RYTELO

1. INDICATIONS AND USAGE 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). RYTELO is an oligonucleotide telomerase inhibitor 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). ( 1 )

2. DOSAGE AND ADMINISTRATION The recommended dosage of RYTELO is 7.1 mg/kg administered as an intravenous infusion over 2 hours every 4 weeks. ( 2.1 ) Premedicate prior to dosing with RYTELO for potential infusion-related reactions. ( 2.2 ) See full prescribing information for preparation and administration instructions. ( 2.4 ) 2.1. Recommended Dosage The recommended dosage of RYTELO is 7.1 mg/kg administered as an intravenous infusion over 2 hours every 4 weeks. Discontinue RYTELO if a patient does not experience a decrease in red blood cell (RBC) transfusion burden after 24 weeks of treatment (administration of 6 doses) or if unacceptable toxicity occurs at any time [see Dosage and Administration (2.3) ] . 2.2. Recommended Premedications Administer the following pre-treatment medications at least 30 minutes prior to dosing to prevent or reduce potential infusion-related reactions: diphenhydramine (or equivalent) 25 mg to 50 mg, intravenously or orally hydrocortisone (or equivalent) 100 mg to 200 mg, intravenously or orally Monitor patients for adverse reactions for at least one hour after the infusion has been completed [see Warnings and Precautions (5.3) and Adverse Reactions (6.1) ] . 2.3. Dosage Modifications for Adverse Reactions Recommended dose reductions for Grade 3 and Grade 4 adverse reactions are found in Table 1. The management of Grade 3 and Grade 4 adverse reactions may require temporary dose delay, dose reduction, or treatment discontinuation and are presented in Table 2 and Table 3. RYTELO treatment should be permanently discontinued if the patient cannot tolerate the lowest dose level of 4.4 mg/kg. Table 1: Recommended Dose Reduction for RYTELO for Grade 3 and Grade 4 Adverse Reactions Dose Reduction Dose Every 4 Weeks First dose reduction 5.6 mg/kg Second dose reduction 4.4 mg/kg Dosage Modifications for Hematologic (Grade 3 and Grade 4) Adverse Reactions Monitor complete blood cell counts prior to administration of RYTELO, weekly for the first two cycles, prior to each cycle thereafter, and as clinically indicated. Delay the next cycle if absolute neutrophil count is less than 1 × 10 9 /L or platelets are less than 50 × 10 9 /L. Modify dose as described in Table 2. Table 2: Dosage Modifications for Patients with Hematologic Adverse Reactions (Grade 3 and Grade 4) Adverse Reaction Severity Grade Severity based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03. Occurrence Treatment Modification Abbreviation: ANC = absolute neutrophil count Thrombocytopenia [see Warnings and Precautions (5.1) ] Grade 3 First Delay RYTELO until recovery of platelets to 50 × 10 9 /L; restart at same dose level. Second and Third Delay RYTELO until recovery of platelets to 50 × 10 9 /L; restart at one dose level lower. Fourth Discontinue RYTELO. Grade 4 First and Second Delay RYTELO until recovery of platelets to 50 × 10 9 /L; restart at one dose level lower. Third Discontinue RYTELO. Neutropenia [see Warnings and Precautions (5.2) ] Grade 3 First Delay RYTELO until recovery of ANC to 1 × 10 9 /L; restart at same dose level. Second and Third Delay RYTELO until recovery of ANC to 1 × 10 9 /L; restart at one dose level lower. Fourth Discontinue RYTELO. Grade 4 First and Second Delay RYTELO until recovery of ANC to 1 × 10 9 /L; restart at one dose level lower. Third Discontinue RYTELO. Dosage Modifications for Non-hematologic Adverse Reactions Dosage modifications for infusion-related reactions and other adverse drug reactions, including elevated liver function tests (LFTs), are described in Table 3. Monitor liver function tests prior to administration of RYTELO, weekly for the first cycle, prior to each cycle thereafter, and as clinically indicated. Table 3: Dosage Modifications for Patients with Non-hematologic Adverse Reactions Adverse Reaction Severity Grade Severity based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03. Occurrence Treatment Modifica…

5. WARNINGS AND PRECAUTIONS Thrombocytopenia : Grade 3 and Grade 4 thrombocytopenia occurred; obtain complete blood cell counts prior to initiation of RYTELO, weekly for the first two cycles, and prior to each cycle thereafter to monitor. Delay or dose reduce as recommended. ( 2.3 , 5.1 ) Neutropenia : Grade 3 and Grade 4 neutropenia occurred; obtain complete blood cell counts prior to initiation of RYTELO, weekly for the first two cycles, and prior to each cycle thereafter to monitor. Delay or dose reduce as recommended. ( 2.3 , 5.2 ) Infusion-Related Reactions : Premedicate before infusion. Interrupt, decrease the rate of infusion, or permanently discontinue RYTELO based on severity. ( 2.2 , 2.3 , 5.3 ) Embryo-Fetal Toxicity : Can cause embryo-fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.4 , 8.1 , 8.3 ) 5.1. Thrombocytopenia RYTELO can cause thrombocytopenia based on laboratory values. In the clinical trial, new or worsening Grade 3 or 4 decreased platelets occurred in 65% of patients with MDS treated with RYTELO [see Adverse Reactions (6.1) ] . Median time to onset of first occurrence of Grade 3 or 4 decreased platelets was 6 weeks (range: 2 to 88 weeks) and median time to recovery from each occurrence of Grade 3 or 4 decreased platelets to Grade 2 or lower, or last value available, was 1.3 weeks (range: 0.1 to 13 weeks). Grade 3 or 4 decreased platelets occurred throughout treatment with RYTELO, with 48% of patients experiencing Grade 3 or Grade 4 thrombocytopenia during cycles 1-3, 31% during cycles 4-6, 33% during cycles 7-12, and 24% during cycles 13 and beyond. Grade 3 or 4 bleeding was seen in 2.5% of patients, including gastrointestinal bleeding (1.7%) and hematuria (0.8%). Monitor patients with thrombocytopenia for bleeding. Monitor complete blood cell counts prior to initiation of RYTELO, weekly for the first two cycles, prior to each cycle thereafter, and as clinically indicated. Administer platelet transfusions as appropriate. Delay the next cycle and resume at the same or reduced dose, or discontinue as recommended [see Dosage and Administration (2.3) ] . 5.2. Neutropenia RYTELO can cause neutropenia based on laboratory values. In the clinical trial, new or worsening Grade 3 or 4 decreased neutrophils occurred in 72% of patients with MDS treated with RYTELO [see Adverse Reactions (6.1) ] . Median time to onset of first occurrence of Grade 3 or 4 decreased neutrophils was 4.6 weeks (range: 1 to 81 weeks) and median time to recovery from each occurrence of Grade 3 or 4 decreased neutrophils to Grade 2 or lower, or last value available, was 1.9 weeks (range: 0 to 16 weeks). Grade 3 or 4 decreased neutrophils occurred throughout treatment with RYTELO, with 65% of patients experiencing Grade 3 or Grade 4 neutropenia during cycles 1-3, 35% during cycles 4-6, 32% during cycles 7-12, and 39% during cycles 13 and beyond. Febrile neutropenia occurred in 0.8% and sepsis in 4.2%. Monitor patients with Grade 3 or 4 neutropenia for infections, including sepsis. Monitor complete blood cell counts prior to initiation of RYTELO, weekly for the first two cycles, prior to each cycle thereafter, and as clinically indicated. Administer growth factors and anti-infective therapies for treatment or prophylaxis as appropriate. Delay the next cycle and resume at the same or reduced dose, or discontinue as recommended [see Dosage and Administration (2.3) ] . 5.3. Infusion-Related Reactions RYTELO can cause infusion-related reactions. In the clinical trial, infusion-related reactions occurred in 8% of patients with MDS treated with RYTELO; Grade 3 or 4 infusion-related reactions occurred in 1.7%, including hypertensive crisis (0.8%). The most common infusion-related reaction was headache (4.2%). Infusion-related reactions usually occur during or shortly after the end of the infusion. Premedicate patients at least 30 minutes prior to infusion with diphenhydramine a…

4. CONTRAINDICATIONS None. None. ( 4 )

8.1. Pregnancy Risk Summary Based on findings in animal studies, RYTELO can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on RYTELO use in pregnant women to evaluate for drug-associated risk. In embryo-fetal developmental toxicity studies, administration of imetelstat to pregnant mice and rabbits during the period of organogenesis resulted in embryo-fetal mortality, which in mice occurred at maternal exposures approximately 2.5 times the human exposure at the recommended clinical dose. Advise pregnant women of the potential risk to a fetus [see Data ] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In embryo-fetal developmental toxicity studies, imetelstat was administered by IV bolus injection at doses of 4.7, 9.4, 14.1 or 28.2 mg/kg/day on gestation days 6, 9, and 12 in mice, or by 2-hour intravenous infusion at doses of 4.7, 14.1, or 28.2 mg/kg on gestation days 6 and 13 in rabbits. In rabbits, the dose of 28.2 mg/kg was maternally toxic. Increased post-implantation loss due to an increase in early resorptions, resulting in a decrease in viable fetuses and litter was noted in mice at 28.2 mg/kg and in rabbits starting at 14.1 mg/kg; corresponding to exposures (based on AUC) that are approximately 2.5-times (mice) or 9.3-times (rabbits) the human exposure at the recommended clinical dose.

6. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Thrombocytopenia [see Warnings and Precautions (5.1) ] Neutropenia [see Warnings and Precautions (5.2) ] Infusion-Related Reactions [see Warnings and Precautions (5.3) ] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Geron Corporation at 1-855-437-6664 (1-855-GERONMI) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Low- to Intermediate-Risk Myelodysplastic Syndromes The safety of RYTELO was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial (IMerge) in 177 adult patients with International Prognostic Scoring System (IPSS) low- to intermediate-1 risk MDS who were transfusion-dependent and relapsed or refractory to or ineligible for ESA treatment [see Clinical Studies (14) ] . The safety population included patients who received at least one dose of either RYTELO (n=118) or placebo (n=59) at 7.1 mg/kg as an intravenous infusion administered over two hours every 4 weeks. The median time on treatment with RYTELO was 8 months (range, 0 to 38 months); 69% of patients were exposed to RYTELO for 24 weeks or longer and 45% were exposed for 48 weeks or longer. The median age of patients who received at least one dose of RYTELO was 72 years (range: 44 to 87 years) with 77% of patients 65 years of age and older and 30% of patients 75 years of age and older. Participants were 60% male, 81% White, 7% Asian, and 0.8% Black. Serious adverse reactions occurred in 32% of patients who received RYTELO. Serious adverse reactions in > 2% of patients included sepsis (4.2%), fracture (3.4%), cardiac failure (2.5%), and hemorrhage (2.5%). Fatal adverse reactions occurred in 0.8% of patients who received RYTELO, including sepsis (0.8%). Permanent discontinuation of RYTELO due to an adverse reaction occurred in 15% of patients. Adverse reactions which resulted in permanent discontinuation of RYTELO in > 2% of patients included neutropenia and thrombocytopenia. Dosage interruptions of RYTELO due to an adverse reaction occurred in 80% of patients. Adverse reactions which required dosage interruption in > 5% of patients included neutropenia, thrombocytopenia and infections. Dose reductions of RYTELO due to an adverse reaction occurred in 49% of patients. Adverse reactions which required dose reductions in > 2% of patients included neutropenia and thrombocytopenia. The most common (≥10% with a difference between arms of >5% compared to placebo) adverse reactions, including laboratory abnormalities, were 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. Table 5 summarizes the adverse reactions in IMerge. Table 5: Adverse Reactions (≥5%) in Patients with MDS Who Received RYTELO with a Difference Between Arms of >2% Compared to Placebo in IMerge Adverse Reaction RYTELO (N=118) Placebo (N=59) All Grades % Grades 3 or 4 % All Grades % Grades 3 or 4 % Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03. General disorders and administrative site conditions Fatigue Fatigue: asthenia, fatigue, and malaise. 29 …