ETV6

On October 23, 2020, the Food and Drug Administration approved the next-generation sequencing (NGS)-based FoundationOne CDx test (Foundation Medicine, Inc.) as a companion diagnostic to identify fusions in neurotrophic receptor tyrosine kinase (NTRK) genes, NTRK1, NTRK2, and NTRK3, in DNA isolated from tumor tissue specimens from patients with solid tumors eligible for treatment with larotrectinib (VITRAKVI, Bayer Healthcare Pharmaceuticals, Inc.). Larotrectinib was granted accelerated approval on November 26, 2018, for adult and pediatric patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment. Approval of larotrectinib was based on data from three multicenter, open-label, single-arm clinical trials: LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431). Identification of positive NTRK gene fusion status was prospectively determined in local laboratories using NGS, fluorescence in situ hybridization (FISH), and reverse transcriptase- polymerase chain reaction (RT-PCR) methods. NTRK gene fusions were inferred in three pediatric patients with infantile fibrosarcoma who had a documented ETV6 translocation by FISH. The major efficacy outcome measures were overall response rate (ORR) and response duration, as determined by a blinded independent review committee according to RECIST 1.1. The FoundationOne CDx assay (F1CDx) approval as a companion diagnostic for larotrectinib was based on the retrospective testing with F1CDx of available tumor tissue samples from patients enrolled in the three clinical trials that supported the accelerated approval of larotrectinib. Efficacy for larotrectinib was shown to be maintained in patients with confirmed NTRK fusion positive results by the F1CDx. F1CDx is a NGS based in vitro diagnostic device that is capable of detecting several mutations in addition to NTRK gene fusions. View the Summary of Safety and Effectiveness for the FoundationOne® CDx test (P170019/S017). Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088. For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov. For information on the COVID-19 pandemic, see the following resources: FDA: Coronavirus Disease 2019 (COVID-19) NCI: Coronavirus: What People With Cancer Should Know CDC: Coronavirus (COVID-19) Follow the Oncology Center of Excellence on Twitter @FDAOncologyExternal Link Disclaimer. > Content current as of: 10/26/2020 Regulated Product(s) Drugs Prescription Drugs 10/26/2020 Drugs Prescription Drugs Resources for Information | Approved Drugs Oncology (Cancer)/Hematologic Malignancies Approval Notifications Ongoing | Cancer Accelerated Approvals Verified Clinical Benefit | Cancer Accelerated Approvals Withdrawn | Cancer Accelerated Approvals Other | Cancer Accelerated Approvals Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Short Description Oncology (Cancer)/Hematologic Malignancies Approval Notifications Ongoing | Cancer Accelerated Approvals Verified Clinical Benefit | Cancer Accelerated Approvals Withdrawn | Cancer Accelerated Approvals Other | Cancer Accelerated Approvals Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Short Description

Subgroup analyses showed consistently higher transfusion independence (TI) response rates than placebo across different risk groups regardless of International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) or IPSS molecular (IPSS-M) Robust TI rates with imetelstat treatment compared with placebo in patients with poor prognosis mutational profiles For the nearly 20% of imetelstat-treated patients who achieved greater than 1-year sustained TI, median duration of TI was more than two years and median hemoglobin increase was more than 5 g/dL Consistent with prior imetelstat clinical experience, the most common adverse events were thrombocytopenia and neutropenia that were manageable and of short duration Imetelstat is currently under regulatory review by the FDA and EMA for the treatment of transfusion-dependent anemia in adult patients with lower risk MDS FOSTER CITY, Calif.--(BUSINESS WIRE)--Geron Corporation (Nasdaq: GERN), a late-stage clinical biopharmaceutical company, today announced the publication of abstracts from the IMerge Phase 3 clinical trial evaluating its first-in-class investigational telomerase inhibitor imetelstat in patients with lower risk myelodysplastic syndromes (MDS). Four abstracts have been accepted for presentation at the 65th American Society of Hematology (ASH) Annual Meeting taking place from December 9-12 in San Diego, California and virtually. “The 2023 ASH abstracts present data and analyses from the IMerge Phase 3 clinical trial that reinforce the differentiated clinical pro imetelstat in lower risk MDS, and specifically highlight that patients achieve TI irrespective of risk status based on classification systems, or specific poor prognostic mutation pro Of particular importance, the nearly 20% of imetelstat-treated patients who achieved one year or greater transfusion independence with accompanying hemoglobin rises of 5 g/dl and reduction of MDS-associated mutations speak to the potential of this novel therapy to provide clinical benefits to patients that have not been observed before in transfusion-dependent lower risk MDS,” said Faye Feller, M.D., Geron’s Executive Vice President, Chief Medical Officer. Imetelstat is currently under regulatory review by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) for the treatment of transfusion dependent anemia in adult patients with lower risk MDS who have failed to respond or have lost response to or are ineligible for erythropoiesis-stimulating agents (ESAs). “The data from IMerge Phase 3 being presented at the ASH annual meeting provides important insight into the breadth of effect of TI achieved with imetelstat across different risk subgroups and across the various underlying mutations associated with MDS, suggesting a broad use for imetelstat in patients eligible for the study, including in difficult-to-treat subgroups. Imetelstat also demonstrated efficacy among patients who were reclassified as higher risk using molecular international prognostic scoring system (IPSS-M),” said Rami S. Komrokji, M.D., Vice Chair, Malignant Hematology Department, Moffitt Cancer Center, one of the principal investigators of IMerge Phase 3 and ASH presenter. “Additionally, our abstract showcasing a real-world data population level analysis of over 5,000 lower risk MDS patients adds to the significant literature suggesting a correlation between TI and improvement in survival. These data support the importance of TI to improve outcomes for patients with lower risk MDS.” Abstract #194: “Efficacy of Imetelstat in Achieving Red Blood Cell Transfusion Independence (RBC-TI) Across Different Risk Subgroups in Patients with Lower Risk Myelodysplastic Syndromes (LR MDS) Relapsed/Refractory (R/R) to Erythropoiesis Stimulating Agents (ESAs) in IMerge Phase 3 Study” Oral Presentation on December 9, 2023, at 2:15 p.m. PT This abstract evaluates TI rates in patients treated with imetelstat vs. placebo across different risk subgroups as defined by International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) or IPSS molecular (IPSS-M) risk profiles and shows that patients treated with imetelstat consistently had higher TI response rates than placebo regardless of risk classification. Further, in patients re-classified as high or very high risk using IPSS-M, TI response rates with imetelstat (and not placebo) were similar to TI response rates in lower risk subgroups. This analysis suggests imetelstat has clinical activity in lower risk MDS patients independent of risk categories. Abstract #4603: “Impact of Mutational Status on Clinical Response to Imetelstat in Patients with Lower Risk Myelodysplastic Syndromes in the IMerge Phase 3 Study” Poster Presentation on December 11, 2023, from 6-8 p.m. PT This abstract evaluates the impact of MDS-associated mutations on clinical efficacy of imetelstat for the 165 of 178 patients for whom mutation data were available and shows that RBC-TI response rates in patients receiving imetelstat occurred regardless of the presence of baseline MDS associated mutations that have a poor prognosis (either specific mutations or multiple concurrent mutations). In patients with mutations associated with poor prognosis (TP53, ETV6, RUNX1, ASXL1, or EZH2), ≥8-week and ≥24-week, TI was observed in 31.8% and 9.1% of imetelstat-treated patients vs 0 on placebo. The 8-week TI rate for patients with 3 or more mutations was 55.6% with imetelstat compared to 14.3% with placebo. This analysis suggests clinical benefit of imetelstat across different molecularly defined subgroups and independent of the underlying molecular pattern. Abstract #4605: “Durable Continuous Transfusion Independence (TI) With Imetelstat in IMerge Phase 3 for Patients with Heavily Transfused Non-Del(5q) Lower Risk Myelodysplastic Syndromes (LR MDS) Relapsed/Refractory (R/R) to or Ineligible for Erythropoiesis-Stimulating Agents (ESAs)” Poster Presentation on December 11, 2023, from 6-8 p.m. PT This abstract evaluates the 1-year TI responders in IMerge Phase 3, including 17.8% of imetelstat-treated patients (21/118; 95% CI, 11.4-25.9) and 1.7% of patients on placebo (1/60; 95% CI, 0-8.9). The median duration of TI for imetelstat ≥1-year TI responders was 123 weeks (95% CI, 80.4 to not evaluable); the median increase in hemoglobin during the longest TI interval was 5.18 g/dL (range, 2.67-13.76 g/dL) for the imetelstat group vs 1.67 g/dL for the placebo patient. Of the 18/21 imetelstat-treated 1-year TI responders for whom mutation data were available, 72.2% achieved ≥50% SF3B1 variant allele frequency (VAF) reduction, including 7 patients in whom there was complete elimination of MDS associated mutations. The abstract concludes that the long-term durable TI, robust increases in hemoglobin and meaningful reductions in mutational burden suggest imetelstat may have disease-modifying activity. Grade 3-4 thrombocytopenia and neutropenia occurred in 14 (67%) and 20 (95%) patients with ≥1-year TI, respectively, and the mean duration of grade 3/4 thrombocytopenia and neutropenia events was 2.25 and 1.78 weeks, respectively. 89% of grade 3/4 thrombocytopenia and 81% of grade 3/4 neutropenia was reduced to grade 1/2 within 4 weeks. Abstract #2440: “Durable Transfusion Independence in Lower Risk Myelodysplastic Syndrome (LR MDS) Is Associated with Better Survival: A Population Level Analysis Based on a Large US Health Insurance Claims Database” Poster Presentation on December 11, 2023, from 6-8 p.m. PT This abstract describes a population level analysis of 5,662 lower risk MDS patients identified through Optum Clinformatics® between October 2015 and June 2022. Among these patients, 35% and 49% were transfusion-dependent before first and second lines of therapy, respectively. The median overall survival from start of second line therapy was 23.4 months overall, and 37.9 months vs 9.3 months among responders becoming transfusion independent vs non-responders, respectively (P < .0001). Despite the currently available therapies, transfusion dependence after any line of therapy is associated with poorer outcomes. Achievement of durable TI was associated with improved survival, supporting the clinical benefit of achieving transfusion independence in lower risk MDS. These abstracts are available on the ASH 2023 Meeting website at . About IMerge Phase 3 The Phase 3 portion of the IMerge Phase 2/3 study is a double-blind, 2:1 randomized, placebo-controlled clinical trial to evaluate imetelstat in patients with IPSS Low or Intermediate-1 risk (lower risk) transfusion dependent MDS who were relapsed after, refractory to, or ineligible for, erythropoiesis stimulating agent (ESA) treatment, had not received prior treatment with either a HMA or lenalidomide and were non-del(5q). To be eligible for IMerge Phase 3, patients were required to be transfusion dependent, defined as requiring at least four units of packed red blood cells (RBCs), over an eight-week period during the 16 weeks prior to entry into the trial. The primary efficacy endpoint of IMerge Phase 3 is the rate of red blood cell transfusion independence (RBC-TI) lasting at least eight weeks, defined as the proportion of patients without any RBC transfusion for at least eight consecutive weeks since entry to the trial (8-week TI). Key secondary endpoints include the rate of RBC-TI lasting at least 24 weeks (24-week TI), the duration of TI and the rate of hematologic improvement erythroid (HI-E), which is defined under 2006 IWG criteria as a rise in hemoglobin of at least 1.5 g/dL above the pretreatment level for at least eight weeks or a reduction of at least four units of RBC transfusions over eight weeks compared with the prior RBC transfusion burden. A total of 178 patients were enrolled in IMerge Phase 3 across North America, Europe, Middle East and Asia. About Imetelstat Imetelstat is a novel, first-in-class investigational telomerase inhibitor exclusively owned by Geron and being developed in hematologic malignancies. Data from non-clinical studies and clinical trials of imetelstat provide strong evidence that imetelstat targets telomerase to inhibit the uncontrolled proliferation of malignant stem and progenitor cells in myeloid hematologic malignancies resulting in malignant cell apoptosis and potential disease-modifying activity. Imetelstat has been granted Fast Track designation by the U.S. Food and Drug Administration for both the treatment of adult patients with transfusion dependent anemia due to Low or Intermediate-1 risk MDS that is not associated with del(5q) who are refractory or resistant to an erythropoiesis stimulating agent, and for adult patients with Intermediate-2 or High-risk myelofibrosis (MF) whose disease has relapsed after or is refractory to Janus associated kinase (JAK) inhibitor treatment. Imetelstat is currently not approved by any regulatory authority. About Geron Geron is a late-stage clinical biopharmaceutical company pursuing therapies with the potential to extend and enrich the lives of patients living with hematologic malignancies. Our first-in-class investigational telomerase inhibitor, imetelstat, harnesses Nobel Prize-winning science in a treatment that may alter the underlying drivers of disease. The New Drug Application (NDA) for imetelstat for the treatment of transfusion dependent anemia in adult patients with lower risk myelodysplastic syndromes (LR MDS) who have failed to respond or have lost response to or are ineligible for erythropoiesis-stimulating agents (ESAs), based on the results from the Phase 3 IMerge clinical trial, is currently under review by the United States Food and Drug Administration (FDA) with a Prescription Drug User Fee Act (PDUFA) target action date of June 16, 2024. In addition, an MAA is under review in the European Union for the same proposed indication. Furthermore, Geron currently has an ongoing pivotal Phase 3 clinical trial evaluating imetelstat in relapsed/refractory myelofibrosis (MF). To learn more, visit or follow us on LinkedIn. Use of Forward-Looking Statements Except for the historical information contained herein, this press release 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: (i) that data from the IMerge Phase 3 clinical trial in the ASH abstracts reinforce the differentiated clinical pro imetelstat in lower risk MDS; (ii)that the nearly 20% of imetelstat-treated patients who achieved one year or greater transfusion independence with accompanying hemoglobin rises of 5 g/dl and reduction of MDS-associated mutations speak to the potential of imetelstat to provide clinical benefits to patients that have not been observed before in transfusion-dependent lower risk MDS; (iii) that data from IMerge Phase 3 associated with the ASH annual meeting suggests a broad use for imetelstat in patients eligible for the study, including in difficult-to-treat subgroups; (iv) that a real-world data population level analysis of over 5,000 lower risk MDS patients adds to the significant literature suggesting a correlation between transfusion independence and improvement in survival and support the importance of transfusion independence to improve outcomes for patients with lower risk MDS; and (v) other statements that are not historical facts, constitute forward-looking statements. 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 regulatory authorities permit the further development of imetelstat on a timely basis, or at all, without any clinical holds; (b) whether any future safety or efficacy results cause the benefit-risk pro imetelstat to become unacceptable; (c) whether imetelstat actually demonstrates that it alters the underlying drivers of disease and has disease-modifying activity in patients; and (d) whether the FDA and EMA will approve imetelstat for the treatment of transfusion-dependent anemia in patients with lower risk MDS. 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 quarter ended September 30, 2023 and future 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.

On November 26, 2018, the Food and Drug Administration granted accelerated approval to larotrectinib (VITRAKVI, Loxo Oncology Inc. and Bayer) for adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment. This is the second tissue-agnostic FDA approval for the treatment of cancer. Approval was based on data from three multicenter, open-label, single-arm clinical trials: LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431). Identification of positive NTRK gene fusion status was prospectively determined in local laboratories using next generation sequencing (NGS) or fluorescence in situ hybridization (FISH). NTRK gene fusions were inferred in three pediatric patients with infantile fibrosarcoma who had a documented ETV6 translocation by FISH. The major efficacy outcome measures were overall response rate (ORR) and response duration, as determined by a blinded independent review committee according to RECIST 1.1. Efficacy was evaluated in the first 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion enrolled across the three trials. All patients were required to have progressed following systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease. Twelve patients were less than 18 years of age. A total of 12 cancer types were represented, with the most common being salivary gland tumors (22%), soft tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid cancer (9%). ORR was 75% (95% CI: 61%, 85%), including 22% complete responses and 53% partial responses. At the time of database lock, median duration of response had not been reached. Response duration was 6 months or longer for 73%, 9 months or longer for 63%, and 12 months or longer for 39% of patients. The safety of larotrectinib was evaluated in 176 patients enrolled across the three clinical trials, including 44 pediatric patients. The most common adverse reactions (≥20%) with larotrectinib were fatigue, nausea, dizziness, vomiting, increased AST, cough, increased ALT, constipation, and diarrhea. The recommended larotrectinib doses are 100 mg orally twice daily for adults and 100 mg/m2 orally twice daily (maximum of 100 mg per dose) for pediatric patients. View full prescribing information for VITRAKVI. This indication is approved under accelerated approval and continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. FDA granted this application priority review, breakthrough therapy designation and orphan product designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics. Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088. Follow the Oncology Center of Excellence on Twitter @FDAOncologyExternal Link Disclaimer. Check out recent approvals at the OCE’s podcast, Drug Information Soundcast in Clinical Oncology (D.I.S.C.O.). Content current as of: 12/14/2018 Regulated Product(s) Drugs 12/14/2018 Drugs Drugs Regulatory Science Research and Education Development & Approval Process | Drugs Drug Safety and Availability Emergency Preparedness | Drugs Guidance, Compliance, & Regulatory Information News & Events for Human Drugs Resources | Drugs Science and Research | Drugs Regulatory Science Research and Education Development & Approval Process | Drugs Drug Safety and Availability Emergency Preparedness | Drugs Guidance, Compliance, & Regulatory Information News & Events for Human Drugs Resources | Drugs Science and Research | Drugs