1、 2022 Boston Consulting Group1Gene Editing Gets Ready for the SpotlightNOVEMBER 11,2022 By Smruthi Suryaprakash,Souparno Bhattacharya,Wen Xie,and Michael ChoyPharma has invested billions in cell and gene therapies.Gene editing ismaking a case for more of this funding,but companies need to understand

2、what theyre investing in and why.In recent years,pharma has turned significant R&D attention and investment tocell and gene therapiesfor the good reason that these innovations hold thepotential for transformational treatments for patients who were previously beyondthe industrys reach.Reports put pri

3、vate funding at almost$68 billion in 2021.Onecutting-edge technologygene editinghas thus far received only a sliver of this 2022 Boston Consulting Group2funding(which GlobalDatas Pharma Intelligence Center pegs at$1.3 billion in2021),but it looks like thats about to change.CRISPR gets much of the at

4、tentionbut is only one of multiple technologies under development.Investment has beengrowing quickly from its small base,and gene editing has attracted the interest(and investment)of industry leaders such as Pfizer,Roche,and Allergan and haseven received financial backing from tech giant Amazon.The

5、reason is as simple as the technology is complex.While first-generation genetherapies work by adding a gene to the patients cells,gene editing“fixes”thebroken gene itself.This innovation has enormous potential for multipletherapeutic areas,such as oncology,hematology,genetic disorders,and metabolicd

6、iseases.Indeed,the promise of gene editing is such that large pharma companieswhile making major strategic and financial decisions in the broader arena of celland gene therapiesshould also be developing specific plans for gene editing.Here are the factors they need to consider.Big Benefits from Rapi

7、d Development So FarCell and gene therapies are demonstrating their transformative potential,withmultiple treatments receiving regulatory approval and many more in development.Viral-vector gene therapies,which enable“missing”genes to be expressed using asupplemental copy,are a major advancement in t

8、reating genetic diseases.Geneediting takes a step further by changing the underlying genetic sequence,offeringthe possibility of improvement or even cure for patients who previously had littlehope.In contrast to gene therapy,edited genes offer a potentially durabletherapeutic effect,since correcting

9、 the underlying defects can cure the condition,whereas the effects of gene therapy products can wane over time.In addition,genealternation at targeted locations reduces the risk of oncogenesis.The early gene-editing tools,zinc fingers and TALENs,showed considerable utilityand are still in use today,

10、but their adoption as therapeutics was slowed by thecomplexity of creating and producing them.The discovery of CRISPR-Cas,which is 2022 Boston Consulting Group3based on a targeted antiviral defense system used by bacteria,has greatlyaccelerated the pace of development for gene-editing therapeutics.T

11、he first human trial of the CRISPR-Cas gene-editing tool in the US started in 2017,and since then the field has taken off.Some 40 companies are currently active,andmore than 200 programs focus on the therapeutic uses of gene editing.The vastmajority of these use CRISPR-Cas.Other editing platforms in

12、clude zinc fingers(Sangamo),TALEN(Cellectis/Allogene),ARCUS(Precision BioSciences),mobilegenetic elements(Tessera),and ADAR for RNA editing(Korro Bio,EdiGene,WaveLife Sciences).The rapid strides in CRISPR-based approaches have significantly expanded thetoolbox as more advanced CRISPR iterations have

13、 led to different types of genealterationreplacement,insertion,single-base modification,and gene writingand enabled the fine-tuning of gene expression without the need for permanentchanges.Together,these techniques can target and potentially cure a wide varietyof genetic diseases that are not addres

14、sable with current viral-vector gene therapiesor first-generation CRISPR-Cas tools.(See Exhibit 1.)2022 Boston Consulting Group4Gene editing is still nascent,with about 85%of programs in the discovery orpreclinical stage,and 20 out of 32 programs have orphan disease designations.(Seethe sidebar,Wher

15、e Gene Editing Activity Is Focused.)The activities of gene-editing companies can be divided into threecategories:WHERE GENE EDITING ACTIVITY IS FOCUSED 2022 Boston Consulting Group5So far,oncology,hematology,metabolic disease,and ophthalmology are the fourmost active therapeutic areas.(See Exhibit 2

16、.)This may be because of theopportunity for ex-vivo manipulation in oncology and hematology,and relativelyeasier in-vivo delivery to the liver and eye using lipid nanoparticles and adeno-associated virus vectors,respectively.Gene editing has become the leading genetherapy in oncology on the strength

17、 of next-generation CAR T-cell innovations.Ex Vivo.CRISPR Therapeutics and Vertex Pharmaceuticalsexagamglogene autotemcel(exa-cel),formerly known as CTX001,isthe most advanced ex-vivo clinical asset in development for betathalassemia and sickle cell disease.It has an anticipated 2023 launch.In Vivo.

18、Intellia Therapeutics NTLA-2001 is the clear frontrunneramong in-vivo products.It has shown durable reduction in serumtransthyretin levels in an ATTR amyloidosis Phase 1 trial.More matureclinical data is expected in the second half of 2022.Next-Gen.Verve Therapeutics VERVE-101 is a single-course bas

19、e-editing treatment that turns off the PCSK9 gene to treat heterozygousfamilial hypercholesterolemia.It entered clinical Phase 1b trials on July12,2022.Beam Therapeutics BEAM-101 is likely the first base editor(CRISPR 2.0)to enter human trials in 2022 for treatment of betathalassemia and sickle cell

20、 disease.2022 Boston Consulting Group6Looking AheadMuch of the excitement surrounding gene editing,especially CRISPR-Cas,is basedon the potential for curative treatments,and rightly so.Several therapies haveshown highly encouraging results for such conditions as transfusion-dependentbeta thalassemia

21、,sickle cell disease,hereditary ATTR amyloidosis,and hereditaryangioedema,for which patients have few,if any,treatment options.Gene editinghas multiple applications across the entire drug development value chain,including research,diagnostics,and therapeutics.(See Exhibit 3.)There may alsobe an oppo

22、rtunity for companies to build out CRISPR-Cas as a platform and focuson optimizing the CRISPR toolbox for use by others,expanding the application ofthe technology without offering any product of their own.2022 Boston Consulting Group7To be sure,as is the case with any emerging technology(especially

23、in life sciences),serious obstacles need to be overcome.As we discussed last year in our interviewwith Peter Marks,director of the Center for Biologics Evaluation and Research atthe US Food and Drug Administration,these involve:Efficacy:Establish clinically meaningful endpoints for improvement.These

24、are not now well defined in many rare diseases.Safety:Resolve lingering questions about the durability and long-term safetyfor recipients.Delivery:Determine how to package and deliver different components(suchas Cas,sgRNA,or template DNA)to the right tissue.This is the biggestremaining technical cha

25、llenge,and overcoming it is critical for in-vivoproducts.Pricing and Reimbursement:It remains to be seen how the market handlesmultiple curative drugs targeting the same patient population and howcompanies differentiate themselves when it takes years to establish the 2022 Boston Consulting Group8You

26、 Need a StrategyGene editing has a lot of momentum.Since 2019,companies in the field(mostlystartups)have cumulatively raised more than$5 billion in venture capital andprivate equity investment.A few have had record-breaking IPOs.Given theadvanced technology and sophisticated know-how involved,we are

27、 starting to seelarge pharma companies explore corporate venture capital investments,R&Dcollaborations,and asset-licensing deals.(See Exhibit 4.)The number oftransactions has risen sharply in the last four years,with average upfront paymentsreaching almost$100 million in 2021.durability of therapeut

28、ic effect and to understand the true value for patientsand payers.2022 Boston Consulting Group9Given the potential,we believe all pharma companies need a gene-editingstrategy,investing toward one(or more)of three ends:a new drug discovery tool,new therapeutics,and a defense against disruptors.Drug D

29、iscovery Tool.Large pharma companies can use gene editing as a tool toaccelerate development in their existing portfolio.For example,first-generationCAR T-cell players such as Gilead and Bristol Myers Squibb want to remain at theforefront of innovation in cancer cell therapies.The GileadSangamo(2018

30、)andBMSArsenalBio(2022)partnerships support this goal.Gilead partnered withSangamo to use zinc finger nucleases technology to create off-the-shelf CAR T-celltherapies to cement its position in this space.BMS is partnering with ArsenalBio 2022 Boston Consulting Group10to develop logic gates and gene

31、expression controls for programmable celltherapies in solid tumors.Therapeutics.Gene editing can be leveraged as a direct therapeutic and as ameans of diversifying a companys capabilities and pipeline.For example,Vertex,the market leader in cystic fibrosis,has been one of the most active gene-editin

32、gdeal makers,with collaborations with CRISPR Therapeutics,MammothBiosciences,and Arbor Biotechnologies intended to diversify its portfolio beyondsmall molecules.Vertex is well positioned to meet the commercial challenges,given its decades-long experience in rare diseases.Regeneron,one of the mostsuc

33、cessful antibody platform-focused biotech companies,with ten approved orauthorized biologics in the last decade,is developing capabilities beyondtraditional biologics through a partnership with Intellia Therapeutics,which usesthe CRISPR gene-editing system.Novartis likewise has a partnership with In

34、tellia,through which it secured rights to use CRISPR for its CAR T-cell program;the twocompanies have also agreed to work together on using CRISPR for stem cell andsickle cell diseases.Defense Against Disruptors.Developing gene-editing capabilities can helpincumbent companies build barriers against

35、market disruptors.Eli Lilly,a leadingdiabetes player,is partnering with Precision BioSciences to use the latters ARCUSplatform to develop in-vivo therapies in multiple indications.The initial focus ismuscular dystrophy,but the partnership includes five other(undisclosed)targets,likely metabolic dise

36、ases.This approach should help Lilly safeguard itself againstpotential disruptors in diabetes and metabolic diseases by investing in geneticmedicines,which now account for more than 20%of its non-oncology researchportfolio.Recent advances in technology and early proof-of-concept data in clinical tri

37、alsmake it imperative for pharma companies to explore gene editing.But before theyinvest,they should make sure they understand the nuances of the market and thescientific,regulatory,and commercial considerations involved.Lessons from the 2022 Boston Consulting Group11development paths of cell and ge

38、ne therapies can help them navigate thetechnical,regulatory,and reimbursement challenges in this exciting new field.AuthorsSmruthi SuryaprakashPrincipalNew JerseySouparno BhattacharyaSenior Knowledge AnalystACC BostonWen XiePrincipalBeijingMichael ChoyManaging Director&PartnerNew JerseyABOUT BOSTON

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