瑞信-美股-生物科技行业-生物科技：AAV基因治疗的价值-2019.12.12-137页.pdf

12 December 2019Equity Research AmericasBiotechnologyFinding Value in AAV Gene Therapy:A Credit Suisse PrimerMartin Auster,MD+1 212-325-6573martin.austercredit-Mark Connolly+1 212 325-7576mark.connollycredit-Tiago Fauth+1 212 325-7569tiago.fauthcredit-Thomas Deal+1 212-325-3719thomasavery.dealcredit-Research AnalystsDISCLOSURE APPENDIX AT THE BACK OF THIS REPORT CONTAINS IMPORTANT DISCLOSURES,ANALYST CERTIFICATIONS,LEGAL ENTITY DISCLOSURE ANDTHE STATUS OF NON-US ANALYSTS.US Disclosure:Credit Suisse does and seeks to do business with companies covered in its research reports.As a result,investorsshould be aware that the Firm may have a conflict of interest that could affect the objectivity of this report.Investors should consider this report as only a single factor in makingtheir investment decision.2Source:Credit Suisse ResearchWhy You Need to Read This Primer,Including:oOur systematic AAV gene therapy framework,which we use to guide our assessment of companies in the space;oA deep-dive analysis of gene therapy manufacturing,with an investigation of production costs per dose,etc.;andoA discussion on how gene therapy is priced and what could change in the future as its pharmacoeconomic benefits are realized.oWe also review key learnings in the space across the past 20+years to frame our thesis on how to invest in this niche(includingnumerous case studies on what has/has not worked and what indications/programs may be interesting moving forward).oA bonus!Please contact us if youd like our comprehensive AAV gene therapy database,a comprehensive referenceguide that details 190 AAV gene therapy clinical trials that have been conducted over the years.(We include details on constructdesign capsid,promoter,doses;results,if applicable;links to publications;etc.)Executive Summary Executive Summary We Highlight 3 Gene Therapy Names Under Coverage with Make-or-Break Catalysts in the Next+/-1 yr:oSarepta.We believe it has the potential to have the largest stock move within our coverage universe over the next 12-15months.SRP-9001(DMD)has had encouraging efficacy in a small Ph1/2 trial and functional results are expected from aplacebo-controlled 40-patient Ph3 trial late 2020.We expect DMD gene therapy to supplant SMA as the most valuable genetherapy(tx)indication if/when SRP-9001 and/or other drugs are approved.As an added kicker,SRPTs LGMD program isexpected to enter Ph3 study next year,following disclosures on efficacy in a higher dose arm Q1 2020.oBioMarin.It is not a pure-play gene therapy company,but we believe the stocks potential is directly linked with its success indeveloping a robust gene therapy platform.Valroxs(hem A)merit has been debated for years by investors over durability andpeak FVIII levels;meanwhile,the drug clearly reduces bleeding events at a level that looks better or at least competitive to FVIII.Well get answers mid-2020 on valroxs expected PDUFA date and subsequent US commercialization.BMN307(PKU gene tx)begins dosing P1/2 patients in Q1 2020;this program leverages BMRNs substantial gene therapy manufacturing investmentsand may have an accelerated filing path that could take place as soon as 2022/2023 on strong P1/P2 data.ouniQure.We believe it has the most optionality within our coverage universe;AMT-130 for Huntingtons disease has blockbusterpotential,with HD market potential possibly rivaling or exceeding that of DMD.Initial safety disclosure from the program isexpected in 2020.Meanwhile,AMT-061(hem B)gene therapy creates a defensible floor value and supports QUREs appeal as apotential M&A target.3Valuations Have Pulled Back on General Risk Aversion and Concern that Valuations Had Gotten Ahead of Real butLimited Clinical Evidence that Exists Across Multiple Indications:Gene Therapy Is a Relevant New Modality,and It Is Likely Here to Stay:oMeaningful efficacy has been demonstrated for the treatment of diseases like SMA and hemophilia,and early commercialsuccess of Zolgensma highlights real and immediate value;oIt has elevated probabilities of clinical success relative to conventional pharma development,with early clinical data allowingfor significant clinical derisking that does not exist with other approaches(i.e.,microdystrophin gene therapy for DMD);oThere is widespread interest in the space from large Pharma,with multiple notable acquisitions in the past few years(AveXis/Novartis,Spark/Roche,Bamboo/Pfizer,Nightstar/Biogen,and Audentes/Astellas)o and 15 gene-therapy IPOs in the past five years along with other major biotechs/pharmas investing in the space.Executive Summary(Cont.)Executive Summary(Cont.)-30%-20%-10%0%10%20%30%40%50%12/31/173/31/186/30/189/30/1812/31/183/31/196/30/199/30/19Gene therapy IndexxbiNovartisannouncesAveXis acquisitionRoche announcesSpark acquisitionAstellas announcesAudentes acquisitionSource:Credit Suisse Research;FactSet;Gene Therapy Index composed of ABEO,ADVM,AGTC,AVRO,AVXS,AXGT,BLUE,BOLD,CRSP,EDIT,FIXX,KRYS,MBIO,MGTX,NITE,NTLA,ONCE,ORTX,PRVL,QURE,RCKT,RGNX,SGMO,SIGHT-PAR,SLDB,SRPT,VYGR 4Table of ContentsTable of Contents Credit Suisse Gene Therapy Framework and Market Assessment5 The Components of a Gene Therapy15 Manufacturing A Key Area of Regulatory Focus32 What Can We Learn From Preclinical Gene Therapy Studies?52 Commercial Implications of Gene Therapy59 Gene Therapy Targets:oEyes65oLiver73oSkeletal Muscle and Heart80oCNS/Brain87oLungs96 Listing of Active Gene Therapy Programs By Company100 Listing of Active Gene Therapy Programs By Indication109 Listing of Historical AAV Gene Therapy Clinical Trials118 Glossary133Credit Suisse Gene Therapy Framework and Market Assessment56 Is the disease well-characterized?Do we have a clear understanding of what causes the disease?Clear Biology What are the symptoms of the disease,what is the current standard of care,and is there a favorable risk/benefit proposition to support the development of a gene therapy?High Unmet Need Does the construct design make sense given our knowledge of the disease?What is the exact treatment approachgene insertion or gene silencing?Is the approach novel,or has it been validated in other programs?How well do the animal models recapitulate human disease?What are the strengths/limitations of the animal models used?Construct Design and Preclinical Models Are there well-validated biomarkers or functional endpoints that can be easily measured in clinical trials?Is the regulatory path defined?How much can we trust initial clinical data(placebo or historically controlled?)What is the manufacturing approachis it a novel or de-risked approach?What is the ability to scale up to meet commercial demand?Regulatory Pathway and Clinical Data Is there a sufficiently large market opportunity?How significant are benefits proposed by the gene tx intervention relative to standard of care?Is this a new market?Has an economic value been previously defined for current standard-of-care treatments?Pharmacoeconomic Argument For indications where there is clear biology,we see commercial arguments as the primary differentiator when evaluating development candidates;pharmacoeconomic arguments can potentially outweigh instances when there is lower unmet need.Therapies that have a more complicated construct design/treatment approach tend to have greater risk,but could have greater upside.Introducing our Gene Therapy FrameworkIntroducing our Gene Therapy FrameworkWeighing Five Different CriteriaSource:Credit Suisse ResearchOur Gene Therapy FrameworkOur Gene Therapy FrameworkClear Disease Biology Is Key for a Successful Gene Therapy7Source:Credit Suisse Research Gene therapy is the transplantation of genes into cells to correct geneticdisorders or to address specific symptoms associated with a disease.At its core,a gene therapy should be based on a solid understanding ofthe disease.Specific things we look for are:o Clear underlying cause of the disease.In general,we favor genetherapies that target monogenic conditions(i.e.,diseases that arecaused by mutations of a single gene),where up-or down-regulationof a single key protein can have a major impact on pathology.o Validation that correction of the gene can improve outcomesfor patients.This often can be elucidated from animal models andnatural experiments that can correlate disease severity with residualgene activity.It is also important to understand how much proteinreplacement will be needed to correct the underlying disease and towhat degree the condition may be reversible/recoverable vs.aslowing of progression that may be achieved with gene replacement.For instance,multiple CNS diseases result in widespread neuronaldamage before patients become symptomatic;therefore,treatingsymptomatic patients may slow or arrest disease progression,but itis unlikely that patients will be able to recover full function.Ultimately,we see gene therapys sound approach of targeting diseases with clear biology as the reason that these programs have a higher probability of success relative to small molecule drug development.Examples of Monogenic DiseasesAdrenoleukodystrophyAlpha thalassaemiaAlpha-1-antitrypsin deficiencyAmyotrophic lateral sclerosisBeta thalassemiaCharcot-Marie-ToothCystic fibrosisDuchenne and Becker muscular dystrophyEmery-Dreifuss muscular dystrophyFamilial amyloidotic polyneuropathyFanconi anaemiaFriedreichs ataxiaHaemophilia A and BHuntingtons diseaseMetachromatic leukodystrophyMucopolysaccharidosis type II(Hunter syndrome)Pompes syndromeSickle cell anaemiaSpinal muscular atrophyTay-Sachs diseaseClear BiologyThe choice of promoter is important(the promoter controls the degree of gene expression),but we see limited ability to predict efficacy based on the promoter used.Our Gene Our Gene T Therapy Frameworkherapy FrameworkThe Devil Is in the Details8Source:Credit Suisse Research,Ultragenyx,Audentes,Ceregene Construct Design Is Critical.o Capsid selection.A capsid is the transport vehicle(most commonly,AAV virus)that delivers the gene to target tissues.Capsids have different degrees of affinity to the bodys various tissues(known as tropism).The choice of capsid should correspond with the exact tissue(s)being targeted.As data accrue,we expect some capsids to(1)prove safer and(2)be less immunogenic(i.e.,broadly usable within populations).Early gene therapy programs failed because of inadequate tools;however,with the development of new capsids,promoters,and preclinical models,many of these risks have been reduced.The key is to confirm that construct design and preclinical studies were systematic and comprehensive.Construct Design and Preclinical ModelsRobustness of preclinical models.Preclinical models may provide useful information on expected efficacy,delivery route,and other translational aspects of the program,though several factors may influence the expected read-through to humans:oAnimal Size:Large animal disease models(i.e.,dogs or ideally,non-human primates NHPs)can have greater predictive value to guide dosing and understand efficacy vs.rodent models.oNatural Occurrence of Disease Model in Animal Species:These models tend to be more informative.oClear signs of benefit,with validated/predictive biomarkers or easy-to-perform functional measures.Serotype OriginTissue tropismAAV1Human or NHPSkeletal muscle,CNS,Retina,Pancreas,KidneyAAV2HumanSkeletal muscle,CNS,Liver Kidney,Retina AAV3HumanHepatocellular cardinoma,skeletal muscleAAV4NHPCNS,Retina,Lung,KidneyAAV5HumanSkeletal muscle,CNS,RetinaAAV6HumanSkeletal muscle,HeartAAV7Rhesus macaque Skeletal muscle,Retina,CNS,LiverAAV8Rhesus macaque Liver,Skeletal muscle,CNS,Retina,Pancreas,Heart,KidneyAAV9HumanLiver,Heart,Skeletal muscle,Lung,Pancreas,CNS,Retina,Testes,AAVrh10Rhesus macaque Liver,Heart,Skeletal muscle,Lung,Pancreas,CNS,Retina,KidneySource:Lisowski et al,2015RAREDTX401BOLDAT132CeregeneCERE-120IndicationGSD1aXLMTMParkinsons DiseasePositive Preclinical ModelDog ModelDog ModelNon-human primateTranslation in Humans?YesYesNoCommentaryDog model,naturally occurring;captures key features of the diseaseDog model,naturally occurring;captures key features of the diseaseDifferences in brain structure likely impacted drug distributionOur Gene Therapy FrameworkOur Gene Therapy FrameworkTherapies Should Target Indications with High Unmet Need9Source:Credit Suisse Research,Novartis,Audentes Unmet need targets are crucial as gene therapy carries substantial known and unknown risks and must command strong pricing power given small populations and a“1-dose”therapeutic model:Severe impairment of quality of lifeLimited treatment optionsRapid progressionExample 1:NVS Zolgensma for SMASevere impairment of quality of life:Monogenic disease;well-detailed natural history;Type 1 patients 92%mortality rate at 20 months old;Type 2 patients live to 25 years of age,but do not stand unassisted.Treatment options:One approved product before gene therapy(Spinraza in Dec.2016),but significant morbidity/mortality remains.Disease progressions:92%mortality by 20 months of age for Type 1 patients;type 2 patients will never be able to stand unassisted.There are multiple easy-to-measure,clinically meaningful endpoints.High Unmet NeedRegulatory Pathway and Clinical DataExample 2:BOLDs AT132 for XLMTMSevere impairment of quality of life:Monogenic disease;high mortality(50%of patients die by the age of 2);profound muscle weakness resulting in invasive respiratory support.Treatment options:None,treatments are palliative in nature.Disease progression:Rapid;high mortality by the age of 2.All patients have profound muscle weakness that impairs ability to perform everyday activities.We tend to favor programs with a more de-risked regulatory pathway/clinical program designoClear precedents for approval in the indication.Having a prior program pave the development path reduces some risk related to potential endpoint selection and the bar in terms of what is approvable.oWell-established/validated biomarkers/endpoints.Regardless of if there are prior precedents,we prefer indications for which there are well-established biomarkers that are correlated with long-term outcomes.oObjective and easy-to-measure endpoints.Related to point 2,these endpoints should be easy to measure and should be able to evidence change in the context of a short-duration clinical trial.Disease areas where entirely new ground is being pioneered may carry enormous upside commercial potential,but they also come with much higher risk.Unambiguous early clinical data when aligned with natural history data can have high predictive value.An important regulatory consideration is manufacturing;built-out commercial-scale manufacturing before entering the clinic can hasten development timelines.10Source:Credit Suisse Research,Novartis,BioMarin,Spark,AudentesIndirect CostsDirect Costs Direct costs include the cost of drugs,medical supplies/equipment,diagnostic tests,hospitalizations and physician visits.With respect to gene therapyo Direct costs are the most persuasive evidence in favor of/against a gene thera