreementsAcquiring companyDivesting companyProduct/TechnologyInitiation date/Completed dateCountriesBiogenAliveGenProduct24-Jul-18-Amarantus BioSciencePower3 Medical ProductsTechnology26-Dec-12-Development and Marketing AgreementsLicensing InLicensing OutProduct/TechnologyInitiaton date/Completed dateCountriesBiogen IdecNeurimmune TherapeuticsProduct39406WorldBiogen Idec,Knopp BiosciencesKnopp NeurosciencesProduct40409WorldBiogen IdecAmorfix Life SciencesProduct38932WorldGenentechNeuronova AGProduct39883Canada,Mexico,USA,WorldLandscape analysis of Amyotrophic Lateral Sclerosis 30A pictorial representation of all the deals covered involving ALS drug development has been added below(fig.12).Notably,according to data from our database,over 40%of the deals are collaborative R&D agreements,while a close 34%are licensing agreements.This highlights the collaborative mindset and fierce competition among market players,where large companies join forces to advance R&D possibilities further.Drugs and technologies that show promising data are quickly secured under exclusive regional licensing or development agreements.Other deals include general agreements(9%)and development and marketing agreements(5%),with purchase agreementswhere a company fully takes ownership of a drugaccounting for 3%of the deals signed for ALS indications.1%1%2%2%3%5%94B%1%1%R&D AgreementLicensingAgreementDevelopment andMarketing AgreementPurchaseLicensing andsupply agreementManufacturing AgreementDistribution AgreementJoint ventureManufacturing and supply agreementMarketing agreement Company agreements for ALS drugsFig.13:Distribution of deals signed involving ALS drug developmentThus,it is evident that various forms of agreements,whether R&D,licensing,or purchase agreements,are immensely popular among pharmaceutical companies.These deals help companies bypass the complex and lengthy development process,making the development of therapeutics for complex orphan diseases like ALS more Landscape analysis of Amyotrophic Lateral Sclerosis30 030VJ|Image:GreenApple78/Getty Images/iStockConclusion:In conclusion,the landscape of ALS(Amyotrophic Lateral Sclerosis)drug development is marked by significant and promising advancements.There has been a gradual increase in the number of ALS drugs in development,reflecting the growing commitment to finding a cure or more effective treatments for ALS patients.This effort is spearheaded by key development companies such as Roche,Biogen,AcuraStem and Pfizer,which are at the forefront of pioneering new treatments.Currently,there are seven drugs marketed specifically for ALS and more than a hundred are actively in development.Among the various drug types,small molecules emerge as the most preferred,signifying a strategic focus on versatile,potentially more accessible treatments.The TDP-43 protein stands out as the most targeted protein for ALS treatment,underscoring the scientific communitys effort to tackle the disease at a molecular level that could lead to more effective interventions.Approximately 40%of ALS drugs are being developed under research and development agreements,highlighting the collaborative efforts in the fight against this debilitating disease.The involvement of these pharmaceutical giants,alongside the strategic targeting of specific proteins and the preference for small molecule drugs,offers hope for more innovative and effective treatments.As the scientific community continues to unravel the complexities of ALS and develop more targeted therapies,the future for ALS patients looks increasingly promising.The ongoing research and development,underpinned by collaborative efforts and a clear focus on effective targets,underscore a dedicated and comprehensive approach to overcoming ALS.About AdisInsightYou need data insights to deliver your organizations objectives and overcome your biggest challenges.That data needs to be trustworthy,up to date,and accurate.How to access and use that data should be up to you:thats why we give you flexibility and control.You can opt to get our rich,validated data plugged straight into your internal analytics platforms and systems,so you have the freedom to explore and interrogate the data to meet your specific needs.Or you can benefit from additional layers of analysis and insights provided by our team of experts,giving you the relevant stories behind the data.In drug development where every day matters,our platform and solutions empower you to quickly understand whats happening and why,so you can reduce risk,make smarter strategic decisions and act with complete confidenceStart exploring-visit and preview the free version of the database today at Contact Landscape analysis of Amyotrophic Lateral Sclerosis 32References: Landscape analysis of Amyotrophic Lateral Sclerosis
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TRAILBLAZINGTHE FUTURE WITHEMERGINGBIOMATERIALS国家自然科学基金委员会NATIONAL NATURAL SCIENCE FOUNDATION OF CHINA1986Project PlanningWestlake University:Yigong Shi,Jiaxing HuangCAS,a division of the American Chemical Society:Manuel Guzman,Gilles Georges,Michael Dennis,Craig Stephens,Dennis McCullough,Dawn Riedel,Dawn George,Caroline MaResearch&AnalysisWestlake University:Yutao Zhan,Xinning Wang,Wen XiaoCAS:Angela Zhou,Kevin Hughes,Chia-Wei Hsu,Rumiana Tenchov,Julian Ivanov,Yi Deng,Eva Nesbit,Robert Bird,Janet Sasso,Leilani Lotti DiazACS International India Pvt.Ltd:Kavita Iyer,Krittika Ralhan,Magesh Ganesan,Saswata Banerjee,Ankush MaindPublicity and Promotion:CAS:Caroline Ma,Jinying Zhang,Peter Carlton,Peter Jap,Tina Tomeo,Erica Brown,Chris Cotton Project Management:Westlake University:Yutao Zhan,Xinning WangCAS:Sunny Yu,Li Zheng,Jennifer Sexton,Christopher Barbosky,Dharmini Patel,Sabrina LewisConsultantsWestlake University:Jianjun Cheng,Bowen Zhu,Chengchen Guo,Huaimin Wang,Lei Wang,Yue ZhangProject TeamAcknowledgementsThis report has also received contribution from Menghua Gao,Yuan Yao,Ran Jin and Zijie Yang of Westlake University and others.We would like to express our heartfelt thanks to all the help!Trailblazing the future with emerging biomaterials|1Synopsis2Introduction3Antibacterial Materials6Lipid-Based Materials29Bioinks52Programmable materials75Protein-Based Materials100Self-Healing materials120Bioelectronic Materials143Sustainable Materials for Biomedical Applications 169Conclusions194Methods197Trailblazing the future with emerging biomaterials|1Table of ContentsI.II.III.IV.V.VI.VII.VIII.IX.X.XI.SynopsisHealth stands as the bedrock of human existence and the linchpin for a high-quality life,therefore research in this area represents a vital global aspiration for a healthier future.Yet,the evolving societal landscape and environmental shifts have ushered in diverse health challenges.Issues such as the rapid transmission of infectious diseases like COVID-19 and environmental pollution pose significant threats to human well-being.Modern lifestyles further elevate the risks of chronic diseases and mental health concerns.Confronting these shared health challenges has become an urgent global imperative.Materials silently influence our quality of life,continually enhancing human health,from commonplace consumer goods to intricate medical devices and surgical materials.Materials science,through its involvement in cutting-edge medical equipment,improved drug delivery systems,innovative diagnostic tools,and the development of intelligent monitoring and sustainable materials,emerges as a key element in improving human health.Strides in material science have become pivotal in propelling advancements in healthcare,and the future augmentation of human health will increasingly hinge on progress in materials science.Ongoing fundamental research and the application of novel materials are not only steering the future trajectory of the health industry but also shaping the industries of the future,catalyzing the formation of transformative productive forces.This report is a collaborative effort between Westlake University and CAS,a division of the AmericanChemical Society.Together,teams from these two organizations delved into the dynamic landscape ofthe future development of materials used in biomedical applications.Westlake University focuses on cutting-edge scientific research,dedicates itself to breakthroughs in advanced technology,emphasizes interdisciplinary collaboration,and consistently places the promotion of human health and well-being as one of its core missions.CAS,with its diverse reservoir of expert scientific knowledge,extensive collection of indexed content,and state-of-the-art data analytics capabilities,stands as a singular hub uniquely positioned to generate panoramic insights into scientific trends.These two organizations have collaborated to explore the role of materials to address the challenges confronting human health,with the goals of unraveling future trends in materials development to provide foresight for pertinent scientific research and industrial advancement,and to spark profound discussions and facilitate extensive exchanges within the scientific,industrial,and investment community,contributing to build a healthy future together.Trailblazing the future with emerging biomaterials|3I.IntroductionOver the past two decades,the realm of biomaterials has undergone a surge in research and development.These materials,which are designed to interact with the human body to perform therapeutic and diagnostic functions,hold the promise of revolutionizing the landscape of healthcare.In this report,you will find materials that allow antitumor drugs to target tumor cells,then release drug payloads;materials that can heal themselves autonomously after being cut or sheared;implantable devices that are safely absorbed by the body over time;and conductive,soft,stretchable composite materials that are used to make two-way electrical interfaces bridging dynamic human tissue and precision electronics.This reports unprecedented level of detail and expansive scope is made possible through a dynamic fusion of interdisciplinary expertise at Westlake University and CAS,coupled with the CAS Content CollectionTM,the largest human-curated collection of scientific data in the word.This database,housing nearly 60 million journal and patent records across chemistry,biomedicine,materials science,and more,has been analyzed by specialists to unveil the substances,chemical reactions,and scientific concepts discussed in each.The eight emerging research areas in this report were identified using the approach described in the Methods section as a representation of the most active and fast-growing fields of biomaterials research(where a field is often signified by its most prominent feature,where the feature may be a specific material type,application,or function).The selection of these fields was the result of a seamlessly integrated research process among data scientists and biomaterial scientists.This process involved utilizing cutting-edge natural language processing methods,with iterative adjustment and refinement by biomaterial scientists,to identify emerging research areas.The report has also undergone multiple peer review cycles,ensuring that each revelation within it stands as a pinnacle of scientific rigor.In this report,each research area has its own chapter and begins by recent publication trends,with information including:Comparison of the growth of journal and patent publications as an indicator of research,development,and commercialization interest in the field.Leading research institutions for journal publications.Leading patent assignees and their geographical distribution.Time trends in patent publications broken down by geography.Chronological flow of filing initial patent applications within patent families,leading eventually to individual patent publications in national patent offices.Next,the materials used in each of the topic areas and their key applications are presented and discussed.Throughout this discussion,examples from literature are provided to illustrate prominent trends.Most chapters also include additional data to address topics that were found to be especially relevant for that chapter.(The chapter on self-healing materials,for example,contains a breakdown of the chemical mechanisms used to provide self-healing properties.)To highlight recent examples of innovative biomaterials research,each chapter includes tables of notable journal articles and patent publications from 2018-2023.These examples represent the range of materials identified through data analysis,and were selected based on journal impact factor,number of citations,and the assignee(for patents).Finally,the most difficult challenges facing each topic are identified.The report has yielded a series of fascinating insights,exploring the ongoing innovation and evolution in the field of biomaterials.Some of the topic areas,for example protein-based materials,have been well known to science for more than 20 years,but have shown continued research interest in recent years.Others,like bioinks,are relatively new fields of research that have undergone rapid expansion,with the majority of research having been published in the past 5 years.In at least two areas,lipid-based materials and sustainable biomaterials,research interest has increased significantly due to the use of these materials in the response to the COVID-19 pandemic.1,2 Antibacterial materialsProgrammableLipid-basedSustainableHydrogelsProtein-basedDrug deliveryWound healingBiosensorsImplantsElectronic skinTissue engineeringSelf-healing materialsBioelectronicsMetalsCarbon nanomaterialsNanocompositesSilkPVAGelsFilmsBioinksNatural polymersPiezoelectric sensorsLiposomesAMPsBioprintingGelMAStem cellsSelf-assemblyPorosityBiocompatibilityChitosanGelatinDNAStimuli-responsiveMultifunctionalPDMSExosomesPEGGrapheneSiliconBiodegradableSynthetic polymersLigninNon-covalent interactionsThe diversification in biomaterial research encompasses both applications and the substances used in them.A representative list of substances that appear in this report includes naturally-derived polymers,such as silk,chitosan,and DNA,chemically modified naturally-derived polymers,stem cells,synthetic polymers including PEDOT:PSS,metals,alloys,and nanoscale materials such as carbon nanotubes.In addition,a strong trend in many of the topic areas is combining individual substances to make highly engineered composites or hybrid materials that can perform complex functions,while maintaining biocompatibility.Notable applications that appear throughout the eight chapters include drug delivery,wound healing,tissue engineering,implantable devices,and sensors,among others.A significant fraction of the research efforts in biomaterials today involves combining or modifying existing materials,or discovering new materials,to achieve improved performance for these applications,with the goal of developing them to the point of clinical use.The materials used in these applications can have several synergistic properties.For example,drug delivery materials can possess both the ability to self-heal,preserving their physical form after placement inside the body,combined with a stimulus-response profile that triggers the release of a drug payload at a specific location,such as tumor or infection sites.3 Multi-functional biomaterials can also cross between application areas,such as self-healing antimicrobial materials developed for wound healing.4,5Overall,this report aims to provide a thorough overview of the rapidly advancing field of biomaterials research,including insightful guidance on the expected future research trajectories in this field.Additionally,we aspire for the information contained herein to serve as a valuable resource for professionals involved in the development and commercialization of emerging biomaterial technologies.By offering data-supported insights into anticipated growth areas,challenges,and opportunities for new materials and applications,we aim to facilitate informed decision-making within this dynamic industry.Figure 1.Word cloud representing key concepts in this report.(blue:8 chapters in the report,light blue:applications,purple:broad material categories,red:specific materials,dark purple:forms,black:properties).Terms were chosen to be representative of the content of this report and are purely illustrative.Trailblazing the future with emerging biomaterials|5References(1)Patrcio Silva,A.L.;Prata,J.C.;Walker,T.R.;Duarte,A.C.;Ouyang,W.;Barcel,D.;Rocha-Santos,T.Increased plastic pollution due to COVID-19 pandemic:Challenges and recommendations.Chemical Engineering Journal 2021,405,126683.DOI:https:/doi.org/10.1016/j.cej.2020.126683.(2)Tenchov,R.;Bird,R.;Curtze,A.E.;Zhou,Q.Lipid Nanoparticles-From Liposomes to mRNA Vaccine Delivery,a Landscape of Research Diversity and Advancement.ACS Nano 2021,15(11),16982-17015.DOI:10.1021/acsnano.1c04996.(3)Wu,M.;Chen,J.;Huang,W.;Yan,B.;Peng,Q.;Liu,J.;Chen,L.;Zeng,H.Injectable and Self-Healing Nanocomposite Hydrogels with Ultrasensitive pH-Responsiveness and Tunable Mechanical Properties:Implications for Controlled Drug Delivery.Biomacromolecules 2020,21(6),2409-2420.DOI:10.1021/acs.biomac.0c00347.(4)Zhao,X.;Liang,Y.;Huang,Y.;He,J.;Han,Y.;Guo,B.Physical Double-Network Hydrogel Adhesives with Rapid Shape Adaptability,Fast Self-Healing,Antioxidant and NIR/pH Stimulus-Responsiveness for Multidrug-Resistant Bacterial Infection and Removable Wound Dressing.Advanced Functional Materials 2020,30(17),1910748.DOI:https:/doi.org/10.1002/adfm.201910748.(5)Hu,C.;Zhang,F.;Long,L.;Kong,Q.;Luo,R.;Wang,Y.Dual-responsive injectable hydrogels encapsulating drug-loaded micelles for on-demand antimicrobial activity and accelerated wound healing.Journal of Controlled Release 2020,324,204-217.DOI:https:/doi.org/10.1016/j.jconrel.2020.05.010.Trailblazing the future with emerging biomaterials|5II.Antibacterial MaterialsIntroductionAntibacterials are a class of antimicrobials that target bacteria.Depending on their effect on bacterial cells,antibacterials can be classified either as bactericidal,which kill the bacterium,or bacteriostatic,if they arrest the bacterial growth.1 Since the discovery of Penicillin G in the 1940s,various classes of antibiotics have been developed.Lack of regulation and overuse of antibiotics in both humans as well as animals has led to various bacteria becoming unresponsive to numerous classes of existing antibiotics and this phenomenon is referred as multidrug resistance(MDR).2-4 The development of resistance towards existing drugs is an urgent problem crippling the world with the World Health Organization(WHO)declaring antimicrobial resistance as one of the top 10 global health threats.5 According to data presented by the Centers for Disease Control and Prevention(CDC),more than 2.8M antimicrobial-resistant(AMR)bacterial infections occur each year leading to 35K deaths per year.6 Amongst resistant bacteria,ESKAPEE pathogens(an acronym for a group of Gram-positive and Gram-negative bacteria such as Enterococcus faecium,Staphylococcus aureus,Klebsiella pneumoniae,Acinetobacter baumannii,Pseudomonas aeruginosa,Enterobacter species,and E.coli)are responsible for the largest fraction of hospital-acquired infections(HAIs).7-9 To create awareness about the diverse and prevalent resistant bacterial species,the CDC has published a list of microbes and classified them as either urgent antimicrobial resistance threats,serious AMR threats,or AMR watchlist(microbes that could become serious threats in the future due to their propensity to become multidrug resistant)in 2019.10,11 The serious AMR threat category comprises of drug-resistant Acinetobacter,Neisseria gonorrhoeae,Clostridioides difficile,and Enterobacterales.Resistant variants of bacteria such as Staphylococcus aureus,Pseudomonas aeruginosa,Enterococcus,Mycobacterium tuberculosis,Salmonella,Shigella,Campylobacter,and Streptococcus pneumoniae are featured in the CDCs serious AMR threat list.Drug-resistant Mycoplasma genitalium and Bordetella pertussis are included in the CDCs watch list as they have the potential to become multidrug-resistant in the near future.To counter the problem of increasing drug resistance,traditional small molecule-based antibiotics continue to be developed.However,development has been slow,and novel classes remain elusive.A continued necessity for newer antibiotics and a lack of newer classes of small-molecule antibiotics have led researchers to explore other avenues.In addition to traditional antibiotics,biomaterials with antibiotic functions,such as antimicrobial polymers,antimicrobial peptides(AMPs),antimicrobial enzymes,nanomaterials,bacteriophages can reduce(not replace)antibiotics usage and biomaterials which are biocompatible as scaffolds for antibiotics,such as glass,ceramics,polymers,can help more effective drug delivery and act,in a way reducing the load of drugs.12-17 This interest is exemplified by the increase in journal publications in the field of antibacterial biomaterials over the last two decades(Figure 1).Growth in patent publications appears to be more modest indicating a gap between research and commercialization of antibacterial biomaterials(Figure 1).In this chapter,we showcase our findings with regards to publication trends from extensive analysis of more than 90,000 documents(journals and patents)from the CAS Content Collection,spanning two decades of research(2003-2023)in the field of antibacterial biomaterials.In addition to a publication trend overview,we also identified emerging materials in the field,their forms,and applications.Trailblazing the future with emerging biomaterials|7JournalPatent200320042005200820072006200920102011201220202019201820172016201520142013202320222021Publication year02,0004,0006,000Number of publications*8,00010,000Figure 1.Number of journal and patent publications per year in the field of antibacterial materials(shown as blue and yellow bars,respectively)for the last two decades(2003-2023).*The data for 2023 only include months from Jan to Aug.Journal and patent publication trendsRanking research institutions firstly by the volume of journal publications followed by the average number of citations per publication allowed identification of the leading organizations in antibiotic research.The top 15 organizations show a diverse spread across different countries or regions(Figure 2).The United States of America(USA)and China(CHN)led by a small margin,each contributing 3 organizations to the top 15,respectively.This was closely followed by the Republic of Korea(KOR)and Singapore(SGP),each contributing 2 organizations.While the University of British Columbia ranked relatively low in terms of the actual number of journal publications(little more than 60),the average number of citations per publication was 90 indicating the scientific impact of those publications.An example of a journal publication from the University of British Columbia with a high number of citations is“Anti-adhesive antimicrobial peptide coating prevents catheter-associated infection in a mouse urinary infection model”.18 The geographical distribution of commercial and non-commercial entities in terms of patent documents published shows overlapping members(Figure 3).China(CHN)leads by a wide margin for both commercial and non-commercial organizations accounting for 50%of patents published.The United States of America(USA)accounts for a much smaller fraction as compared to its contribution to patent publications for other biomaterials discussed in this report.This may indicate low interest in antibiotic development because of the high costs associated with antibiotic discovery and development and limitations on the use of new antibiotics which reduce their market size and thus potential earnings.Additionally,bacterial infections,especially of the multi-drug resistant variety,are perceived to be more prevalent in and therefore a bigger problem in developing or low-and middle-income countries as compared to developed or high-income countries.19 However,this perception might be flawed as due to extensive globalization the world has become extremely interconnected and increasingly diseases affecting human beings can no longer be contained in any given geographical area,perhaps best exemplified by the COVID-19 pandemic.Other key countries or regions in the University of British ColumbiaSharif University of TechnologyMassachusetts Institute of TechnologyXian Jiaotong University The University of Hong KongSeoul National UniversityBar-Ilan UniversityNanyang Technological UniversityChonbuk National UniversityUniversity of CaliforniaNational University of SingaporeHubei UniversityUniversity College LondonHarvard UniversityNanjing UniversityAverage number of citations per publicationNumber of journal publicationsCitations per publicationNumber of journal publications(CAN)Number of journal publications(USA)Number of journal publications(IRN)Number of journal publications(GBR)Number of journal publications(CHN)Number of journal publications(SGP)Number of journal publications(KOR)Number of journal publications(ISR)Number of journal publications(HKG,CHN)commercial and non-commercial sectors include:Japan(JPN),Republic of Korea(KOR),Germany(DEU),Russia(RUS),India(IND),Italy(ITA),United Kingdom(GBR)and France(FRA).Japan in particular appears to have a more favorable contribution in patent publications by commercial organizations as compared to non-commercial organizations(Figure 3).Among the commercial patent assignees,Chinese companies led the way accounting for 60%of the top 15.This was followed by Japan with 25%and the United States which made up the remainder.The Japanese companies Lion Corporation and Kao Corporation appear to have been more active in the early part of the 2010s with patent publications related to the use of antibiotics in oral hygiene including incorporating antibacterial agents in dentifrices(JP2010150155A20 and JP2011136956A21).Similarly,Colgate-Palmolive,a US-based company,also has patents mostly focused on antibacterial agents in oral care(US20190185490A122).The Chinese company Guangdong Taibao Medical Technology Co.,Ltd.applied for patents starting in 2013 for the use and incorporation of biomaterials such as chitosan and alginate among others in medical dressings aimed at wound healing(CN103356692A23 and CN106267309A24).Other Chinese commercial organizations part of the top 15 such as Suzhou BEC Biology Technology Co.,Ltd.as well as Guangzhou Rainhome Pharm&Tech Co.,Ltd.also appeared to have similar commercial pursuits i.e.use of chitosan and other biomaterials in wound healing(CN105617451A25 and CN107970488A26).In terms of non-commercial organizations,the leading entities all originate from China with Sichuan University,South China University of Technology,and Zhejiang University leading of the rest by a modest margin(Figure 3).Sichuan University appears to have been more prolific after 2010 with patents revolving around diverse areas including iron oxide nanoparticles for targeted delivery of antibacterial agents(CN115040662A27)and use of a polymer,polyurethane,in antibacterial coatings(CN103214646A28).The overall growth of patent publications shows a distinct upward trend for the Republic of Korea and Japan post-2020 and India post-2018(Figure 4A).Germany and the United Kingdom also show modest increases in the number of patents published.While the US showed an increase in patent publications in the early 2000s(between 2003 and 2008),this was followed by a decrease in 2009-2010 with a more or less flat trajectory until the present year.Among the leading countries or regions,China is the only one that shows a sharp and dramatic increase in patent publications,Figure 2.Leading research organizations in the field of antibacterial biomaterials over the last two decades(2003-2023)from the CAS Content Collection.Bar graphs have been color coded by country/region with standard three letter codes used to represent countries/regions.Trailblazing the future with emerging biomaterials|9Number of patent publicationsEast China University of Science and TechnologyLion Corp.Hainan Weikang Pharmaceutical(Qianshan)Co.,Ltd.Guangzhou Rainhome Pharm&Tech Co.,Ltd.Guangdong Taibao Medical Technology Co.,Ltd.Suzhou BEC Biology Technology Co.,Ltd.Wuxi Zhongke Guangyuan Biomaterials Co.,Ltd.Jinan Kangquan Pharmaceutical Science and Technology Co.,Ltd.Toyobo Co.,Ltd.Kao Corp.Toray Industries,Inc.Kimberly-Clark Worldwide,Inc.Colgate-Palmolive CompanyNon-commercialCommercialPatent assignees250152010305354045Suzhou Koumei New Materials Co.,Ltd.South China University of TechnologyZhejiang Sci-Tech UniversitySichuan UniversityDonghua UniversityJinan UniversityChina Pharmaceutical UniversitySoochow UniversityJilin UniversityInstitute of Metal Research,Chinese Academy of SciencesSouthwest UniversityJiangnan UniversityZhejiang UniversitySoutheast UniversityBeijing University of Chemical TechnologyNumber of patent publications100060804020120Patent assigneesUSACHNDEUKORFRA(1%)JPNRUSGBR(2%)INDTop 10patent assignees2003-202353%9%3%Others3%9%USACHNDEU(2%)KORFRAINDITA60%7%6%2%Top 10patent assignees2003-2023JPNRUSOthers2%3%ITA(2%)5%BRZ(1%)3%4%2lian Sansheng Technology Development Co.,Ltd.Jinan Shuaihua Pharmaceutical Science and Technology Co.,Ltd.Figure 3.Leading patent assignees in the field of antibacterial biomaterials over the last two decades(2003-2023)as reflected in the CAS Content Collection.Patent assignees have been separated in to two groups:commercial and non-commercial.Bar graphs have been color coded by country/region to match color scheme used in donut charts.Standard three letter codes used to represent countries/regions.almost doubling between 2012 and 2016.This growth appears to have continued beyond 2016 to the present year at a fast rate.In terms of the sheer volume of patent publications,China clearly dominates having 16 times as many patent publications in 2021-2022 as USA.An analysis of patent family activity data in Figure 4B shows the flow from the patent assignee country(left)to the patent office where the first application in a given family is filed(center)and finally to the destination patent office for individual patent publications within the family.For China,the country leading in terms of sheer volume of patent publications,an overwhelming majority of patent applications appear to have been filed and granted at their home office.The US and UK had a greater number of patent filings at the World Intellectual Patent Office(WIPO)than at their respective home offices.On the other hand,Japan,Republic of Korea,and India showed a distinct preference for their respective home offices both for the initial and destination patent filings.Germany and Italy appear to only show preference for their respective home offices for the initial patent filing(A)USA:8,928CHN:15,587DEU:1,690ITA:642KOR:1,618JPN:2,644CAN:557FRA:919USA:4,875CHN:16,107EUR:2,106CAN:1,050JPN:2,489BRZ:415KOR:1,533DEU:260MEX:313IND:906Others:1,567(B)Publication yearNumber of patent publications2003-20042005-20062007-20082009-20102011-20122013-20142015-20162017-20182019-20202021-2022JPNRUSKORINDUSA2,0001,50002,5003,0005001,0002003-20042005-20062007-20082009-20102011-20122013-20142015-20162017-20182019-20202021-2022USACHN050100150200250KORGBR:1,135IND:963WIPO:8,807KOR:1,423USA:3,184EPO:667ITA:367CHN:15,624FRA:543JPN:1,881IND:788DEU:1,174JPNINDRUSDEUGBRGBRDEUOTH:495Figure 4.(A)Growth in patent publications in the field of antibacterial biomaterials for the leading countries or regions over the last two decades(2003-2022)from the CAS Content Collection.(B)Sankey graph depicting flow of patent families in the antibacterial biomaterials field between assignee countries or regions(left),office where the first application in a family is filed(center)and the office where individual patent publication activities take place(right).Trailblazing the future with emerging biomaterials|11StaphylococciEscherichiaPseudomonasBacilliKlebsiellaSalmonellaeStreptococciEnterococciAcinetobactersProteiHaemophili(0.1%)Burkholderia(0.2%)Saccharomyces(0.3%)Citrobacteria(0.4%)Clostridia(0.4%)Helicobacters(0.4%)Aeromonas(0.5%)Serratia(1%)Mycobacteria(1%)Lactobacilli(1%)Shigellae(1%)Micrococci(1%)Enterobacteria(1%)Vibrios(1%)Listeria(1%)(A)(B)27%5%3%3%3%7%2%2!%9%4%4%3%6%4%3%2%2%2%2%2%2%2%1%2%1%2%2%1%0.5%(C)Staphylococcus aureusAcinetobacter baumanniiKlebsiella pneumoniaePseudomonas aeruginosaEnterobacter spp.Enterococcus faeciumRelative publication growth(%)010203035251552013-20142015-20162017-20182019-20202021-20222011-20122003-20042005-20062007-20082009-2010Publication year2013-20142015-20162017-20182019-20202021-20222011-20122003-20042005-20062007-20082009-2010Publication yearRelative publication growth(%)01020307060504080Carbapenem-resistant EnterobacteralesDrug-resistant Neisseria gonorrhoeaeClostridioides difficileCarbapenem-resistant AcinetobacterFigure 5.(A)Distribution of publications(journals and patents)in the field of antibacterial biomaterials across various bacterial species.Growth in publications(journals and patents)associated with(B)ESKAPEE pathogens and bacteria classified as(C)“urgent”threats by the CDC in the field of antibacterial biomaterials.Data includes both journal and patent publications from the CAS Content Collection for the last two decades(2003-2022)in the field of antibacterial biomaterials.with a more or less even spread across various patent offices worldwide in terms of the final destination.We analyzed both journal and patent publications in our dataset exhaustively in an effort to identify the research interest distribution across different bacterial species(Figure 5A).The two genera,Staphylococcus and Escherichia account for half of all publications associated with bacterial species.Other key bacterial species that appear to be of interest in the field of antibacterial biomaterials include Pseudomonas,Bacillus,Klebsiella,Salmonella,Streptococcus,Enterococcus,Acinetobacter,and Proteus(Figure 5A).Drug-resistant strains for several of these species have been identified and classified as threats by authorities such as the WHO and CDC.Publications associated with the ESKAPEE pathogens show steady and consistent growth for the last two decades(Figure 5B).Similarly,publications associated with bacterial species classified as“Urgent”threats by the CDC also show steady growth(Figure 5C).Overall,these trends are indicative of the interest in developing antibacterial biomaterials to combat the very real and growing threat of multidrug-resistant bacteria.Key materials,properties/forms and applicationsData mined from the CAS Content Collection allowed the identification and classification of biomaterials occurring/used frequently in the field of antibacterial biomaterials into the following broad categories:Polymers Organic molecules Metals and metal oxides Carbon-based materials Protein-based materials OthersThe quantitative distribution of identified materials and their breakdown across various categories are shown in Figure 6.Three of the bigger categories have been further sub-divided to give a more nuanced/granular view of emerging materials polymers into synthetic,natural,and conductive,organic molecules into antibiotics,and others(consisting of substances such as steroids,quaternary ammonium compounds,zinc chloride,silver chloride,etc.)and metal into noble and transition metals.Relative growth in publications of a few shortlisted materials identified as emerging across the last two decades are shown in Figure 7A.Graphene shows a sharp and continued increase in publications post-2014.The use of graphene oxide29 and graphene-based hybrid nanocomposites in the form of hydrogels for antibacterial effect has been reported.30,31 Other emerging materials include polycaprolactone(PCL)and chitosan a synthetic and a natural polymer,respectively;metals such as zinc,copper,and silver known for their antibacterial properties;antimicrobial peptides(AMP)and quaternary ammonium-containing compounds.Chitosan is among the few biomaterials that possess inherent antimicrobial activity.32 This along with other favorable properties such as biocompatibility,biodegradability,and abundance along with reduced propensity of development of resistance by bacterial species means that chitosan has been explored in novel ways including as a carrier for drug delivery,33 in combination with other materials34 and incorporated into hydrogels along with other polymers and loaded with antibiotics for drug delivery and wound healing.35 Recently,a light-responsive chitosan nano-assembly36 and a synthetic analog of chitosan with improved antimicrobial efficacy have been developed.37 Chitosan and its derivatives continue to be of high interest in the field of antibacterial biomaterials.The synthetic biodegradable polymer,polycaprolactone,is often used in conjunction with other biomaterials such as gelatin,38 silica,39 and others40 fashioned into nanostructures,41-43 hydrogels,etc.for applications such as targeted drug delivery44 and wound healing.41 Despite the antimicrobial effect/activity of metals such as silver,45,46 copper,47,48 and zinc49 being well-known,interest in these materials has sustained over the years with efforts being made to use these metals in combination with other biomaterials in novel ways.Silver in particular continues to be utilized along with other biomaterials in combating multi-drug resistant strains50,51 including for the disruption of biofilms.52 In addition,dead bacteria with accumulated silver appear to retain the ability to kill other living bacteria in its vicinity,53,54 an effect that can be exploited for increased/greater antimicrobial effect.AMPs are small peptides of variable length composed of natural amino acids55 which are classified by their structures,sources,activities,and other properties.56 Interest in AMPs has been consistent with several AMP candidates currently in clinical trials.57 A large majority of the protein-based materials identified in our dataset result from AMPs.In terms of growth in publications,we see a steady growth over the last two decades.This is in agreement with the overall sustained interest in AMPs as alternatives to traditional antibiotics.A few examples of AMPs in the context of biomaterials include the use of AMPs as anti-biofilm agents for medical implants and devices58-60 as well as incorporation of AMPs in hydrogels61 and AMP-polymer conjugates.62-64 Ceramics loaded with antibiotics have been used for local/targeted delivery of antibiotics for prolonged periods of time(up to several days),especially in bone-related applications.65,66 Biomaterials such as bamboo,which are naturally antibacterial,are being explored in their natural or composite forms for biomedical applications such as designing medical gauze and would dressing for accelerated wound healing.67-69Trailblazing the future with emerging biomaterials|13PolymersOrganicmoleculesMetals andmetal oxidesOthersProtein-basedCarbon-basedNaturalSyntheticConductiveAntibioticsOthersTransitionmetalsOthersNoblemetalsMetaloxides*Figure 6.Distribution of materials in the field of antibacterial biomaterials over the last two decades(2003-2022)from the CAS Content Collection.Size of the circle corresponds to number of publications(journals and patents).Growth of materials marked with an asterisk are shown in Figure 7.Established classes of antibiotics such as tetracyclines,macrolides,and others have reportedly been used in conjunction with biomaterials often to aid in their delivery and to boost their antibacterial effectiveness in applications such as tissue engineering and wound healing.70-73 Among the various classes of antibiotics,we identified a few that appear to be most prolific and show a steady rate of increase in publications(Figure 7B).These classes of antibiotics are most often formulated/incorporated into either hydrogel,nano-based systems such as nanoparticles,nanofibers,nanosheets,etc.,or liposomes.Among the various forms listed,nano-based systems appear to dominate(Figure 8A).All the forms show steady growth more so over the last decade.Hydrogels and quantum dots in particular show a sharp growth in publications post-2016(Figure 8B).Liposomes,a subtype of nanocarriers was originally focused on packaging and delivery of anticancer drugs,but is increasingly being explored for effective delivery of antibiotics.74-76 For instance,a hydrogel comprising lignin and silver nanoparticles has shown antibiotic activity against S.aureus,a Gram-positive bacterium,and E.coli,a Gram-negative bacterium indicating its applicability and versatility.77 In another recent example,a self-assembled peptide hydrogel made from naphthyl anthranilamide capped,short cationic peptides that showed promising antibacterial activity against S.aureus and E.coli.78 The high surface area to volume ratio of nanoparticles allows them to deliver antibacterial drugs effectively.79,80 Nanoparticles made using silver,gold,selenium,calcium oxide,copper,titanium dioxide,iron oxide,poly(lactic-co-glycolic acid)(PLGA),chitosan,etc.are widely used in the field of antibacterials.81-86To understand the preference for a particular form,we searched for various classes of antibiotics and forms and generated a Sankey graph to visually represent these co-occurrences(Figure 9).Among the different classes of antibiotics,a majority had a higher number of co-occurrences with nano-based systems as compared to other forms,the exceptions being oxazolidinones,glycylcyclines,phosphonic acids,amphenicols,and aminocyclitol which showed co-occurred more or less evenly across hydrogels,nano-based systems,and liposomes(Figure 9).We generated a heat map to effectively showcase co-occurrences between specific bacterial species and the classes 2013-20142015-20162017-20182019-20202021-20222011-20122003-20042005-20062007-20082009-20102013-20142015-20162017-20182019-20202021-20222011-20122003-20042005-20062007-20082009-2010Publication yearPublication yearRelative publication growth(%)Relative publication growth(%)(B)(A)AmphenicolsPenicillins&Beta lactamsLincosamidesTetracyclinesSulfonamidesQuinolones&fluoroquinolonesNitroimidazolesMacrolidesCarbapenemAnthracyclines01020304035251550102025155GraphenePolycaprolactoneZincChitosanAntimicrobial peptidesSilverCeramicLigninQuaternary compoundsCopperPhosphonic acidsGlycylcyclinesAnsamycinsAminoglycosidesOxazolidinonesAminocyclitols45Figure 7.Growth in publications for(A)emerging materials and(B)major classes of antibiotic drugs in the field of antibacterial biomaterials from the CAS Content Collection for 2003-2022.Data includes both journal and patent publications.Trailblazing the future with emerging biomaterials|15of antibiotics deployed against them(Figure 10).The bacterial species we chose to focus on were based on our findings described earlier i.e.,the most prevalent bacterial species in the current dataset of antibacterial materials(Figure 5A).Discussed below are a few observations from the heat map:1.The bacterial species that co-occurred most frequently across the different classes of antibiotics are Staphylococcus,Escherichia,Pseudomonas,and Klebsiella.This is unsurprising since drug-resistant strains of Staphylococcus,Pseudomonas,and Klebsiella have long been identified.2.Certain classes of antibiotics are more effective against Gram-negative bacteria while some have a preferential effect against Gram-positive bacterial species.For instance,carbapenems(including imipenem,doripenem,and meropenem)are mostly effective against Gram-negative bacteria belonging to genera such as Acinetobacter,Escherichia,Klebsiella,Pseudomonas,Enterobacter etc.87,883.Certain broad-spectrum antibiotics such as tetracycline and their derivatives like glycylcycline are effective against both Gram-positive(Staphylococcus)and Gram-negative bacteria(Escherichia)which also correlates well with literature.89,90The distribution of applications that antibacterial biomaterials can be utilized for is shown in Figure 11A.One of the biggest applications is the use of biomaterials to effectively target and deliver antibiotics accounting for nearly 12K publications in the last two decades(2003-2023).Biomaterials such as antimicrobial peptides,enzymes,and biopolymers are being used effectively in the field of antibiotics.12 Another major application involves the use of antibacterial biomaterials in the design and fabrication of medical apparatuses,devices,and implants to reduce the risk of infections.Various polycationic polymers(including quaternary ammonium salt-containing polymers),zwitterions,polyethylene glycol(PEG),and antibacterial peptides are used to design antimicrobial coatings for preventing bacterial infections.91-93 Besides these,other notable Nano-basedQuantum dotsLiposomesHydrogels2003-20042005-20062007-20082009-20102011-20122013-20142015-20162017-20182019-20202021-2022Publication year05101520253050Relative growth in publications(%)(B)(A)Nano-basedHydrogelsLiposomesQuantum dotsNumber of publications(Journals and patents)2003-202332K5.6K3K522354045Figure 8.(A)Distribution of various forms in the field of antibacterial biomaterials and(B)relative growth in publications related to chosen forms in the field of antibacterial biomaterials over the last two decades from the CAS Content Collection.applications of antibacterial biomaterials appear to be in the food industry and as antifouling agents.PEG-based materials,zwitterions,hydrogels,cationic,and fluoropolymers are some commonly used antifouling agents94,95 used to coat surfaces in order to prevent bacterial infections.In the food industry,antibacterial biomaterials are Penicillin and beta lactams:3,822Fluoroquinolones:1,671Quinolones:1,542Others:1,338Tetracyclines:1,155Aminoglycosides:1,031Macrolides:711Anthracyclines:461Carbapenems:373Ansamycins:417Sulfonamides:357Lincosamides:270Nitroimidazoles:236Oxazolidinone:122Glycylcyclines:75Phosphonic acids:62Amphenicols:31Aminocyclitol:42Nano-based:9,979Hydrogels:1,894Liposomes:1,843Figure 9.Sankey graph showing co-occurrences between various classes of antibiotics and the forms such as nano-based,hydrogels and liposomes.Data is for publications(journals and patents)in the field of antibacterial biomaterials from the CAS Content Collection for the period 2003-2023.used to increase the shelf-life of perishable food products by preventing bacterial infections.Phenolic compounds,enzymes such as lysozyme,and antimicrobial peptides are a few examples of biomaterials being actively utilized to design more effective and safer food preservatives.95-97 Trailblazing the future with emerging biomaterials|1726.714.07.88.76.010.23.72.80.51.61.82.62.51.50.60.38.7Penicillin&lactamsQuinolones&fluoroquinolonesTetracyclinesCarbapenemMacrolidesAminoglycosidesAnsamycinLincosamideAnthracyclinesOxazolidinoneGlycylcyclineSulfonamidePhosphonic acidNitroimidazoleAminocyclitolAmphenicolsOthersStaphylococcus24.917.915.36.516.313.019.218.324.021.67.114.214.812.28.08.517.5Escherichia16.517.916.615.112.815.712.110.324.29.315.217.918.511.910.016.917.8Pseudomonas12.615.610.917.211.417.49.29.210.67.77.713.514.06.89.36.911.0Bacillus4.14.85.81.65.44.74.74.68.62.91.44.01.55.04.85.85.2Klebsiella8.38.37.014.85.99.15.25.54.25.316.57.78.04.05.53.26.9Streptococcus2.93.34.21.95.42.64.36.03.16.02.33.03.17.75.29.03.6Salmonella3.03.34.62.04.03.73.23.73.62.82.53.23.33.14.66.34.1Enterococcus3.94.35.53.16.94.46.37.43.911.33.54.14.36.54.85.35.1Proteus2.12.52.22.81.92.52.02.01.42.23.12.22.31.43.21.62.0Enterobacter4.23.63.39.52.64.52.73.40.83.811.64.44.62.34.11.63.4Acinetobacter4.84.84.110.43.26.33.93.71.93.59.85.15.32.33.91.63.5Micrococcus0.60.60.80.31.00.70.80.61.10.10.20.50.50.40.70.50.9Mycobacterium0.91.41.71.22.31.97.02.42.53.41.71.71.72.84.62.63.2Lactobacillus1.01.12.20.52.61.22.13.70.31.50.51.51.65.32.11.61.7Vibrio1.01.22.50.81.91.52.12.30.61.70.92.11.12.14.37.91.8Listeria1.01.01.70.82.11.31.82.41.71.70.51.31.41.82.12.11.7Shigella1.11.21.80.91.81.31.81.71.41.41.71.31.41.72.70.51.7Clostridium0.90.81.71.01.91.12.83.61.43.31.52.12.18.24.34.21.3Burkholderia0.70.91.21.11.11.21.41.20.61.70.91.92.01.12.71.61.1Serratia1.41.41.32.71.21.51.21.30.31.63.51.92.01.03.01.11.3Helicobacter1.00.71.40.53.50.61.71.40.81.50.91.01.07.12.11.11.1Aeromonas0.80.91.50.91.40.91.11.50.61.00.72.12.10.41.85.31.3Citrobacter1.61.41.43.40.91.81.11.00.31.54.51.71.81.02.52.61.4Haemophilus0.70.91.00.91.60.81.61.91.42.71.41.11.22.43.42.10.9Saccharomyces0.30.30.50.20.70.40.70.80.80.40.30.60.61.70.50.00.4LowHighFigure 10.Heat map showing co-occurrences between major antibiotic classes and bacterial species.Data is for publications(journals and patents)in the field of antibacterial biomaterials from the CAS Content Collection for the period 2003-2023.Values shown are in percentages.(B)(A)2003-20042005-20062007-20082009-20102011-20122013-20142015-20162017-20182019-20202021-2022HydrogelsDrug deliveryWound healingTissue engineeringFood industryAnti-foulingMedical apparatus050010001500200025003000Publication yearNumber of publicationsNumber of publications(Journals and patents)2003-2023Drug deliveryMedical apparatusHydrogelsWound healingTissue engineeringFood industryAntifouling12K11K5.6K5.4K1.7K1K1KFigure 11.(A)Distribution of applications in the field of antibacterial biomaterials and(B)and growth in publications related to chosen applications in the field of antibacterial biomaterials over the last two decades from the CAS Content Collection.Notable journal articles and patents Table 1 consists of a set of research articles published from 2020-2023 that are representative of emerging trends in this field.Articles were selected on the basis of collective factors such as journal impact factor,citations,and type of study and describe the usage of different antibacterial materials for various bacterial species.Notable examples from Table 1 include an article titled“Graphdiyne-modified TiO2 nanofibers with osteoinductive and enhanced photocatalytic antibacterial activities to prevent implant infection”published in 2020 in Nature Communications.The article describes the use of a stable carbon allotrope-based nanomaterial(GDY),that forms a composite with titanium oxide(TiO2)nanofibers to improve the antibacterial properties of titanium oxide.TiO2/GDY nanofibers have enhanced photocatalytic and ROS production activity.98 Another example includes a recent publication titled Injectable wound dressing based on carboxymethyl chitosan triple-network hydrogel for effective wound antibacterial and hemostasis”which describes the synthesis of a hydrogel comprising carboxymethyl chitosan(CMCS),oxidized dextran(OD),and poly-glutamic acid(-PGA).Components of CMCS-OD-PGA(COP)hydrogel such as CMCS and OD are responsible for antibacterial action while-PGA is responsible for wound healing and maintaining homeostasis at the wound site.Furthermore,researchers at Westlake University have developed chitin and cellulose nanofibril-based adhesive tape which can be incorporated with antibiotics.In this article,nanofibril-stabilized latex(poly-2-ethylhexyl acrylate-co-polymethyl acrylate)was infused with the antifungal drug miconazole nitrate.The resultant antibiotic-loaded tape was used to effectively inhibit the growth of Staphylococcus aureus.99Table 2 shows notable patents in the field of antibacterial biomaterials published from 2018 to 2023.Patents were selected based on relevance,novelty,applicability,and field of study.Most of these involve different forms of biomaterials and their diverse applications.For instance,US10662203B2 by Hoffmann La Roche Inc.describes the synthesis of heterocyclic compounds that can be used as DNA gyrase/topoisomerase inhibitors thereby eliminating bacterial infections.100In another example,US11234997B2 describes the topical formulation that comprises varying ratios of galactooligosaccharide and xylitol(ranging from 1:10 to 10:1).These formulations selectively inhibited the formation of biofilm by Staphylococcus aureus and helped to reduce atopic dermatitis without causing skin inflammation and irritation.101In a recent example,CN113277563B describes a composite powder made using molybdenum-doped cesium tungsten bronze/montmorillonite where montmorillonite acts as a carrier for molybdenum doped cesium tungsten bronze which is loaded on to the surface of the film.These composites were used to inhibit the growth of E.coli.102Trailblazing the future with emerging biomaterials|19Table 1.Notable journal articles in the field of antibacterial biomaterials in recent years.YearTitleJournalResearch InstituteApplication2020Designing a 0D/2D S-scheme heterojunction over polymeric carbon nitride for visible-light photocatalytic inactivation of bacteria103Angewandte ChemieWuhan UniversityAntibacterial coating effective against S.aureus.2020Graphdiyne-modified TiO2 nanofibers with osteoinductive and enhanced photocatalytic antibacterial activities to prevent implant infection98Nature CommunicationsGuangzhou Laboratory and Wuhan UniversityGraphdiyne(GDY)composite TiO2 nanofiber with antibacterial properties.2021Dual-Dynamic-Bond Cross-Linked Antibacterial Adhesive Hydrogel Sealants with On-Demand Removability for Post-Wound-Closure and Infected Wound Healing104ACS NanoXian Jiaotong UniversitySelf-healing antibacterial containing quaternized chitosan(QCS)for wound healing after methicillin-resistant Staphylococcus aureus(MRSA)infection.2021Anti-bacterial and wound healing-promoting effects of zinc ferrite nanoparticles105Journal of NanobiotechnologyUniversity of CaliforniaSynthesis and testing antibacterial activity of zinc ferrite(ZnFe2O4)nanoparticles against S.aureus and E.coli.2020Near-Infrared Light-Triggered Nitric-Oxide-Enhanced Photodynamic Therapy and Low-Temperature Photothermal Therapy for Biofilm Elimination106ACS NanoChongqing UniversityAnti-biofilm activity of AI-MPDA Nanoparticles containing mesoporous polydopamine(MPDA),L-arginine(l-Arg),and indocyanine green(ICG).2021Dy2BaCuO5/Ba4DyCu3O9.09 S-scheme heterojunction nanocomposite with enhanced photocatalytic and antibacterial activities107Journal of the American Ceramic SocietyUniversity of KashanNanoparticles made from a semiconductor combination(Dy2BaCuO5/Ba4DyCu3O9.09)were synthesized and tested for antibacterial activity against E.faecalis,S.aureus,K.pneumonia,and E.coli.2022Facile formation of injectable quaternized chitosan/tannic acid hydrogels with antibacterial and ROS scavenging capabilities for diabetic wound healing108International Journal of Biological MacromoleculesWenzhou Medical UniversityAntibacterial activity of hydrogel made by introducing tannic acid(TA)into quaternized chitosan(QCS)matrix against S.aureus and E.coli.2022Promoting the healing of infected diabetic wound by an anti-bacterial and nano-enzyme-containing hydrogel with inflammation-suppressing,ROS-scavenging,oxygen,and nitric oxide-generating properties109BiomaterialsZhejiang UniversityAntibacterial activity of Poly(PEGMA-co-GMA-co-AAm)(PPGA)based hydrogels crosslinked with hyperbranched poly-L-lysine(HBPL)-modified manganese dioxide(MnO2)against methicillin-resistant S.aureus(MRSA)infection.2022Cellulose or chitin nanofibril-stabilized latex for medical adhesion via tailoring colloidal interactions99Carbohydrate PolymersWestlake UniversityUsing cellulose and chitin nanofibrils to form adhesive tapes which exhibit antibacterial activity 2022Multi-crosslinking hydrogels with robust bio-adhesion and pro-coagulant activity for first-aid hemostasis and infected wound healing110Bioactive MaterialsSichuan UniversityHydrogels comprising carboxymethyl chitosan(CMCS),sodium alginate(SA),and tannic acid were tested for antibacterial activity against S.aureus and E.coli.2023Injectable wound dressing based on carboxymethyl chitosan triple-network hydrogel for effective wound antibacterial and hemostasis111International Journal of Biological MacromoleculesShanghai UniversityAntibacterial effect of a hydrogel comprising carboxymethyl chitosan(CMCS)/oxidized dextran(OD)/poly-glutamic acid(-PGA).Table 2.Notable patent publications in the field of antibacterial biomaterials in recent years.Patent numberPublication yearPatent assigneeTitleDescription of patented technologyJP2018159860A1122018Tokai Optical Co LtdOptical product containing metal ion-carrying zeoliteAn optical multilayer product with an antireflective film coated with an organic antibacterial agent.CN107536725A1132018Guangzhou Weimeizi Industrial Co LtdA kind of multiple-effect oral cavity composition and its application containing hyaluronic acid mixturesOral care composition comprising different combinations of hyaluronic acid(in some cases with zinc citrate)used as antibacterials.JP2019065375A1142019Harada Metal Industry Co.,Ltd.,National Institute of Advanced Industrial Science&Technology,JapanCopper alloy powder having antibacterial properties and antivirus properties and article using the sameAntibacterial coating formulation containing copper alloy powder(comprising 0.10%tin,0.01%phosphorus and remaining copper).US10662203B21002020Hoffmann La Roche IncNovel pyrido 2,3-b indole compounds for the treatment and prevention of bacterial infectionsHeterocyclic compound to inhibit bacterial DNA gyrase and/or topoisomerase IV,in turn inhibiting bacterial growth.US11065223B21152021University of Texas System,USAAntibacterial composition and its useAntimicrobial composition in the form of wound ointment containing esterified polygalacturonic acid and a C6-12 fatty acid.CN110067042B1162021Donghua UniversityKonjac glucomannan-based antibacterial hydrogel fiber and preparation method thereofAntibacterial hydrogel fiber comprising Konjac glucomannan polymerizable monomer,alginate,guanidine salt polymerizable monomer,deionized water,and polymerization initiator.US11459296B21172022Infex Therapeutics Ltd Medivir ABPreparation of sulfamoyl pyrrolecarboxylic acids as antibacterial agentsNitrogen-containing heterocyclic compounds that act as Metallo-lactamase inhibitors.US11234997B21012022Rottapharm SpAAntibacterial activity of galactooligosaccharide and xylitol in dermatological treatmentsAnti-biofilm activity of topical formulation comprising galactooligosaccharide and xylitol in different ratios.US11691967B21182023The Board of Trustees of the University of Illinois,USAAntibiotics effective for gram-negative pathogensOrganic compounds with antibiotic activity,selectively against gram-negative bacteria.CN113277563B1022023Nanjing Zhouninglin Advanced Materials Technology Co Ltd,Nanjing Normal UniversityMolybdenum doped cesium tungsten bronze/montmorillonite composite powder and preparation method and application thereofSynthesis and antibacterial activity of molybdenum doped cesium tungsten bronze/montmorillonite composites.Trailblazing the future with emerging biomaterials|21Challenges and perspectivesDevelopment of novel antibiotics requires a thorough understanding of the host immune system and the interaction of host cells with antibiotics.There are various traditional antibiotic approaches/materials being used to treat bacterial infections but the major challenges in this area are:One common challenge in this field is the development of antimicrobial resistance in bacterial species,which happens at a much faster pace as compared to the of development of any novel antibiotic.1,119 The same levels of antibiotic treatment produce varied results in different individuals in 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carriercubosomeIII.Lipid-based materialsIntroductionThe field of pharmaceuticals has witnessed remarkable progress recently,driven by innovations in drug delivery technologies.Traditionally,drug delivery has been a complex puzzle,often challenged by the limited solubility,stability,and bioavailability of many therapeutic agents.These constraints have led researchers on a quest to find more effective ways to deliver drugs to their intended targets within the body.Therefore,drug delivery systems play a crucial role in optimizing the therapeutic benefits of medications while minimizing side effects and improving patient compliance.Among the transformative advancements in drug delivery technologies,lipid-based drug delivery systems have emerged as a formidable force in the world of pharmaceutical science and practice offering a dynamic range of solutions that transcend traditional pharmaceutical boundaries.Lipid-based drug delivery systems are ingeniously designed carriers,benefitting from the inherent biocompatibility and versatility of lipids and tailored to encapsulate,transport,and release a wide array of therapeutic agents,including small molecule drugs,genes,and biologics.Their elegance lies in their ability to overcome some of the most pressing challenges in drug delivery.These challenges include improving the solubility of poorly water-soluble drugs,protecting labile compounds from degradation,and precisely targeting disease sites within the body.1-9Lipid nanocarriers can be divided into various categories,including solid lipid nanoparticles(SLNs),nanostructured lipid carriers(NLCs),liposomes,lipid-based micelles,and lipid prodrugs(Figure 1).SLNs consist of solid lipids,while NLCs combine solid and liquid lipids,offering enhanced drug-loading capacity and Figure 1.Schematic representation of various types of lipid nanoparticles.Adapted from Tenchov et al.1flexibility.Liposomes are spherical vesicles with lipid bilayers surrounding an aqueous core,while lipid-based micelles have amphiphilic molecules forming micellar structures.Lipid nanocarriers offer several advantages,such as improved drug solubility,enhanced bioavailability,controlled drug release,targeted delivery,and protection of labile drugs from degradation.1,5,8,10,11 Exosomes are similar to liposomes but originating from biological systems and secreted by most eukaryotic cells.They possess unique properties such as innate stability,low immunogenicity,biocompatibility,and good bio-membrane penetration capacity,making them superior natural nanocarriers for efficient drug delivery and diagnostics.12-15Lipid nanocarriers have revolutionized drug delivery by overcoming limitations related to drug solubility,stability,bioavailability,and targeted delivery.They continue to play a pivotal role in improving drug delivery,expanding treatment options,and enhancing patient outcomes across a wide spectrum of diseases and conditions.Their versatility,biocompatibility,and ability to address specific drug delivery challenges make them valuable tools in pharmaceutical research and development.Besides drug delivery,lipid-based materials have also found applications in other fields such as cosmetics16,17 and agriculture18,19 among others.These diverse applications have led to a sustained interest in lipid-based materials as seen by the more or less steady increase in journal publications(Figure 2).Growth in patent publications have been more modest indicating unmet commercial potential(Figure 2).In the present report we showcase our findings with regards to publication trends from extensive analysis of more than 46,000 documents(journals and patents)spanning across two decades(2003-2023)in the field of lipid-based materials from the CAS Content Collection.In addition to a publication trend overview,we also identified emerging materials in the field and their applications.Figure 2.Number of journal and patent publications per year in the field of lipid-based materials(shown as blue and yellow bars respectively)over the period of the last two decades(2003-2023).*The data for 2023 only include months from Jan to Aug.JournalPatent200320042005200820072006200920102011201220202019201820172016201520142013202320222021Publication year05001,0001,5002,000Number of publications*2,5003,0003,500Trailblazing the future with emerging biomaterials|31Journal and patent publication trendsFrom the top 150 organizations in terms of volume of journal publications,we identified leading organizations involved in research related to lipid-based materials on the basis of average number of citations per publications.Nearly half of the top 15 organizations originate in the USA which is followed closely by China contributing 4 institutions(Figure 3).The University of Alberta,the only organization originating in Canada leads the pack with an average number of citations per publication of 160(Figure 3).One such highly cited article from the University of Alberta titled“Spray-freeze-dried liposomal ciprofloxacin powder for inhaled aerosol drug delivery”describes the formation and characterization of liposomal-encapsulated ciprofloxacin,a broad-spectrum antibiotic designed to be delivered via inhalation to prevent bacterial infections.20The trends in geographical distribution of patent assignees separated into commercial and non-commercial organizations show a high degree of overlap,a trend echoed in other biomaterials addressed in this report(Figure 4).Across both categories,the USA and China dominate with the former contributing greater numbers of patent publications in terms of commercial organizations.On the other hand,non-commercial organizations in the USA and China have published similar numbers of patent documents.Other important/key countries or regions in terms of volume of patent publications include:Germany(DEU),Japan(JPN),the Republic of Korea(KOR),France(FRA),Italy(ITA),India(IND)and Switzerland(CHE).More than 65%of the leading commercial organizations involved in research in lipid-based materials originate in the USA.Patents from ModernaTX,a biotechnology company from the USA,appear to be related to the use of lipid nanoparticles to deliver active payloads including drug molecules,proteins and mRNA for the treatment of cancer and other disorders(WO2021243207A1,21 WO2023076605A122)as well as development and delivery of vaccines(WO2018170260A1,23 WO2023154818A124).Other US based companies such as Codiak Biosciences and Transdermal Biotechnology have filed patent applications relating to the use of lipid-based materials such as exosomes for drug and vaccine delivery(WO2023056468A1,25 WO2020191361A226)and transdermal delivery(US20160136169A127)and wound healing(WO2014159986A228),respectively.The Japanese company,Konica Minolta Medical&Graphic,Inc.appears to have been more active in the late 2000s and was focused on the Figure 3.The top 15 research institutions in terms of average citation numbers per journal publication between 2003-2023.delivery of X-ray contrast agents using liposomes(JP200520654029)and the use of liposomes in photodynamic therapy(EP2374825A130).Lipotec,a Spanish company,has explored the use of liposomes in cosmetics(US20130078295A1,31 EP2740484A1,32)such as for the delivery of peptides and botulinum toxin.Distribution for the top 15 commercial organization appears to split between China and the USA with 9 organizations originating in China(Figure 5).Among the non-commercial organizations in China,Shenyang Pharmaceutical University leads with 90 patent publications,closely followed by China Pharmaceutical University.Patents by Shenyang Pharmaceutical University appear to be centered around manufacturing liposomes(CN102552142A33)as well as their application in drug delivery(WO2021043231A134)especially cancer therapy(CN109718228A,35 CN116440287A36).Examples of patent publications by China Pharmaceutical University include designing remdesivir liposomes to be administered by inhalation route(CN111991375A37),liposomes for targeted delivery(CN111001011A38),as well as other drug delivery applications(CN107837234A39).Patent documents filed by the University of California seem to be related to use of lipid nanocarriers for drug delivery for cancer immunotherapy(WO2021076630A140)as well as Alzheimers disease(WO2018081085A141)and viral infections(WO2021207632A142).The overall growth in patent publications across the last decade shows a positive upward trend pronounced more so for the USA,China,the Republic of Korea,Germany,and India(IND)(Figure 5A).On the other hand,Italy and France display a more modest growth in patents over the last decade.Despite this upward trend,the actual number of patents for lipid-based materials is relatively low.Detailed analysis of patent family data showing the complex flow of patents from patent assignee countries or regions(left)to the patent office wherein the first application in a given family is filed(center)and the patent office where the individual patent publication activity takes place(right)is shown in Figure 5B.Unlike other biomaterials,for patents related to lipid-based materials a majority of applications were first filed at the European Patent Office(EPO).This is especially true for the USA,Germany,Japan,Canada,Israel(ISR)and the United Kingdom(GBR)wherein nearly half of the patent applications were filed at the EPO first(Figure 5B).In contrast,patent applications originating from China and Spain(ESP)appear to show only a minor preference for home office(CHN)and EPO,respectively,while a majority of the patents were filed more or less evenly across WIPO,their respective home offices as well as other patent offices across the world(Figure 5B).For USA,the rest of the patent application filings are split between their home office(US)and the World Intellectual Patent Office(WIPO).In terms of the final destination patent office,more than a third of the patents initially filed at the EPO make their way to the United States Patent Office(USA)followed by the EPO itself.Other important/key/major destinations offices include the Japanese,Canadian,Chinese,Korean,Indian,Spanish,Mexican,and Brazilian patent offices.Trailblazing the future with emerging biomaterials|33Figure 4.Geographical distribution(top panel)and leading patent assignees in the field of lipid-based materials in terms of numbers of patent publications between 2003-2023.Patent assignees have been separated in to two groups:commercial and non-commercial.Bar graphs have been color coded by country/region to match color scheme used in donut charts.Standard three letter codes used to represent countries/regions.(A)USA:23,286CAN:1,743CHN:1,100ITA:931JPN:2,210CHE:1,139GBR:1,052FRA:1,371USA:11.308CHN:2,485EUR:5,398CAN:3,218JPN:3,255BRZ:853KOR:1,362MEX:804ESP:869IND:1,236OTH:4,267(B)Publication yearNumber of patent publications2011-20122013-20142015-20162017-20182019-20202021-2022ITADEUINDFRA5004000800200USACHN04080120160KORISR:1,134ESP:833EPO:18,024US:8,771WIPO:4,846CHN:1,560ESP:660CAN:711JPN:722Others:1,212DEU:586FRA:440ITA:264JPN2011-20122013-20142015-20162017-20182019-20202021-2022DEU:2,997Figure 5.(A)Growth in patent publications over the last decade(2011-2022)in the field of lipid-based materials.(B)Sankey graph depicting flow of patent families in the lipid-based materials field between assignee countries(left),office where the first application in a family is filed(center)and the office where individual patent publication activities take place(right).Trailblazing the future with emerging biomaterials|35Key materials,forms and applicationsA detailed and comprehensive exploration of our document and substance data from the CAS Content Collection aided in the identification of key materials across three major categories utilized in the development and application of lipid-based materials.Broadly speaking,these include:Lipids Payloads EmulsifiersFigures 6 and 7 show a detailed breakdown of materials across these categories.The category of lipids was further sub-classified into the following general classes:Sphingolipids Sterols Phospholipids Glycerides Cationic lipids Oil and waxes PEG-lipid conjugates In order to identify lipids that have seen an increase in interest over time,we plotted the relative publication growth rates for 50 lipids over 2012-2023 and used this information to shortlist key lipids shown in Figure 8.The biggest takeaway from our data analysis was that of the identified lipids,cationic lipids such as 2,3-dioleyloxy-N-2-(sperminecarboxamido)ethyl-N,N-dimethyl-1-propanaminium(DOSPA;CAS number:282533-23-7),dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium(DMRIE;CAS number:153312-64-2),1,2-dioleoyl-sn-glycero-3-ethylphosphocholine(EDOPC;CAS number:183283-20-7)and dioctadecylamidoglycylspermine(DOGS;CAS number:124050-77-7)and the PEG-lipid conjugate DMPE-mPEG(CAS number:474922-82-2)show a sharp increase in publications post 2018(Figure 8A).Phospholipids such as 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine(DOPE,CAS number:4004-05-1)and 1,2-dioleoylphosphatidylserine(DOPS,CAS Number:70614-14-1)and sphingomyelin(CAS number:85187-10-6),a sphingophospholipid,also show an increase in publications after 2018 but the increase was of a more modest magnitude as compared to the cationic lipids listed above(Figure 8A).Finally,publications related to the phospholipid 1,2-dierucoyl-sn-glycero-3-phosphatidylcholine(DEPC,CAS number:51779-95-4)grew rapidly from 2018 to 2020 and then appears to have plateaued(Figure 8A).During the COVID-19 pandemic,a number of lipids were utilized in the delivery of vaccines being developed.The growth in interest(in terms of relative growth in publications)for these diverse lipids belonging to classes such as cationic lipids,PEG-lipid conjugate,phospholipids and sterols are shown in Figure 8B.Of particular note are the cationic lipids ALC-0315(CAS number:2036272-55-4)and SM-102(CAS number:2089251-47-6)and the PEG-lipid conjugates 2-(Polyethylene glycol)-2000-N,N-ditetradecylacetamide(ALC-0159,CAS number:18496164-2-7)and DMG-PEG(CAS number:160743-62-4)which show a 5-6-fold and 3-fold increase in publications,respectively.The above-mentioned lipids can all be utilized to form various types of lipid nanocarriers including liposomes,lipid nanoparticles,exosomes,and emulsions,among others.We conducted a systematic search for the various types of lipid nanocarriers and their associated terms and showcase their distribution and growth in the lipid-based materials document dataset in Figure 9.Liposomes,consisting of vesicles,PEGylated,echogenic,stimuli-responsive,and bubble liposomes account for more than half while lipid nanoparticles comprising of solid nanoparticles(solid NPs),nanostructured lipid carriers(nanostructured LCs),ethosomes,cubosomes,and hexosomes account for a quarter of publications of the overall distribution(Figure 9A).Exosomes,a type of nanosized vesicles enclosed by a lipid bilayer membrane that can be used as drug delivery systems,and emulsions account for about 12%and 10%of publications.Virus-like particles(VLPs),well-ordered complex structures composed of viral proteins that do not retain the pathogenicity of viruses,have been increasing explored in nanomedicine.43,44 While first discovered in the late 1960s,45 the use and exploration of VPNs appears to have proceeded in a modest fashion and accounts for a small fraction of overall publications in our dataset.Noteworthy,recently a selective endogenous encapsulation platform for cellular delivery has been developed based on mammalian capsid protein homologs that form virus-like particles,and a long terminal repeat retroviral-like protein,which preferentially binds and facilitates vesicular secretion of its own mRNA.46 This modular platform,engineered to package,secrete,and deliver specific RNAs,has been demonstrated to be suitable for development as an efficient therapeutic delivery unit,which potentially provides an endogenous vector for RNA-based gene therapy.In terms of growth and time trends,among the subtypes of liposomes,stimuli-responsive liposomes47,48 show a sharp growth after 2016 while vesicles show a more controlled/modest but sustained growth for the last two decades(Figure 9B).Interest in PEGylated liposomes49 appears to be more or less steady with neither a sharp increase nor decrease.Finally,echogenic and bubble liposomes appear to show a slight decline in interest around the same time(i.e.,post 2018)however the volume of publications associated with these subtypes are much smaller than the others.The diverse stimuli that have been utilized in the context of lipid nanocarriers can be broadly categorized into exogenous and endogenous with the former accounting for nearly 2/3rd of publications related to stimuli-induced release(Figure 10A).Of the various exogenous stimuli magnetic field based50,51 and light or photosensitive/photo responsive52 release systems appear to be more popular than temperature53 and ultrasound54,55 based signaling.In terms of growth over time,publications related to endogenous stimuli,especially enzyme56,57 and redox,58,59 appear to show a sharp growth after 2014(Figure 10B)while those related to pH60 showed a more modest increase.Publications relate
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Unveiling the Potential of Biosimilars:Past Achievements and Future P2ContentsIntroduction3Biosimilars versus generics3Advantages of biosimilars3Global distribution of biosimilars approvals(5 years)4The first biosimilar9Change in regulatory guidelines for the approval process10Interchangeable biosimilars10Sales analysis of reference biologic post biosimilar launch(2019-2023)11Comparative account of Year-Over-Year sales of reference products16Global distribution of launched biosimilars18Key players in the market for launched biosimilars19The next wave of biosimilars20Global distribution of upcoming biosimilars27Key players in the upcoming market29Conclusion30References32Unveiling the Potential of Biosimilars:Past Achievements and Future Prospects IntroductionBiosimilars are safe and effective treatment options for many illnesses,such as chronic skin and bowel diseases(like psoriasis,irritable bowel syndrome,Crohns disease,and colitis),arthritis,kidney conditions,and cancer.These medicines are very close in structure and function to biologic medicines and increase access to lifesaving medications at potentially lower costs.They are highly similar to a biologic medication already approved by a regulatory body the original biologic(also called the reference product).Both a biosimilar and its original biologic:Are made from the same types of sources(e.g.living sources)Provide the same benefits when treating diseases or medical conditions Are provided at the same strength and dosage Are not expected to cause new or worsening side effectsBiosimilars versus genericsBiosimilars and Generics are alternate versions of medications that are already approved by a regulatory body,but these two types of medicines show some significant differences:Advantages of biosimilars Biosimilars provide a lower-cost option to replace original-brand products Improve access to patients when compared to the reference biologics Provide more treatment options for patients with serious and life-threatening diseases Similarly effective as the reference biological medicines3BiosimilarsGenericsGenerally made from living organismsVERSUSGenerally made from chemicalsRequire a specialized processHave a simpler process to copyVery similar but not identical to original biologicCopy of brand-name drugsFaster development process using public information from original biologic approvalFaster development process using public information from brand-name drug approvalUsually less expensive than original biologicUsually less expensive than brand-name Unveiling the Potential of Biosimilars:Past Achievements and Future ProspectsGlobal distribution of biosimilars approvals(5 years)In recent years,biosimilars have gained significant attention and importance in healthcare,particularly in the United States and Europe.These biological products,which are highly similar to reference biologic medicines,offer increased access to cost-effective treatments and can potentially lower healthcare expenditures.In 2019,the United States witnessed a remarkable number of biosimilars being approved,which resulted in the Food and Drug Administration(FDA)granting marketing authorization to a record-breaking number of these products(10).These FDA approvals covered various therapeutic areas,including oncology,immunology,and endocrinology.The greater availability of biosimilars in the United States is expected to enhance competition,potentially leading to reduced healthcare costs and increased patient access to critical biological treatments.The European Medicines Agency(EMA)has been involved in the approval of biosimilars in Europe since 2006.Europe has been at the forefront of biosimilar adoption,with the highest number of biosimilar approvals observed in previous years.As of 2021,the European Union has continued to see a significant number of biosimilar approvals(9),with numerous products gaining authorization for use.In the last five years the US FDA and EMA have approved 28 and 30 biosimilars respectively(Table 1 and Table 2).The highest number of biosimilars have been approved for cancer(19),followed by immunological disorders(17).4Biosimilars approved in 5 yearsFig.1:Yearly trend of biosimilars approved from 2019-2023 in US and EUTable 1:Approved biosimilars in USA(5 Years)02468101220192020202120222023Number of drugs aaprovedYearUSAEuropeNameCompany NameFDA Approval dateActemra(tocilizumab)biosimilarsTofidence(tocilizumab-bavi)Biogen Inc.29-Sep-23Avastin(bevacizumab)biosimilarsAvzivi(bevacizumab-tnjn)Bio-Thera Solutions,Ltd.6-Dec-23Vegzelma(bevacizumab-adcd)Celltrion,Inc.27-Sep-22Unveiling the Potential of Biosimilars:Past Achievements and Future Prospects 5NameCompany NameFDA Approval dateAlymsys(bevacizumab-maly)Amneal Pharmaceuticals,Inc.13-Apr-22Zirabev(bevacizumab-bvzr)Pfizer Inc.27-Jun-19Enbrel(etanercept)biosimilarsEticovo(etanercept-ykro)Samsung Bioepis Co.,Ltd.25-Apr-19Herceptin(trastuzumab)biosimilarsKanjinti(trastuzumab-anns)Amgen Inc.13-Jun-19Trazimera(trastuzumab-qyyp)Pfizer Inc.11-Mar-19Ontruzant(trastuzumab-dttb)Samsung Bioepis Co.,Ltd.18-Jan-19Humira(adalimumab)biosimilarsYuflyma(adalimumab-aaty)Celltrion,Inc.23-May-23Idacio(adalimumab-aacf)Fresenius Kabi13-Dec-22Yusimry(adalimumab-aqvh)Coherus BioSciences,Inc.17-Dec-21Hulio(adalimumab-fkjp)Mylan Pharmaceuticals Inc.6-Jul-20Abrilada(adalimumab-afzb)Pfizer Inc.15-Nov-19Hadlima(adalimumab-bwwd)Samsung Bioepis Co.,Ltd.23-Jul-19Lantus(insulin glargine)biosimilarsRezvoglar(insulin glargine-aglr)Eli Lilly and Company17-Dec-21Lucentis(ranibizumab)biosimilarsCimerli(ranibizumab-eqrn)Coherus BioSciences,Inc.2-Aug-22Byooviz(ranibizumab-nuna)Samsung Bioepis Co.,Ltd.17-Sep-21Neulasta(pegfilgrastim)biosimilarsStimufend(pegfilgrastim-fpgk)Fresenius Kabi USA,LLC1-Sep-22Fylnetra(pegfilgrastim-pbbk)Amneal Pharmaceuticals,Inc.26-May-22Nyvepria(pegfilgrastim-apgf)Pfizer Inc.10-Jun-20Ziextenzo(pegfilgrastim-bmez)Sandoz Inc.4-Nov-19Neupogen(filgrastim)biosimilarsReleuko(filgrastim-ayow)Kashiv BioSciences,LLC25-Feb- Unveiling the Potential of Biosimilars:Past Achievements and Future Prospects6NameCompany NameEMA Approval dateAvastin(bevacizumab)biosimilarsAbevmyMylan(now Viatris)21-Apr-21Alymsys(Bevacizumab-maly)mAbxience Research26-Mar-21AybintioSamsung Bioepis19-Aug-20OnbevziSamsung Bioepis11-Jan-21Oyavas(Bevacizumab-maly)Stada Arzneimittel26-Mar-21VegzelmaCelltrion Healthcare17-Aug-22ZirabevPfizer14-Feb-19Humira(adalimumab)biosimilarsAmsparity(Adalimumab-afzb)Pfizer13-Feb-20Hukyndra(Adalimumab-EVA)Alvotech/Stada Artnimettel15-Nov-21Idacio(adalimumab-aacf)Fresenius Kabi2-Apr-19YuflymaCelltrion Healthcare11-Feb-21Libmyris(Adalimumab-EVA)Alvotech/Stada Artnimettel12-Nov-21Soliris(Eculizumab)biosimilarsBekemvAmgen24-Feb-23EpysqliSamsung Bioepis31-Mar-23NameCompany NameFDA Approval dateRemicade(infliximab)biosimilarsAvsola(infliximab-axxq)Amgen Inc.6-Dec-19Rituxan(rituximab)biosimilarsRiabni(rituximab-arrx)Amgen Inc.17-Dec-20Ruxience(rituximab-pvvr)Pfizer Inc.23-Jul-19Stelara(ustekinumab)biosimilarsWezlana(ustekinumab-auub)Amgen Inc.31-Oct-23Tysabri(natalizumab)biosimilarsTyruko(natalizumab-sztn)Sandoz Inc.24-Aug-23Table 2:Approved biosimilars in Europe(5 Years)Unveiling the Potential of Biosimilars:Past Achievements and Future Prospects 7NameCompany NameEMA Approval dateLucentis(ranibizumab)biosimilarsByoovizSamsung Bioepis18-Aug-21Ranivisio(ranibizumab-eqrn)Bioeq/Teva Pharma25-Aug-22XimluciStada Arzneimittel/Xbrane Biopharma9-Nov-22Neulasta(pegfilgrastim)biosimilarsCegfila(previously Pegfilgrastim Mundipharma)Mundipharma Biologics19-Dec-19GrasustekJuta Pharma(USV)20-Jun-19Nyvepria(Pegfilgrastim-apgf)Pfizer18-Nov-20Stimufend(Pegfilgrastim-fpgk)Fresenius Kabi24-Mar-22NovoRapid(insulin aspart)biosimilarsInsulin aspart SanofiSanofi-Aventis25-Jun-20Kirsty(previously Kixelle)Biocon/Viatris(formerly Mylan)5-Feb-21Truvelog Mix 30Sanofi-Aventis1-Apr-22Forsteo(teriparatide)biosimilarsLivogivaTheramex Ireland27-Aug-20SondelbayAccord Healthcare24-Mar-22Enbrel(etanercept)biosimilarsNepextoMylan25-May-20Rituxan(rituximab)biosimilarsRuxience(Rituximab-pvvr)Pfizer1-Apr-20Herceptin(trastuzumab)biosimilarsTrazimeraPfizer26-Jul-18ZercepacAccord Healthcare27-Jul-20Although the biosimilar pathway has seen numerous successes,the market has witnessed a few setbacks in the form of voluntary market withdrawal of some biosimilar drugs by the sponsors.For instance,Boehringer Ingelheim developed and received marketing approval from the EMA for an adalimumab biosimilar(Cyltezo).However,the company notified the European Commission of its decision not to market the product in the EU for commercial reasons,resulting in withdrawal of the marketing authorization from the EU.Similarly,the marketing authorization for Equidacent(bevacizumab biosimilar)was withdrawn at the request of Centus Biotherapeutics.Further examples are listed in Table Unveiling the Potential of Biosimilars:Past Achievements and Future Prospects8Product nameActive substance Market withdrawal dateCompany nameCyltezoadalimumab15-Jan-19Boehringer IngelheimEquidacentbevacizumab23-Nov-21Centus BiotherapeuticsHalimatozadalimumab29-Jan-21SandozInpremziainsulin human20-Apr-23BaxterKromeyaadalimumab17-Dec-19Fresenius KabiLextemybevacizumab14-Dec-21Mylan(now Viatris)Qutavinateriparatide18-Jan-21EuroGenerics HoldingsRitemviarituximab16-Aug-21CelltrionRituximab Mabionrituximab16-Mar-20MabionRituzena(previously Tuxella)rituximab10-Apr-19CelltrionSolymbicadalimumab5-Mar-19AmgenThorinaneenoxaparin sodium24-Oct-19PharmathenUdenycapegfilgrastim15-Feb-21ERA Consulting(Coherus Biosciences)Table 3:List of biosimilars voluntarily withdrawn by sponsors in EuropeUnveiling the Potential of Biosimilars:Past Achievements and Future Prospects 9The first biosimilarThe EU was the first region in the world to define a policy and legal framework for the approval of biosimilar medicines.With the legal framework for biosimilars having been established,the EMA,together with the Committee for Medicinal Products for Human Use(CHMP),the Biotechnology Working Party,and the Working Party on Similar Biological Medicinal Products released specific guidelines to deal with all aspects of the development,production,testing,and regulation of biosimilar medicines.Omnitrope(Sandoz)was the first biosimilar medicine to be approved and introduced on the European market.Approved in 2006 by the European Medicines Agency(EMA),Omnitrope is a biosimilar version of the previous reference medicine,Genotropin(somatropin).It is used for the treatment of growth disorders in children and adults caused by inadequate or deficient growth hormone production.To gain regulatory approval,Omnitrope underwent a rigorous development process.Extensive physicochemical and biological characterization,as well as non-clinical and clinical studies,were conducted to demonstrate its comparability to Genotropin.These studies included assessments of pharmacokinetics,pharmacodynamics,and immunogenicity.The results showed no clinically meaningful differences between Omnitrope and Genotropin.Omnitrope and subsequent biosimilars have had the potential to revolutionize healthcare by expanding access to effective and safe biological therapies to a broader patient population.However,it is crucial to maintain robust regulatory frameworks to ensure the quality,safety,and efficacy of these biosimilar Unveiling the Potential of Biosimilars:Past Achievements and Future Prospects10Change in regulatory guidelines for the approval processOver the years,there have been several regulatory guideline changes for the approval of biosimilars.Some of the challenges faced in the old guidelines of biosimilar approval include:Lack of Regulatory Pathway:Earlier there was no specific regulatory pathway for the approval of biosimilars Complex Molecular Structure:The complexity of biosimilar manufacturing processes and structure made it challenging to establish similarity to the reference biologic Clinical Development:Conducting clinical trials to demonstrate the safety and efficacy of biosimilars was challenging Extrapolation of Indications:Determining whether biosimilars can be extrapolated to different indications without conducting clinical trials for each specific indication was a challenge Reference Product Availability:Obtaining and accessing the reference biologic for comparative studies was difficult,especially when the reference product was still under patent protection Interchangeability and Substitution:There were uncertainties regarding the rules and regulations for interchangeability and substitution of biosimilars with reference biologics.This created challenges for healthcare providers and patients in adopting biosimilars Naming and Pharmacovigilance:The lack of a distinct naming system for biosimilars created challenges in differentiating them from reference biologics in pharmacovigilance,traceability,and adverse event reportingWith the advent of the interchangeable biosimilars,the guidelines for these products have undergone some changes.Below are a few changes:Currently,the guidelines outline the criteria and standards that biosimilar manufacturers need to meet to demonstrate interchangeability,which includes conducting additional studies to demonstrate that the biosimilar can be used interchangeably with the reference product without compromising the safety or efficacy for patients These guidelines now provide specific requirements for the labeling of interchangeable biosimilars The approval of interchangeable biosimilars has raised the possibility of automatic substitution by pharmacists without the need for specific prescriber approval(*as per the regulations and laws of individual countries or regions)Presently,robust pharmacovigilance programs are required to monitor the safety and effectiveness of interchangeable biosimilars after launch.Interchangeable biosimilars in the USAn interchangeable product is a biological product that meets all the requirements for a biosimilar product but also meets additional requirements outlined by the Biologics Price Competition and Innovation Act.These products may be replaced at the pharmacy level without the involvement of the healthcare provider who has prescribed the reference product.To date,there are five interchangeable biosimilars approved by the US FDA.Unveiling the Potential of Biosimilars:Past Achievements and Future Prospects 11Table 4:Interchangeable biosimilars along with their therapeutic focus.In addition to the products detailed in the above table,the following is a list of biologics which are pursuing interchangeable status,along with their involved companies:Table 5:Companies and their respective biosimilars pursuing interchangeable biosimilars statusSales analysis of reference biologics post biosimilar launch(2019-2023)To identify the impact the launch of a biosimilar has on the sale of its reference drug,we identified drugs that have seen one or more biosimilars launched recently and analyzed the impact of their launch on the cumulative sales of the reference drug.We identified nine drugs that recently saw the launch of related biosimilars:Rituximab,Adalimumab,Alteplase,Darbepoetin alfa,Insulin aspart,Ranibizumab,Denosumab and Tocilizumab.We compiled the sales revenue generated by the sale of the drugs from company disclosed financial reports and SEC filings.For some countries,the company had not disclosed the full sales data for 2023.Hence,our coverage stops at the last available disclosed data.The following is a short analysis of each drug:Rituximab(Rituxan)Rituximab,originally developed by Biogen,was launched as Rituxan for Non-Hodgkins lymphoma in 1997.Rituximab captured a high market share due to the companys policy of actively launching the drug in other indications(such as thrombotic thrombocytopenic purpura,systemic scleroderma,pemphigus vulgaris,etc.)along with proactive expansion in the launched territories.The first biosimilar(Truxima)became available on the market in October 2019,which did not seem to affect sales drastically in 2019.However,the launch of RUXIENCE and RIABNI in 2020 and 2021 respectively,lead to the drug demonstrating extreme downward trends.The drug registered a Year-Over-Year(YoY)percentage sales decline of-74.40%and-64.95%in 2020 and 2021 Unveiling the Potential of Biosimilars:Past Achievements and Future ProspectsInterchangeable biosimilarReference biologicInterchangeable status approvalTherapeutic FocusSemglee(insulin glargine-yfgn)Lantus(insulin glargine)2021DiabetesCyltezo(adalimumab-adbm)Humira(adalimumab)2021Autoimmune disordersCimerli(ranibizumab-eqrn)Lucentis(ranibizumab)2022Eye conditionsRezvoglar(insulin glargine-aglr)Lantus(insulin glargine)2022DiabetesWezlana(ustekinumab-auub)Stelara(ustekinumab)2023Multiple inflammatory diseasesCompanyReference biologicBiosimilarAlvotechHumiraAVT02CelltrionHumiraYuflymaPfizerHumiraAbrilada(adalimumab-afzb)Samsung BioepisHumiraHadlima(adalimumab-bwwd)12Sales analysis of Rituximab(5 years)Sales analysis of Adalimumab(5 years)Fig 2:Sales data by year(in$USD billions)of Rituximab along with its YoY percentage change in revenueFig 3:Sales data by year(in$USD billions)of Adalimumab along with its YoY percentage change in revenue-0.8-0.6-0.4-0.200.20.40246810121416182020192020202120222023YoY percentage sale changeSales of drugs(in$USD billions)YearsSales per yearPercentage changeAdalimumab(Raheara;Humira)Adalimumab(Raheara and Humira),is a monoclonal IgG1 antibody specific for tumour necrosis factor(TNF)-alpha developed by AbbVie and AstraZeneca.It is launched worldwide for the treatment of rheumatoid arthritis,juvenile rheumatoid arthritis,psoriatic arthritis,spondylarthritis,ankylosing spondylitis,axial spondyloarthritis,plaque psoriasis,Crohns disease and ulcerative colitis.The patents on Humira expired in Europe in Oct 2018 and the first adalimumab biosimilar,Hulio(Mylan)was launched in Oct 2018.A downward trend in Humira sales in Europe were observed following the entry of biosimilars in Europe though the overall market sales were high due to high demand and absence of any Humira biosimilars in the US.Although the composition of matter patent covering Humira expired in December 2016 in the US,the non-composition of matter patents covering Humira expire no earlier than 2022.Therefore,AbbVie has made settlement agreements with Amgen and Samsung Bioepis delaying the launch of Humira biosimilars in the US until January 2023.The year-on-year sales analysis of adalimumab seems to show a downward trend which has taken sharper falls recently.Following the launch of its biosimilar drugs in the EU and rest of the world,the reference drug has experienced a significantly decreased revenue,with 2021 and 2022 reporting roughly similar amounts.The least revenue in the last five years was observed in 2023 following the launch of Humira biosimilars in the US market in 2023.-0.4-0.3-0.2-0.100.10.20.30.4051015202520192020202120222023YoY percentage sale changeSales of drugs(in$USD billions)YearsSales per yearPercentage changeUnveiling the Potential of Biosimilars:Past Achievements and Future Prospects Unveiling the Potential of Biosimilars:Past Achievements and Future ProspectsSales analysis of Alteplase(5 years)Fig 4:Sales data by year(in$USD billions)of Alteplase along with its YoY percentage change in revenueAlteplase(Actilyse;Activacin;Activase;Cathflo;GRTPA)Alteplase(Actilyse;Activacin;Activase;Cathflo;GRTPA)is a recombinant tissue plasminogen activator developed by Boehringer Ingelheim.It is launched worldwide for the treatment of catheter thrombosis,myocardial infarction,pulmonary embolism and stroke in 1988.With the prevalance of cardiovascular diseases increasing,the cost of alteplase has more than doubled over the past decade leading to a concomitant increase in its global revenue.The company reported a steady increase in 2023 with a revenue of$USD 2.2 billion.Though the first Alteplase biosimilar(Reveliza)was launched in 2021 in Russia,there is a high demand in the major markets like US and Europe for a more affordable alternative to alteplase.00.020.040.060.080.10.121.61.71.81.922.12.22.320192020202120222023YoY percentage sale changeSales of drugs(in$USD billions)YearsSales per yearPercentage changeDarbepoetin alfa(Nesp;Nespo;Aranesp)Darbepoetin alfa,developed by Kyowa Kirin and Amgen,has been available in the market for anaemia under the brand names Nesp,Nespo and Aranesp.It is a long-acting erythropoiesis-stimulating glycoprotein which has half-life three-fold longer than that of Erythropoietin alfa(EPO).Its first biosimilar(Cresp)was launched in India by Dr.Reddys in 2010 followed by launch of Actorise by Hetero Drugs and Darbatitor by Torrent in China in 2014.A biosimilar was also launched in Japan by Dong ST in 2019.Subsequently,the drug has experienced a significant downward trend in global revenue in the past 5 years.Both 2022 and 2023 sales data till September demonstrated an annual sales figure of roughly$USD 1.1 billion which is a dip of 29%in revenue.14Sales analysis of Insulin aspart(5 years)Fig 6:Sales data by year(in$USD billions)of Insulin aspart along with its YoY percentage change in revenueInsulin aspart(NovoLog;NovoRapid)Insulin aspart,originally developed by Novo Nordisk,has been available in the market since 1999 under the brand names NovoLog and NovoRapid for the treatment of Type-1 and 2 diabetes mellitus.The global sales of insulin aspart have shown a decreasing trend owing to the presence of many competing products for treatment and management of diabetes mellitus.The first biosimilar of Insulin aspart,Rapilin,has been available in China since 2021 followed by RinFast(GEROPHARM)in Russia and Kixelle(Biocon)in Canada in 2021 and 2023 respectively.The stiff competition is evident in the drugs annual gross revenue,with decreased earnings showing every year.In the data frame we considered,the drug had yielded$USD 2.61 billion in 2019 which has dropped to$USD 1.91 billion in 2023.-0.12-0.1-0.08-0.06-0.04-0.02000.511.522.520192020202120222023YoY percentage sale changeSales of drugs(in$USD billions)YearsSales per yearPercentage changeSales analysis of Darbepoetin alfa(5 years)-0.35-0.3-0.25-0.2-0.15-0.1-0.05000.20.40.60.811.21.41.61.8220192020202120222023YoY percentage sale changeSales of drugs(in$USD billions)YearsSales per yearPercentage changeFig 5:Sales data by year(in$USD billions)of Darbepoetin alfa along with its YoY percentage change in revenueUnveiling the Potential of Biosimilars:Past Achievements and Future Prospects Unveiling the Potential of Biosimilars:Past Achievements and Future ProspectsSales analysis of Ranibizumab(5 years)Fig 7:Sales data by year(in$USD billions)of Ranibizumab along with its YoY percentage change in revenue-0.35-0.3-0.25-0.2-0.15-0.1-0.0500.050.100.511.522.533.544.520192020202120222023YoY percentage sale changeSales of drugs(in$USD billions)YearsSales per yearPercentage changeRanibizumab(Lucentis;ACCENTRIX)Ranibizumab(Lucentis;ACCENTRIX)a humanized recombinant monoclonal antibody targeting vascular endothelial growth factor A(VEGF-A),was developed by Novartis and Chugai pharmaceuticals.The drug was initially launched for wet age-related macular degeneration in 2006 and later for choroidal neovascularisation,degenerative myopia,diabetic macular oedema,diabetic retinopathy,retinal oedema and retinopathy of prematurity.The first biosimilar,Ranibizumab-BS,was launched by Kidswell Bio and Senju Pharmaceutical in Japan in 2021,while BYOOVIZ was made available in the US,Canada,Germany by Samsung Bioepis in 2022.Ranibizumab biosimilars offer a promising avenue for the management of retinal diseases,especially in countries with lower socioeconomic status,where there is a lack of availability of innovator ranibizumab.The drug has faced stiff competition from multiple biosimilars launches that brought down the annual sales revenue for the drug from$USD 4 billion to$USD 2 billion,a 50crease in the market base,suggesting the pronounced impact the launch of the biosimilars has had on the sale of its reference drug.16Sales analysis of Denosumab(5 years)Fig 8:Sales data by year(in$USD billions)of Denosumab along with its YoY percentage change in revenueDenosumab(PRALIA;Prolia;Ranmark;Xgeva)Denosumab is a fully human monoclonal antibody that targets the receptor activator of NF-B ligand(RANKL),being developed by Amgen and marketed by various organizations across the world.The drug was launched in 2021 under the brand names PRALIA;Prolia;Ranmark and Xgeva.The first biosimilar DenosuRel was launched in India by Reliance LifeSciences in 2022 and the impact of it can be seen in the sales figures of the drug.While prior to 2022 the drug was reporting a YoY increase in revenue yield,in 2023 the drug registered a decrease in sales value for the first time.However,it is to be noted here that Amgen has only disclosed the sales data for the drug through the third quarter of 2023(i.e.September 2023)so the final data could provide different results.The denosumab biosimilars will enter the major markets in 2025 since patents on Prolia/Xgeva will expire in the US on 19th February 2025 and will expire in Europe on 25th June 2022,except for France,Italy,Spain and the UK,where they will expire in 2025.Tocilizumab(RoActemra;Actemra)Tocilizumab is an interleukin 6(IL-6)targeting monoclonal antibody,developed by Roche for various autoimmune diseases.The drug was launched around 2009 for giant lymph node hyperplasia and in our timeline analysis,the drug registered roughly$USD 1 billion in sales each year.The first biosimilar TOFIDENCE for the drug was launched in 2023 by Bio-Thera Solutions in China and,while the company registered a similar revenue from the drug as compared to 2022,with a minor decrease of-0.87%.Another tocilizumab biosimilar,Tyenne(MSB11456)was launched in 2023 by Fresenius Kabi in the European Union which has the potential to expand access to IL-6 inhibitors for patients with moderate to severe rheumatoid arthritis(RA),the FDAs approval of the tocilizumab biosimilar is a breakthrough in bringing high-quality,affordable,and accessible autoimmune treatment options to patients and health care providers.It will be interesting to observe the sales in the upcoming year to fully understand the impact of the Tocilizumab biosimilar in the sales figure of its reference drug.-0.25-0.2-0.15-0.1-0.0500.050.10.150.2012345620192020202120222023YoY percentage sale changeSales of drugs(in$USD billions)YearsSales per yearPercentage changeUnveiling the Potential of Biosimilars:Past Achievements and Future Prospects 17In summary,we can see that the launch of a biosimilar can have a profound impact on the sales of its reference drug.However,major players in the market have devised multiple ways to bypass the effect of biosimilars which include geographical expansion,launching the drug in a variety of new formulations along with expansion of the therapeutic focus.The sales data for all recently-approved drugs with competition from biosimilars,along with comprehensive year-on-year sales percentage data has been added below:INN nameOrganisationYear wise sales data(in$US billions)20192020202120222023Rituximab (Rituxan)Roche19.735.051.772.052.66Adalimumab(Humira)AbbVie19.215.9220.721.214.4Alteplase (Actilyse,Activase)Boehringer Ingelheim/Roche1.841.92.092.12.2Darbepoetin alfa(Aranesp;Nesp;Nespo)Amgen/Kyowa Kirin1.821.731.621.151.13Insulin aspart(NovoLog;NovoRapid)Novo Nordisk 2.612.362.232.161.92Ranibizumab(Lucentis;AMD Fab)Novartis Ophthalmics/Chugai Pharmaceutical4.173.583.73.032Denosumab(Xgeva;Prolia)Amgen4.694.625.265.644.52Tocilizumab(Actemra,RoActemra)Roche0.871.160.971.151.14Table 6:Annual sales of biologics with recently launched biosimilarsSales analysis of Tocilizumab(5 years)Fig 9:Sales data by year(in$USD billions)of Tocilizumab along with its YoY percentage change in revenue-0.2-0.100.10.20.30.400.20.40.60.811.220192020202120222023YoY percentage sale changeSales of drugs(in$USD billions)YearsSales per yearPercentage changeUnveiling the Potential of Biosimilars:Past Achievements and Future Prospects Unveiling the Potential of Biosimilars:Past Achievements and Future ProspectsChange in the percentage of sales for Rituximab and AdalimumabChange in the percentage of sales for Ranibizumab,Denosumab and TocilizumabFig 10A:Comparative analysis of YoY percentage change in revenue for Rituximab and AdalimumabFig 10B:Comparative analysis of YoY percentage change in revenue for Ranibizumab,Denosumab and TocilizumabComparative account of Year-Over-Year sales of reference products-0.8-0.6-0.4-0.200.20.420192020202120222023Percentage of sales of drugsYearsRituximabAdalimumab-0.4-0.3-0.2-0.100.10.20.30.420192020202120222023Percentage of sales of drugsYearsRanibizumabDenosumabTocilizumab19Change in the percentage of sales for Alteplase,Darbepoetin alfa and Insulin aspartGeographical distribution of launched biosimilarsFig 10C:Comparative analysis of YoY percentage change in revenue for Alteplase,Darbepoetin alfa and Insulin aspartFig.11:Geographical distribution of launched biosimilars-35.00%-30.00%-25.00%-20.00%-15.00%-10.00%-5.00%0.00%5.00.00.00 192020202120222023AlteplaseDarbepoe?n alfaInsulin aspartGlobal distribution of launched biosimilarsThe global distribution of launched biosimilars worldwide can be quite diverse,with variations in regulatory approaches,market access,and adoption rates across different regions.Detailed analysis of all the launched biosimilars revealed that India has emerged as a key player in the global biosimilar market with 81 launched biosimilars to date,due to its strong generic pharmaceutical industry,favorable regulatory environment and affordability that has improved patient accessibility to essential treatments.This is followed by the Middle East and Latin America with 46 and 44 launched biosimilars respectively.Unveiling the Potential of Biosimilars:Past Achievements and Future Prospects Unveiling the Potential of Biosimilars:Past Achievements and Future ProspectsMajor players in the marketTop 3 companiesThe following image provides an overview of the top three players with their respective available biosimilars in the market:Fig 13:Top three companies with launched biosimilars Key players in the market for launched biosimilarsBiosimilars are emerging as a significant segment within the pharmaceutical industry,providing cost-effective alternatives to biologic medicines.As the demand for biosimilars continues to grow,several key players have emerged as market leaders in this sector.According to Fig.12,Reliance Life Sciences(18),Sandoz(14)and Pfizer(13)are leading the market with the highest number of launched biosimilars.Biocon(11),Intas Pharmaceuticals(10),and Zydus Cadila(10)are also prominent contributors which have improved patient access to life-changing therapies.02468101214161820Number of Marketed biosimilarsCompaniesErelziMarketedDenosuRelTrastuRelRituxiRelAdaliRelBOW015ReliBetaEtanerRelReliGrastSomatoRelChorioRelFostiRelReliFeronTenecteRelEpostimMiRelDarberelAbcixiRellNeustimReliance LifeSciencesSandozPfzerRapilinCIMERLIAvziviHalimatozRixathonPrandilinBasalinIXIFIZiextenzoErelziFilgrastimHexalAbseamedOmnitropeLosminaMFENTRAVegzelmaYufymaRUXIENCEBlitzimaZIRABEVYUSIMRYHerzumaTRAZIMERAZESSLYNivestymLifmiorFig.12:Top 15 companies with launched biosimilars21Four years of sales dataFig 14:Annual sales(in$USD billions)of Insulin aspart(2020-2023)The next wave of biosimilarsIn the previous section we analysed how biosimilars disrupt the reference drug market.Here we will explore biosimilar drugs grouped according to their therapeutic focus and we will analyze their sales in the last four years,specifically from 2020 to 2023.We identified the following main therapeutic areas:metabolic disorders,musculoskeletal disorders,autoimmune disorders,immunological disorders,supportive care,ophthalmology,bone health,and oncology,and created an in-depth analysis for each.Metabolic disordersInsulin has been one of the most explored drugs in the biosimilar market with ongoing work to launch biosimilar for Insulin aspart(NovoLog).If we analyze the sales data of the drug for the last four years,we can see that the drug has been performing decently with an average revenue of roughly$USD 2.3 billion,with the first significant dip happening in 2023 owing to fierce competition.Musculoskeletal disordersTocilizumab,Ustekinumab,Golimumab,Etanercept,Secukinumab are currently launched for musculoskeletal disorders and their biosimilars are either launched in selected markets or to be launched in Major markets like US and Europe in the coming years.From the chart,we can observe a fluctuating sales performance for each drug across the years.Tocilizumab shows a notable peak in sales in 2021,while Ustekinumab has a consistent upward trajectory,reaching its highest sales in 2023.Golimumab displays modest sales figures without significant peaks.Etanercepts sales appear to have declined over the years,with the lowest sales recorded in 2023.Lastly,Secukinumab shows an initial increase in sales,followed by a drop in the subsequent years.These biologics are in Focus since biosimilars for tocilizumab are available in countries like China and the European Union,but not in the US where they are either awaiting launch or in late clinical development.Similarly,an ustekinumab biosimilar is launched in Canada and not in any other locations.Etanercept on the other hand has biosimilars available in many countries,yet an upcoming biosimilar SB4 has garnered interest since it is just as effective as the originator drug(Enbrel)in treating Australian patients with rheumatoid arthritis(RA).The introduction of biosimilars for these drugs could significantly impact their sales patterns.2.442.32.231.4800.511.522.532020202120222023Yearwise sales data(in$US billions)YearsUnveiling the Potential of Biosimilars:Past Achievements and Future Prospects Unveiling the Potential of Biosimilars:Past Achievements and Future ProspectsAutoimmune disordersAutoimmune diseases result when ones own immune system is overactive,causing it to attack and damage the bodys tissues.There are multiple drugs available on the market catering to different autoimmune diseases.One of these,Natalizumab,is available for the treatment of Crohns disease and multiple sclerosis.We evaluated the drugs earnings in the last four years and we can see a significant downtrend in its revenue compared to 2020-2021.Since 2022 the company has reported a 75cline in its revenue and it may get worse as the drug receives significant competition from its upcoming biosimilar counterparts.A biosimilar of natalizumab,Tyruko,is available in Germany only and was approved in the USA in 2023.Immunological disordersAn immunological disorder is a condition in which the immune system malfunctions leading to abnormal responses which may cause tissue damage and infections.Different allergies and hypersensitive reactions also fall under this broader therapeutic area.One candidate in this area is Omalizumab which has been approved for various allergies and hypersensitivity reactions.If we analyze the financial earnings of the drug we can see that the drug has been performing pretty decently in the last four years averaging a yield of roughly$USD 1.3 billion.Genolair,an omalizumab biosimilar,was launched in Russia whereas other biosimilar candidates are in late clinical development.With the entry of these biosimilars in major markets around the world,the drug may experience a significant downtrend in future global revenue.Fig 16:Annual sales(in$USD billions)of Natalizumab(2020-2023)Four years of sales data1.942.060.480.4500.511.522.52020202120222023Yearwise sales data(in$US billions)YearsFig 15:Annual sales(in$USD billions)of Tocilizumab,Ustekinumab,Golimumab,Etanercept,Secukinumab(2020-2023)Four years of sales data0246810122020202120222023Yearwise sales data(in$US billions)YearsTocilizumabUstekinumabGolimumabEtanerceptSecukinumab23Four years of sales dataFig 18:Annual sales(in$USD billions)of Pegfilgrastim(2020-2023)2.291.731.110.600.511.522.52020202120222023Yearwise sales data(in$US billions)Years?ll Sept2023Supportive careSupportive care during serious ailments like cancer is very important for the survival and recovery of patients.Pegfilgrastim is used to reduce the risk of infection while being treated with cancer medicines and is also used to improve survival in cancer patients who have been exposed to radiation.If we analyze the sales data for the drug,we can clearly see that the drug has experienced significantly decreased YoY yield.This is partly due to similar drugs available in the market and stiff competition.However,it is to be noted that data for 2023 is only provided until September i.e.the third quarter as per the final data disclosed by the company.19 biosimilars available worldwide indicate that the global pegfilgrastim biosimilars market is growing with increased prevalence of cancer.In comparison to filgrastim,pegfilgrastim provides important medical advantages,such as a 42%relative decrease in the incidence of febrile neutropenia.Pegfilgrastim continues to generate interest in the biosimilar industry as future pegfilgrastim biosimilars will provide better access to this treatment option.Fig 17:Annual sales(in$USD billions)of Omalizumab(2020-2023)Four years of sales data1.251.41.361.461.11.151.21.251.31.351.41.451.52020202120222023Yearwise sales data(in$US billions)YearsUnveiling the Potential of Biosimilars:Past Achievements and Future Prospects 4.945.799.61.440246810122020202120222023Yearwise sales data(in$US billions)Y Unveiling the Potential of Biosimilars:Past Achievements and Future ProspectsFour years of sales dataFig 19:Annual sales(in$USD billions)of Aflibercept(2020-2023)Bone healthDenosumab is a fully human monoclonal antibody that targets the receptor activator of NF-B ligand(RANKL),being developed by Amgen.The antibody is available for multiple indications worldwide,which include various bone disorders such as bone metastases,corticosteroid-induced osteoporosis,giant cell tumour of bone,male osteoporosis,malignant hypercalcaemia,postmenopausal osteoporosis as well as rheumatoid arthritis.As the drug is available in multiple therapeutic areas,this is very well captured in the drugs annual sales data registering$USD 4.5 billion revenue each year.It is to be noted that the sales data for 2023 is only limited to September 2023(i.e.third quarter)as per company disclosed information.The sale value could very well cross$USD 5 billion in 2023,which accentuates the high demand for the drug in the market.This high demand coupled with large market share induces the biosimilar development companies to take notice and develop biosimilars which can take a slice from this huge market.Denosumab biosimilars are launched in India and China,and recently in Feb 2024,the US FDA approved Wyost and Jubbonti by Sandoz as the first and only FDA-approved denosumab biosimilars to treat all indications of the reference products Xgeva and Prolia.OphthalmologyAflibercept is a fully-human recombinant fusion protein that is available in multiple eye disorder therapies,including wet age-related macular degeneration,retinopathy of prematurity,diabetic retinopathy,retinal oedema,glaucoma,diabetic macular oedema,choroidal neovascularization,retinal vein occlusion as well as colorectal cancer.The availability of the drug in so many indications is also demonstrated in their financial figures with the drug reporting a steep growth in market sales between 2020 to 2022.The year 2023 was the weakest for the drug and,with new biosimilars coming up soon,the drug may have trouble returning to its peak figure of 2022.European Commission has approved the first aflibercept biosimilar,Yesafili in March 2024.Biocon Biologics,a subsidiary of Biocon,officially announced a settlement with Bayer and Regeneron Pharmaceuticals which allows Biocon Biologics to launch Yesafili in the Canadian market.25OncologyPertuzumab is a recombinant monoclonal antibody,which inhibits HER dimerisation(HDI)for the treatment of HER2(ERBB2)-positive cancers,particularly breast cancers.The drug has been developed by Roche and the utility of a biologic cancer drug is evident in the sales figure of the drug where it has regularly achieved roughly$USD 4 billion in sales each year.This highlights the prevalence of the disease wherein the availability of biosimilars will help meet the needs of the patients at lower cost.It will be interesting to analyze how the launch of its biosimilar drug affects the sales of the reference drug here.Fig 21:Annual sales(in$USD billions)of Pertuzumab(2020-2023)Four years of sales data3.844.31.0400.511.522.533.544.552020202120222023Yearwise sales data(in$US billions)YearsFour years of sales data4.625.265.644.5201234562020202120222023Yearwise sales data(in$US billions)YearsFig 20:Annual sales(in$USD billions)of Denosumab(2020-2023)Unveiling the Potential of Biosimilars:Past Achievements and Future Prospects 26Table 7A:Pipeline of reference drugs along with their biosimilars in development Therapeutic focusMetabolic disordersMusculoskeletal disordersAutoimmune disordersImmunological disorderBiologicInsulin aspartTocilizumabUstekinumabGolimumabEtanerceptSecukinumabNatalizumabOmalizumabReference Products(Manufacturer)NovoLog(Novo Nordisk)RoActemra(Chugai Pharmaceutical)STELARA(Centocor)Shinponi(Centocor)Enbrel(Amgen)Cosentyx(Novartis)Tysabri(Elan Corporation)Xolair(Genentech)Pipeline(Manufacturer development stage)Launched PhaseRapilin30(Gan&Lee Pharmaceuticals)Kixelle(Biocon)RinFast(GEROPHARM)TOFIDENCE(Bio-Thera Solutions)Tyenne(Merck KGaA)JamtekiTM(Alvotech)13 biosimilars launchedTyruko(Polpharma Biologics)Genolair(GENERIUM Pharmaceuticals)Registered PhaseBOW-070(EPIRUS Biopharmaceuticals)Etanercept biosimilar(Rus Biopharm),Davictrel(Hanwha Chemical)Preregistered PhaseSAR-Asp(Sanofi)CT-P47(Celltrion)DMB 3115(Dong-A ST),FYB 202(Formycon),SB-17(Samsung Bioepis),Bmab 1200(Biocon)The table below highlights drugs whose biosimilars are planned to be launched very soon along with their other counterparts and their respective development stages as captured from our AdisInsight database.Unveiling the Potential of Biosimilars:Past Achievements and Future Prospects 27Therapeutic focusMetabolic disordersMusculoskeletal disordersAutoimmune disordersImmunological disorderBiologicInsulin aspartTocilizumabUstekinumabGolimumabEtanerceptSecukinumabNatalizumabOmalizumabPipeline(Manufacturer development stage)Phase IIIHS 628(Zhejiang Hisun Pharmaceutical),DRL-TC(Dr Reddys Laboratories),TEMZIVA(AryoGen Pharmed)BAT-2206(Bio-Thera Solutions),CT P43(Celltrion),QX 001S(Qyuns Therapeutics)AVT-05(Alvotech),BAT-2506(Bio-Thera Solutions)SCB 808(Clover Biopharmaceuticals),Enerceptan(Amega Biotech)BAT-2306(Bio-Thera Solutions)rhuMAb-E25(CuraTeQ Biologics),ADL-018(Adello Biologics),Xolair biosimilar(Celltrion),Aomaishu(Shanghai Zhangjiang Biotechnology),Omalizumab biosimilar(CinnaGen),TEV-45779(Teva Pharmaceutical)Phase II/IIII-004(Amphastar Pharmaceuticals)Phase IIAT-247(Arecor)QX-003S(Qyuns Therapeutics)Phase IBFI-751(BioFactura Australia)RT-111(Rani Therapeutics)SBDM-002(Shilpa Biologicals)BR 201(BioRay Pharmaceutical),CMAB-015(Mabpharm) Unveiling the Potential of Biosimilars:Past Achievements and Future Prospects28Therapeutic focusSupportive careOphthalmologyBone healthOncologyBiologicPegfilgrastimAfliberceptDenosumabPertuzumabReference Products(Manufacturer)Neulasta(Kirin-Amgen)EYLEA(Regeneron Pharmaceuticals)Xgeva(Amgen)Perjeta (Genentech)Pipeline (Manufacturer development stage)Launched Phase19 biosimilars launchedMAILISHU (Jiangsu T-mab BioPharma),Boluojia (Luye Pharma),DenosuRel (Reliance Life Sciences)Registered PhasePegfilgrastim biosimilar(Rus Biopharm),FILPEGLA(Cipla),Pegfilgrastim biosimilar(Hospira)Yesafili(Momenta Pharmaceuticals)Denosumab biosimilar(Intas Pharmaceuticals)Preregistered PhaseFYB-203(Formycon)GP-2411(Hexal)Phase IIISB-15(Samsung Bioepis),BA-9101(Shandong Boan Biotechnology)SOK583A1(HEXAL),AVT-06(Alvotech),CT-P42(Celltrion),ABP 938(Amgen),ALT L9(Alteogen),SBDM-004(Shilpa Biologicals),Aflibercept biosimilar(CinnaGen),SCD-411(Sam Chun Dang Pharm),QL1207(Qilu Pharmaceutical),9MW-0813(Mabwell(Shanghai)Bioscience)HLX 14(Shanghai Henlius Biotech),SB 16(Samsung Bioepis),RGB 14-P(Gedeon Richter),FKS-518(Fresenius Kabi),CT-P41(Celltrion),CMAB-807(Shanghai Biomabs Pharmaceuticals),QL-1206(Qilu Pharmaceutical),ENZ-215(Alkem Laboratories)QL-1209(Qilu pharmaceutical),Pertuzumab biosimilar(CinnaGen),BCD-178(Biocad),SYSA-1901(CSPC ZhongQi Pharmaceutical Technology),TQB-2440(Chia Tai Tianqing Pharmaceutical Group),HLX 11(Shanghai Henlius Biotech)Table 7B:Pipeline of reference drugs along with their biosimilars in Unveiling the Potential of Biosimilars:Past Achievements and Future Prospects29Therapeutic focusSupportive careOphthalmologyBone healthOncologyBiologicPegfilgrastimAfliberceptDenosumabPertuzumabPipeline (Manufacturer development stage)Phase IIXZP-KM118(Xuanzhu Biopharmaceutical)Phase IDYRUPEG(CuraTeQ Biologics),TX-04(Tanvex Biopharma)EG-1206A(Genentech),Pertuzumab biosimilar(Mabscale)Unveiling the Potential of Biosimilars:Past Achievements and Future Prospects Unveiling the Potential of Biosimilars:Past Achievements and Future ProspectsGlobal distribution of upcoming biosimilarsDetailed analysis of all upcoming biosimilars revealed that China is emerging as a key player in the global biosimilar market with 22 biosimilars in the pipeline,followed by the USA having 19 biosimilars in the pipeline.Fig.22:Distribution by country of upcoming biosimilarsGeographical distribution of upcoming biosimilarsNumber of upcoming biosimilars 31Snapshot of biosimilars 2023 and beyondFig.23:A roadmap of upcoming biosimilars2 0 2 92 0 2 52 0 2 42 0 2 32029Etanercept (Enbrel)2024/2025Pertuzumab (Perjeta)2024/2025Golimumab (Simponi)2024Aflibercept (Eylea)2023Pegfilgrastim (Neulasta Onpro)2023Insulin aspart (NovoLog)2029Secukinumab (Cosentyx)2025Omalizumab (Xolair)2025Denosumab (Prolia/Xgeva)2023/2024Natalizumab (Tysabri)2023/2024Ustekinumab (Stelara)2023Tocilizumab (Actemra)Unveiling the Potential of Biosimilars:Past Achievements and Future Prospects Unveiling the Potential of Biosimilars:Past Achievements and Future ProspectsKey players in the upcoming marketWith the expiration of patents on several blockbuster biologics,pharmaceutical companies are actively investing in the development of biosimilar products.These companies are actively engaged in clinical-stage development,focusing on various therapeutic areas.Cellitron,Sandoz,Teva Pharmaceuticals and Ligand Pharmaceuticals are some of the key players making significant contributions to the biosimilars market.Their dedication to innovation and commitment to improving patient access to affordable biologic therapies position them as frontrunners in this high-potential market.The following are the top three players with their respective biosimilars in development:Fig 24:Top 15 companies involved in upcoming biosimilarsUpcoming key players in clinical developmentTop three companies Fig 25:Top three companies for upcoming biosimilars 012345678Number of biosimilarsCompaniesTrastuRelTrastuzumabbiosimilar-EirGenixSandozCelltrionTevaTyrukoTVB-009NypoziUpcomingCT-P47RT-111CT-P53CT P43CT-P 39CT-P41CT-P42GP-2411SB-17SOK583A1AVT 04Tuznue AVT-05AVT-06TEV-45779RegisteredPreregisteredClinicalConclusionIn this report,we have analyzed the impact of biosimilar launches on the sales of the original biologic,the landscape of anticipated biosimilar launches,and the key market players.This conclusion synthesizes data-driven insights to offer a forward-looking perspective on the biosimilar industrys trajectory.Our analysis reveals a notable trend of decreasing sales for original biologics following the introduction of biosimilars,with an average sales decline of 20-30%.This effect underscores the competitive pricing strategies employed by biosimilar manufacturers,which,in turn,have fostered a more cost-conscious healthcare environment.The data suggests that the presence of biosimilars not only catalyzes price reductions but also expands patient access to essential therapies.Looking ahead,the pipeline of upcoming biosimilars is robust,targeting treatments for a range of conditions from autoimmune diseases to cancers.This surge emphasizes a growing industry focus on biosimilar development,propelled by the impending expiry of patents for several high-profile biologics.The biosimilar market landscape is characterized by a mix of established pharmaceutical giants and emerging biotech firms.Companies such as Reliance,Pfizer,and Sandoz are noted for their extensive portfolios and aggressive expansion strategies into new therapeutic areas.Meanwhile,emerging players such as Teva,Celltrion and Samsung Bioepis are carving out niches through innovative manufacturing techniques and strategic partnerships.The interplay among these entities fosters a vibrant competitive environment,driving innovation,and ensuring a continuous supply of biosimilars to meet growing demand.In essence,the biosimilar market is at a critical juncture,with significant opportunities and challenges ahead.The data-driven analysis of sales impact,upcoming launches,and key market players provides a nuanced understanding of the current state and prospects of biosimilars.Stakeholders across the healthcare ecosystem must navigate regulatory complexities,market acceptance,and the intricacies of biologic drug development to fully capitalize on the potential of biosimilars.As we move forward,the strategic actions of these stakeholders will determine the pace at which biosimilars can contribute to sustainable healthcare systems and improved patient outcomes Unveiling the Potential of Biosimilars:Past Achievements and Future Prospects33About AdisInsightYou need data insights to deliver your organizations objectives and overcome your biggest challenges.That data needs to be trustworthy,up to date,and accurate.How to access and use that data should be up to you:thats why we give you flexibility and control.You can opt to get our rich,validated data plugged straight into your internal analytics platforms and systems,so you have the freedom to explore and interrogate the data to meet your specific needs.Our organizations objectives and overcome your biggest challenges.That data needs to be trustworthy,up to date,and accurate.How to access and use.In drug development where every day matters,our platform and solutions empower you to quickly understand whats happening and why,so you can reduce risk,make smarter strategic decisions and act with complete confidence.To find out more visit AdisInsight on Contact 34030VJ-4th|Image:Tatiana Shepeleva/ Unveiling the Potential of Biosimilars:Past Achievements and Future Prospects Unveiling the Potential of Biosimilars:Past Achievements and Future ProspectsReferences:1.Home-AdisInsight()2.fda.gov/drugs/therapeutic-biologics-applications-bla/biosimilars3.cancer.org/cancer/managing-cancer/treatment-types/biosimilar-drugs/what-are- Approves Interchangeable Biosimilar for Multiple Inflammatory Diseases.() the Potential of Biosimilars:Past Achievements and Future Prospects Unveiling the Potential of Biosimilars:Past Achievements and Future P
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