中小型生物科技企業(yè)研究：NASH行業(yè)展望和競爭前景概要

1、Morgan SMID Biotech ResearchNorth America EquityResearchJuly 2019NASH Sector Outlook and Competitive Landscape CompendiumUS SMid BiotechnologyEric Joseph AC+1 212-622-0659 HYPERLINK mailto:eric.w.joseph eric.w.josephTurner Kufe,MD+1212-622-4104 HYPERLINK mailto:turner.kufe turner.kufeJ.P. Morgan Sec

2、urities LLCSee the end pages of this presentation for analyst certification and important disclosures, including non-US analyst disclosures.J.P. Morgan does and seeks to do business with companies covered in its research reports. As a result, investors should be aware that the firm may have a confli

3、ct of interest that could affect the objectivity of this report. Investors should consider this report as only a single factor in making their investment decision.NASH represents an estimated $20-35 billion untapped therapeutics market and growingNASHprevalenceintheUScurrentlyestimatedat17M,expected

4、torise50%by2030 withrisingratesinobesity(125%rise anticipate among higher-risk / fibrosis stagepatients)Highpharmacoeconomic burdenassociatedwithlaterstagediseaseimpact(cirrhosismanagement,livertransplantation, hepatocellularcarcinoma)Marketresearchanticipatingfavorablepricing&reimbursementlandscape

5、,particularlyforlater/higherfibrosisstagesettings. An overall high volume arena where reasonable pricing can drive largeopportunities however, not without several challenges to market development and therapeutic penetrationHighneedfornon-invasivediagnostictoolsandcriteria toidentifyearlier-stagedise

6、ase,patientswhowouldotherwisenot undergo biopsy fordiagnosisPotentiallylowpatientcomplianceduetosilentnatureofdiseaseprogression(NASHisgenerallyasymptomaticthrough cirrhosis / HCC) may also hinder marketpotentialDrug developers are benefited by a constructive regulatory framework in placeDraftguidan

7、cefromFDAspecifiesendpointrequirementsinordertoestablishinitialproofofconceptandacceptablesurrogate endpoints for registration directed studies in F2/F3 (non-cirrhotic)patientsRecentguidancespecifyingoutcome-basedendpointselectioninthecirrhotic population,albeitconservative,istobeexpected given non-

8、applicability of surrogate markers NAS and fibrosis this most severe form ofdisease.Thenetimpacthoweverislikelylongerdevelopmenttimelines,largerstudies,higher-riskdevelopmentinthecirrhotic F4 population vs non-cirrhotic F1-F3.That said, given the relatively higher unmet need in F4 patients, we would

9、 not be surprised to some reversal allowing registrationonthebasisofsurrogateendpoints(andpotentialnovelones),thoughultimatelyrequiresmoreclinical datain F4patientsRegulatory consistency between US and EU agencies on registration enablingendpointsInitial product approvals more likely to be deep stri

10、des rather than breakthrough leaps in patient outcomes; accordingly, we see ample room for multiple products / product categoriesMolecular mechanisms mediating NASH are complex, and industry understanding remains early stage, in ourviewPreclinical animal models only go so far and dont faithfully rep

11、licate all aspects of NASH presentation inhumanA point further evidenced by trial failures and confounding data sets (ex. ASK1,Combinationapproaches arealmostcertaintoplayaroleinthelonger-termevolutionofNASHdrugdevelopmentand treatmentparadigmIts that a / Wunderdrug emerges, in our Net-net, NASH lik

12、ely continue as store of value for multiple players for years tocomePotential for renewed sub-sector momentum with a catalyst rich outlook over the next 12 months. We anticipate 6-7 phase 2 / phase 3 readouts and pivotal program updates with in the NASH fieldphase 2a ARGON-1 data, end3Q19sNDA filing

13、 3Q19, MAA filing 4Q19AKRO: AKR-001 BALANCED phase 2a MRI-PDFF data 1Q20. Histology data2Q20NGM: NGM282 phase 2a exploratory cohort interim biopsy analysis 2H19. Phase 2b ALPINE 2/3 topline2020/ updates 1H20 (estimated)Full phase 2b histological data YE19- Phase 3 interim analysis YE19Inventiva: Pha

14、se 2b topline data1H20AXLA: AXA1125-003 IRB-approved human trial in subjects with NAFLD topline data 2H20AXLA: AXAA1957-002 non-IND, IRB-approved clinical trial in adolescent subjects with NAFLD topline data2H20Akero Therapeutic (AKRO | OW | $28 Dec-20 PT | Joseph)Best-in-class potential among the e

15、ndocrine FGF classAKR-001 Fc conjugated FGF21 analog, amenable to weekly subcutaneousinjectionFGF21acentralregulatoroflipidmetabolismandglycemiccontrol(viaFGFR1c),butalsohepaticstressandinflammation(FGFR2c/3c)Fat fraction data (MRI-PDFF) for competitor molecules (pegbelfermin, NGM282) support mechan

16、ismproof-of-conceptClass-leading lipid profile activity from phase 1b evaluation in T2DsubjectsBALANCEDphase2astudyreadoutsin1H20aresignificantvalueinflectionpoints.12-weekMRI-PDFFand20-24weekshistopathologysetupto meaningfully de-risk registration path/ trial design (for more, refer our initiation

17、report ( HYPERLINK /research/content/GPS-3056167-0 here) and slide 37 in this presentation)ValuationDCF and SOTP peak sales multiple analyses support YE20 price target of$28AKR-001 peak US revenue opportunity of $2.5B in F3 NASH (35% POS; $20/share) and $1B in F4 (10% POS;$3/share)Cashrunwaythrough2

18、022, coveringphase2aPOCdata(1H20),productscaleupforregistrationprogram,EOP2regulatoryfeedbackDownsideriskstoourvaluation:failureofAKR-001todemonstrateefficacyorregulatoryapprovalinlightofAKR-001beingthe companys only/leadasset.Enanta Pharmaceuticals (ENTA | N | $86 Dec-19 PT | Joseph)Potentially dif

19、ferentiated second generation FXR agonist; phase 2a (ARGON-1) data incremental to POSEPD305 wholly owned non-bile acid, non-carboxylic FXRagonistMechanism de-risked byOCA phase 3 REGENERATE data; nonclinical and HV data suggest favorable effects on LDL regulation / pruritusFor phase 2a ARGON-1 NASH

20、readout (end-3Q19), significant ALT reduction by 25% (12-week f/u) seen as the bar for successDe-riskingpotentialofARGON-1limitedby1)phenotypicNASHdiagnosis(biopsyDxoptional);2)moderateread-throughfromALTsurrogateto NAS/fibrosischange;3)absenceofhistopathologicalassessment(pairedbiopsy),requiringadd

21、itionalstudy(phase2b)priortoregistrationtrial (for more, refer to slide 51 in thispresentation)ValuationEDP-305 - $17 of our $86 Dec-19 pricetargetEst. $775M WW royalties ($2.3B US peak sales) at 40% POS. ARGON-1 data bearing 5-10% upside / 5-25% downside to current levels, in ourviewCash generating

22、 business; phase 3 development partnershipdependentDownsideriskscouldemergefromclinicalsetbacksforkeycandidates(Mavyret,EDP-305,EDP-938)andlower-than-expectedsalesforMavyret. Upside risks include accelerated timelines for 305 and 938 and better-than-expected HCVroyaltiesAxcella (AXLA| OW | $20 Dec-2

23、0 PT | Jessica Fye)Novel approach with potential to address multifactorial diseasesAxcellaisdevelopinganewclassoftherapeuticscalledAXAcandidatesanchored byaminoacidsindistinctratiosanddesignedto address dysregulated metabolism across diseases driven by multiplefactorsLead assets are both focused on

24、complications of cirrhosis (HE/sarcopenia andNASH)lowsafetyrisk;PlatformreliesonGRASstatusofaminoacidstosavetime/moneyonpreclinical developmentandmovestraight into humantestingacknowledge an amino acid based approach like this may need to deliver more data to drive investorcomfortValuationDCF suppor

25、ts yearend 2020 PT of $20ForpotentialNASHprogramsweproject$2bnWW2035revsforAXA1125 (25%POS)and$500mm inpediatricNASH(25%POS). Estimate lead program in cirrhotic OHE + sarcopenia 2035 WW revs of $1bn+ (25% POS).With 1.5xULN45 years old and is obese or diabetic (risk of advancedfibrosis)Biopsy diagnos

26、tic criteriaOnbiopsy,twoprimarymeasurementsaremadetogradeNASHandfibrosisNonalcoholic fatty liver activity score (NAS) a fully histological evaluation of NAFLD / NASH to grade diseaseactivityComprisedofa0-8scorebasedupontheextentofsteatosis,lobular inflammation and hepatocyteballooningScore of 0-2 is

27、 largely not diagnostic ofNASHScores of 3-4 is borderlineNASHScores of 5-8 is indicative ofNASHFibrosis StagingVarioushistologicalcriteriaareutilizedtogradefibrosisfromstage F1 to F4(cirrhosis)Nonalcoholic Fatty Liver Disease Activity Score (NAS)FeaturePointsCriteriaSteatosis033 to 66%366%Lobular In

28、flammation0None(microscopic pre sence12 foci per 20 x fieldof immune cells) 22 to 4 foci per 20 x field3foci per 20 xfieldBallooning0None(amount of ballooning1Few ballooning cellshepatocytes) 2Many cells/prominent ballooningNASH Fibrosis StagingStageCriteriaStageCriteriaPerisinusoidalorperiportalfib

29、rosis1AMildperisinusoidalfibrosis(zone3)1BModerate perisinusoidal fibrosis (zone3)1CPortal/periportalfibrosisPerisinusoidal and portal/periportalfibrosisBridgingFibrosisCirrhosisSource: UpToDate; Kleiner et al. Hepatology 2005; Hjelkrem et al. Aliment Pharmacol Ther 2011Earlier stage NASH is often a

30、symptomatic, however, progressive fibrosis increases risk of liver and non-liver related mortalityNAFLDandNASHpatientsareoftenasymptomatic,andcanpresentwithnon-specificsignssuchasfatigue,malaise,abdominalpainFibrosisstaginglargelydeterminesNASHprognosis,withpatientsprogressingone fibrosisstage every

31、 7 yearsWith progressive fibrosis, NASH patients are at increased risk of all-cause mortality, particularly cardiovascularmorbidity/mortalityCardiovascularcomplicationsarethemostfrequentcauseofdeathinNASHpatients,largelyduetohighlyassociatedmetabolicco-morbidities (diabetes, obesity,hyperlipidemia)P

32、rogressiontoNASHcirrhosis(F4)hasthehighestriskofliverrelatedmortalitylargelyduetolossofliverfunctionrequiringtransplantationor transitioning to hepatocellularcarcinomaProgression from F3 NASH (“bridging”) occurs at a rate of 0.25-3% /yearProgressionfromF4NASHcirrhosistohepatocellularcarcinomaoccursa

33、tarateof0.3to2.6%peryearFibrosis Stage Specific MortalityMortality Rate (per 1,000 PYF)50 Mortality Rate (per 1,000 PYF)50F0F1F2F3F4Fibrosis StageLiverRelatedMortalityNon-Liver RelatedMortalitySource: Akero company reports; Younossi et al. Hepatology 2016; Dulai et al. Hepatology 2017; Sing et al. C

34、lin Gastroenterol Hepatol 2015Currently there are no approved therapies, with lifestyle modifications as the mainstay of treatmentPatientswithF0andF1NASHhaveverygoodprognosiswithlifestylemodificationconsistingof:Lose 7% of bodyweight if overweight orobeseLimit consumption of fructose-enrichedbeverag

35、esLimit consumption of alcohol (1 drink/day for women and 2 drinks/day formen)Drink two or more cups of caffeinated coffeedailyAdjunctive therapy with vitamin E or insulin sensitizers may beconsideredPioglitzaone(PPAR-agonistimproveshistologicalfeaturesexpectfibrosis)The same lifestyle modifications

36、 are also recommended for more advanced fibrotic patients(F3-F4)More rigorous follow-up is required to detect life threateningcomplicationsPatientswithNASH cirrhosis/liverfailureand/orhepatocellularcarcinomaarelivertransplantationcandidatesSource: Diehl and Day, NEJM 2017Currently, there are 17M peo

37、ple in the US with NASH, expected to grow to 27M in 2030Fibrosis population expected to grow from 13M to23MAnticipating 8M F3 and F4 NASH patients in2030TheF3andF4populationsareexpectedtoincreaseby165k and 145k patients per year,respectivelyGlobally, prevalence estimates of NASH range from 1.5%to 6.

38、45% of the adultpopulationEstimated US NASH Prevalence by Fibrosis Stage25 Millions of Patients20Millions of Patients151050F1F2F3While the true NASH market size unknown, we estimate an initial $10B+ oppy from high overlap with diabetesWe could see the existing diabetes market serve as a staging grou

39、nd for initial NASH productlaunchesEst. $35B+ therapeutic market in theUS338 million prescriptions written in 2017 at 4%CAGRNASH rates as high as 55% in T2DM adults andincreasing with ageAnticipatinghighlevelT2DoverlapintheF2-F3/non-cirrhotic NASH population of focus for initial productapprovalsUS F

40、2-F3 pop growing from 5.5 to 10 million by2030;Est. $8-13 billion high traction F2-F3/T2D NASHopportunitySource: Company reports; Estes et al Hepatology 2018; Younossi Clin Liver Dis 2018; Firneisz World J Gastroenterol 2014, IQVIAMolecular Mechanisms and Target RationaleUnderstanding pathophysiolog

41、y of NASH requires revisiting normal lipid metabolismFat metabolism is a complex process involving three key pathways: endogenous and exogenous lipid metabolism and reverse cholesterol transportExogenous lipid pathway (dietaryintake)Dietaryfats,includingcholesterol,areingestedandabsorbedbytheGIsyste

42、m.Inthesmallintestineepitheliallayer,triglycerides(TGs)are formed from free fatty acids (FFAs). TGs and cholesterol combine to formchylomicrons.ChylomicronsentercirculationviathelymphaticsystemandaretransportedforstorageinadiposetissueTheadiposetissueenzyme,lipoproteinlipase(LPL),cleavesoffTGsfromch

43、ylomicronstoformFFAsandglycerolwhichareusedasenergyin skeletalmuscleChylomicronremnantsarerecycledbythelivertoformhigh-densitylipoproteins(HDL)Endogenous lipidpathwayVerylowdensitylipoproteins(VLDL)aresynthesizedfromTGsandcholesterolbytheliver.LPLalsocleavesoffTGsfromVLDLtocreateFFAsthat are stored

44、in adipose tissue or utilized for energy in skeletalmuscle.The remaining VLDL products are intermediate density lipoprotein (IDL) orLDLIDL and LDL products are internalized by the liver and are converted to bileacidsExcess LDL can be retained by hepatictissueReverse cholesteroltransportHDL transfers

45、 cholesterol from non-hepaticperipheral tissues to theliverThe complex pathophysiology of NASH has led to numerous treatment candidates addressing a wide array of mechanismsCompanyProductMechanism of ActionCompanyProductMechanism of ActionCompanyProductMechanism of ActionAkero BMYAKR-001Pegbelfermin

46、MK-3655 (NGM-313)FGFR21 analog FGF21 analog-Klotho/FGFR1c agonistIntercept Metacrine Gilead NovartisEnantaObeticholic acid MET409Cilofexor (GS-9674) TropifexorEDP-305FXRagonist FXRagonist FXRagonist FXRagonistFXRagonistGileadConatusSelonsertibEmricasanASK-1 inhibitorCaspase inhibitorGileadFirsocosta

47、t (GS-0976)ACC inhibitorNGM-282FGF19 analogAllerganCenicrivirocCCR2/5 antagonistGenfitElafibranorPPAR-/ agonistGalmedAramcholSCD-1 modulatorCymabayInventivaSeladelparLanifibranorPPAR- agonistPan-PPAR (/) agonistMadrigalVikingResmetiromVK2809THR-agonistTHR-agonistGalectinGR-MD-02Galectin-3 inhibitorT

48、he endocrine fibroblast growth factors (FGFs) regulate important metabolic processes in the liver and adipose tissueEndocrineFGFs,includingFGF19,FGF21andFGF23,areoneofseven FGF subfamiliesThese endogenous ligands require the Klotho family of co- receptors for cell signaling because they lack a hepar

49、in-binding domain(thebroaderFGFfamiliesthatregulatecellfunctiondo not requireKlotho)FGF19/21/23 signal through distinct FGFRisoformsFGF19ismostbroadlyactivatingthroughtheFGFR1c,FGFR2c, FGFR3c and FGFR4receptorsFGF21 activates FGFR1c, FGFR2c, FGFR3c but notFGFR4FGF23 interacts with FGFR1c, FGFR3c and

50、FGFR4 SummaryofFGF19FamilyFunctionProfileFGF19FGF21FGF23Tissue ExpressionIleum, small intestin epithelial cellsLiver primarilyBoneActivation SignalsBile acid secretion, FXR activationmetabolic stressors, including starvation, obesity, diabetes, and hepatosteatosisActivated form of Vitamin D (1,25(OH

51、)2D)Obligate ReceptorKlothoKlothoKlothoTarget FGFRs & Organ(s)FGFR1c/2c/3c/4Liver & Adipose tissueFGFR1c/2c/3cLiver & adipose tissueFGFR1c/3c/4 KidneyActivation of FGFRs have specific effects on the regulation of fat and carbohydrate metabolismFGFR1c is expressed in adipose tissue. Activation increa

52、ses insulinsensitivity,glucoseuptake,improvelipidprofileand promotes the utilization of fat asenergy.FGFR2/3c is expressed on the liver. Activationreduces endogenous production of fat andLDL.FGFR4isexpressedontheliver.Activationsuppressesbileacid production and promotes hepatocyteregeneration.FGF an

53、alogs have shown promise as a therapeutic modality for NASHTherearetwoFGF21analogscurrentlybeinginvestigated:AKR-001 (Akero) and pegbelfermin (BristolMyers-Squibb)AKR-001 targets FGFR1c/2c/3c (liver and adiposetissue).Ostensibly, pegbelfermin has similar receptor targeting profile, however, clinical

54、 effects concentrated to the liverwould suggest lower relative activity at FGFR1c than2c/3cNGM282 (NGM) is a FGF19 analog, and targets the FGFR1c/2c/3cand FGFR4 receptor. Of note, targeting the FGFR4 receptor may increase LDL-C levels. NGM313 (NGM) is a FGFR1c agonist, limiting its effects to only t

55、he 1creceptorSummary of Engineered Endocrine FGF Therepeutic CandidatesFGF21 MimeticsFGF19 MimeticsNativeAKR-001AkeroPegbelferminBristolLY2405319Li lly NGM313NGMNativeNGM282NGMDevelopment StagePhase 2aPhase 2bSuspendedPhase 1bPhase 2bMol Size22kDa24kDaHalf-life in circulation2hrs3-4 days, 12-30hrsUn

56、disclosed 2hrsUndisclosedAdministration, intervalSC injection, weeklySC injection, weeklySC injections, daily SC injection, monthlySC inje cti on, daily FGFR activating profileFGFR1c/2c/3cFGFR1c/2c/3cFGFR1c/2c/3cFGFR1c/2c/3cFGFR1c/BklothoFGFR1c/2c/3c/4Modifications from Native PeptideFc-fusionL98R s

57、ubsti tuti on to reduce aggregation- P171G, A180Esubsti tutions to prevent degradation by FAP- PEGylationC-terminal A134C disulphide bondS167A to reduce O- glycosylationN-terminal HPIP deletion to a void yeast degredation- N/A; humized anti-FGFR1c mAbP24-S28 residue deletionaa substi tuti ons A30S,

58、G31S, H33Lcreate FGFr4 biased acti vati onCulture OrganismE. ColiUndisclosedYeast (P. pastoris)undisclosedE. ColiFarnesoid X receptor (FXR) is an intracellular nuclear receptor that responds to bile acids and promotes expression of metabolic regulators of bile acid, lipid, cholesterol and glucoseFXR

59、hasanumberofbiologicfunctions,butpredominatelymaintainsbile acid homeostasis, thereby preventing relatedtoxicitiesNotably,intestinalFXRactivationsuppressesbileacidsecretionby FGF19 signalingThroughFGF19,FXRalsoworkstoreducelipogenesisand gluconeogenesis while promoting hepaticregenerationHowever,FXR

60、isassociatedwithrisingLDLpotentiallythrough reduction in bileacid.FXR agonism is a validated target in the treatment of NASHTheFXRagonist,obeticholicacid(Ocaliva)hascompletedaphase3studyF2/F3NASHandmettheprimaryendpointoffibrosisimprovement withoutworseningNASH. InterceptplansonfilingwiththeFDAandEM