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1、Corporate PresentationOur mission is to change lives by changing the course of blood cancerJanuary 2025Our mission is to change lives by changing the course of blood cancer2Forward-Looking StatementsExcept for the historical information contained herein,this presentation contains forward-looking sta
2、tements made pursuant to the“safe harbor”provisions of the Private Securities Litigation Reform Act of 1995.Investors are cautioned that such statements,include,without limitation,those regarding:(i)the Companys belief that RYTELO is a highly differentiated treatment with blockbuster potential for e
3、ligible LR-MDS patients,including the potential to achieve$1B+in net revenue;(ii)the Companys estimate of net revenues for the fourth quarter of 2024;(iii)the Companys views,estimates and expectations concerning the commercial launch of RYTELO,including the size of market opportunity and ability to
4、compete for market share;(iv)the Companys assumptions and expectations regarding the expected commercial opportunity for RYTELO in R/R MF;(v)the Companys projections of its ability to reach profitability without the need for additional financing if internal revenue and operating expense expectations
5、 are met;(vi)the potential for differentiated benefits associated with RYTELOs mechanism of action;(vii)the Companys views,estimates and expectations concerning the commercial launch of RYTELO,including size of market opportunity and ability to compete for market share;(viii)the potential impact on
6、clinical decision-making,prescriber behavior,and reimbursement decisions of the inclusion of RYTELO in the NCCN Guidelines as a Category 1 and 2A treatment of symptomatic anemia in patients with lower-risk MDS and the favorability of RYTELOs U.S.labeling;(ix)the market opportunity for RYTELO and the
7、 estimated treatment-eligible patient populations in LR-MDS and R/R MF;(x)the trajectory of RYTELOs U.S.commercial launch,including breadth of prescriber penetration and payor coverage and product utilization across lines of therapy and RS status;(xi)that the Phase 3 IMpactMF trial has registrationa
8、l intent and that an interim analysis is expected in early 2026 and a final analysis is expected in early 2027,together with the assumptions used in making these estimates;(xii)the status,plans and expected timing of the Companys clinical programs on its pipeline chart;(xiii)the Companys estimates o
9、f net revenues in the fourth quarter of 2024,operating expenses in 2024,and cash and marketable securities as of December 31,2024;(xiv)that certain potential future events represent opportunities for value creation,including potential EU approval in LR-MDS,expected launch in select EU countries in L
10、R-MDS,results from the expected interim and final analyses of the Companys Phase 3 R/R MF trial,and results from the expected analysis of the Companys Phase 1 IMprove MF trial;(xv)the significance of RYTELOs commercial opportunity in LR-MDS as driven by Phase 3 IMerge data,favorability of U.S.Prescr
11、ibing Information,and NCCN guidelines;(xvi)the expected length of regulatory,market and patent exclusivity and plans to file for patent term extension in the EU;(xvii)the potential for RYTELO to offer differentiated clinical benefits and become a second-line therapy of choice across LR-MDS patients
12、irrespective of ring sideroblast status or high transfusion burden,including sustained and durable transfusion independence,increases in hemoglobin levels,and improvement in patient-reported fatigue,all within a well-characterized safety profile of generally manageable cytopenias;(xviii)the potentia
13、l for LR-MDS patients who had prior treatment with luspatercept to experience clinical benefit from imetelstat treatment;(xix)the suggestion that imetelstat demonstrates clinical activity regardless of number or type of prior therapies;(xx)the association of clinical benefit and reduction of disease
14、 markers in imetelstat-treated MF and MDS patients;(xxi)any projections of revenue,patient populations,commercial opportunity and similar forecasts,along with the underlying assumptions;and(xxii)other statements that are not historical facts,constitute forward-looking statements.These forward-lookin
15、g statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements.These risks and uncertainties,include,without limitation,risks and uncertainties related to:(a)whether Geron is successful in commercializing RYTELO(imetelsta
16、t)for the treatment of certain patients with LR-MDS with transfusion dependent anemia;(b)whether the European Commission will approve RYTELO for the treatment of patients with LR-MDS with transfusion dependent anemia and whether the FDA and European Commission will approve imetelstat for other indic
17、ations on the timelines expected,or at all;(c)whether Geron overcomes potential delays and other adverse impacts caused by enrollment,clinical,safety,efficacy,technical,scientific,intellectual property,manufacturing and regulatory challenges in order to have the financial resources for and meet expe
18、cted timelines and planned milestones;(d)whether regulatory authorities permit the further development of imetelstat on a timely basis,or at all,without any clinical holds;(e)whether RYTELO(imetelstat)may cause,or have attributed to it,adverse events that could delay or prevent the commencement and/
19、or completion of clinical trials,impact its regulatory approval,or limit its commercial potential;(f)whether the IMpactMF Phase 3 trial for R/R MF has a positive outcome and demonstrates safety and effectiveness to the satisfaction of the FDA and international regulatory authorities,and whether the
20、Companys projected rates for enrollment and death events differ from actual rates,which may cause the interim and final analyses to occur later than anticipated;(g)whether any future safety or efficacy results of RYTELO treatment cause its benefit-risk profile to become unacceptable;(h)whether imete
21、lstat actually demonstrates disease-modifying activity in patients and the ability to target the malignant stem and progenitor cells of the underlying disease;(i)whether Geron meets its post-marketing requirements and commitments in the U.S.for RYTELO;(j)whether there are failures or delays in manuf
22、acturing or supplying sufficient quantities of RYTELO(imetelstat)or other clinical trial materials that impact commercialization of RYTELO or the continuation of the IMpactMF trial and other trials;(k)whether Geron is able to establish and maintain effective sales,marketing and distribution capabili
23、ties,obtain adequate coverage and third-party payor reimbursement,and achieve adequate acceptance in the marketplace;(l)whether Geron is able to obtain and maintain the exclusivity terms and scopes provided by patent and patent term extensions,regulatory exclusivity,and have freedom to operate;(m)th
24、at Geron may be unable to successfully commercialize RYTELO due to competitive products,or otherwise;(n)that Geron may decide to partner and not to commercialize independently in the U.S.or in Europe and other international markets;(o)whether Geron stays in compliance with and satisfies its obligati
25、ons under its debt and synthetic royalty agreements;and(p)the impact of general economic,industry or political climate in the U.S.or internationally and the effects of macroeconomic conditions on the Companys business and business prospects,financial condition and results of operations.Additional in
26、formation on the above risks and uncertainties and additional risks,uncertainties and factors that could cause actual results to differ materially from those in the forward-looking statements are contained in Gerons filings and periodic reports filed with the Securities and Exchange Commission under
27、 the heading“Risk Factors”and elsewhere in such filings and reports,including Gerons report on Form 10-Q for the quarter ended September 30,2024,and subsequent filings and reports by Geron.Undue reliance should not be placed on forward-looking statements,which speak only as of the date they are made
28、,and the facts and assumptions underlying the forward-looking statements may change.Except as required by law,Geron disclaims any obligation to update these forward-looking statements to reflect future information,events,or circumstances.3A first-in-class telomerase inhibitor with a unique mechanism
29、 of action representing a highly differentiated treatment with blockbuster potential for eligible U.S.patients with lower-risk myelodysplastic syndromes(LR-MDS)*RYTELO(imetelstat)is approved by FDA for adults with low-to intermediate-1 risk MDS with transfusion-dependent anemia requiring four or mor
30、e red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents(ESAs).See U.S.Prescribing Information and Medication Guide:https:/ 4U.S.RYTELO commercial launch off to a very strong start:$28.2M Q3 2024 net revenues$45M-$
31、46M Q4 2024 estimated net revenues*LR-MDS represents a potential blockbuster market opportunity for RYTELO based on high unmet need and significant product differentiation Phase 3 trial in JAKi R/R MF with overall survival(OS)primary endpoint is 75%enrolled;if positive,an approval in this indication
32、 would potentially double the RYTELO commercial opportunityExpect to reach profitability without additional financing if current internal sales and opex expectations are metLR-MDS=lower-risk myelodysplastic syndromes;JAKi R/R MF=Janus kinase inhibitor relapsed/refractory myelofibrosis*The estimate o
33、f net revenues is preliminary and unaudited and is subject to change upon completion of the Companys financial statement closing procedures and the audit of the Companys consolidated financial statements.Gerons Value Drivers 5Based on Nobel-Prize winning science,imetelstat is wholly owned by GeronTe
34、lomerase Inhibition Represents a Novel MOA with Unique BenefitsScientific evidence suggests reduction in proliferation of malignant cells and production of new healthy cells drive differentiated clinical benefits*Imetelstat binds to telomerase,inhibiting its activityImetelstatTelomerase increased in
35、 malignant cellsMalignant clonesUpregulated telomeraseApoptosis of malignant cells and recovery of effective hematopoiesisApoptotic malignant clonesMOA=mechanism of action*Robinson NJ,Schiemann WP.Telomerase in Cancer:Function,Regulation,and Clinical Translation.Cancers.2022;14(3):808;Schrank Z,Khan
36、 N,Osude C,et al.Oligonucleotides Targeting Telomeres and Telomerase in Cancer.Molecules.2018;23(9):2267;Platzbecker U and Santini V,et al.The Lancet,2024.https:/doi.org/10.1016/S0140-6736(23)01724-5;Tefferi A et al.A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis.NEJM.2015;373
37、:908-919;Mascarenhas et al.Randomized,Single-Blind,Multicenter Phase II Study of Two Doses of Imetelstat in Relapsed or Refractory Myelofibrosis.JCO.2021 Sep 10;39(26):2881-2892.Santini et al.Disease Modifying Activity of Imetelstat in Patients with Heavily Transfused Non-Del(5q)Lower-Risk Myelodysp
38、lastic Syndromes Relapsed/Refractory to Erythropoiesis Stimulating Agents in IMerge Phase 3.EHA 2023.6Strong U.S.Launch in LR-MDS with Significant Commercial Opportunity 7LR-MDS=lower-risk myelodysplastic syndromes;ESA ineligible=erythropoiesis-stimulating agent ineligible(serum EPO level 500 mU/mL)
39、;RS=ring sideroblast*RYTELO(imetelstat)is approved by the Food and Drug Administration(FDA)for adults with low-to intermediate-1 risk MDS with transfusion-dependent anemia requiring four or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible fo
40、r erythropoiesis-stimulating agents(ESAs).See U.S.Prescribing Information and Medication Guide:https:/ National Comprehensive Cancer Network(NCCN)makes no warranties of any kind whatsoever regarding their content,use or application and disclaims any responsibility for their application or use in any
41、 way.Favorable U.S.Label and NCCN Guidelines Position RYTELO to Compete for Significant Market Segments in LR-MDS3rd line&laterRS+(25%)RS-(75%)Market Segments Consistent With the FDA Label*MDS NCCN Guidelines2nd lineRS+(25%)RS-(75%)Category 1 treatment in 2nd line RS+/RS-patients regardless of prior
42、 treatmentESA Ineligible(20%)1st lineCategory 2A treatment for 1st line ESA-ineligibleRS+/RS-patients8Sources:(1)2025 patient volumes based on IQVIA projected claims 2023,DRG LR MDS incidence projected growth rate(2022)*Assuming the duration of therapy observed in IMerge Phase 3 clinical trial(8mo)a
43、nd current net priceLarge U.S.Market Opportunity with Blockbuster Potential for RYTELO in LR-MDS1L Patients(Non-del 5q)2L Patients(ESA R/R)3L+Patients(ESA R/R)ESA Ineligible:3,400 16,800 7,600 4,400ESA Eligible:13,400RS-:5,700RS+:1,900RS+:1,100RS-:3,300 45%1L patients expected to progress to 2L trea
44、tment in 2025 59%2L patients expected to progress to 3L treatment in 2025 2025 U.S.RYTELO Treatment-Eligible Population Consistent with U.S.LabelPotential for$1B+in net revenueby treating only 1/3 of treatment-eligible patients*15,400Treatment-eligible LR-MDS patients consistent with FDA label in 20
45、259RYTELO U.S.Launch Off to a Strong StartBroad Payor Coverage80%payor coverageas of the end of Q4 2024Permanent J-Code effective as of Jan.1,2025 Breadth of Prescriptions590ordering centersfrom launch through Q4 2024,representing 70%of our key targeted accounts Strong Early Launch Trajectory$28.2M
46、Q3 2024net revenue Utilization across 1L ESA ineligible,2L and 3L patients(RS+/RS-)$45-$46M Q4 2024estimated net revenue*The estimate of net revenues is preliminary and unaudited and is subject to change upon completion of the Companys financial statement closing procedures and the audit of the Comp
47、anys consolidated financial statements.Payors responsible for 80%U.S.covered lives have implemented RYTELO medical coverage policies consistent with FDA label,clinical trials and/or NCCN Guidelines through Q4 202410Compelling Opportunity in JAKi R/R Myelofibrosis11Source:US IQVIA Claims through 2023
48、(MF Market Sizing Report delivered March 2024);DRG Epi(2022 Report)Growth Rates applied through 2040*Patient estimates as of 2028.Phase 3 Trial in JAKi R/R MF Would Potentially Double the RYTELO Commercial Opportunity,if Positive 12,000U.S.JAKi nave/well-controlled MF patients(currently only 3 appro
49、ved treatments all JAK inhibitors)75%of those JAKi treated patients fail or discontinue treatmentPotentialto treatU.S.JAKi R/R MF patients*10,00012Mascarenhas et al.Randomized,Single-Blind,Multicenter Phase II Study of Two Doses of Imetelstat in Relapsed or Refractory Myelofibrosis.JCO.2021 Sep 10;3
50、9(26):2881-2892;.Kuykendall AT,Shah S,Talati C et al.Between a rux and a hard place:evaluating salvage treatment and outcomes in myelofibrosis after ruxolitinib discontinuation.Ann.Hematol.97(3),435441(2018).;Mascarenhas J,Mehra M,He J,Potluri R,Loefgren C.Patient characteristics and outcomes after
51、ruxolitinib discontinuation in patients with myelofibrosis.J.Med.Econ.23(7),721727(2020).;Newberry K,Patel K,Masarova L et al.Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation.Blood 130(9),11251131(2017).;Palandri F,Breccia M,Bonifacio M et al.Life after ruxolitinib:re
52、asons for discontinuation,impact of disease phase,and outcomes in 218 patients with myelofibrosis.Cancer 126(6),12431252(2020).;6.Schain F,Vago E,Song C et al.Survival outcomes in myelofibrosis patients treated with ruxolitinib:a population-based cohort study in Sweden and Norway.Eur.J.Haematol.103(
53、6),614619(2019)IMbark Phase 2 data compared to real world data(RWD)from a closely-matched cohort of patients at the Moffitt Cancer Center who had discontinued ruxolitinib and were subsequently treated with best available therapy(BAT)29.9 months median OSSurvival Probability33.8 mos12.0 mosBATMoffitt
54、Imetelstat 9.4 mg/kgMedian OS in Phase 2 IMbark Compares Favorably Historical Controls(11-16 months)Median OS More than Double Compared to BAT in RWD StudyKuykendall et al.Favorable overall survival with imetelstat in relapsed/refractorymyelofibrosis patients compared with real-world data.Ann Hemato
55、l.2022 Jan;101(1):139-146.RWD BAT vs.Imetelstat 9.4 mg/kgSurvival ProbabilityClinicalTrials.gov Identifier:NCT0242608629.9 mos13INT-1/INT-2/HR MF=Intermediate-1/Intermediate-2/High Risk MF;TSS=total symptom score;SVR=spleen volume reduction;PROs=patient-reported outcomes*These projections are based
56、on expectations about event rates(deaths)and enrollment,which can change over time and may differ from our current expectations#imetelstat salt form Best available therapies include hydroxyurea,corticosteroids,danazol,and othersPhase 3 IMpactMF Trial Designed to Confirm Strong OS Signal Observed in
57、Phase 2 StudyClinicalTrials.gov Identifier:NCT04576156Interim Analysis expected early 2026*Final Analysis expected early 2027*75%Enrolled as of December 2024Primary Endpoint:OSSecondary Endpoints:TSS(50%)at week 24,SVR(35%)at week 24,PROs,safetyImetelstat9.4mg/kg IV#every 3 weeks(n 214)Best Availabl
58、e Therapy(n 106)INT-1/INT-2/HR MFR/R to JAKi(n=320)14Development Pipeline15LR-MDS:lower-risk myelodysplastic syndromes;EU=European Union;R/R MF:relapsed/refractory myelofibrosis;MF:myelofibrosis;R/R AML:relapsed/refractory acute myeloid leukemia;HR-MDS:higher-risk myelodysplastic syndromes;TI:telome
59、rase inhibitor*RYTELO(imetelstat)is approved by the FDA for adults with low-to intermediate-1 risk MDS with transfusion-dependent anemia requiring four or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents
60、(ESAs).See U.S.Prescribing Information and Medication Guide:https:/ These projections are based on expectations about event rates(deaths)and enrollment,which can change over time and may differ from our current expectationsExploring the Potential of Telomerase Inhibition Across Multiple Hematologic
61、MalignanciesIndicationsDiscoveryPreclinicalPhase 1Phase 2Phase 3ApprovedLR-MDSSingle AgentR/R MFSingle AgentFrontline MFCombination TherapyR/R AML&HR-MDSSingle AgentR/R AMLCombination TherapyNext Generation TI ProgramIMpactMFIMproveMFIMpressTELOMERE*Ongoing;Investigator LedPlanned;Investigator LedOn
62、going;Company SponsoredInterim Analysis est.early 2026Final Analysis est.early 2027Dosing schedule modified for second cohort of patients August 2024Leads identified;optimization ongoingProgressed to Part 2,designed to confirm the safety profile of imetelstat 9.4 mg/kg in combination with ruxolitini
63、bTo follow single agent data from IMpressEU approval expected 1H 2025Approved in the U.S.*16Positioned for Profitability Without Additional Financing17*The estimate of net revenues is preliminary and unaudited and is subject to change upon completion of the Companys financial statement closing proce
64、dures and the audit of the Companys consolidated financial statements.Financial OverviewQ3 2024 net product revenue$28.2MCash and marketable securities as of 12/31/24*$500M2024 expected OpEx range*$250M to$260MNet RevenueCash BalanceOperating Expenses$45-46MQ4 2024 estimated net product revenue*2025
65、 expected OpEx range$270M to$285MExpect to Reach Profitability without Additional Financing if Current Internal Sales and OpEx Expectations Are MetThank you!Contact:Investor R1819Appendix20Multiple Opportunities to Fuel Growth in 2025&BeyondJune 2024FDA approval&U.S.launch of RYTELO in LR-MDSQ3 2024
66、$28.2M product revenue in first full commercial quarterDec 2024Positive CHMP opinion in LR-MDS1H 2025EU approval in LR-MDSEarly 2026Ph3 interim analysis in R/R MF*2026Primary analysis from Ph1 IMproveMFEarly 2027Ph3 final analysis in R/R MF*Nov 2024Secured up to$375M in non-equity financings2026Laun
67、ch in select EU countries in LR-MDS2024ACHIEVEMENTSEXPECTEDOPPORTUNITIESFORVALUECREATIONFDA=U.S.Food&Drug Administration;LR-MDS=lower-risk myelodysplastic syndromes;CHMP=Committee for Medicinal Products for Human Use;EU=European Union;R/R MF=relapsed/refractory myelofibrosis *These projections are b
68、ased on expectations about event rates(deaths)and enrollment,which can change over time and may differ from our current expectations 21LR-MDS Represents a Significant Commercial Opportunity for RYTELOPhase 3 IMerge data,FDA label and NCCN Guidelines position RYTELO as highly differentiated treatment
69、 22If PTE Applied to COM3COM Patent Term+2 years61.New Chemical Entity(NCE)exclusivity for 5 years after first approval.2.Orphan drug exclusivity in U.S.for 7 years after any indication.3.U.S.Patent Term Extension(PTE)can only be applied to one patent;if our composition of matter(COM),expected to co
70、nfer exclusivity through December 2030,but if applied to our methods of use(MOU)patent,expected to confer exclusivity through August 2037 and may apply to all approved uses covered by the patent,i.e.,both MDS and MF(if approved),under 35 USC 156(b)(2).4.New Active Substance(NAS)exclusivity for 10 ye
71、ars after approval.5.Orphan drug exclusivity in EU for 10 years after approval.6.Pediatric exclusivity of 2 years could be added for successful completion of PIP.7.PTE could extend EU patent term by as much as 5 years.Exclusivity for LR-MDS Expected into 2037 in the U.S.and 2038 in the EUStrong IP P
72、osition for RYTELO Supports Commercial OpportunityExpected Regulatory Exclusivities and Patent TermsIf PTE Applied to MOU3Mar 2033Dec 2025Dec 2030Jun 2024Jun 2031Jun 2024Jun 2029U.S.Data/Market Exclusivity1Patent TermPatent Term Extension(PTE)Orphan Drug ExclusivityData/Market ExclusivityEU Data/Mar
73、ket Exclusivity4EU Orphan Drug Exclusivity5Q1 2025Q1 2025Q1 2035PTE7US PTE Applications filed in U.S.for RYTELO patents PTE review can take years Strategy to retain optionality on PTE applications until review is completed RYTELO patents listed in FDAs Orange Book Plans to file in the EU for PTE fol
74、lowing expected MAA approvalU.S.Methods of Use(MOU)Patent(MDS and MF)EUEU Methods of Use Patent(MDS)Aug 2037TBD 2038U.S.Orphan Drug Exclusivity2Nov 203323ThrombocytopeniaNeutropeniaInfusion-Related ReactionsEmbryo-Fetal ToxicityWarning and PrecautionsSee U.S.Prescribing Information and Medication Gu
75、ide:https:/ active moietyFavorable U.S.Prescribing Information for RYTELO Supports Significant Market OpportunityRYTELO is indicated for the treatment of adult patients with low-to intermediate-1 risk myelodysplastic syndromes(MDS)with transfusion-dependent anemia requiring 4 or more red blood cell
76、units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents(ESA).Indication and UsageNo boxed warningNo REMS programNo contraindications7.1 mg/kg*administered as an intravenous infusion over 2 hours every 4 weeksRecommended DosageMost
77、 common adverse reactions(incidence 10%with a difference between arms of 5%compared to placebo),including laboratory abnormalities are decreased platelets,decreased white blood cells,decreased neutrophils,increased AST,increased alkaline phosphatase,increased ALT,fatigue,prolonged partial thrombopla
78、stin time,arthralgia/myalgia,COVID-19 infections,and headache.Adverse ReactionsComplete blood counts and liver function tests are required,as detailed in the PI.24*Poor probability to respond to immunosuppressive therapy(IST)RS=ring sideroblast;ESA=erythropoietin stimulating agents;EPO=erythropoieti
79、n;HMA=hypomethylating agents;G-CSF=granulocyte-colony stimulating factor;NCCN Guidelines=NCCN Clinical Practice Guidelines in Oncology#National Comprehensive Cancer Network(NCCN)makes no warranties of any kind whatsoever regarding their content,use or application and disclaims any responsibility for
80、 their application or use in any way.NCCN Guidelines#Guide Clinical,Formulary and Treatment Pathway Decision-Making and Position Imetelstat as 2nd Line Therapy of ChoiceMDS NCCN Guidelines include imetelstat for use in both RS+and RS-1st-line ESA ineligible patientsand in both RS+and RS-2nd-line pat
81、ients,regardless of prior 1st line-treatmentTreatment of Symptomatic Anemia in Patients with LR-MDSIn 1st line,imetelstat is a Category 2A treatment for RS+and RS-ESA-ineligible patients1STLine2NDLineRS-serum EPO 500 mU/mL*serum EPO 500 mU/mLazacitidine (preferred)ESA(preferred)luspaterceptCategory
82、2a(preferred)imetelstatCategory 2aOther HMAivosidenib or olutasidenibor clinical trial(if mIDH1)imetelstatCategory 1(preferred)ESA+/-G-CSFlenalidomideRS+serum EPO 500 mU/mLserum EPO 500 mU/mLluspaterceptCategory 1(preferred)imetelstatCategory 2aimetelstatCategory 1(preferred)ESA+/-G-CSForluspatercep
83、t Category 2a(preferred,if not previously used)2+LineluspaterceptCategory 1(preferred,if not previously used)ivosidenib(if MIDH1)or olutasidenib(if MIDH1)(Category 2b)azacitidine(preferred)Other HMAConsider lenalidomideClinical trial or consider allo-HCT(if no MIDH1)luspaterceptCategory 1(preferred)
84、imetelstat Category 2a(preferred,if not previously used)orororIn 2nd line,imetelstat is a Category 1 treatment for RS+and RS-patients regardless of prior treatment258,24-week data cut off was October 2022;1-year represents 3 additional months of data(cut off January 2023)P-value is based on Cochran
85、Mantel Haenszel test stratified for prior RBC transfusion burden(6 units or 6 units of RBCs/8 weeks)and baseline IPSS risk score(Low or Intermediate-1)8-week TI=proportion of patients without any RBC transfusion for at least eight consecutive weeks since entry to the trial;24-week TI=proportion of p
86、atients without any RBC transfusion for at least 24 consecutive weeks since entry to the trial;1-year TI=proportion of patients without any RBC transfusion for at least 52 consecutive weeks since entry to the trialPlatzbecker U and Santini V,et al.The Lancet,2024.https:/doi.org/10.1016/S0140-6736(23
87、)01724-5 Durable Red Blood Cell Transfusion Independence and Response Rates Differentiate Imetelstat39.8%28.0%17.8%15.0%3.3%1.7%0.05.010.015.020.025.030.035.040.045.050.0 8-week RBC-TI 24-week RBC-TI 1-year RBC-TIPercentage of Patients(%)P0.001Nominal P=0.002Imetelstat(n=118)Placebo(n=60)P0.00152 we
88、eksmedian duration80 weeksmedian duration123 weeksmedian duration(exploratory endpoint)(secondary endpoint)(primary endpoint)26Platzbecker U and Santini V,et al.The Lancet,2024.https:/doi.org/10.1016/S0140-6736(23)01724-5.Meaningful Hemoglobin Rises and Reduction in Transfusions Observed with Imetel
89、stat3.6 g/dL median Hgb rise in 8-week RBC-TI responders4U/8 weeks transfusion reduction in 60%of imetelstat-treated patientsNominal P-value is based on a mixed model for repeated measures with change in RBC transfusion as the dependent variable,week,stratification factors,prior transfusion burden,a
90、nd treatment arm as the independent variables with autoregressive moving average(ARMA(1,1)covariance structure.NOTE:graph starts at Week 1-8 with the number of the patients with transfusion follow-up data available at least eight weeks on study for imetelstat and placebo armsNumber of patientsThe me
91、an changes from the minimum Hgb of the values that were after 14 days of transfusions in the 8 weeks prior to the first.Data points that have fewer than four patients are not shown.Nominal P-value is based on a mixed model for repeated measures with Hgb change as the dependent variable,week,stratifi
92、cation factors,dose date,and treatment arm as the independent variables with autoregressive moving average(ARMA(1,1)covariance structure.Number of patients-1012345Mean Change in HGB(g/dL;+/-SE)ImetelstatPlacebo-5-4-3-2-101191725334149576573818997Mean Change in RBC Transfusion(units;+/-SE)ImetelstatP
93、laceboWeeksWeeksNominal P6 units of RBCs/8 weeks)and baseline IPSS risk score(Low or Intermediate-1)One patient on imetelstat arm missing RS categoryPlatzbecker U and Santini V,et al.The Lancet,2024.https:/doi.org/10.1016/S0140-6736(23)01724-5.Consistent Responses Observed Across MDS Subgroups with
94、Imetelstat(8-week RBC-TI Responses)Imetelstat,n/N(%)Placebo,n/N(%)%Difference(95%CI)Overall47/118(39 8)9/60(15 0)24 8(9 936 9)WHO categoryRS+33/73(45 2)7/37(18 9)26 3(5 942 2)RS-14/44(31 8)2/23(8 7)23 1(-1 3 to 40 6)Prior RBC transfusion burden per IWG 20064-6 U/8 week28/62(45 2)7/33(21 2)23 9(1 941
95、 4)6 U/8 week 19/56(33 9)2/27(7 4)26 5(4 741 8)IPSS risk categoryLow32/80(40 0)8/39(20.5)19 5(-0 1 to 35 2)Intermediate-115/38(39 5)1/21(4 8)34 7(8 852 4)Baseline sEPO500 mU/mL39/87(44 8)7/36(19 4)25 4(5 2740 70)500 mU/mL7/26(26 9)2/22(9 1)17 8(-8 17 to 40 25)-20-100102030405060Favors ImetelstatFavo
96、rsPlacebo28Exploratory analysis in the supplemental appendix of The Lancet:Platzbecker U and Santini V,et al.The Lancet,2024.https:/doi.org/10.1016/S0140-6736(23)01724-5.Improvement in Patient-Reported Fatigue Associated with Clinical Responses with Imetelstat Per Exploratory AnalysisMeaningful pati
97、ent-reported fatigue improvementsin 8 and 24-week RBC-TI respondersSustained meaningful improvement in fatigue reported in imetelstat-treated patients70.272.766.736.641.220.933.350.041.941.740.038.5010203040506070808-Week RBC-TI24-Week RBC-TIHI-E per IWG 2006Imetelstat RespondersImetelstat Nonrespon
98、dersPlacebo RespondersPlacebo NonrespondersPatients,n/NResponders33/473/924/331/250/7513/31Nonresponders26/7120/4835/8522/559/4310/26Kaplan-Meier estimate of time to first sustained meaningful improvement in the FACIT Fatigue score.HR is from the Cox proportional hazard model,stratified by prior RBC
99、 transfusion burden(4 to 6 vs 6 RBC units/8-weeks during a 16-week period prior to randomization)and baseline IPSS risk category(low vs intermediate-1),with treatment as the only covariate.Sustained Improvementin FACIT-Fatigue,%1009080706050403020100Number at riskTime to first sustained improvement
100、in the FACIT-Fatigue score,weeks0110100908070605040302010120115135671216192854781ImetelstatPlacebo56011471014163240PlaceboImetelstatPlacebo:Imetelstat:65.028.3CensoredHR=1.34(95%CI,0.822.20)Median time-to-episode(weeks)Sustained Improvementfor 2 cycles0%20%40%60%80%Patients,%50.0%40.4%ImetelstatPlac
101、ebo291.Platzbecker U and Santini V,et al.The Lancet,2024.https:/doi.org/10.1016/S0140-6736(23)01724-5.2.Platzbecker U,Santini V,Zeidan AM,Sekeres MA,Fenaux P,Raza A,et al.Effect of Prior Treatments on the Clinical Activity of Imetelstat in Transfusion-Dependent Patients with Erythropoiesis-Stimulati
102、ng Agent,Relapsed or Refractory/Ineligible Lower-Risk Myelodysplastic Syndromes.66th American Society of Hematology(ASH)Annual Meeting and Exposition;December 2024;Presentation 352ESA R/R/Ineligible LR-MDS Patients With Prior Luspatercept Treatment Experienced Clinical Benefit from Imetelstat Treatm
103、entClinical activity of imetelstat was evident across lines of prior therapy(including luspatercept,lenalidomide and HMA)regardless of prior response status,suggesting that imetelstat demonstrates clinical activity regardless of number or type of prior therapies30These are familiar adverse reactions
104、 for hematologists who are experienced with managing cytopeniasWell-Characterized Safety Profile with Generally Manageable and Short-Lived Thrombocytopenia and NeutropeniaConsistent with prior clinical experience,the most common imetelstat AEs were hematologicAEs were generally manageable with suppo
105、rtive care and dose modifications 74%of patients treated with imetelstat had dose modifications;mostly due to grade 34 neutropenia and thrombocytopenia 15%of patients discontinued treatment due to TEAEs generally late in treatment(median 21.1 weeks)Non-hematologic AEs were generally low grade No cas
106、es of Hys Law or drug-induced liver injury observed Clinically relevant adverse reactions in 5%of patients who received imetelstat included febrile neutropenia,sepsis,gastrointestinal hemorrhage,and hypertensionAEs(10%of patients),n(%)Imetelstat(N=118)Placebo(N=59)Any GradeGrade 34Any GradeGrade 34H
107、ematologicThrombocytopenia89(75%)73(62%)6(10%)5(8%)Neutropenia87(74%)80(68%)4(7%)2(3%)Anemia24(20%)23(19%)6(10%)4(7%)Leukopenia12(10%)9(8%)1(2%)0Grade 3-4 thrombocytopenia and neutropenia:Most often reported during cycles 1-3 Lasted a median duration of less than two weeks Resolved to grade 35%Activ
108、ely enrolling patients for dose confirmation with imetelstat 9.4mg/kgPart 1 Findings Suggest Tolerability of Imetelstat Combined with Ruxolitinib in Patients with MFClinicalTrials.gov Identifier:NCT05371964 Well-tolerated,and no dose-limiting toxicities were reported at any imetelstat dose level wit
109、hin the first 28 days of Cycle 1 The PK profiles were consistent with previous monotherapy studies Preliminary results showed VAF reductions in driver mutations associated with MF across all four dose cohorts Objective:Confirm safety of doses and evaluate efficacy Primary Week 24 Endpoints:Safety,TS
110、S Other Week 24 Endpoints:TSS,SVR35,FibrosisPART 1:Dose FindingResults Presented at ASH 2024Frontline treatmentInitial results from Part 2 expected 2026Imetelstat 9.4 mg/kg+Ruxolitinib individualized dose per patientINT-1/INT-2/HR MFPatients treated with imetelstat 9.4 mg/kg experienced stable hemat
111、ology values over timeImetelstat 4.7mg/kg(n=3)+Ruxolitinib dosesImetelstat 7.5 mg/kg(n=4)+Ruxolitinib dosesImetelstat 6.0 mg/kg(n=3)+Ruxolitinib dosesImetelstat 9.4 mg/kg(n=7)+Ruxolitinib dosesPART 2:Dose Confirmation&Expansion Currently Enrolling20 JAKi nave patients planned9.4 mg/kg Imetelstat eve
112、ry 4 weeks selected for dose confirmation and expansion34Clinical Benefits Observed in LR-MDS and MF with Unique Mechanism of Action35From left to right:Image A:Tefferi A,Lasho T,Begna K,Patnaik M,et al.A pilot study of the telomerase inhibitor imetelstat for myelofibrosis.New Engl J Med 2015;3;373(
113、10)L:908-919.;Image B:Mascarenhas J,Komrokji R,Palandri F,et al.Randomized,Single-Blind,Multicenter Phase II Study of Two Doses of Imetelstat in Relapsed or Refractory Myelofibrosis.American Society of Clinical Oncology.p.JCO.20.02864,2021.;Image C:Steensma DP,Fenaux P,Van Eygen K,Raza A,Santini V,G
114、erming U,et al.Imetelstat Achieves Meaningful and Durable Transfusion Independence in High Transfusion-Burden Patients With Lower-Risk Myelodysplastic Syndromes in a Phase II Study.J Clin Oncol.2021;39(1):48-56.;Image D:Santini V,Platzbecker U,Fenaux P,Sekeres MA,Savona MR,Madanat YF,et al.Disease m
115、odifying activity of imetelstat in patients with heavily transfused non-del(5q)lower-risk myelodysplastic syndromes relapsed/refractory to erythropoiesis stimulating agents in IMERGE Phase 3.European Hematology Association(EHA)2023;Presentation S164Association of Clinical Benefit and Reduction of Di
116、sease Markers Observed in Imetelstat-Treated MF and MDS Patients A.Disappearance of bone marrow fibrosis in imetelstat treated HR MF patientB.Association of survival improvement and reduction in VAF for HR R/R imetelstat treated MF patients on MYF2001C.Association of SF3B1 VAF reduction and longest TI in imetelstat treated LR MDS patients in PH2 and PH3 MDS3001D.Association of SF3B1 VAF reduction and 8week,24week and 1 yr TI duration in imetelstat treated LR MDS patients in PH2 and PH3 MDS3001BACD