Viral Hepatitis: The Search For A Cure
7/27/2017We will begin momentarily at 2pm ETSlides available now! Recordings available as an exclusive ACS member benefit.www.acs.org/acswebinarsContact ACS Webinars at acswebinars@acs.org1Have Questions?Type them into questions box!“Why am I muted?”Don’t worry. Everyone is mutedexcept the presenter and host.Thank you and enjoy the show.Contact ACS Webinars at acswebinars@acs.org21
7/27/2017Have you discovered the missing element?http://bit.ly/benefitsACSFind the many benefits of ACS membership!3Benefits of ACS MembershipChemical & Engineering News (C&EN)The preeminent weekly news source.NEW! Free Access to ACS Presentations on Demand ACS Member only access to over 1,000 presentationrecordings from recent ACS meetings and select events.NEW! ACS Career NavigatorYour source for leadership development, professionaleducation, career services, and much more.http://bit.ly/benefitsACS42
7/27/2017Let’s get Social post, tweet, and link to ACSWebinars during today’s ch for “acswebinars”and connect!5How has ACS Webinars benefited you?http://bit.ly/TBchemNathan“Excellent speaker, clearly enunciated, wellformed thoughts, comprehensive overview ofsubject matter, excellent, relevant visual aids,all-in-all, superb!”Dr. Joseph Gerstner,Laboratory Director (retired),City of Bristol ConnecticutBe a featured fan on an upcoming webinar! Write to us @ acswebinars@acs.org63
7/27/2017youtube.com/acswebinarsSearch for “acswebinars” and connect!7Learn from the best and brightest minds in chemistry! Hundredsof webinars presented by subject matter experts in the chemicalenterprise.Recordings are available to current ACS members one week afterthe Live broadcast date. www.acs.org/acswebinarsBroadcasts of ACS Webinars continue to be available to the generalpublic LIVE every Thursday at 2pm ET!www.acs.org/acswebinars84
7/27/2017An individual developmentplanning tool for you! Know your career options Develop strategies to strengthen your skills Map a plan to achieve your career goalsChemIDP.org9Upcoming ACS Webinarswww.acs.org/acswebinarsThursday, August 3, 2017Discovering Vismodegib in the Fight Against Skin CancerSession 7 of the 2017 Industrial Science SeriesDan Sutherlin, Principal Scientist and Director, Discovery Chemistry, GenentechMark Jones, Executive External Strategy and Communications Fellow, Dow ChemicalThursday, August 10, 2017Caesar’s Last Breath and the Fascinating Science andHistory of the Air We BreatheSam Kean, New York Times bestselling authorCelia Arnaud, Senior Editor, Chemical & Engineering NewsContact ACS Webinars at acswebinars@acs.org105
7/27/2017www.aaps.org/DDDIRM1711Join the ACS Division of MedicinalChemistry Today!For 25 ( 10 for students), You Will Receive: A free copy of our annual medicinal chemistry review volume(over 600 pages, 160 retail price) Abstracts of MEDI programming at national meetings Access to student travel grants and fellowshipsFind out more about the ACS MEDI Division! www.acsmedchem.org126
7/27/2017Catch up on Last Year’s Design andDelivery Symposiumhttp://bit.ly/2016ddds132017 Drug Design and Delivery SymposiumSave the Date for the next webinar!“Spinal Muscular Atrophy: Novel Approaches for Treatment”Kevin Hodgetts of Harvard Medical School147
7/27/2017Inaugural Pharma Leaders SymposiumACS National Meeting in DCAug. 21, 2017 - 1 to 4 PMWalter E. Washington Convention Center - Room 146C“ACS Pharma Leaders: Working together to make a difference” neglected diseases chemistry collaborations predictive scienceSpeakers:Richard Connell of PfizerLisa Shewchuk of GlaxoSmithKlineBradley Sherborne of MerckAnil Vasudevan and Dale Kempf of AbbViePeter Warner of The Gates FoundationOrganizers:Philip Kym of AbbVie, Catherine Peishoff (formerly of GSK), and Wendy Young of GenentechFor more information, Contact: Susan Ainsworth at s ainsworth@acs.org152017 Drug Design and Delivery Symposium“Viral Hepatitis: The Search for a Cure”Michael SofiaCo-founder and Chief ScientificOfficer, Arbutus BiopharmaStephen MasonExecutive Director, Discovery,CaroGen CorporationSlides available now! Recordings are an exclusive ACS member benefit.www.acs.org/acswebinarsThe 2017 DDDS is co-produced with ACS Division of Medicinal Chemistry and the AAPS168
7/27/2017Viral Hepatitis:The Search for a CureMichael J. Sofia, Chief Scientific OfficerArbutus Biopharma, Inc.17Forms of Viral HepatitisFive forms of viral hepatitis: Hepatitis A, B, C, D, E Hepatitis A– Acute self-limiting infection– Contracted by eating contaminated foods– Rarely leads to permanent liver damage Hepatitis B– Acute infection can lead to chronic infection– Contracted by vertical infection or from contaminated blood sources– Lead to liver damage and HCC Hepatitis C– Acute infection can lead to chronic infection– Contracted from contaminated blood sources– Lead to liver damage and HCC Hepatitis D– Occurs only in conjunction with HBV– Leads to a more sever form of HBV-related liver disease Hepatitis E– Typically only an acute self-limiting infection – problem in immune compromisedindividuals– Fecal to oral transmission route189
7/27/2017Chronic Viral Hepatitis: HBV & HCV Every third person on the planet shows evidence of infection with viralhepatitis 500 million people are chronically infected with hepatitis B or C 1 million die every year: 1 every 30 seconds Globally 57% of cirrhosis and 78% of primary liver cancer are due tothese 2 diseases 80-90% of liver transplants associated with HBV & HCV infection The majority of those chronically infected are undiagnosed – hepatitis Band C are often asymptomatic for years The sheer size of the problem is intimidating - as many people arechronically infected with viral hepatitis in 2 African countries as there arepeople living with HIV/AIDS in the whole world19Summary of Epidemiology and NaturalHistory of Chronic Viral Hepatitis HCV––––170-200 Million infected20% lifetime risk of cirrhosis4% lifetime risk of HCCLeading cause of liver transplant in North Americaand Europe– No vaccine availableHBV––––2 Billion ever infected 400 Million infected now1 Million die each year of HCC or cirrhosis25% life time risk for each HBsAg patient of HCCor cirrhosis– Second most common carcinogen (liver cancer)after cigarettes– Preventive vaccine available 20-30 years NormalCirrhoticHCCLinked to the co-existence of multiple comorbidities2010
7/27/2017Challenge QuestionANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENTWhich chronic viral disease has the highestworldwide prevalence rate? HIV HCV HBV None of the above21HBV vs HIV vs HCVHIVHCVHBVU.S. Prevalence1 million3 million1.3– 3 millionWorldwide Prevalence35 million160 million350 millionPercent Diagnosed in U.S.80%50%30%Percent Diagnosed Who AreTreated in U.S.70%33%6-10%NatureRNA retrovirusRNA virusDNA virusVirions Produced per Day101010121013Enzyme Targets for TherapyMultipleMultipleOneCurable?Unclear; lifelong suppressionwith HAART therapyYesUnclear; lifelong suppressionwith Nuc therapyWhy Easy / Difficult?Proviral DNA integrated into hostgenome, difficult to eliminateRNA virus existing in the hostcytoplasm; can eradicate withcocktail of small moleculesDAAscccDNA inside the nucleus, alsointegrated into host genome,difficult to eliminateNeed Immune Component inTherapeutic Regimen forCure?MaybeNoMaybeTransmissionInfected blood/needles, sexInfected blood/needles, sexInfected blood/needles, sexVertical TransmissionYesNoYesVaccineNoNoYes2115 U.S. Sales 9.3 billion 13.3 billion 700 million2211
7/27/2017Can it become a disease of the past?23HCV: Prevalence, Total Infected, GenotypeNorth AmericaEurope, WesternEurope, CentralEurope, EasternAsia, CentralAsia Pacific, High IncomeCaribbeanAsia, SoutheastAsia, EastLatin America, CentralPrevalence(Viremic)Latin America, TropicalLatin America, AndeanTotal 0.8%-1.3%650K-1.9M1.3%-2.9%1.9M-3.5M2.9%-7.8%Latin America, SouthernAsia, SouthNorth Africa/Middle EastAustralasia3.5M-9.2MSub-S Africa, CentralRazavi H, Gower E, Estes C, Hindman S. Global HCV Genotypes. AASLD 2013; 2013 Nov 1-5; Washington, DC, United States.Sub-S Africa, SouthernSub-Saharan Africa, West2412
7/27/2017Growing Burden of Mortality Associated withViral Hepatitis in the US (1999-2007) National multiple-cause mortality data1999-2007 Mortality rates of HBV, HCV, and HIV;United States 1999-2007 73 % of HCV and 59 % ofHBV-related deaths in personsaged 45-64 Co-morbidities associated with increasedodds ratio of mortality––––Chronic Liver Disease(32.1;HCV and 34.4;HBV)co-infection with other hepatitis virus(29.9;HCV and 31.5;HBV)Alcohol related(4.6;HCV and 3.7;HBV)HIV co-infection(1.8;HCV and 4.0;HBV)Holmberg SD , et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 2432513
7/27/2017Hepatitis C Virus:Morphology and Characteristics Nucleic Acid: 9.6 kb ssRNA( ) Classification: Flaviviridae, Hepacivirus Genotypes: 1 to 6 Enveloped No known viral reservoir Does not integrate into host genome27High Risk of Infection170 Million InfectedWorldwide Clotting factor treatment prior to1987 Injection drug use Injection treatments prior touniversal precautions Long-term hemodialysisCDC, MMWR 1998; 47:41 in 30Baby BoomersInfected2814
7/27/2017The Hepatitis C VirusHCV Lifecycle HCV GenomeError-prone RNA-dependent, RNA polymerase- poor proofreading function- high replication rate in vivo 9.6 kb genome: 0.1-1 error per RNA synthesizedReplication RatesHCVHIV10121010-1011Lindenbach, B and Rice, C., Nature, 2005, 436,93329Key Target Areas of DrugDiscovery Focus and Key DrugsProtease Inhibitors NS5A tasvirOmbitasvirElbasvirAdapted from : Liver Internationalpages 69-78, 23 DEC 2013 DOI: se abuvirBeclabuvir3015
7/27/2017Challenge QuestionANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENTWhat was the first IFN-free HCV cure therapy tobe approved by the US FDA? Harvoni (sofosbuvir ledipasvir) Viekira Pak (ombitasvir paritaprevir dasabuvir ritonavir) Zepatier (grazoprevir elbasvir) Sovaldi (sofosbuvir) RBV31FDA Approved IFN-FreeHCV Cure Drug Combinations2013201420152016Year and Order of Approval20173216
7/27/2017The History of HCV Therapy Development48100%90%80%24 67- 75%1660%40% 42-46% 33-36%08RBVIFN 019893x Weekly 10-11% PEG IFN 3x Weekly1998ProteaseSovaldi RBV IFN Weekly2001SVR (Genotype 1)Treatment Duration (Weeks) 94 - 99%RBV10%RBV PEG IFN HarvoniPEG IFN Weekly201120%Weekly2013Daily0%2014Time33HCV Curative Therapy Today IFN-Free curative therapies are a reality Simple oral fixed-dose and short duration therapies 95% cure rates across multiple genotypes High cure rates in difficult to treat patient populations Patient access is the issue HCV can become a rare disease in the future343417
7/27/2017Is there a path to a cure?35Hepatitis B Virus (HBV) Hepadnaviridae member that primarily infects liver cellsDNA virus100 times more infective than HIVFound in blood and body fluids Viral reservoir: cccDNA in nucleus of hepatocytesSmall segments of viral DNA do integrate but do not code for viralproteins– Able to survive in dried blood for longer than 1 weekOtt et al. J Pediatr Health Care. 1999;13(5):211-216.Ribeiro, et al. Microbes and Infection. 2002;4:829-835.MMWR. 2003;52:1-33.3618
7/27/2017Chronic Hepatitis B: By The NumbersMoreGenotypesthan 350 million or 1 in(based20 people worldwidehave chronic hepatitisB infection 7 HBVon completeHBV(Compared with the 33 million living with HIV )genome): A-G– A – World-wide14 million in Europe112 million in Asia-Pacific– Bmillion& Cpeople– Asia1.46-2in(93 million people in China)the United States are–chronicallyD – SouthernEurope, Middle Eastinfected– E – Africadie eachAmerica,year of HCC or Polynesia– 1FMillion– Southcirrhosistime riskandfor eachHBsAg – 25%G –lifeUSAEurope123,41,25patient of HCC or cirrhosisSecond most common carcinogen(liver cancer) after cigarettes7 HBV Genotypes (based on complete HBV genome): A-GA – World-wideB & C – AsiaD – Southern Europe, Middle EastE – AfricaF – South America, PolynesiaG – USA and Europe1 WHO. Available at: www.who.int/csr/disease/hepatitis/en/. 2 Ferlay et al. Globocan 2002, Cancer incidence, mortality and prevalence worldwide, IARC Press, Lyon 2004.3 Records of the thematic press conference of the Ministry of Health of the PRC at April 21, 2008, from the website of the Ministry of Health of the People's Republic ofChina; 4 Ulmer, T et al. (2007). European orientation towards the better management of hepatitis B in Europe; 5. CDC. Hepatitis B FAQs for Health Professionals. Availableat ew.37The Hepatitis B Virus 4 Promoter elements 2 enhancer elements 10 start sites5 mRNAs: Pregenomic/core/pol (3.5 kb) Precore (3.5 kb) PreS1 (2.4 kb) PreS2/S (2.1 kb) X (0.7 kb)Genome Structure of HBVSource: Gerlich, W. 2013. Virology Journal,10:239Glebe, D., et al, Sem. Liver Dis, 33, 2013, 1033819
7/27/2017Transmission of HBVHorizontal TransmissionHostVertical ted NeedlesSexualHealth Care WorkerTransfusion6% infected after age 5 years becomechronically infectedPerinatalInfant90% infected infants becomechronically infectedNo clear risk factors in 20-30% of patientsCDC Fact Sheet. http://www.cdc.gov/ncidod/diseases/hepatitis/b/. Accessed: October 2, 2004.Lee. N Engl J Med. 1997;337(24):1733-1745.Lavanchy. J Viral Hepat. 2004;11(2):97-107.39Three Phases of Chronic HBV InfectionSource: Gerlich, W. 2013. Virology Journal, 10:2394020
7/27/2017REVEAL-HBV:Clearance of HBV DNA Reduces Risk of HCC REVEAL-HBV study cohort (N 2946; aged 30-65 yrs)– Pts recruited 1991-1992, serum markers evaluated every 6-12 mos until June 30,2004; HCC rates followed until December 31, 2008 HBV DNA suppression independently associated with significantly reducedrisk of HCC– Pts with HBeAg suppression (n 185) still had high HBV DNA levels and still athigh risk of HCC– HBsAg suppression not associated with reduced incidence of HCC, but study notpowered to detect difference Greatest reduction in HCC incidence observed among pts with high baselineHBV DNA ( 100,000 copies/mL) who cleared HBV DNA during follow-up– HCC incidence highest in pts HBeAg seropositive throughout follow-up41HBV Approved deVEMLIDY Gilead Sciences2016TenofovirVIREAD Gilead Sciences2006TelbivudineTYZEKA Idenix/Novartis2006EntecavirBARACLUDE Bristol-Myers Squibb2005Adefovir DipivoxilHEPSERA Gilead Sciences2002LamivudineEPIVIR-HBV PEGASYS Roche Laboratories2005Interferon alfa-2brecombinantINTRON ASchering/Merck1992Preferred Therapies – AASLD Guidelines4221
7/27/2017Relative Efficacy of Approved HBV TherapiesHBeAg positiveEntecavir1,2Tenofovir3PEG-IFN α-2a4,5n 354n 176n 271HBV DNA undetectable67%76%25%aHBeAg seroconversion21%21%27%ALT normalisation68%68%39%HBsAg loss2%3.2%2.9%bn 325n 250n 177HBV DNA undetectable90%93%63%aALT normalisation78%76%38%HBsAg loss0.3%0%0.6%bHBeAg negativeResults at 48 weeksa HBV DNA 400 copies/mL; b At 72 weeks1.2.3.Chang T-T, et al. N Engl J Med 2006;354:1001–10.Lai C-L, et al. N Engl J Med 2006;354:1011–20.Marcellin P, et al. N Engl J Med 2008;359:2442–55.4.5.Lau GKK, et al. N Engl J Med 2005;352:2682–95.Marcellin P, et al. N Engl J Med 2004;351:1206–17.43HBV DNA change from baseline (log 10 c/mL)Long-term Therapy is Requiredto Maintain Viral Suppression Werle et al, Gastroenterology 20044422
7/27/2017What Does a Cure Look Like?Functional CureAbsolute CureClinical ScenarioAs if recovery afteracute HBV infectionAs if never itiveSerum HBV DNANot DetectedNot DetectedHBV cccDNADetected, but nottranscriptionallyactiveNot DetectedHepatic integratedHBV DNADetectedNot DetectedCurrent StatusAchievable in a fewpatientsNot yet achievableJiang, et al., DDW, 201645HBV Chronic InfectionAntigen presenting cellCD4 T cell 1013 virons produced per day Infection is not cytopathic Outcome of infection andseverity of associated liverdisease are determined bynature and magnitude of hostimmune responseCD8 T cellHBVCore particleplus strandsynthesisVesiculartransportto cell membraneCore particleminus strandsynthesisCoreassemblyand iptionRepairEndoplasmiHBV ViralLife Cyclec reticulum46HepatocyteNucleusCytoplasm4623
7/27/2017HBV and the Host Immune Response Inhibition of innate immune signalingInhibition of HBV specific T cell responsesInhibition of antibody responses to HBVOutcome: Immune tolerance, chronicity47 Control viral replication– Cripple the virus Reactivate the host immune response– Release immune toleranceAbsoluteCureFunctionalCureHow to Achieve a Cure? Clear cccDNA4824
7/27/2017HBV Cure: Potential DAA Drug Targets49HBV Cure: Emerging StrategiesViral Attachment Inhibition Preclinical and Clinical POC Clinical results modest and variable Effects in HDV also5025
7/27/2017Entry Inhibition: Myrcludex B1. Infection of PHH-transplanted uPA/SCID micewith HBV for 3 weeks2. Treatment of infected mice with Myrcludex Bfor another 3 weeks blocks HBV spreadMyrcludex B monotherapy in chronically infected patientsMyrcludex reduces HBV DNA by 0.8log (w12)2016 AASLD/EASL HBV Workshop Sept. 8th 201651Nucleoside ProdrugsLiver Targeted Tenofovir ProdrugsCMX157Launched as Vemlidy Phase II Clinical DevelopmentAdvantages Increase drug levels in liver Reduce renal and bone toxicity associated with Tenofovir5226
7/27/2017Inhibition of HBV Capsid Assemblyand pgRNA Encapsidation Hepatitis B virus replication is strictlydependent upon capsid assemblyClass IIClass Iaround pregenomic RNA (pgRNA) priorto rcDNA synthesis and subsequentcccDNA synthesis. Assembly of HBV nucleocapsid isdependent on ordered folding of theviral capsid protein. Interfering with HBV capsid assemblywith small molecule inhibitors has beenshown to translate into antiviral activityin vitro and in vivo and constitutes anovel mechanism that is distinct fromthe nucleos(t)ide analogues currentlyavailable for clinical use.HBV capsid assembly pathway and examples of inhibitors[core protein allosteric modulators (CpAM)]53First Clinical POC of Capsid Inhibitors (NVR-3-778)NVR 3-778 PEG IFNalpha-2a Combo in treatment naïve HBeAg positive patientsIFN aloneNVR 3-778IFN NVRYuen et al EASL 2016 Oral PresentationOArSummary TableO OSRNR'NHR"d28 HBV DNATreatment(log10 from BL)NVR 3-778-1.72PegIFNa-2a-1NVR3 -778 PegIFN-1.97d28 HBV RNA(log10 from BL)-0.82-0.73-1.51(NVR 3-778 @ 600 mg BID; Peg-IFN 180 ug/wk)5427
7/27/2017Capsid Assembly Inhibitor AB-423 Data suggests AB-423 has a dual mode of inhibition: Inhibits encapsidation of pgRNA during ongoing infection Inhibits cccDNA synthesis presumably via inhibition of thecapsid uncoating stepcopy number/cell4.03.02.01.00.0cccDNAETVA B -4 2 3 , 1 0 0 m g / k g B IDA B -4 2 3 E T VA B -4 2 3 P e g a s y s1010 .107142128DayDual mode of inhibition by capsid assembly inhibitorsSubviral par: cles Cytoplasm Infected MyrcludexB1.5V e h ic le100S e r u m H B V D N A (% P r e - D o s e ) In vitro AB-423 showed: additive/synergistic activity in combination with Nucs and RNAiagents potent activity against HBV NucR variants and pan-genotypicactivity no significant activity against unrelated virusesAB-423 inhibited cccDNA synthesis during de novo HBVinfection of C3AhNTCP cellspgRNA relative level IFNαAB-423Intermediate Compartment Vesicular transport to Golgi and cell membrane HBV virion pgRNAEndoplasmic re: culum Surface an: gen Mul: vesicular body NTCP (receptor) 1.0DNA synthesis xpgRNA Core Pol Transla: on Nucleus Core assembly RNA packaging Intracellular amplifica: on 0.5HBV enters cell 0.0Infected MyrcludexIFN-αxCapsid disassembly ProteinFfree viral DNA Repair cccDNA AB-423Transcrip: on 55Capsid (Core Protein) Assembly InhibitorsClass IHeteroaryldihydropyrimidine (HAP)Class IIPropenamidesSulfonylbenzamides5628
7/27/2017Capsid Assembly Inhibitor Patent LandscapeJanssenBayerFOArOClMeONNHO OSRNR'NHRocheNoviraOArOO OSNNHOHNHRNN NnR"R"ArFE ANArFBAY-41-4109BDNHO OSRNR'OArO ArO OSNNHOHOOArO ORSNX NHR'XNHFONnNHSunshine Lake PharmR'ArNHR"NHRRNYXOOArBrEtONNNHGLS-4NR4 ONRNR'AssemblyONHSOArOONHNHONOORNR'R"SHN R57Crystal Structure of BoundCapsid Assembly InhibitorHAP (Class I)- Proc. Natl. Acad. Sci. 2015, 112, 15196.5829
7/27/2017HBV Cure: Emerging StrategiesInhibit HBsAg Production or SecretionRNAi Approach Clinical and preclinicalPOCPotency & safety LNP DeliveryTriple Trigger Chol-siRNA GalNAc-siRNANucleic Acid PolymersSequestration Clinical POC?MOA?Small Molecules Preclinical in vitroPOC? 40 mer59Controlling S-Antigen Productionvia RNAi (ARC-520) Preclinical study in 9 HBVinfected chimpanzees (9-37y) NUC pretreatment 8-24w,repeated injections of ARC520 Dose escalation study (single dose i.v.):32 HBeAg-, 8 HBeAg CHB patientsunder ENTWell tolerated up to 4 mg/kg underpretreatment with oral antihistamineReduction of serum HBsAg up to0.5 log (HBeAg- patients)0.7 log (HBeAg patients)Reduction of HBeAg up to 2 logProgram Terminated do to tox signal6030
7/27/2017Controlling S-Antigen Productionvia RNAi (ARB-1467)PXB Mouse Study LNP Delivery Technology Triple trigger RNAi Serum HBsAgTKM-HBV 0.3 mg/kg120100806040200% Untreated at Day 42Serum HBsAg as% BaselineUntreatedLivercccDNA071421Day2835HBV DNALiverSerum125100755025042Day 42 (terminal analysis)n 5, mean SEMTreatmentsHuman Clinical Study Single-dose results showsignificant reductions in serumHBsAg levelsMulti-dose results show a stepwise, additive reduction inserum HBsAgReductions of 1.0 log10 in 3/5patients (after 3 monthly doses at 0.4mg/kg)Streinu-Cercel, A., et al., EASL 2017, Abst # SAT-15561Controlling sAg viaNucleic Acid Polymers (NAPS)Mono therapy with REP 2139-CaAl-Mahtab M, Bazinet M, Vaillant A (2016) Safety and Efficacy of NucleicAcid Polymers in Monotherapy and Combined with Immunotherapy inTreatment-Naive Bangladeshi Patients with HBeAg Chronic Hepatitis BInfection. PLoS ONE 11(6): e0156667. doi:10.1371/6231
7/27/2017Reducing or Eliminating cccDNAVirusentryrcDNA to cccDNAConversioncccDNAdecay? Can inhibitioncontribute to reductionof cccDNA pool?pgRNA to rcDNA conversion Long term nuc treatment results in multi-logreduction of cccDNA pool IFN treatment inhibits transcription and capsid stability,reduces cccDNA pool63cccDNA Formation and StabilityWhat We Know and What We Don’t Know Chromatization--Complexed with H3 and H4 histones,acetylation regulates HBV replication Regulation of expression--HBX destabilizes SMC5/6episomal silencing complex Capsid conformationalshift rcDNA deproteinization--TDP2 implicated butunconfirmed Completion of ( ) strandand removal of RNA primer---PolK implicated--HBX itself is likely transcribed veryearly, active at low levels Modulation of cccDNA copy numberin non-dividing cells?--IFN/TNF/LTß upregulation ofAPOBEC3A DNA ligation of bothstrands over gap--Factors? DNA ligase 1 3 implicated6432
7/27/2017Regulating cccDNA TranscriptionEpigenetic Control of cccDNAHDAC1HDAC1 ICATIVE STATEHIGH-REPLICATIVE STATESilencingInterferon alpha,Capsid inhibitors,Epigenome modifyers Epigenetic regulation:- Histones acetylases, deacetylases,methyltransferases- Transcription factors- Binding of viral proteins: HBc & HBxPollicino et al. Gastroenteroplogy 2006Levrero et al. J Hepatol, 2009Lucifora et al, J Hepatol 2012Belloni et al, PNAS 20O9Belloni et al, J Clin Invest 201265cccDNA: A Target for Gene EditingGene EditingTargeted DNA Cleavage EndpointsEngineered EndonucleasesMeganucleases/Homingendonucleases (HEs)Tal-effectornucleases (TALENs)Zinc FingerNucleases (ZFNs)CRISPR/Cas9NHEJ – Non-Homologous End-Joining; results in short mutations, insertions and deletions (indels)HR – Homologous Recombination; accompanied by donor DNA, capable to insert / replace sequenceNishimasu et al, Cell 2014Stone et al, Curr Opin HIV/AIDS 20136633
7/27/2017cccDNA: A Target for Gene EditingGene Editing: Targeting HBV with CRISPR/Cas9 Co-transfection of 1.3x WT HBV and sgRNA-Cas9-2A-mCherry plasmid by HDI inmice, followed by monitoring viral markers in mouse blood Total HBV DNA and cccDNA exhibit dramatic, increasing reductions over time67Immunmodulation:Challenges on the Path to a Cure1. Heterogeneous host immunity among HBV patients.-whatis a clinical biomarker for host immune re-awakening?2. Lack of understanding of the immunological functionof viral proteins.-allinhibitory? or stimulatory?HBV cure6834
7/27/2017HBV Cure: Potential ImmuneModulatory Drug Targets69HBV Cure: Emerging StrategiesRestoration of Antiviral ImmunityBertoletti A, Gehring AJ (2013) Immune Therapeutic Strategies in Chronic Hepatitis B Virus Infection:Virus or Inflammation Control?. PLoS Pathog 9(12): e1003784. doi:10.1371/journal.ppat.10037847035
7/27/2017TLR7 Agonist GS-9620Woodchuck StudyHBV DNA LevelsGS-9620 HBsAg Levels 5 mg/kg QOD, 4-8 weeksMean Max viral load decline of 6.12.9, and 5.8 observedsAg levels reduced to undetectablein 100% of animalsReduced sAg levels were sustainedafter cessation of therapyHuman Clinical Study Discontinued due to lack ofefficacy Dose limiting toxicity?Menne, S, et al., J. Hepatology, 2015, 62, 1237-124571RIG-I Agonist: SB9200 Dinucleotide Reduction inserum HBV DNA Reduction in sAglevels Induction of ISGs Induction of type 1IFNFletcher SP, Menne S (2015) PLOS Pathogens (Sept. 2015).7236
7/27/2017STING Activation Controls HBV Replicationand Induces Cytokine Production STING expressed in hepatocytes (low level), antigen presenting cells and T cells An innate immune adaptor that regulates responses to cytosolic/viral dsDNAD ose50001 234000IL - 6 ( p g /m L )Dose7300020001000BLO Qg25.5mmgg/k/kg1212.5mmIFgN/k- dteaetrU500g06nS e ru m H B V D N AL o g 1 0 ( C o p ie s /m L )81 2 3IP - 1 0 ( p g /m L dteaentrg5DM XAA400cG AM P300200100BLO QDMXAA2’3’ cGAMP bisphosphorothioateMouse STING agonistHuman/multi-species activegg/k/km1225.5mgg/kgm1U2n.5mtreIFaNted- g0DM XAAcG AM PThi, E. et al., ICAR, 2017 Abs # 13573HBV Cure:The Drug Discovery LandscapeImmune modulation Toll-like receptorsagonists, Gilead,Roche Anti-PD-1 mAb,BMS, Merck, Roche,Medimmune, others Vaccine therapyTransgene, Gilead,Roche Innovio, others STING: ABUS Cyclophilin:Contravir RIG-I: Springbank,RigontecRNA interference,ABUS, ARWR, ALNY,GSK/Ionis, Arcturus/JNJTargeting HBsAgABUS, Replicor, RocheSurfaceproteinsHBxPolymerasepgRNAPolymerase inhibitors Nucleoside :Gilead,BMS, CoCrystal,ContavirCorecccDNArcDNAEndosomeEntry inhibitors Lipopeptides, e.g.Myrcludex-BTargeting cccDNA ABUS, JNJ, Chromis,Enyo, Intellia, Gilead,Precision BioInhibition of nucleocapsid assembly,JNJ, Assembly, Gilead, Janssen, Roche,ABUS, Enanta, Sunshine LakeZoulim F, et al. Antiviral Res 2012;96(2):256–9; HBF Drug Watch, Available at: http://www.hepb.org/professionals/hbf drug watch.htm.7437
7/27/2017Current Pipeline ofInvestigational AgentsPreclincalEnantaCapsidPhase IIPhase IIILaunchARB-1740JNJ-379AicurisAIC 649EnyoFXRChomiscccDNAPhase isionGene EditingDicernaRNAiMyrcludex BAB-423ALN-HBVCMX157Assembly ABIH0731Ionis-HBVrxNVR3-778 ARB-1467GS-5801SB-9200TenofovirAlafenamideREP 9AC’GS-9620RG-7834RIG-IRNAiTherapeutic VaxCyclophilin InhibitorHBsAg Release Inhib.NucleotideCapsid InhibitorViral Entry InhibitorTLRGene Editing7575Combination Therapy General belief that no single approach will besufficient to deliver a cure As in HCV and HIV combinations of drugs withdifferent MOA will be the solution Which combination will deliver the ultimate “cure” isyet to be determined How to assess combinations pre-clinically that mayguide clinical studies is developing7638
7/27/2017Combination TherapyS e r u m H B V D N A ( lo g 1 0 c o p ie s / m L )101V e h ic le fo r A B -4 2 38ETVP e g IF NA R B -1 7 4 07A B -4 2 3A B -4 2 3 E T VA B - 4 2 3 P e g IF N60 .1A B -4 2 3 A R B - 1 7 4 0A B -4 2 3 A R B -1 7 4 0 E T VA B -4 2 3 A R B - 1 7 4 0 P e g IF N50LLOQ.0 10077114 42 12 1282835D ay6 wk Treatment PhaseS e ru m H B s A g ( lo g 1 0 IU /m L )S e ru m H B V D N A ( % B a s e lin e )1003 54 2D ay442954696 35 64 wk requency(CapsidAssemblyinhibitor)100 mg/kgPOBIDETV (Nuc)1.2 µg/kgPOQDPegIFN(ImmuneStimulator)30 µg/kgSQ2 /wkARB-1740(RNAi)3 mg/kgIVbiweeklyAB-423D ay6 wk Treatment Phase4 wk Follow-UpLee, A., et al., AASLD 2016, Abs # 23277Key Challenges in Finding an HBV Cure How to completely control viral replication? How to address the virus’ ability to control the hostimmune response? How to eradicate the viral reservoir, cccDNA? What is the best combination of MOA? Can significant reduction in the duration of therapybe achieved?7839
7/27/2017HBV: Is There a Path to a Cure? Increased focus by both academic and industry labswell beyond historic levels Many new targets and strategies under investigation Increased efforts to understand the virus and howthe host immune system responds to the virus Combination of drugs with different MOA have thepotential to deliver major therapeutic advances79A Cure Yet To Be Realized: HBVEntecavirLamivudineAdefovirPegIFNTenofovirIFNα asOT1966HBVDiscovered1982 19831987HBVcccDNAidentified1992 1994 1998 2002 2003 trolTelbivudine20062008 2010
Jul 27, 2017 · Chronic Viral Hepatitis: HBV & HCV Every third person on the planet shows evidence of infection with viral hepatitis 500 million people are chronically infected with hepatitis B or C 1 million die every year: 1 every 30 seconds Globally 57% of cirrhosis an
May 02, 2018 · D. Program Evaluation ͟The organization has provided a description of the framework for how each program will be evaluated. The framework should include all the elements below: ͟The evaluation methods are cost-effective for the organization ͟Quantitative and qualitative data is being collected (at Basics tier, data collection must have begun)
Silat is a combative art of self-defense and survival rooted from Matay archipelago. It was traced at thé early of Langkasuka Kingdom (2nd century CE) till thé reign of Melaka (Malaysia) Sultanate era (13th century). Silat has now evolved to become part of social culture and tradition with thé appearance of a fine physical and spiritual .
HAV hepatitis A virus anti-HBc hepatitis B core antibody anti-HBe hepatitis B e-antibody anti-HBs hepatitis B surface antibody HBeAg hepatitis B e-antigen HBIg hepatitis B immune globulin HBV hepatitis B virus HBsAg hepatitis B surface antigen HCC hepatocellular carcinoma HCP healthcare provider HCV hepatiti
Hepatitis C 2 What is hepatitis C? Hepatitis C is a disease caused by a virus that infects the liver. This virus, called the hepatitis C virus or HCV for short, is just one of the hepatitis viruses. The other common hepatitis viruses are A and B, which differ somewhat from hepatitis C in the way they are spread and treated.
Viral Hepatitis C: Introduction “Viral hepatitis," refers to infections that affect the liver and are caused by viruses. It is a major public health issue in the United States and worldwide. Not only does viral hepatitis carry a high morbidity, but it also stresses medical resources and can have severe
Viral Hepatitis B: Introduction “Viral hepatitis," refers to infections that affect the liver and are caused by viruses. It is a major public health issue in the United States and worldwide. Not only does viral hepatitis carry a high morbidity, but it also stresses medical resources and can have severe economic consequences. .File Size: 412KB
On an exceptional basis, Member States may request UNESCO to provide thé candidates with access to thé platform so they can complète thé form by themselves. Thèse requests must be addressed to esd rize unesco. or by 15 A ril 2021 UNESCO will provide thé nomineewith accessto thé platform via their émail address.
̶The leading indicator of employee engagement is based on the quality of the relationship between employee and supervisor Empower your managers! ̶Help them understand the impact on the organization ̶Share important changes, plan options, tasks, and deadlines ̶Provide key messages and talking points ̶Prepare them to answer employee questions
