《艾意凱咨詢（L.E.K.）：2022年基于病毒的基因療法研究報告-主要挑戰與生物工藝創新（英文版）（17頁）.pdf》由會員分享，可在線閱讀，更多相關《艾意凱咨詢（L.E.K.）：2022年基于病毒的基因療法研究報告-主要挑戰與生物工藝創新（英文版）（17頁）.pdf（17頁珍藏版）》請在三個皮匠報告上搜索。

1、SPECIAL REPORTViral-Based Gene Therapy:Key Challenges and Bioprocessing Innovations2 L.E.K.ConsultingSPECIAL REPORTContentsAbout L.E.K.ConsultingWere L.E.K.Consulting,a global strategy consultancy working with business leaders to seize competitive advantage and amplify growth.Our insights are cataly

2、sts that reshape the trajectory of our clients businesses,uncovering opportunities and empowering them to master their moments of truth.Since 1983,our worldwide practice spanning the Americas,Asia-Pacific and Europe has guided leaders across all industries from global corporations to emerging entrep

3、reneurial businesses and private equity investors.Looking for more?Visit .L.E.K.Consulting is a registered trademark of L.E.K.Consulting LLC.All other products and brands mentioned in this document are properties of their respective owners.2022 L.E.K.Consulting LLCIntroduction.3Key challenges and bi

4、oprocessing innovations.4-12Conclusion.13Endnotes.143 L.E.K.ConsultingSPECIAL REPORTIntroductionIn recent years viral vector gene therapies reentered the advanced modality spotlight notably with the 2017 approval of Sparks Luxturna and the subsequent approval of Novartis/AveXis Zolgensma.Both of the

5、se therapies conveyed transformational potential for patients in high morbidity or mortality indications with significant unmet medical need.The immense promise of the budding adeno-associated virus(AAV)gene therapy field drove a flurry of M&A deal activity,with large biopharma and global contract d

6、evelopment and manufacturing organizations participating in many billion-dollar-plus deals.1 While the field has experienced several setbacks related to safety and efficacy,the global pipeline continues to grow,reaching hundreds of preclinical assets and more than 100 clinical assets by May 2022,2 a

7、nd in November 2022,CSL Behring received Food and Drug Administration(FDA)approval for Hemgenix for hemophilia B.3 For the pipeline to translate into a significant number of marketed therapies,the field will need to address eight key challenges inherent in the gene therapy design(i.e.,what is made)a

8、nd the manufacturing process(i.e.,how it is made).In this special report,L.E.K.Consulting reviews these challenges and the bioprocessing solutions that could shape the trajectory of the viral-based gene therapy landscape.SPECIAL REPORTKey challenges and bioprocessing innovations L.E.K.has identified

9、 eight challenges related to either gene therapy design or the current manufacturing process:1.Reach more patients by targeting a broader range of organs2.Improve safety at higher doses3.Maximize durability of response4.Overcome pre-and post-treatment immunity5.Improve transfection efficiency6.Incre

10、ase cell culture scalability7.Increase purity 8.Improve batch-to-batch inconsistencyChallenges in gene therapy designFour main challenges require changes in the gene therapy design itself:reach more patients by targeting a broader range of organs,improve safety at higher doses,maximize durability of

11、 response,and overcome pre-and post-treatment immunity.1.Reach more patients by targeting a broader range of organs:Todays marketed and pipeline gene therapies have mainly targeted organs that are relatively easy to reach namely,the eye,the brain and the liver.The eye and the brain have two main adv

12、antages therapies can be administered directly to them,and they are immune-privileged,meaning that foreign tissues can survive for long periods of time without eliciting a significant immune response.As the bodys filter,the liver is also thought to be a relatively easy-to-reach organ,since gene ther

13、apies administered systemically naturally tend to accumulate there.Gene therapies in development for hemophilia target the liver because it is the primary site of clotting factor synthesis.Two major issues must be addressed to move to other organs.First,the gene therapy must be able to reach the des

14、ired tissue when it is not directly injected,and once there,it must be able to survive that organs immune response if the organ is not immune-privileged.If these are addressed,the range of applications and therefore the overall market for viral-based gene therapies could greatly expand.4 L.E.K.Consu

15、ltingSPECIAL REPORT2.Improve safety at higher doses:Luxturna,locally administered to the eye,has a dose of 1.5 x 1011(150 billion)vector genomes(vg)per eye.Systemically dosed gene therapies,which are necessary for reaching a broader range of organs,typically require dosages of 1013-1014(tens to hund

16、reds of trillions)vg per kilogram of body weight on the order of thousands of times greater than Luxturna because not all the vector genomes will reach the desired tissue.And these figures only represent vector genomes.There is an additional(usually undisclosed)number of empty capsids,making the tot

17、al amount of virus the patient is exposed to even higher.The higher the dose,the more significant a patients potential immune response to that dose may be and indeed,serious adverse events such as severe liver damage and sepsis,and ultimately deaths,have been observed in clinical trials of these the

18、rapies.4 This has resulted in some recent clinical holds,including on Pfizers PF-06939926 for Duchenne muscular dystrophy(since lifted)and Astellas AT132 for X-linked myotubular myopathy.Several high-dose gene therapy pipeline assets should have readouts in the coming 18 months that will be instruct

19、ive as to the magnitude of this challenge,including in Duchenne muscular dystrophy(see Figure 1).Note:BLA=Biologics License ApplicationSource:Clinicaltrials.gov,company websites and press releases,U.S.Food and Drug Administration,NeurologyLive,product labels,L.E.K.research and analysisFigure 1Duchen

20、ne muscular dystrophy gene therapy pipeline assets compared to Luxturna and ZolgensmaCompanyAssetDisease StageDose(vg/kg)Next inflection pointSpark TherapeuticsLuxturnaRetinal dystrophyMarketed1.5 x 1011(150 billion)per eye N/ANovartisZolgensmaSpinal muscular atrophyMarketed1.1 1014(110 trillion)N/A

21、SareptaSRP-9001Duchenne muscular dystrophyPhase 31.33 x 1014(133 trillion)BLA submitted for accelerated approval Oct.2023:Phase 3 primary completion datePfizer PF-06939926Duchenne muscular dystrophyPhase 31-3 x 1014(100 to 300 trillion)Jan.2024:Phase 3 primary completion dateSolid BiosciencesSGT-001

22、Duchenne muscular dystrophyPhase 1/22 x 1014(200 trillion)(high-dose cohort)Early 2023:Long-term data from phase 1/25 L.E.K.ConsultingSPECIAL REPORT3.Maximize durability of response:The once broadly disseminated hypothesis that gene therapies would be curative one-time treatments has come into quest

23、ion.AAV gene therapies do not integrate into the patients DNA,meaning that their expression could wane as cells divide without them being copied in each new cell.There have been gene therapy trials that demonstrated five-year durability in efficacy,but concerns persist.For example,BioMarin received

24、a Complete Response Letter from the FDA in 2020 for its submission of valoctocogene roxaparvovec for treatment of severe hemophilia A because Factor VIII expression waned significantly over the course of a few years.5 The company recently generated new phase 3 data showing two years of therapeutic b

25、enefit,released phase 1/2 data showing five years of therapeutic benefit and refiled this September.Ultimately,more time and more data will tell whether gene therapies can be curative one-time therapies.4.Overcome pre-and post-treatment immunity:Once patients are exposed to an AAV gene therapy,they

26、may develop neutralizing antibodies against it.The percentage of individuals with neutralizing antibodies varies greatly across studies and AAV serotypes(from as few as 3%to the majority of patients).6,7 Neutralizing antibodies mobilize a patients immune system to neutralize the AAV gene therapy bef

27、ore it can have a meaningful therapeutic effect.As a result,a significant proportion of patients otherwise eligible for gene therapy cannot receive it,and re-dosing with the same AAV serotype is not possible because patients develop neutralizing antibodies from the first dose.If re-dosing was requir

28、ed to prolong therapeutic effects,gene therapy developers would need to determine how a re-dosed therapy could evade the immune system,likely by further engineering the viral capsids used to deliver it and/or modulating the immune system response.Challenges in the manufacturing processThe above gene

29、 therapy design challenges must be solved in order for the growing gene therapy pipeline to remain viable.And if they are solved,more assets in the pipeline,larger target patient populations,higher doses per asset and the potential need for re-dosing will cause an exponential increase in market dema

30、nd for viral-based gene therapy.BioMarins Valrox alone would require over 100,000 times more bioprocessing output than Luxturna,based on dosing and prevalent population differences(see Figure 2).In order to meet this demand,there will need to be a large increase in manufacturing yield.Manufacturing

31、costs will also need to decrease because therapies addressing broader patient populations and requiring re-dosing will not be able to command the ultraorphan pricing models of todays therapies.6 L.E.K.ConsultingSPECIAL REPORTSeveral additional limitations across todays AAV bioproduction process driv

32、e overall cost and limit total yields.They challenge the industry to:5.Improve transfection efficiency:The first step of gene therapy manufacturing is transfection,whereby DNA containing the genes required for virus production is introduced into a cell line to produce genetically modified cells.For

33、todays AAV therapies,this is typically accomplished through transient triple transfection,whereby three plasmids containing genes required for AAV production are simultaneously introduced to cells to produce AAV.However,these plasmids are not integrated into the cells genome,and thus the process mus

34、t be repeated for every new batch of gene therapy produced.This method was adopted because it was the historical approach to producing AAV and was perceived as the fastest and lowest-risk path to market given uncertainties about the feasibility of establishing stable producer AAV cell lines.However,

35、repeating this process for each batch is very inefficient,is difficult to scale and drives high batch costs(e.g.,each batch requires significant good manufacturing practice GMP plasmid input and labor costs)and batch-to-batch variability.*Values represent dose per eye or per kg,multiplied by relevan

36、t multiplier(e.g.,average kg for patient of age to receive therapy),multiplied by U.S.disease prevalence or incidence.Does not account for patients ineligible due to preexisting neutralizing antibodies.Source:Company websites and press releases,U.S.Food and Drug Administration,hemophilia.org,Journal

37、 of Neuromuscular Diseases,Orphanet Journal of Rare Diseases,Centers for Disease Control and Prevention,Hemophilia,product labels,L.E.K.research and analysisFigure 2Relative addressable US vector genome(vg)demand for different gene therapies*Trillions of vgLuxturnaRetinal dystrophyPrevalence-drivenZ

38、olgensmaSpinal muscular atrophyIncidence-drivenSRP-9001Duchenne musculardystrophyIncidence-drivenValoctocogeneroxaparvovecSevere hemophilia APrevalence-driven450 trillion280,000 trillion860,000 trillion75,000,000 trillionDIRECTIONAL100,000,00010,000,0001,000,000100,00010,0001,0000115,000 x7 L.E.K.Co

39、nsultingSPECIAL REPORT6.Increase cell culture scalability:After genetic modification comes cell expansion,in which transfected cells are cultured to scale in a bioreactor.Many of todays gene therapies are produced using adherent cell culture(where cells are cultured in a monolayer on an artificial s

40、urface)instead of suspension cell culture(where cells are cultured in a three-dimensional liquid volume).Adherent culture is common for AAV gene therapy manufacturing because commonly used adherent HEK293 cell lines are available“off the shelf”and the process can be quickly and easily developed at l

41、ab scale with less bioengineering expertise required.8 However,adherent culture is limited in scale by the surface area available for cell growth.Adherent culture may not be sufficient to produce the amount of virus required for high-dose gene therapies,or to produce doses for large addressable popu

42、lations.7.Increase purity:The final steps are purification and polishing,in which viral vector products are separated from process impurities as well as from low-quality AAV products.One key measure of purity from this process is the ratio of full AAV capsids(i.e.,properly packaged capsids containin

43、g the therapeutic gene of interest)to empty capsids(i.e.,AAV capsids that are improperly packaged and lack the gene of interest).With todays purification methods,a significant portion of empty capsids remains in most batches.This means that significantly more AAV capsids need to be produced(and deli

44、vered into the patient)to achieve an effective gene therapy dose,which strains capacity,increases costs and likely increases the rate of adverse events.8.Improve batch-to-batch inconsistency:Across the AAV bioproduction process,the complexity and high degree of variability lead to inconsistency in y

45、ields and high rates of batch failures.This in turn strains capacity and increases cost,because manufacturers must plan to make even more virus to account for these inefficiencies.The bioprocessing innovationsWhen reviewing the challenges facing the gene therapy field,there is no doubt that bioproce

46、ssing limitations are part of the problem and that bioprocessing must also be a part of the solution.Enabling technology and bioproduction players across the value chain are working toward a range of potential innovations to help overcome the above challenges(see Figure 3).A.Next-generation capsids

47、to address gene therapy design challenges:Addressing the challenges in gene therapy design can involve changing the payload(i.e.,the gene of interest or other promoter genes)or the delivery vehicle(i.e.,the AAV capsid or a different viral or nonviral delivery vehicle).While changes to the payload ar

48、e core competencies of biopharma companies,bioprocessing companies are working on 8 L.E.K.ConsultingSPECIAL REPORTnext-generation AAV capsids.Companies like 4D Molecular Therapeutics,AskBio,Dyno Therapeutics,Oxgene and others are using directed evolution and/or artificial intelligence-informed ratio

49、nal design to develop capsids that more effectively target desired tissue types(even when dosed systemically),reduce immune responses,do not have the prevalent pool of existing neutralizing antibodies in patients and/or transduce a greater proportion of target cells.These developments could increase

50、 the margin of safety for gene therapy drugs and potentially enable re-dosing of patients in some indications.Other potential approaches to next-generation vectors include non-AAV vectors(e.g.,herpes virus),nonviral vectors(e.g.,lipid nanoparticles)that could circumnavigate barriers to re-dosing,and

51、 co-dosing of immunomodulators(e.g.,Selecta Biosciences ImmTOR platform).Figure 3Overview of gene therapy bioprocessing workflow,challenges and bioprocessing innovationsNote:AAV=adeno-associated virusSource:L.E.K.research and analysisSimplified bioprocessing workflowChallengesGene therapydesignTrans

52、fectionAAV bioproduction processHarvest and purificationCell culture and virus productionDNA/RNA containing the gene(s)of interest,capsid formation genes,and other helper genes are designedDNA/RNA is transfected into a living cell to produce genetically modified cellsCells are transferred to and gro

53、wn in a bioreactor with a growth medium and produce the viral vector productProtein/viral vector products are separated from the cells and other impurities for therapeutic useDecrease cost and increase yield1.Reach more patients by targeting a broader range of organs2.Improve safety at higher doses8

54、.Improve batch-to-batch inconsistency3.Maximize durability of response4.Overcome pre-and post-treatment immunity5.Improve transfection efficiency7.Increase purity6.Increase cell culture scalabilityBioprocessing innovationsA.Next-generation capsidsE.Stable producer cell linesB.Next-generation transfe

55、ction reagentsD.Improved purification and polishingC.Intensified cell culture9 L.E.K.ConsultingSPECIAL REPORTNext-generation capsid engineering,though,will not solve the challenges that contribute to high cost and low yields.Some solutions that are actively being invested in include:B.Next-generatio

56、n transfection reagents to increase yield:Reagent providers such as Polyplus,MiRus and others have developed next-generation GMP transfection reagents that enhance transfection efficiency,increase the proportion of cells in culture that contain all three plasmids required for AAV production,and affo

57、rd a higher functional titer of virus produced.Though material,these improvements alone are unlikely to be sufficient to overcome the significant scale-up cost challenges that limit the fields potential.C.Intensified cell culture to increase yield,increase speed and decrease human labor requirements

58、:Given that AAV has historically been produced using adherent cell culture,high-dose programs such as Novartis Zolgensma took advantage of fixed-bed bioreactors(e.g.,Palls iCELLis),in which fibrous layers are tightly assembled to allow adherent cells to attach while utilizing more of the available v

59、olume of the media and reactor.Going forward,manufacturers are continuing to look for ways to intensify the cell culture processes and increase scale and yield;suspension culture,which is commonly used for commercial-scale bioproduction of other biological drugs(e.g.,monoclonal antibodies),is viewed

60、 as a way to do this.Compared to adherent culture,it is operationally simpler,can be performed at a larger scale,requires less employee hands-on time and likely results in higher batch yields.To change to suspension culture,manufacturers can switch to suspension-adapted cell lines such as Sf9 and He

61、La(accepting potential drawbacks these production systems might present compared with HEK293 cells),or they can adapt and engineer HEK293 cells for suspension culture.Improvements in suspension HEK293 cell lines are allowing manufacturers to increasingly pursue this approach.Suspension culture also

62、opens the possibility of moving from fed-batch culture to perfusion culture,in which the cell culture is continuously fed.This can further enable higher-yielding and more cost-effective production processes,especially in conjunction with stable producer cell lines(see section E below).D.Improved pur

63、ification and polishing to increase yields,improve full-to-empty ratio and therefore improve safety:Purification and polishing are two downstream steps in the manufacturing process that are accomplished through chromatography.10 L.E.K.ConsultingSPECIAL REPORTIn purification,a capture ligand or resin

64、 is used to extract the AAV capsids.Purification players are investing in next-generation resins and capture ligands to increase the amount of AAV recovered,as well as optimized buffers to improve recovery from anion exchange chromatography,which would increase yield per batch.In polishing,high-qual

65、ity AAV is separated from low-quality AAV(such as empty capsids).Suppliers are also investing in improvements at this step to enable the delivery of the same therapeutic benefit(number of full capsids)with a lower overall dose of AAV capsids,potentially reducing immune response and thus improving sa

66、fety,of particular concern for high-dose gene therapies.E.Stable producer cell lines to increase scale and decrease cost:Among all solutions,developing stable producer cell lines,in which some or all of the necessary genes required to produce the vector are fully integrated into the cell lines genom

67、e,may be the most impactful.Switching from transient triple transfection to a stable producer cell line would be a significant step forward in improving scalability and reducing cost of manufacturing.It could reduce batch costs by 30%,driven by reduction in GMP plasmids,transfection agents and labor

68、/time costs.9 These cell lines can also be optimized for output(functional titer)and quality(full-to-empty ratio),which could further reduce costs by producing a higher concentration of more efficient drug from a smaller-scale bioreactor.10 Stable producer cell lines are used today to manufacture mo

69、noclonal antibodies,but they are much more challenging to engineer for viral-based gene therapies.For viral-based gene therapies,the cell line would need to have more than 10 different genes stably integrated into its genome,compared with only one or two for most antibodies.Innovators such as Ultrag

70、enyx have demonstrated scaled manufacturing with their proprietary Pinnacle PCL platform,including 2,000-liter batch production for clinical trials.Similarly,CEVEC Pharmas HEK293-based ELEVECTA platform allows efficient stable producer cell line generation for AAV,and ELEVECTA cells have been succes

71、sfully scaled up using both batch and perfusion processes.11 CEVEC has licensed its technology to several large pharma players,including Biogen and Roche/Spark,and the company was recently acquired by Cytiva.Other partnerships(e.g.,Thermo Fisher and Berkeley Lights)are exploring new methods of scree

72、ning and identifying stable clones for application as producer cell lines,a critical bottleneck in the process of developing a stable producer cell line.It may take several years for producer cell lines to gain traction in the gene therapy pipeline.Developing a producer cell line can take significan

73、t time(driven by clone screening).Also,this additional development may be perceived as slowing time to 11 L.E.K.ConsultingSPECIAL REPORTclinic or driving additional execution risk.Ultimately,switching to a stable producer cell line will be driven by a risk/reward assessment for each potential AAV pi

74、peline program.Factors that would potentially drive switching to a stable producer cell line include(a)higher dose required,(b)larger addressable patient population,(c)less in-class competition and pressure of speed to market and(d)incidence-driven indication,where a significant portion of the patie

75、nt pool is replenished each year.Producer cell lines could play a critical role in the future industrialization of AAV-based gene therapy for programs that fit one or more of the above archetypes.12 L.E.K.ConsultingSPECIAL REPORTThe growth of advanced therapeutic modalities like viral-based gene the

76、rapies is triggering a step change in bioprocessing complexity and variability and is placing increased and evolving demands on bioprocessing manufacturers.This is a market that is fundamentally supply constrained there is a large gap in overall capacity and many manufacturing limitations to address

77、.The bioprocessing ecosystem is actively exploring innovations to solve the key challenges and write the next chapters of the gene therapy market.As of 2021,gene therapy represented 0.5%of global bioprocessing capacity in liters.12 Advances in bioprocessing will play a critical role in determining w

78、hat that figure will be a decade from now.L.E.K.has significant experience advising pharmaceutical manufacturers,contract manufacturers,and bioprocessing equipment and consumables manufacturers on how to best participate in the growing gene therapy market and maximize value in the face of the signif

79、icant uncertainty in the industry.For more information,please contact .Conclusion13 L.E.K.Consulting14 L.E.K.ConsultingSPECIAL REPORTEndnotes1Examples include Novartis/AveXis,Roche/Spark,Astellas/Audentes,Pfizer/Bamboo,Thermo Fisher/Brammer Bio,Catalent/Paragon.2L.E.K.analysis of Citelines PharmaPro

80、jects.3CSL Behring.“U.S.Food and Drug Administration approves CSLs HEMGENIX(etranacogene dezaparvovec-drlb),the first gene therapy for hemophilia B.”https:/ Engineering&Biotechnology News,“Gene Therapy:Its Time to Talk about High-Dose AAV.”https:/ Biotech,“FDA gets out its red pen again,rejecting Bi

81、oMarins gene therapy valrox amid durability worries.”https:/ 6Human Gene Therapy Methods,“Pre-existing AntiAdeno-Associated Virus Antibodies as a Challenge in AAV Gene Therapy.”https:/www.ncbi.nlm.nih.gov/pmc/articles/PMC3732124/7Frontiers in Immunology,“Anti-AAV Antibodies in AAV Gene Therapy:Curre

82、nt Challenges and Possible Solutions.”https:/www.frontiersin.org/articles/10.3389/fimmu.2021.658399/full8Cell&Gene Therapy Insights,“Adherent versus suspension based platforms:what is the near future of viral vector manufacturing?”https:/insights.bio/cell-and-gene-therapy-insights/journal/article/22

83、44/Adherent-versus-suspension-based-platforms-what-is-the-near-future-of-viral-vector-manufacturing#:text=In%20biologics%2C%20two%20techniques%20o-f,floating%20in%20the%20culture%20medium9L.E.K.research and analysis.10Companies have used baculovirus-based cell lines to generate scale,but this approa

84、ch has led to a relatively poor full-to-empty ratio compared with virus produced using transient triple transfection.11Company presentations at BioProcess International Conference,Boston,Massachusetts,October 2022.12BioProcess International,“Total Global Capacity Finally Shows Improved Productivity.

85、”https:/ REPORT15 L.E.K.ConsultingAbout the authorsJeffrey Holder MANAGING DIRECTOR,SAN FRANCISCO Jeff Holder,Ph.D.,is a Managing Director in L.E.K.Consultings San Francisco office.Jeff specializes in strategic engagements that advise clients who are looking to commercialize advanced research tools

86、and novel technologies across the biopharma,clinical diagnostics and bioprocessing markets.Adam Siebert MANAGING DIRECTOR,NEW YORKAdam Siebert is a Managing Director in L.E.K.Consultings New York office and a member of the Life Sciences practice.Adam has been with L.E.K.for over eight years,and has

87、experience across diagnostics and research tools,bioprocessing,and pharma services,as well as emerging,mid-cap and large pharma.He has helped a number of clients in the life sciences industry with growth strategy,life cycle management,portfolio optimization and M&A projects.Jenny MackeyPRINCIPAL AND

88、 DIRECTOR,NEW YORKJenny Mackey is a Principal in L.E.K.s Life Sciences practice and the Director of L.E.K.s Healthcare Insights Center.Jenny focuses on the biopharmaceutical sector and advises clients on a range of issues including R&D portfolio prioritization,new product planning,forecasting and va

89、luation,and organizational performance and development.Tian Han MANAGING DIRECTOR,LOS ANGELESTian Han is a Managing Director in L.E.K.Consultings Los Angeles office.Tian joined L.E.K.in 2008 and is one of the leaders of the firms Diagnostics and Research Tools practice,where he specializes in precis

90、ion medicine,advanced diagnostics,life sciences research tools and advanced therapeutic bioprocessing.He advises clients on corporate and business strategy,product strategy,commercial planning,and transaction support.SPECIAL REPORT16 L.E.K.ConsultingAbout the authors(cont.)Authors note:The authors w

91、ould like to thank Adrian Slusarczyk for his important contributions to this special report.Alex VadasMANAGING DIRECTOR,LOS ANGELES Alex Vadas,Ph.D.,is a Managing Director in L.E.K.Consultings Los Angeles office,where he leads the firms Diagnostics and Research Tools practice.Alex joined L.E.K.in 2000 and focuses on diagnostics,research tools and personalized medicine.Within those areas,he has worked with a range of established and emerging clients in the areas of corporate strategy,product strategy,commercial planning and transaction support.