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1、Click here or press enter for the accessibility optimised versionASH 2023 PreviewOnes to WatchClick here or press enter for the accessibility optimised versionContentsContentsForewordArcellxRegeneronGileadVertexMorphoSysClick here or press enter for the accessibility optimised versionCAR-T Safety an
2、d Sickle Cell DiseaseTwo big themes are set to dominate this year.The firstis safety.The FDAs investigation of T-cell malignanciesassociated with CAR-T products approved for bloodcancers may make these treatments less appealing.However,many patients with autoimmune diseases andcancer already accept
3、some risk of secondarymalignancies,so this isnt necessarily going to derail thewhole CAR-T space.We can expect plenty ofdiscussion of the likely impact of the news in the panelsessions and the networking gigs throughout theASH weekend.The other hot topic will be the latest data in sickle celldisease
4、,sparked by the go-ahead for Vertexs geneediting therapy in the UK.The US is expected to followwith approved very soon,but questions remain aboutthe very small number of patients who can truly benefitfrom this sophisticated but expensive therapy.Expect to hear many views on how we balance thesenew t
5、reatments with existing,more accessible,therapies and how we track the long-term risk of thesetechnologies.As ever,ASH will see the latest data reveals on CAR-Tproducts,multiple myeloma,leukaemia and more.In thiseBook,we outline five key players-Arcellx,Gilead,Regeneron,Vertex and MorphoSys-with a s
6、napshotof their pipelines,commercial outlook,and the datatheyre set to present at the conference.CAR-T Safety and Sickle CellDiseaseThe American Society of Hematology(ASH)Annual Meeting and Exposition is the lastbig clinical conference of the year.As wehead into 2024,which areas are set toattract in
7、vestment with their latest datasets,and which are in danger of falling flat?Click here or press enter for the accessibility optimised versionCompaniesWhats expected at ASH?Arcellx will reveal the latest results of its lead asset,CART-ddBCMA.Todate,data from its Phase 1 CART-ddBCMA trial in relapsed
8、or refractorymultiple myeloma show that the median DoR,PFS,and OS have not beenreached at a medium follow-up of 22 months after CART-ddBCMAinfusion.The therapy also continued to be well-tolerated,with noobserved delayed neurotoxicities or Parkinsonian symptoms.At ASH,Arcellx will be presenting updat
9、ed data from this trial,with a medianfollow-up of 26.5 months.In June,the FDA implemented a hold on the Phase 2 iMMagine-1 studyinvestigating CART-ddBCMA in multiple myeloma due to a death;however,this was later lifted in August and was attributed to limitationson bridging therapy in place in the tr
10、ial protocol.The FDA has since signedoff on an updated trial protocol to address this.Arcellx now expect CART-ddBCMA to launch in 2026,with Chairman and CEO Rami Elghandour inNovember re-iterating the groups belief in the therapys“best-in-classpotential”based on its safety and efficacy profile.CART-
11、ddBCMA isforecast to hit sales of$307m in 2028(50/50 split between Gilead andArcellx).It will face a crowded market.J&Js BCMA-targeting CAR-T therapyCarvykti is forecast to be the market leader,with$3.8 billion in projected2028 sales.Other competitors in relapsed or refractory multiple myelomainclud
12、e Bristol Myers Squibbs Abecma,plus Janssens bispecificantibodies Tecvayli and Talvay,and Pfizers recently approved Elrexfio.These off-the-shelf therapies dont require T-cell collection,making themless cumbersome and expensive to administer.Tecvayli is forecast to sell$2.0 billion in 2028.See our da
13、ta highlights for Arcellx on the next page.ArcellxArcellxArcellx(ACLX)is a Maryland based biotechnology company focused on development of immunotherapies forpatients with cancer and other incurable diseases.IPO DetailsIPO in February 2022(NASDAQ),raising$142mWhats it worth today?Market Cap(Nov 2023)
14、$2.5bnWhat is the 2028 Sales Forecast?$234mMomentumCAGR(2023-2028)15%Specialist Subject:ClinicalOncology&ImmunomodulatorsSpecialist Subject:TechnologyCell therapyKey Asset(s)CART-ddBCMA.A gene-modified cell therapy for multiple myeloma.Due to launch in 2026,this asset isexpected to account for 85%of
15、 Arcellxs sales in 2028.Phase 1 data update at ASH.In the Pipeline?Research projects:5Preclinical:1Phase 1:2Open full table in browser:https:/evaluate.turtl.co/story/ash-preview-ones-to-watch/page/4/2Whats expected at ASH?Regeneron will present new and updated data across six investigationalmedicine
16、s,including pivotal trials results for its lead blood cancercandidate,the CD20 xCD3 bispecific antibody odronextamab.Thecompany will share Phase 2 data from the ELM-2 pivotal trial in relapsed/refractory follicular lymphoma(R/R FL)and R/R diffuse large B-celllymphoma(R/R DLBCL),and Phase 1 data from
17、 the ELM-1 trial in R/RDLBCL patients who have progressed after CAR-T therapy.Primary endpoint results and longer follow-up data from the pivotal Phase2 LINKER-MM1 trial of BCMAxCD3 targeting linvoseltamab will alsofeature at the conference.Regeneron believes that both bispecifics stand apart from c
18、ompetitorsTecvayli(J&J)and recently-approved Elrexfio(Pfizer).For linvoseltamab inparticular,that differentiation could result from potentially lower rates ofsevere cytokine release syndrome(CRS)and thus lower hospitalisationburden.The therapy may also be dosed every four weeks if a good partialresp
19、onse is achieved at the six-month mark.Regeneron reported high rates of treatment-emergent adverse events,particularly Grade 3 or higher CRS,in prior studies with both assets.TheFDA placed a clinical hold on odronextamab in December 2020 oversafety concerns.Such adverse effects are,however,common to
20、 allCD3-based bispecific activity;any reduction in CRS rates would be anadvantage.Regeneron is initiating studies of both assets in earlier setting,where itbelieves most of the revenue opportunity lies.Odronextamab is projectedto reach worldwide sales of$160m in 2028,including$83 million outsideChin
21、a,Hong Kong,Macau,and Taiwan,where Regeneron retainscommercialisation rights.See our data highlights for Regeneron on the next page.RegeneronRegeneronSummaryRegeneron Pharmaceuticals(REGN)is a New York based biotechnology company focused on development&marketing of medicines for the treatment of eye
22、 diseases,allergic and inflammatory diseases,cancer,cardiovascular and metabolic diseases,pain,hematologic conditions,infectious diseases,and rare diseases.IPO DetailsIPO in April 1991Whats it worth today?Market Cap(Nov 2023)$85.8bnWhat is the 2028 Sales Forecast?$15.8bnMomentumCAGR(2023-2028)4%Spec
23、ialist Subject:ClinicalOncology,Sensory Organs,Systemic Anti-infectives,ImmunomodulatorsSpecialist Subject:TechnologyMonoclonal antibodies,gene therapyKey Asset(s)Odronextamab-Phase 2.A CD20 x CD3 bispecific antibody being evaluated for relapsed/refractory follicularlymphoma and relapsed/refractory
24、diffuse large B-cell lymphoma.Filed at FDA and EMA,with an FDA targetaction date of March 31,2024.Linvoseltamab-Phase 2.BCMA x CD3 bispecific antibody for heavily pre-treated multiple myeloma.Research projects:9Open full table in browser:https:/evaluate.turtl.co/story/ash-preview-ones-to-watch/page/
25、4/4Whats expected at ASH?Long-term data for marketed CAR-T cell therapy Yescarta in relapsed/refractory large B-cell lymphoma(R/R LBCL)across three lines of therapy,including overall survival data from the ZUMA-7 trial in patients aged 65+.Real-world data for marketed CAR-T Tecartus in adult R/R B-c
26、ell acutelymphoblastic leukaemia(ALL)and R/R mantle cell lymphoma(MCL).Yescarta is projected to sell$2.6bn in 2028,with$603m for Tecartus.Gilead stated in their Q3 earnings call that despite strong clinical data,only 10%of eligible 2L LBCL patients in the US are currently treated with acell therapy,
27、leaving significant room to increase adoption.The company isworking on further shortening their 16-day median turnaround treatment?time in the US,which they state is already industry-leading.Maincompetitors to Yescarta in LBCL are Novartis Kymriah and Bristol MyersSquibbs Breyanzi.The CAR-T cell the
28、rapy class is undergoing extra scrutiny from the FDA,which on November 28,2023 announced an investigation into reports ofT-cell malignancies in patients who have received BCMA-orCD19-directed genetically modified autologous CAR-T cellimmunotherapies such as but not limited to Yescarta and Tecartus.T
29、hese reports were received from clinical trials and post-marketingadverse events data sources.Although the risk of developing secondarymalignancies with this class of therapy is already stated in US prescribinginformation,the FDA is now evaluating the need for regulatory action.See our data highligh
30、ts for Gilead on the next page.GileadGileadSummaryGilead Sciences(GILD)is a California based pharmaceutical company focused on development of therapies forlife-threatening diseases&unmet medical needs in virology,oncology&other therapeutic areas.IPO DetailsIPO in January 1992Whats it worth today?Mar
31、ket Cap(Nov 2023)$92.8bnWhat is the 2028 Sales Forecast?$32.1bnMomentumCAGR(2023-2028)4%Specialist Subject:ClinicalOncology,Systemic Anti-infectives,ImmunomodulatorsSpecialist Subject:TechnologySmall molecules,monoclonal antibodies,cell therapyKey Haematology Asset(s)Yescarta and Tecartus-Marketed.C
32、D19-directed CAR-T cell therapies approved for a variety of blood cancers.In the pipeline?Research projects:27Preclinical:26Phase 1:38Open full table in browser:https:/evaluate.turtl.co/story/ash-preview-ones-to-watch/page/4/6Whats expected at ASH?Vertex will present updated Phase 3 clinical trial d
33、ata for exa-cel as a one-time functional cure for sickle cell disease and transfusion-dependentbeta thalassemia.Additional presentations will cover quality of life metrics.FDA granted exa-cel priority review for sickle cell disease and standardreview for transfusion-dependent beta thalassemia,with P
34、DUFA dates ofDecember 8,2023 and March 30,2024,respectively.EMA is alsoreviewing the therapy.The UK approval is currently restricted to patients 12 years and older,though Vertex continues to enroll patients in two global Phase 3 studies inpatients between 5 to 11 years.The company is also working on
35、 preclinicalassets that allow gentler conditioning for exa-cel,which could furtherbroaden the eligible patient population.During Vertexs Q3 earnings call,Vertexs CEO,Stuart Arbuckle,referred to exa-cel as a multibillion dollaropportunity and stated that Vertex are on-track in the US and Europewith r
36、egards to their supply network and launch preparations.Analysts forecast$2.8bn in exa-cel sales by 2028 which will be split 60/40 between Vertex and CRISPR Therapeutics.Key competitors includebluebird bios gene therapies lovo-cel for sickle cell disease and Zynteglofor transfusion-dependent beta tha
37、lassemia.bluebird bio abandoned theEuropean market in 2021 due to pricing challenges it encountered withZynteglo.See our data highlights for Vertex on the next page.VertexVertexs CEO,Stuart Arbuckle,referred toexa-cel as a multibillion dollar opportunityVertexSummaryVertex Pharmaceuticals(VRTX)is a
38、Massachusetts based pharmaceutical company focused on thedevelopment&commercialising medicines for serious diseases.IPO DetailsIPO in July 1991Whats it worth today?Market Cap(Nov 2023)$89.4bnWhat is the 2028 Sales Forecast?$13.8bnMomentumCAGR(2023-2028)7%Specialist Subject:ClinicalRespiratory,CNS,En
39、docrine,MusculoskeletalSpecialist Subject:TechnologySmall molecules,gene editingKey Asset(s)Exa-cel-Phase 3.An autologous,ex vivo CRISPR/Cas9 gene-edited cell therapy being evaluated for sickle celldisease or transfusion-dependent beta thalassemia.Exa-cel(branded Casgevy)received conditional approva
40、l inthe UK in November,becoming the first CRISPR-edited therapy.In the pipeline?Research projects:14Preclinical:9Phase 1:9Open full table in browser:https:/evaluate.turtl.co/story/ash-preview-ones-to-watch/page/4/8Whats expected at ASH?Detailed data from the Phase 3 MANIFEST-2 study investigatingpel
41、abresib in myleofibrosis.In a press release on November 20,2023,MorphoSys reported that the trial had met its primary endpoint:in JAKinhibitor-naive patients,pelabresib in combination with the JAK inhibitorruxolitinib demonstrated statistically significant and clinically meaningfulimprovements in th
42、e proportion of patients achieving at least a 35%reduction in spleen volume at week 24(SVR35)compared to placebo plusruxolitinib.Key secondary endpoints also favoured pelabresib plusruxolitinib.However,the MANIFEST-2 study fell short on a key secondary endpoint,50%reduction in total symptom score(TS
43、S50).This was achieved by52%of patients in the pelabresib plus ruxolitinib arm at week 24,compared with 46%in the placebo plus ruxolitinib arm(p=0.216).Throughout pelabresibs development,MorphoSys had stated thatstatistically significant improvements in both SVR35 and TSS50 at week24 would be key to
44、 attaining regulatory approval.Following a Type C FDAmeeting in September 2023,M added a new key secondaryendpoint.hoping this might help it gain approval.Based on the MANIFEST-2 results,MorphoSys stated that the companyintends to file for the approval of pelabresib plus ruxolitinib in the US andEur
45、ope in mid-2024.If approved,pelabresib is projected to hit$145m insales in 2028.See our data highlights for MorphoSys on the next page.MorphoSysMorphoSysSummaryMorphoSys(MOR)is a Germany based biotechnology company focused on development of therapeuticantibodies for the treatment of cancer,rheumatoi
46、d arthritis and Alzheimers disease.IPO DetailsIPO in March 1999Whats it worth today?Market Cap(Nov 2023)$732mWhat is the 2028 Sales Forecast?$794mMomentumCAGR(2023-2028)24%Specialist Subject:ClinicalOncologySpecialist Subject:TechnologyMonoclonal antibodies,small moleculesKey Asset(s)Pelabresib-Phas
47、e 3.A small molecule BET inhibitor being investigated for the treatment of myelofibrosis.In the pipeline?Research project:1Preclinical:5Phase 1:3Phase 2:10Open full table in browser:https:/evaluate.turtl.co/story/ash-preview-ones-to-watch/page/4/10Click here or press enter for the accessibility opti
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