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Corporate Presentation November 2025 Our mission is to change lives by changing the course of blood cancer
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2 Forward-Looking Statements Except for the historical information contained herein, this presentation contains forward-looking statements 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 Company’s efforts to maximize the value of RYTELO, including the expected success of the Company’s efforts to expand patient impact and advance a differentiated hematology portfolio, the deep hematology and oncology experience of its leadership team, the ability of RYTELO to improve lives, and the Company’s focused investment and execution; (ii) the Company’s belief that RYTELO is a highly differentiated treatment for eligible lower-risk MDS patients; (iii) the Company’s efforts to prioritize U.S. RYTELO commercial success, the Company’s EU commercialization plans, and the Company’s belief that success in the Phase 3 ImpactMF trial in R/R MF will generate long-term value; (iv) the potential for differentiated benefits associated with RYTELO’s unique mechanism of action; (v) the Company’s views and expectations regarding the significant potential of the U.S. market opportunity for RYTELO in lower-risk MDS and estimates regarding the total addressable patient population, including by line of therapy and RS status, and ability to compete for market share across patient segments; (vi) the Company’s beliefs, plans and expectations regarding its commercial and medical affairs strategy for RYTELO, including strategies to educate healthcare providers, increase the Company’s presence at hematology forums and expand the Company’s investigator sponsored trial program with U.S. clinical sites, and the anticipated success of those efforts; (vii) the Company’s beliefs, plans and expectations regarding specific opportunities and investments the Company is making and its efforts to enhance its leadership team to deliver on the Company’s full potential, including accelerating momentum, driving growth, maximizing the potential of RYTELO and strengthening the foundation for potential future portfolio expansion, and the expected success of those efforts; (viii) the Company’s beliefs, assumptions, and expectations regarding the potential market opportunity for RYTELO in R/R MF, including estimates regarding the addressable patient population; (ix) the potential impact on 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 RYTELO’s U.S. labeling and NCCN Guidelines listing; (x) that the Phase 3 IMpactMF trial in R/R MF has registrational intent and the Company’s beliefs regarding the progress and status of the trial and expectations regarding the interim analysis occurring in the second half of 2026 and the final analysis occurring in the second half of 2028, together with the assumptions used in making these estimates; (xi) the status, plans and expected timing of results from the Company’s clinical programs, including as set forth on its pipeline chart; (xii) the Company’s plans and expectations regarding the timing for commercializing RYTELO in select EU countries in 2026, pending strong reimbursement and favorable pricing; (xiii) the Company’s projections for total operating expenses in fiscal year 2025; (xiv) that certain potential future events represent opportunities for value creation, including expected launch in select EU countries in lower-risk MDS, results from the expected interim and final analyses of the Company’s Phase 3 R/R MF trial, and results from the expected analysis of the Company’s Phase 1 IMprove MF trial; (xv) the expected length of regulatory, market and patent exclusivity for RYTELO; (xvi) the significance of RYTELO’s commercial opportunity in lower-risk MDS, as driven by Phase 3 IMerge data, favorability of U.S. Prescribing Information, and NCCN guidelines; (xvii) the potential for RYTELO to offer differentiated clinical benefits and become a second-line therapy of choice across lower-risk MDS patients irrespective of RS 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 potential for lower-risk 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 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, including statements of past performance, efforts, trends, or results of the Company’s clinical trials, commercialization efforts or performance indicators, about which inferences or assumptions may be made, also constitute forward-looking statements and are not indicative of future performance or results. These forward-looking 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 (imetelstat) for the treatment of certain patients with lower-risk MDS with transfusion dependent anemia and achieves market acceptance across the breadth of the eligible patient segments in RYTELO’s approved indication; (b) whether the FDA and European Commission will approve imetelstat for other indications on the timelines expected, or at all; (c) Geron’s plans to commercialize RYTELO in the EU and risks related to operating outside of the U.S.; (d) whether Geron overcomes potential delays and other adverse impacts that may be caused by enrollment, clinical, safety, efficacy, technical, scientific, intellectual property, manufacturing and regulatory challenges in order to have the financial resources for and meet expected timelines and planned milestones; (e) whether regulatory authorities permit the further development of imetelstat on a timely basis, or at all, without any clinical holds; (f) whether RYTELO (imetelstat) may cause, or have attributed to it, adverse events that could delay or prevent the commencement and/or completion of clinical trials, impact its regulatory approval, or limit its commercial potential; (g) whether the Phase 3 IMpactMF trial in 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 Company’s projected rates for death events differ from actual rates, which may cause the interim and final analyses to occur later than anticipated; (h) whether any future safety or efficacy results of RYTELO treatment cause its benefit-risk profile to become unacceptable; (i) whether imetelstat actually demonstrates disease- modifying activity in patients and the ability to target the malignant stem and progenitor cells of the underlying disease; (j) whether Geron meets its post-marketing requirements and commitments for RYTELO; (k) whether there are failures or delays in manufacturing 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; (l) whether Geron is able to establish and maintain effective sales, marketing and distribution capabilities, obtain adequate coverage and third-party payor reimbursement, and achieve adequate acceptance in the marketplace; (m) 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; (n) that Geron may be unable to successfully commercialize RYTELO due to competitive products, or otherwise; (o) that Geron’s past performance, clinical data and results, or commercial performance indicators and demand trends, may not be replicated in or predictive of future results, performance or trends; (p) whether Geron stays in compliance with and satisfies its obligations under its debt and synthetic royalty financing agreements; and (q) the impact of general economic, industry or political climate in the U.S. or internationally and the effects of macroeconomic conditions on the Company’s business and business prospects, financial condition and results of operations. Additional information 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 Geron’s filings and periodic reports filed with the Securities and Exchange Commission under the heading “Risk Factors” and elsewhere in such filings and reports, including Geron’s quarterly report on Form 10-Q for the period ended June 30, 2025, 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, 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.
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3 Maximizing the value of RYTELO® while advancing our first-in-class telomerase inhibitor Geron – Proven Science. Expanding Patient Impact. Experienced Leadership Team Deep hematology and oncology expertise, driving disciplined execution Demonstrated Patient Benefit Durable, meaningful clinical outcomes shown in LR-MDS – validating telomerase inhibition and improving lives Focused Investment and Execution Executing the U.S. launch of RYTELO® with urgency and precision to reach every patient who can benefit – while strategically investing in the science and people to build for tomorrow Advancing a Differentiated Hematology Portfolio Stage Program Indication(s) Commercial RYTELO® (imetelstat) Lower-risk MDS* Phase 3 Imetelstat Relapsed/refractory Myelofibrosis Discovery Next-Gen Telomerase Inhibitors Across Hematologic Malignancies Building a long-term growth engine powered by telomerase inhibition *RYTELO (imetelstat) is approved by the FDA and EMA 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 (ESAs). See U.S. Prescribing Information and Medication Guide: https://pi.geron.com/products/US/pi/rytelopi.pdf
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4 RYTELO® (imetelstat) *RYTELO (imetelstat) is approved by the FDA and EMA 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 (ESAs). See U.S. Prescribing Information and Medication Guide: https://pi.geron.com/products/US/pi/rytelopi.pdf Approved in the U.S. and EU based on results from the pivotal IMerge Phase 3 trial A first-in-class telomerase inhibitor with a unique mechanism of action representing a highly differentiated treatment approved for eligible patients with lower-risk myelodysplastic syndromes (LR-MDS)*
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5 INT-1/INT-2/HR MF: Intermediate-1/Intermediate-2/High Risk MF; PROs: patient-reported outcomes; SVR: spleen volume reduction; TSS: total symptom score. *These projections are based on expectations about event rates (deaths), which can change over time and may differ from our current expectations # imetelstat salt form ^Best available therapies include hydroxyurea, corticosteroids, danazol, and others Phase 3 IMpactMF Trial Now Fully Enrolled Primary Endpoint: OS Secondary Endpoints: TSS (≥ 50%) at week 24, SVR (≥35%) at week 24, PROs, safety Imetelstat 9.4mg/kg IV# every 3 weeks (n ~214) Best Available Therapy^ (n ~106) INT-1/INT-2/HR MF R/R to JAKi (n=320) Designed to Confirm Strong OS Signal Observed in Phase 2 Study Interim Analysis expected 2H 2026* Final Analysis (base case) expected 2H 2028* ClinicalTrials.gov Identifier: NCT04576156
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6 Significant Commercial Opportunity in LR-MDS
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7 Durable Red Blood Cell Transfusion Independence and Response Rates Meaningful Hemoglobin Rises and Reduction in Transfusions Observed Consistent Responses Across Subgroups Generally Manageable Safety Profile Platzbecker U and Santini V, et al. The Lancet, 2024. https://doi.org/10.1016/S0140-6736(23)01724-5. 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 their application or use in any way. Key RYTELO® Highlights RYTELO positioned to be second-line treatment of choice on FDA label and NCCN Guidelines®# First and only approved telomerase inhibitor, bringing a differentiated mechanism of action
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8 ~15,400 U.S. RYTELO total addressable LR-MDS patients in 2025 ESA: erythropoiesis-stimulating agents; LR-MDS: lower risk myelodysplastic syndromes; RS-: ring sideroblast negative; RS+: ring sideroblast positive. ^Non-del 5q. Sources: 2025 patient volumes based on IQVIA projected new patient claims 2023, DRG LR MDS incidence projected growth rate (2022); Ring sideroblasts present in ~23%-33% of patients with MDS and are associated with anemia (references: 2.Papaemmanuil E, Gerstung M, Malcovati L, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122(22):36163627. 3. Malcovati L, Cazzola M. Recent advances in the understanding of myelodysplastic syndromes with ring sideroblasts . Br J Haematol 2016;174(6):847 858). Total addressable patient population includes patients recommended in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines) for the treatment of MDS as a Category 1 and 2A treatment. Geron promotes RYTELO within its FDA-approved indication for patients requiring four or more red blood cell units over eight weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents (ESAs). 1L Patients^ 2L Patients^ 3L+ Patients^ ESA Ineligible: ~3,400 ∼ 16,800 ∼ 7,600 ∼ 4,400 ESA Eligible: ~13,400 RS-: ~5,700 RS+: ~1,900 RS+: ~1,100 RS-: ~3,300 ∼45% 1L patients expected to progress to 2L treatment in 2025 ∼59% 2L patients expected to progress to 3L treatment in 2025 Estimated 2025 U.S. RYTELO Total Addressable LR-MDS Patient Population RYTELO LR-MDS U.S. Market Opportunity with Significant Potential
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9 Refined Commercial Targeting to Reach Accounts Treating the Majority of Diagnosed Patients Accounts Treating Eligible LR-MDS Patients Identified >10,000 HCPs treat diagnosed MDS patients in the U.S. ~6,300 HCPs treat ~80% of the diagnosed MDS patients ~1,300 HCPs treat ~50% of the diagnosed MDS patients Marketing/Digital: Non-personal promotion* Field Sales: Personal promotional efforts* *Geron promotes RYTELO within its FDA-approved indication for patients requiring four or more red blood cell units over eight weeks who have not responded to or have lost response to or are ineligible for ESAs. Source: IQVIA claims data, January 2025
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10 Additional Actions Underway to Maximize Value of RYTELO and Explore Opportunities for Imetelstat Educate U.S. HCPs on RYTELO Increase Presence in Hematology Forums Expand IST Program with U.S. Clinical Sites Path to Accelerating Momentum and Expanding RYTELO (imetelstat) 1 2 3
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11 Compelling Opportunity in JAKi R/R Myelofibrosis
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12 JAKi: Janus kinase inhibitor; MF: myelofibrosis; R/R MF: relapsed/refractory. Source: US IQVIA Claims through 2023 (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 Could Potentially Double the RYTELO Commercial Opportunity, if Successful and Approved ~12,000 U.S. JAKi naïve / well-controlled MF patients (currently only 3 approved treatments – all JAK inhibitors) 75% of those JAKi treated patients fail or discontinue treatment Potential to treat U.S. JAKi R/R MF patients*~10,000
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13 OS: overall-survival 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; . 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), 435–441 (2018).; Mascarenhas J, Mehra M, He J, Potluri R, Loefgren C. Patient characteristics and outcomes after ruxolitinib discontinuation in patients with myelofibrosis. J. Med. Econ. 23(7), 721–727 (2020).; Newberry K, Patel K, Masarova L et al. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. Blood 130(9),1125–1131 (2017).; Palandri F, Breccia M, Bonifacio M et al. Life after ruxolitinib: reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis. Cancer 126(6), 1243–1252 (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(6), 614–619 (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 OS Survival Probability 33.8 mos 12.0 mos BAT Moffitt Imetelstat 9.4 mg/kg Median OS in Phase 2 IMbark Compares Favorably to Historical Controls (11-16 months) Median OS More than Double Compared to BAT in RWD Study Kuykendall et al. Favorable overall survival with imetelstat in relapsed/refractory myelofibrosis patients compared with real-world data. Ann Hematol. 2022 Jan;101(1):139-146. RWD BAT vs. Imetelstat 9.4 mg/kg Survival Probability ClinicalTrials.gov Identifier: NCT02426086 29.9 mos
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14 INT-1/INT-2/HR MF: Intermediate-1/Intermediate-2/High Risk MF; PROs: patient-reported outcomes; SVR: spleen volume reduction; TSS: total symptom score. *These projections are based on expectations about event rates (deaths), which can change over time and may differ from our current expectations # imetelstat salt form ^Best available therapies include hydroxyurea, corticosteroids, danazol, and others Phase 3 IMpactMF Trial Designed to Confirm Strong OS Signal Observed in Phase 2 Study ClinicalTrials.gov Identifier: NCT04576156 Interim Analysis expected 2H 2026* Final Analysis (base case) expected 2H 2028* 100% Enrolled at the end of Sept 2025 Primary Endpoint: OS Secondary Endpoints: TSS (≥ 50%) at week 24, SVR (≥35%) at week 24, PROs, safety Imetelstat 9.4mg/kg IV# every 3 weeks (n ~214) Best Available Therapy^ (n ~106) INT-1/INT-2/HR MF R/R to JAKi (n=320)
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15 Development Pipeline
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16 Based on Nobel Prize-winning science, imetelstat is wholly owned by Geron Telomerase Inhibition Represents a Novel MOA with Unique Benefits Scientific evidence suggests reduction in proliferation of malignant cells and production of new healthy cells drive differentiated clinical benefits* Imetelstat binds to telomerase, inhibiting its activity Imetelstat Telomerase is increased in malignant cells Malignant clones Upregulated telomerase Apoptosis of malignant cells and recovery of effective hematopoiesis Apoptotic malignant clones MOA: mechanism of action *Robinson NJ, Schiemann WP. Telomerase in Cancer: Function, Regulation, and Clinical Translation.Cancers. 2022;14(3):808; Schrank Z, Khan 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;373:908-919; 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 Myelodysplastic Syndromes Relapsed/Refractory to Erythropoiesis Stimulating Agents in IMerge Phase 3. EHA 2023.
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17 Exploring the Potential of Telomerase Inhibition Across Multiple Hematologic Malignancies Therapeutic Areas Discovery Preclinical Phase 1 Phase 2 Phase 3 Approved LR-MDS Single Agent R/R MF Single Agent Frontline MF Combination Therapy R/R AML & HR-MDS Single Agent R/R AML Combination Therapy Next Generation TI Program IMpactMF IMproveMF IMpress IMAGINE* Ongoing; Investigator Led Planned; Investigator LedOngoing; Company Sponsored Approved in the U.S. & EU *Formerly TELOMERE HR-MDS: higher-risk myelodysplastic syndromes; LR-MDS: lower-risk MDS; MF: myelofibrosis; R/R AML: relapsed/refractory acute myeloid leukemia; R/R MF: relapsed/refractory MF; TI: telomerase inhibitor. * RYTELO® (imetelstat) is approved in the U.S. and the EU for the treatment of certain adult patients with lower-risk myelodysplastic syndromes (LR-MDS) with transfusion-dependent anemia. See U.S. Prescribing Information and Medication Guide: https://pi.geron.com/products/US/pi/rytelo_pi.pdf; see Summary of Product Characteristics for RYTELO in the EU: https://pi.geron.com/products/rytelo/eu/rytelo_smpc_eu.pdf
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18 Financial Overview
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19 Financial Overview Q3 2025 total OpEx $61.1M Cash and marketable securities as of 9/30/25 $421.5M Cash Balance Operating ExpensesNet Revenue Q3 2025 net product revenue $47.2M Expected 2025 OpEx Range $270M to $285M PreviousUpdated $250M to $260M
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Executive Leadership Team Experienced Leaders in Hematology and Oncology Shaping Geron’s Next Chapter Harout Semerjian President and Chief Executive Officer, Board of Directors Member Joseph Eid, M.D. Executive Vice President, Research and Development, Chief Medical Officer Bryan Ridgell Senior Vice President, Portfolio and Project Management and Chief of Staff Dawn Schottlandt Senior Vice President, Investor Relations and Corporate Affairs Ahmed ElNawawi (“Nawawi”) Executive Vice President, Chief Commercial Officer Scott Samuels, Esq. Executive Vice President, Chief Legal Officer and Secretary Shannon Odam Executive Vice President, Chief People Officer Michelle Robertson Executive Vice President, Chief Financial Officer and Treasurer Shanthakumar (Shantha) Tyavanagimatt, Ph.D. Senior Vice President, Chief Technical Officer
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21 Appendix
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22 Multiple Opportunities to Support Long-Term Growth June 2024 FDA approval & U.S. launch of RYTELO in LR-MDS Q3 2024 $28.2M product revenue in first full commercial quarter Dec 2024 Positive CHMP opinion in LR-MDS 2H 2026 Ph3 interim analysis in R/R MF* 2026 Initial Results from Part 2 of Ph1 IMproveMF 2H 2028 Ph3 final analysis in R/R MF* Nov 2024 Secured up to $375M in non-equity financings 2026 Launch in select EU countries in LR-MDS March 2025 EU approval in LR-MDS CHMP: Committee for Medicinal Products for Human Use; EU= European Union; FDA: U.S. Food & Drug Administration; LR-MDS; lower-risk myelodysplastic syndromes; R/R MF = relapsed/refractory myelofibrosis *These projections are based on expectations about event rates (deaths), which can change over time and may differ from our current expectations. Q4 2024 $47.5M product revenue YE 2025 Enrollment completed in Ph3 R/R MF
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23 LR-MDS Represents a Significant Commercial Opportunity for RYTELO Phase 3 IMerge data, FDA label and NCCN Guidelines position RYTELO as highly differentiated treatment
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24 If PTE Applied to COM3COM Patent Term +2 years6 1. 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 confer exclusivity through December 2030, but if applied to our 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 years 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 (i.e., Supplemental Protection Certificates (SPCs)) 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 EU Strong IP Position for RYTELO Supports Commercial Opportunity Expected Regulatory Exclusivities and Patent Terms If PTE Applied to MOU3 Mar 2033Dec 2025 Dec 2030 Jun 2024 Jun 2031 Jun 2024 Jun 2029U.S. Data/Market Exclusivity1 Patent Term Patent Term Extension (PTE) Orphan Drug Exclusivity Data/Market Exclusivity EU Data/Market Exclusivity4 EU Orphan Drug Exclusivity5 March 2025 March 2025 March 2035 PTE7 US • 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 FDA’s Orange Book • PTE Applications filed in EU for RYTELO MOU (MDS) patent • PTE review occurs on country-by-country basis and can take years U.S. Methods of Use (MOU) Patent (MDS and MF) EU EU MOU Patent (MDS) ~Aug 2037 ~Nov 2038 U.S. Orphan Drug Exclusivity2 Nov 2033
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25 • Thrombocytopenia • Neutropenia • Infusion-Related Reactions • Embryo-Fetal Toxicity Warning and Precautions See U.S. Prescribing Information and Medication Guide: https://pi.geron.com/products/US/pi/rytelo_pi.pdf *imetelstat active moiety Favorable U.S. Prescribing Information for RYTELO Supports Significant Market Opportunity RYTELO 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 units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis- stimulating agents (ESA). Indication and Usage No boxed warning No REMS program No contraindications 7.1 mg/kg* administered as an intravenous infusion over 2 hours every 4 weeks Recommended Dosage Most 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 thromboplastin time, arthralgia/myalgia, COVID-19 infections, and headache. Adverse Reactions Complete blood counts and liver function tests are required, as detailed in the PI.
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26 All recommendations are category 2A unless otherwise indicated. 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 way. aOther recommended. bPoor probability to respond to immunosuppressive therapy (IST). RS: ring sideroblast; ESA: erythropoietin stimulating agents; EPO: erythropoietin; HMA: hypomethylating agents; G-CSF: granulocyte-colony stimulating factor; NCCN Guidelines®: NCCN Clinical Practice Guidelines in Oncology. NCCN Guidelines Recommend Imetelstat as a Preferred Second-Line Treatment Option NCCN MDS Guidelines include imetelstat for use for both RS(+) and RS(-) populations in 1st line ESA-ineligible patients and in 2nd line patients regardless of prior therapy Treatment of Symptomatic Anemia in Patients with LR-MDS In 1st line, imetelstat is a Category 2A treatment option for RS+ and RS- ESA-ineligible patients 1ST Line 2ND Line In 2nd line, imetelstat is a Category 1 treatment option for RS+ and RS- ESA-eligible patients, and Category 2A treatment option for RS+ ESA-ineligible patients RS(-) ESA Imetelstat Category 1 (preferred) ESA +/- G-CSF or Lenalidomidea or Luspatercept-aamt (preferred, if not previously used) Ivosidenib (if mIDH1)b Clinical trial or consider allo-HCT (no mIDH)b Enasidenib (if mIDH2)b Azacitidine or other HMAb Imetelstat (preferred, if not previously used)b Consider Lenalidomideb Clinical trialb orLuspatercept-aamt (preferred for patients with EPO>200mU/mL) Serum EPO >500 mU/mLSerum EPO ≤500 mU/mL RS(+) Imetelstata (if sEPO>500 mU/mL, ineligible for ESAs) Luspatercept-aamt Category 1 (preferred) Luspatercept-aamt Category 1 (preferred, if not previously used) Consider Lenalidomidea Imetelstat (preferred, if not previously used) or Imetelstat Category 1 (preferred) ESA +/- G-CSFa or or Serum EPO >500 mU/mLSerum EPO ≤500 mU/mL
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27 8, 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 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 patients 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 trial Platzbecker U and Santini V, et al. The Lancet, 2024. https://doi.org/10.1016/S0140-6736(23)01724-5 Durable Red Blood Cell Transfusion Independence and Response Rates Differentiate Imetelstat 39.8% 28.0% 17.8% 15.0% 3.3% 1.7% 0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 ≥ 8-week RBC-TI ≥ 24-week RBC-TI ≥ 1-year RBC-TI Percentage of Patients (%) P<0.001 Nominal P=0.002 Imetelstat (n=118) Placebo (n=60) P<0.001 52 weeks median duration 80 weeks median duration 123 weeks median duration (exploratory endpoint)(secondary endpoint)(primary endpoint)
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28 RBC-TI: red blood cell transfusion-independence. Platzbecker 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 Imetelstat 3.6 g/dL median Hgb rise in 8-week RBC-TI responders ≥4U/8 weeks transfusion reduction in ~60% of imetelstat-treated patients Nominal 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, and 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 arms Number of patients The mean 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, stratification factors, dose date, and treatment arm as the independent variables with autoregressive moving average (ARMA(1,1) covariance structure. Number of patients -1 0 1 2 3 4 5 Mean Change in HGB (g/dL; +/- SE) Imetelstat Placebo -5 -4 -3 -2 -1 0 1 1 9 17 25 33 41 49 57 65 73 81 89 97 Mean Change in RBC Transfusion (units; +/- SE) Imetelstat Placebo Weeks Weeks Nominal P<0.001 Nominal P=0.042
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29 Exploratory Analysis; Cochran 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) ^ One patient on imetelstat arm missing RS category Platzbecker 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 Imetelstat (≥ 8-week RBC-TI Responses) Imetelstat, n/N (%) Placebo, n/N (%) % Difference (95% CI) Overall 47/118 (39⋅8) 9/60 (15⋅0) 24⋅8 (9⋅9–36⋅9) WHO category^ RS+ 33/73 (45⋅2) 7/37 (18⋅9) 26⋅3 (5⋅9–42⋅2) RS- 14/44 (31⋅8) 2/23 (8⋅7) 23⋅1 (-1⋅3 to 40⋅6) Prior RBC transfusion burden per IWG 2006 4-6 U/8 week 28/62 (45⋅2) 7/33 (21⋅2) 23⋅9 (1⋅9–41⋅4) >6 U/8 week 19/56 (33⋅9) 2/27 (7⋅4) 26⋅5 (4⋅7–41⋅8) IPSS risk category Low 32/80 (40⋅0) 8/39 (20.5) 19⋅5 (-0⋅1 to 35⋅2) Intermediate-1 15/38 (39⋅5) 1/21 (4⋅8) 34⋅7 (8⋅8–52⋅4) Baseline sEPO ≤500 mU/mL 39/87 (44⋅8) 7/36 (19⋅4) 25⋅4 (5⋅27–40⋅70) >500 mU/mL 7/26 (26⋅9) 2/22 (9⋅1) 17⋅8 (-8⋅17 to 40⋅25) -20 -10 0 10 20 30 40 50 60 Favors Imetelstat Favors Placebo
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30 Exploratory 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 Analysis Meaningful patient-reported fatigue improvements in 8 and 24-week RBC-TI responders Sustained meaningful improvement in fatigue reported in imetelstat-treated patients 70.2 72.7 66.736.6 41.2 20.933.3 50.0 41.941.7 40.0 38.5 0 10 20 30 40 50 60 70 80 8-Week RBC-TI 24-Week RBC-TI HI-E per IWG 2006 Imetelstat Responders Imetelstat Nonresponders Placebo Responders Placebo Nonresponders Patients, n/N Responders 33/47 3/9 24/33 1/2 50/75 13/31 Nonresponders 26/71 20/48 35/85 22/55 9/43 10/26 Kaplan-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 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 Improvement in FACIT-Fatigue, % 100 90 80 70 60 50 40 30 20 10 0 Number at risk Time to first sustained improvement in the FACIT-Fatigue score, weeks 0 110100908070605040302010 120 115 13567121619285478 1Imetelstat Placebo 56 011471014163240 PlaceboImetelstat Placebo: Imetelstat: 65.0 28.3 Censored HR=1.34 (95% CI, 0.82–2.20) Median time-to-episode (weeks) Sustained Improvement for ≥2 cycles 0% 20% 40% 60% 80% Patients, % 50.0% 40.4% Imetelstat Placebo
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31 1. 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-Stimulating Agent, Relapsed or Refractory/Ineligible Lower-Risk Myelodysplastic Syndromes. 66th American Society of Hematology (ASH) Annual Meeting and Exposition; December 2024; Presentation 352 ESA R/R/Ineligible LR-MDS Patients With Prior Luspatercept Treatment Experienced Clinical Benefit from Imetelstat Treatment Clinical 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 therapies
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32 These are familiar adverse reactions for hematologists who are experienced with managing cytopenias Well-Characterized Safety Profile with Generally Manageable and Short-Lived Thrombocytopenia and Neutropenia Consistent with prior clinical experience, the most common imetelstat AEs were hematologic AEs were generally manageable with supportive care and dose modifications • 74% of patients treated with imetelstat had dose modifications; mostly due to grade 3–4 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 cases of Hy’s 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 hypertension AEs (≥10% of patients), n (%) Imetelstat (N=118) Placebo (N=59) Any Grade Grade 3–4 Any Grade Grade 3–4 Hematologic Thrombocytopenia 89 (75%) 73 (62%) 6 (10%) 5 (8%) Neutropenia 87 (74%) 80 (68%) 4 (7%) 2 (3%) Anemia 24 (20%) 23 (19%) 6 (10%) 4 (7%) Leukopenia 12 (10%) 9 (8%) 1 (2%) 0 Grade 3-4 thrombocytopenia and neutropenia: • Most often reported during cycles 1-3 • Lasted a median duration of less than two weeks • Resolved to grade < 2 in under four weeks in more than 80% of patients Clinical consequences of Grade 3–4 infection and bleeding were low and similar for imetelstat and placebo AE: adverse event; TEAE: treatment-emergent adverse event. Platzbecker U and Santini V, et al. The Lancet, 2024. https://doi.org/10.1016/S0140-6736(23)01724-5.
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33 Imetelstat Represents a Potential First-in-Class Treatment with a New Mechanism of Action in MF
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34 *These projections are based on expectations about event rates (deaths), which can change over time and may differ from our current expectations. First Myelofibrosis Trial with Overall Survival Primary Endpoint Based on Significant Imetelstat Clinical Experience Single Institution Pilot Study 2015 Pivotal Ph 3 Trial ONGOING Ph 2 Dose Finding Study 2021 Basis for Ph2 IMbark Median OS in 9.4 mg/kg arm more than double compared to BAT in RWD Study First and only Phase 3 trial in MF with overall survival as primary endpoint N=59 (9.4 mg/kg), N=48 (4.7 mg/kg) N=320N=33 Fully Enrolled Enrollment Complete Interim Analysis expected 2H 2026* Final Analysis (base case) expected 2H 2028* Phase 2 Dose Finding Study in JAKi R/R MF NCT02426086 Phase 3 Study in JAKi R/R Int-2 or HR MF NCT04576156 Pilot Study in HR/Int-2 MF (~50% of patients received prior JAKi therapy)
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35 PK = pharmacokinetic profiles; VAF = variant allele frequency; SET = Study Evaluation Team; RP2D = Recommended Phase 2 Dose; DIPSS = dynamic international prognostic scoring system; INT-1 = intermediate-1; INT-2 = intermediate-2; HR = high risk; TSS = total symptom score; SVR35 = spleen volume reduction > 35% Actively enrolling patients for dose confirmation with imetelstat 9.4mg/kg Part 1 Findings Suggest Tolerability of Imetelstat Combined with Ruxolitinib in Patients with MF ClinicalTrials.gov Identifier: NCT05371964 • Well-tolerated, and no dose-limiting toxicities were reported at any imetelstat dose level within 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, TSS • Other Week 24 Endpoints: TSS, SVR35, fibrosis PART 1: Dose Finding Results Presented at ASH 2024 Frontline treatment Initial results from Part 2 expected 2026 Imetelstat 9.4 mg/kg + Ruxolitinib individualized dose per patient INT-1/ INT-2/ HR MF Patients treated with imetelstat 9.4 mg/kg experienced stable hematology values over time Imetelstat 4.7mg/kg (n=3) + Ruxolitinib doses Imetelstat 7.5 mg/kg (n=4) + Ruxolitinib doses Imetelstat 6.0 mg/kg (n=3) + Ruxolitinib doses Imetelstat 9.4 mg/kg (n=7) + Ruxolitinib doses PART 2: Dose Confirmation & Expansion Currently Enrolling ~20 JAKi naïve patients planned 9.4 mg/kg Imetelstat every 4 weeks selected for dose confirmation and expansion
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36 Clinical Benefits Observed in LR-MDS and MF with Unique Mechanism of Action
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37 From 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(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, Germing 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 modifying 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 S164 Association of Clinical Benefit and Reduction of Disease Markers Observed in Imetelstat-Treated MF and MDS Patients A. Disappearance of bone marrow fibrosis in imetelstat treated HR MF patient B. Association of survival improvement and reduction in VAF for HR R/R imetelstat treated MF patients on MYF2001 C. Association of SF3B1 VAF reduction and longest TI in imetelstat treated LR MDS patients in PH2 and PH3 MDS3001 D. Association of SF3B1 VAF reduction and 8week, 24week and 1 yr TI duration in imetelstat treated LR MDS patients in PH2 and PH3 MDS3001 BA C D