for diseases. previously intractable cine,’ even offering cures ofmajoradvancesandperhaps theprospect represent majoradvances inthebroader fieldof ‘regenerative medi different,is somewhat andfocused ononcology, theotherapprovals Duchenne musculardystrophy (DMD). Whereas theCAR-T approach atrophy (SMA) and Sarepta Therapeutics’ Exondys 51 (eteplirsen) for amyloidosis, Biogen’s Spinraza(nusinersen)for spinalmuscular for polyneuropathy transthryetin-mediated causedby hereditary few years, including Ionis Pharmaceuticals’ Tegsedi (inotersen), also mechanismsinthepast therapies withantisenseandexon-skipping There have alsobeennotableapprovals ofoligonucleotide-based of string remarkable ‘firsts’ medicine. for cell-basedandgene-based amyloidosis, transthryetin-mediated roundedby offa hereditary RNAitherapy for(patisiran), apioneering polyneuropathy caused Then in 2018, the FDA approval of Alnylam Pharmaceuticals’ Onpattro FDA-approved invivo genetherapy, for retinal inherited dystrophy. Therapeutics’ (voretigene Luxturna becamethefirst neparvovec) non-Hodgkin’s inthesameyear, after lymphoma(NHL).Shortly Spark Pharma’s (now GileadSciences’) Yescarta (axicabtagene ciloleucel)for (tisagenlecleucel) forKymriah and Kite acute lymphoblastic leukemia approved by the USFood andDrugAdministration (FDA)—Novartis’s CAR-T 2017, the first harnessing products In cells to treat cancer were age of comes medicine gene-based and Cell-based few years. inthenext alike observers industry segmentswatched pharma for businessdevelopment groups and ofthemost keenly continue to be—one has been—and willlikely compound annualgrowth rate $1 billion in2017to $44billionin2024,resulting 65% inastaggering from of the combined cell, geneandnucleicacidtherapy market sell-side consensusforecasts from Evaluate growth Pharma project ing fuelto thebroader fire raging around drugpricing. Nonetheless, them intense debate aboutpayment modelsandaffordability, add medicine. gene-based receptor (CAR)-T cells are in era a for new ushering cell-based and arsenal, antigen ofchimeric and coupledwiththehigh-profile arrival ference (RNAi)are amuchmore recent additionto thetherapeutic andtranslation-targetedtranscription approaches suchasRNAinter been available for more thanadecade. therapy Gene andothergene repair havefor treatment cartilage burn for andchondrocytes knee example, techniques basedoncultured cells autologous epidermal Therapeutic approaches employing wholecellsare notnew—for Paul Verdin Urquhart Lisa and pharma interest, allof which are analyzed in this feature. market has gained momentum sales andbig in dealmaking, product At oneof its mostexciting phases of growth, thecell and genetherapy pace therapy gathers gene and cell therapeutics: Next-generation programs medicine, andwhilethere for cell-basedandgene-based Evaluate’s analysis reveals research >5,000active anddevelopment However, theserecent catalystsmightonlybe thetipoficeberg. These groundbreaking scientificadvanceshave alsobrought with (Fig. 1) . With this suchvalueatstake, - - - The valuepicturereveals asimilaroverall distribution—indications (65%) across indications. thecombinedpipelineare innon-oncology inoncology,is substantialongoingwork ofprograms themajority to 2024. Fig. growth 1|Sales trends of cell, geneandnucleicacidtherapy from products 2017 2024 sales. Overall, Sarepta’s pipelineisforecasted to generate >$3billionin antisense andgenetherapy programsskipping inmusculardystrophy. exon-of nucleic-acid-basedpipelineprograms includingfurther Exondys 51for DMD, through growth butprimarily from avariety forecasted by themarketed 2024salesisSarepta, driven inpart Biogen, Celgene and Takeda players are includedinthetop Gilead, 20by 2024sales:Novartis, only five companies thatare considered establishedlarge pharma space, thusfar, haslargely majorpharma stayed ontheperiphery— ofthecompaniesinvolved terms In inthecellandgenetherapy field therapy gene and cell the in Participants (including DMD, NHLandSMA), forecasts. helpingto derisk forecasts includethosefor whichdrugshave already beenapproved a more complexetiology. thebiggestsales The indicationsattracting therapies are beingexplored inoncologyandthoseindicationswith focused onthosediseaseswithaclearer geneticbasis, whereas cell lateral sclerosis. Logically, nucleicacidapproaches are onthewhole celldisease, Huntington’sA andB, sickle diseaseandamyotrophic of indications, including SMA,wide variety amyloidosis, hemophilia 20 indicationsby 2024forecast sales value, and only three oncology indications are included in the top outside oncologyaccountfor 76%ofthe2024forecasted sales Product sales ($ billions) 10 15 20 25 30 35 40 45 0 5 Source: EvaluatePharma, March 2019. 2017 1.3 Cell therapy DNA andRNAtherapeutics therapyGene 1.0 0.2 2018 2.0 2.7 0.03 0.6 (Fig. 3) 2019 4.1 2.7 (Fig. 2) . companyThe top by ranked 1.1 0.2 . The top 20listreveals a

2020 6.9 2.3 3.5 biopharmadealmakers.nature.com |June2019 | 1.0 11.9 2021 4.5 4.4 2.8 2022 20.3 7.6 6.1 5.7 31.9 2023 12.0 8.9 9.4 43.7 2024 16.8 12.0 13.6 B15 B15

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feature feature B16 TiGenix for $626 million,providing access to aplatform basedon For Gilead, thishas already delivered product in a marketed Yescarta. groups access to CAR-T platforms andadvancedpipelinecandidates. ($11.9 billion)andCelgene ($9billion),respectively, gave thelarger celltherapy,ing SMA. In andJuno by Gilead theacquisitionsofKite a pipelineofassetsinlife-threatening neurological diseases, includ companymium), enablingthebigpharma accessto technology and biggest dealingenetherapy at$8.7billion(an 88%share pre price yielded results ber ofacquisitionsandstrategic collaborationsthathave already standout deals by major playersOther inrecent years include anum Leading dealmakers by bigpharma. Q2 2019,isproof that thisarea willcontinueto becloselywatched acquisition of the latter by in February, Roche to expected close in Pharmaceutical andSpark—theAlnylam, announced BioMarin medicine, includingbluebird bio,on cell-basedandgene-based rapidly becomewell-watched namesonthebasisoftheirfocus R&D programs. Fig. 2| Top 20indications inthefieldofcell, geneandnucleicacidtherapies, basedon2024salesforecasts andnumberofactive b a Outside oncology, Takeda announcedin2018itsintent to acquire The top 20listispopulated by othersmallerplayers thathave |June2019 | Rare eye disordersRare (achromatopsia, choroideremia, Sanfilippo syndrome III) (mucopolysaccharidosis (Table 1) biopharmadealmakers.nature.com R&D, research anddevelopment. Source: EvaluatePharma, March 2019. Usher syndrome andStargardt disease) Dry age-related maculardegeneration age-related Dry General cardiovascularGeneral indications . Novartis’s 2018acquisitionofAveXis isthe Diabetes, type I (juvenile onset) Diabetes, I(juvenile type Duchenne musculardystrophy Duchenne musculardystrophy Other neurological indications Other Bone repair andregeneration Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis Acute lymphocytic leukemia Acute lymphocytic General bloodmalignanciesGeneral Non-small-cell lungcancer Non-small-cell Non-Hodgkin's lymphoma Non-Hodgkin's Non-Hodgkin's lymphoma Non-Hodgkin's General cancerindications General Glioblastoma multiforme Graft-versus-host disease Acute myeloid leukemia Spinal muscularatrophy Hepatoma (liver cancer) Congestive heart failure Congestive heart Solid tumorindications Solid Gastro-intestinal fistula Gastro-intestinal General eye disordersGeneral Huntington's disease Retinitis pigmentosaRetinitis Parkinson's disease Multiple myelomaMultiple myelomaMultiple Sickle celldisease Sickle Phenylketonuria Hyperlipidemia Hemophilia A Hemophilia B Thalassemia Amyloidosis Melanoma Melanoma 0 0 14 7 155 504 499 50 573 582 - - - 686 735 57 58 58 755 59 60 62 1,000 65 827 65 856 68 884 69 71 911 946 78 80 1,046 the market, reasonable difficult to valuationsthe market, are measure. very The but unsolved commercial challenges for such products once on cesses inrecent years. However, owing to the well-documented cause for excitement suc withtherangeandprofile ofregulatory in diseasemanagementand, potentially, cure. There is justifiable era medicine asanew their eyes oncell-basedandgene-based RNAi approval in2018. areas the interest underlined inthisplatform following thefirst in Alnylam to collaborate onRNAitherapies across multipledisease Pharmaceuticals’ announcement that itwould invest $800 million delivered 2019,Regeneron AndinApril Spinrazato themarket. eases. The collaboration buildsonarelationship thatsuccessfully on developing antisenseproductsfor arangeofneurological dis a total of$1 billionupfront for aten-year collaborationfocused oftheexpanded2018deal,Under theterms Biogen willpay Ionis acquisitions, butBiogen’s expandedtieupwith Ionisisnotable. based therapeuticslandscapehasbeenlessofatarget for standout group assetinAlofisel(darvadstrocel). amarketed The nucleic-acid- troenterology conditions—adealthathasdelivered thelarger stem cellstargeted atgas allogeneic expandedadipose-derived 1,073 100 92 Clearly many major players—as well as industry observers—have observers—have manyClearly majorplayers—as well asindustry 96 1,237 1,309 106 113 113 Number of active R&DprogramsNumber ofactive 1,730 150 Sales forecasts ($millions) 2,000 200 2,614 3,000 250 3,290 273 300 4,000 3,872 4,021 350 342 2024 2017 5,000 400 - - - Whatever thecase, theclinicalandcommercial oftherecently impact itmightbereasonable more to dealsinthisspace. expect Otherwise lations involved to could reduce such an endeavour. the barriers (many alreadymarket have), andthefocused eligible patient popu numerous to goitaloneto smallerplayers leadingtheway could try announced inFebruary 2019.Source: EvaluatePharma, March 2019. Fig. 3| Top 20companies inthefieldofcell, geneandnucleicacidtherapies, basedon2024salesforecasts. CAR-T, antigenreceptor-T chimeric cell;RNAi, RNA interference. Source: EvaluatePharma, March 2019. Table recent 1|Selected dealsrelated to cell, gene andnucleicacidtherapies April 2016 April 2016 August 2017 October 2018 January 2018 April 2018 May July 2018 2018 August 2018 September 2018 October 2019 February 2019 April date Deal BrainStorm Cell Therapeutics BrainStorm Alnylam Pharmaceuticals BioMarin Pharmaceutical BioMarin The Medicines CompanyThe Medicines Iovance Biotherapeutics Moderna Therapeutics Moderna Abeona Therapeutics Sarepta Therapeutics Spark Therapeutics* Spark Akcea Therapeutics Akcea WAVE Life Sciences Intellia Therapeutics Intellia Pharmaceuticals and Regeneron Therapeutics Pfizer andBamboo Pharma Gilead andKite Therapeutics Celgene and Juno Pharmaceuticals Biogen andIonis andAveXisNovartis Takedaand TiGenix Agilis Biotherapeutics and PTC Therapeutics Celenex and Amicus Therapeutics Pharmaceuticals Arrowhead and &Johnson Johnson Therapeutics andSpark Roche Alnylam Pharmaceuticals Pharmaceuticals and Regeneron Companies Gilead Sciences bluebird bio Mesoblast Celgene Novartis uniQure Autolus Biogen Takeda 0 6 7 155 500 Acquisition Acquisition Acquisition In-licensing Acquisition In-licensing Deal type In-licensing Acquisition Acquisition Acquisition In-licensing Acquisition 582 725 727 765 790 795 877 1,000 884 964 therapy Gene therapy Gene therapy Cell therapy Cell skipping and exon- Antisense therapy Gene therapy Cell therapy Gene therapy Gene RNAi therapy Gene RNAi Platform 1,183 1,210 Sales forecasts ($millions) 1,291 1,382 1,500 -

1,586 for $75 millionupfront andatotal potential dealvalueof>$3 billion toPharmaceuticals develop hasrights CRISPR-basedproductsagainst upto ten liver targets technology for therapeuticdevelopment; over asix-yeargene-editing Regeneron period Regeneron Pharmaceuticals acquires exclusive to advance CRISPR–Cas rights worldwide system diseases forneuromuscular $645million and centralnervous Pfizer acquires Bamboo Therapeutics andaccess to genetherapy candidates for rare Gilead acquires Pharma, accessingitsCAR-T Kite for portfolio $11.9billion Celgene acquires Juno Therapeutics, accessingitsCAR-T for portfolio $9billion Biogento pay atotal of$1billionupfront of theinnerearandneuropsychiatry; diseases diseases includingdementia,neuromuscular diseases, movement disorders, ophthalmology, ten-yeara new to term develop novel antisensedrugcandidates for abroad rangeofneurological Biogen andIonisPharmaceuticals expandthecollaborationthatdelivered Spinraza(nusinersen)with neurological geneticdiseasesfor $8.7billion acquires AveXisNovartis to advance itspipelineofgenetherapiesinlife-threatening of allogeneicstem cells, for $626million Takeda acquires properties TiGenix, accessingnovel technology basedontheanti-inflammatory for system diseases, rare for monogeniccentralnervous $945million PTC Therapeutics acquires Agilis Biotherapeutics, accessing aninnovative genetherapy platform Children’s Hospital, for $452million($100upfront pluscontingent components) Amicus Therapeutics acquires Celenex, ofNationwide agenetherapy company spin-out a total dealvalueofupto £3.7billion collaborate onupto three RNAicandidates new for $250millionupfront with (cash plusequity) licenseforJanssen obtainsaworldwide Arrowhead Pharmaceuticals’ andanoptionto ARO-HBV Spark Therapeutics continuingoperationsasanindependentcompany Group withintheRoche announcestheacquisition ofSpark Roche Therapeutics for valueof$4.8billion,with atotal equity $1 billion,including$800millionupfront from (cash Regeneron plusequity) commercialize RNAitherapeuticsfor eye andneurological disorders, upto whichcouldbeworth withAlnylam Pharmaceuticals inadealto developRegeneron and Pharmaceuticals partners Deal summary 1,661 1,694 introduced cell-based and gene-based therapies will be fascinating therapieswill befascinating introduced cell-basedandgene-based Paul Verdin are andLisaUrquhart atEvaluate Ltd. of$44billionsalesin2024willbeputtothe sell-sideview thetest. to watch andwillnodoubtcontinueto generate headlines—and 2,000 1,970 2,128 2,129 2,500 2,787 3,000 3,033 2024 2017 3,500 *Acquisition by Roche biopharmadealmakers.nature.com |June2019 |

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