in March 2019, Roche asked theregulator asked in March 2019,Roche to approve thedrugin 2018underthenameXofluza. Andaged 12andolderinOctober uncomplicated fluinpeople justonce—for the drug—apilltaken disclosed. The USFood andDrugAdministration (FDA) approved thefluvirususesto replicate; financialswerease, anenzyme not baloxavir marboxil, aninhibitor ofpolymeraseacidicendonucle- fora dealwithRoche (outside Japanand globalrights Taiwan) to Japan-based Shionogi & Co. 2016, Osaka, neuraminidase. struck In theneedforunderlining improved alternatives. therapy issmall, andresistance to thedrugshasbeenreported, offluinfection fromcases thereduction inthedurationorseverity while these drugs represented advance, in some an important role that has a in key the viral life ( cycle enzyme Bothtarget neuraminidase, themarket. an (zanamivir)—reached flu—Roche’s Tamiflu (oseltamivir) andGlaxoSmithKline’s Relenza antiviraldrugsfor decadessincethemostwidelyknown istwo It Antiviral opportunities vaccines. novel therapeutic modalities, including prophylactic mRNA-based influenza has also become a proving for ground a handful of ofsorts virology hotbeds such as hepatitis B and hepatitis C. Furthermore, fieldcompared withother up inwhathasbeenanunder-the-radar ininfluenzamay alsobepicking dealmaking and growing, therefore in fluantivirals and vaccines. flupipeline is industry’s The biopharma efforts Foundation Gates the Billand Melinda industry has rekindled ofHealthandphilanthropiesas theUSNationalInstitutes including several years aninfluxofcapitalfrom government agenciessuch venture capitalinvestment oncology. like inthepast Nevertheless, same from year to year. to developlaboring anarsenalagainstflutargets thatremain the cines, dampeningtheiruse. are As such,drugandvaccinemakers tightened, canmisfire anderode thepublic’s confidenceinthevac- a wrench from a toolbox before the size knowing of the nut to be viruswillstrike. of theever-changing These choosing guesses, like designed halfayear before whichstrains researchers exactly know The bestfludefense remains seasonalvaccines, whichmustbe however, andlimited there treatment are options. onlyimperfect offlu, andubiquity old. theseverity Despite young andvery very in vulnerable populations such as the immunocompromised or the year,thousands of people worldwide in a typical those inparticular Flu isadeadly, hundreds of epidemic, annuallyrecurring killing Morrison Chris is increasingly focused to ontargets treatments. evade lesslikely Antiviral andvaccineR&Dfor thecommon,deadly, andelusive influenzavirus flu battle to viral denominators common targeting Biopharmas high-risk populations; a decision is expected inNovember populations;adecisionisexpected 2019.high-risk As part of this search, drug companies haveAs movedpart beyond isnotahotbedof diseaseingeneralandfluparticular Infectious Fig. 1).

However, that have becomeresistant to Tamiflu. offlustrains,Xofluza iseffective includingthose againstavariety private virologyprivate company’s indiscovering nucleoside expertise bytion ofAliosBioPharma in2014—adealthatwasdriven the which targets fluRNApolymerase, viaits$1.75billionacquisi- upthephase1candidate AL-794picked asJNJ-5806), (now known to theemerging ofcombinationtherapy influ. possibility J&Jalso with standard of care, which istypically Tamiflu, whichalsopoints is notable that are these trials ceuticals evaluating unit. pimodivir It infections R&DatJ&J’sand headofrespiratory Janssenpharma- patients in the outpatient setting, said Jason Chien, vice president plicated influenzaAinfection andthesecondistreating high-risk studies: oneistesting the druginhospitalized adultswithcom- influenza RNApolymerase(Fig. 1 milestones androyalties. Pimodivir inhibitsthePB2unitof VX-787) from Vertex Pharmaceuticals for $30millionupfront plus 2014,itlicensedpimodivir(formerlybusiness development. In virus to mutate to generate resistance to smallmolecules.” andthatare, are“that inprinciple, mostconserved thehardest for the tiple strainsofinfluenzavirus, sothecompaniescanidentifytargets , saidCocrystal’s platform gives itinsightacross mul- and CSOfor thecompany’s sciencecenter inCambridge, exploratory atMerckpresident &Co. ofinfectious diseasesandvaccinediscovery inhibitor ofthePB2subunitfluRNApolymerase. Hazuda,vice Daria separately developing itsleadpreclinical candidate CC-42344, an closed thetargets are they together, exploring is thoughCocrystal upfront andmilestone payments. The collaborators have notdis- the collaboration’s andcouldpay upto R&Defforts $156millionin 2019(Table 1drug design specialistinJanuary ). Merck isfunding Pharma, anantiviral-focused structure-based ance withCocrystal related to theprograms, plusroyalties (Table 1 ). $291 millionindevelopment andcommercial milestone payments anundisclosedupfront feeNovartis andisonthehookfor upto deal. Gileadpaid but declinedto detailthefluassetinNovartis company as “broadly interested infections” viralrespiratory inserious virus.”influenza, andherpes the described AGileadspokesperson tigational agents with the potential to treat human rhinovirus, three preclinical antiviralprograms from Novartis, “including inves- plus milestones and royalties. July 2019, Gilead said it licensed In oseltamivir, whichitlicensedto in1996for Roche $10millionupfront inthe field, havingSciences, discovered whichhasalonghistory Amongthemisthevirology behemothGilead too. antivirals flu Other large biopharma companies are pursuing next-generation large companies are biopharma pursuing next-generation Other Johnson & Johnson hasalsoaddedseveral fluantiviralsthrough & Johnson Johnson Also signalling itsinterest inthearea, Merck &Co. aflualli- inked ) and is in two globalphase3) andisintwo biopharmadealmakers.nature.com |November 2019 |B3

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feature feature B4 |November 2019 | of avian fluthatcrossed over into humansinrecent years—were showing thatvaccinestargeting strains H10N8andN7N9—two The firsthumanstudiesofthattechnology read 2019, outinMay cine platform, althoughfluisnotoneofitscommercial priorities. covered by eachseason’s vaccine. amoreto make accurate prediction for thestrainsthatshouldbe eggs. This would give the World HealthOrganization more time tional seasonalfluvaccines, whichare produced typically inchicken to design andmanufacture, compared with5–6monthsfor conven strategies. For example, only3months an mRNAvaccinewould take fighting thefluvirus, orenableimprovements inexistingvaccine Emerging technology platforms may provide approaches new to Platform potential fluvirusparticles. cancers—interferes withformation offunctional says ATR‑002’s inhibitionofMEK—a well-trodden target invarious candidate ATR in animal models of severe influenza. Finally, Atriva Therapeutics’ lead andmortality to morbidity the presence ofviralRNA—contributes other viralinfections, sinceexcessive TLR3 signaling—triggered by but it was not effective. Provention says it may pivot toward flu and inulcerative trial colitis, endpointsinanearly-stage and tolerability ative 2019,itwasannounced thatthedrugmetsafety May colitis. In the biotech licensedfrom Janssenasapotential treatment for ulcer the fluvirus. Provention Bio’s PRV it wasnoteffective againstinfluenza B, saidChien). latter program because althoughit was scientifically interesting, discontinuedthe advantagesoverpractical abiologic (Janssen fighting therapies, anorallyavailable smallmoleculehasmany protein; althoughsuchantibodieshave beenconsidered asflu- the bindingofbroadly neutralizingantibodiesagainstthatviral cal studies(Science was effective against a group of common flu strains in preclini regionmolecule inhibitor ofhemagglutinin ofahighlyconserved of researchers from organizations thatasmall- thetwo reported basis for ahumanvaccine. AndinMarch 2019,aseparate group infection (Science nin anddelivered by AAV genetherapy protected micefrom flu antibody targeting hemaggluti that a multi-domain reported candidates. late 2018,researchers In from organizations thetwo hassofaryieldedmultiplepreclinical Research Institute Scripps titis C Janssen andotherviruses. and the between A2013 pact virus, flu, syncytial hepa analogue antiviralsagainstrespiratory Table recent 1 |Selected influenzadevelopment dealsduring 2018–2019 August 2018 Date July 2019 July 2019 July 2019 2019 January September 2018 hasusedfluasaprovingModerna ground for itsmRNAvac companiesare attempting toOther target hostproteins to hobble ‑ 002, a MEK inhibitor, entered phase 362, 598–602;2018)—potentially forming the biopharmadealmakers.nature.com 363, eaar6221;2019). The compoundmimics BioNTech Roche Novartis Vaxart, Inc. Inc. Pharma, Cocrystal (AstraZeneca) MedImmune Licensor ‑300 isananti Licensee Pfizer Sanofi Gilead B.V. (Janssen) and Prevention Janssen Vaccines Merck &Co. Biotechnology Vir TLR3 antibodythat

1 in May. Atriva Financials ($millions) investment inBioNTech) of which $425 (including$120upfront $291 $156 $343 (including10upfront) ------was an equity $70 was anequity into various strains.into various by—for example, H1N1. subdivided These viruses canbefurther 11 NAvariations, theHandNnumbersvirusesare identified A’s ofthevirus. Influenza the surface 18HAand comprise subtypes proteins found on (HA) andneuramidase(NA)whichare spike-like are RNAvirusesthatcodefor 11proteins, includinghemagglutinin whichAinfectsof fluvirus(A, humansmostvirulently) B, andC—of Fig. oftheinfluenzaAvirus. 1|Structure Allthreetypes distinct expect to beginexpect aclinicalprogram by theendof2020. upfront, includinga$70 millioninvestment inBioNTech. The partners $120 million mRNA vaccinesagainstseasonalflu, inadeal worth platform company BioNTech teamed upwithPfizer to develop remains inpreclinical development. AndinAugust 2018,themRNA hasdissolved, CureVac’spartnership mRNAinfluenzavaccine CV7301 Janssen alliedwithCurevac onanmRNAfluvaccine;althoughthat funding, to thecompany external only advancesubject says. 2013, In virusandchikungunya, will vaccinesagainstZika health-oriented being moved into phase 2. The fluvaccines, similar to otherpublic seat to Moderna’s vaccinemRNA‑1647,whichis cytomegalovirus company’s September 2019 highly immunogenicandsafe inhealthy volunteers. the During PB2 1 PB1 2 Deal summary Roche licenses Sanofi Roche OTCrights to Tamiflu influenza viruses to potentially treat rhinovirus, and herpes programs againstthree undisclosedtargets to develop three preclinical antiviral dealwithNovartis Gilead signs partnership universal influenza vaccineprogram development ofanoralvaccinefor Janssen’s use ofitsoralvaccineplatform for the withJanssento evaluate the Vaxart partners influenzaA/Bantiviraldrugs certain million dealwithMerck &Co. to develop Pharma signs potential $156 Cocrystal MedImmune Vir Biotechnology licenses VIR-2482 from vaccines for influenza to collaborate onthedevelopment ofmRNA BioNTech signs $425milliondealwithPfizer PA 3 80–120 nm HA R&D day, thefluprograms took aback 4 NP 5 NA 6 M 7 NS 8 Hemagglutinin Neuramidase Nucleoprotein (PA, PB1,PB2) Polymerase complex M2 ionchannel M1 matrix protein Lipid envelope after yearafter hasproved elusive. mid-2019,for example, In GSK messenger RNA. be expressed inavirusor, inthecaseofseveral biotech approaches, and thosevaccinesare emerging from several platforms—they can regions ofthevirustoserved create universal vaccines, henotes, are &Johnson, including oneatJohnson targeting highlycon programs withupto saidPalese. 50,000subjects, groups, Other vaccines mustclear, theFDA requires large andexpensive clinical bars that thehighsafety and efficacy funding is alifeline—given Foundation,the Gates and has begun phase a hostcell. tional restraints,” he said, because it’s what the virus uses to enter architects. stalkismuchmore functional, andsoithasfunc “The chair ofmicrobiology Sinaiandoneofthevaccine’s atMount frequently, the stalk ismuch more conserved,” said Peter Palese, amushroom andwhiletheheadofmushroomlike changes regiona conserved of flu hemagglutinin. “Hemagglutinin looks Sinai to fund developmentMount ofa universal vaccine targeting $132 million to researchers at from ofMedicine IcahnSchool Pharmaceuticals. 2019, the NIH And awarded in October up to universal flu vaccine candidate from the Israeli biotech BiondVax for Diseasebeganaclinicaltrial Allergy M-001, andInfectious 2018,theNIH’sdidate, May saidChien.In for NationalInstitute (BARDA) Authority and Development on auniversal vaccine can with the US Biomedical AdvanceJanssen is working Research arestage clinicaltrial. But several efforts ongoing. Amongthese, disclosed universal fluvaccinecandidate, amid- itflunked after abandoned development ofGSK3277526A,thecompany’s only duration ofinfection anditsspread to others. for and reduce mostvulnerablepeopleanddooften theseverity Although seasonal flu vaccines aren’t tend they to be free perfect, Ltd, Sanofi,AstraZeneca’s unitandGlaxoSmithKline. MedImmune worldwide, is supplied by only a few companies, including CSL estimated atroughlyThe $3–4billion seasonalfluvaccinemarket, goals Universal The Mount SinaivaccinehasalsoreceivedThe Mount fundingfrom GSKand far,So a universal flu vaccine thatwould remain effective year 1 testing. The NIH - - -

Palese. vaccinetechnologies mRNAare New emerging like and tocontributed thepromise ofcreating a universal vaccine, said second halfof2020. populations should be available in high-risk in theclinical trial an entire flu season, the company says. Data from a phase theantibody’sextended half-life sothatasingledosewilllast a dealwiththeantibodyengineering company Xencor, Vir has regiontargets ofinfluenzaAhemagglutinin.Under aconserved $10 licensed from AstraZeneca’s inSeptember 2018for MedImmune ment oftheantibody VIR‑2482 for theprevention offlu, whichit public on the NASDAQ. The company is already pursuing develop $500 million from investors private intotal, andrecently filedto go Foundationthe Gates and Arch Venture Partners, and has raised Vir was launched in 2017 with $150 Biotechnology, which calls the platform ’immune programming’. to prompt an immune response, and has been licensed to Vir viralantigensintoogy incorporates abenign cytomegalovirus and tuberculosis vaccineplatform toward flu. The technol which landed$1.7 millionto repurpose itsexistingvaccineHIV $12 millioningrants. whichtogetherDevelopment, earned the winnersofitsGrandChallengefor Universal Influenza Vaccine Foundation,Gates alongsidethenon-profit Flu Lab, announced the threat ofinfluenza” withauniversal August vaccine. 2019,the In ever to marshalresources toward thegoalofdramaticallyreducing biology that “make thecurrent momentamore promising timethan and computational confluence of advances in vaccine manufacturing Chris Morrisonisawriter forthebiopharmaindustry. universal vaccine.” oftimethere period will be real progress short in afairly toward a incremental, but these are real differences. I’m hopeful that very better adjuvantsare being developed, hesays. mightsound “It demonstrating long-lastingandeffective immuneresponses, and Ongoing work in viral sequencing and structural analysis hasOngoing work in viral sequencing and structural One ofthewinnerswasOregon University, Health&Science issuedby theSabin A July2019report Vaccine pointed to Institute a million upfront and up to $343 million in milestones. VIR million from investors led by biopharmadealmakers.nature.com |November 2019 |B5 ‑ 2482 1/2 - -

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