Imetelstat

12.1. Mechanism of Action Imetelstat is an oligonucleotide human telomerase inhibitor that binds to the template region of the RNA component of human telomerase (hTR), inhibits telomerase enzymatic activity and prevents telomere binding. Increased telomerase activity and human telomerase reverse transcriptase (hTERT) RNA expression have been reported in MDS and malignant stem and progenitor cells. Nonclinical studies showed imetelstat treatment led to reduction of telomere length, reduction of malignant stem and progenitor cell proliferation, and induction of apoptotic cell death.

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 Modification Abbreviation: LFT = liver function test Infusion-Related Reactions [see Warnings and Precautions (5.3) ] Grade 2 or 3 First and Second Interrupt the RYTELO infusion until resolution of the adverse reaction or until the intensity of the reaction decreases to Grade 1; restart infusion at 50% of the infusion rate administered prior to the adverse reaction. Third For Grade 2, stop infusion. May restart at next cycle. For Grade 3, permanently discontinue RYTELO. Grade 4 First Stop infusion, administer supportive care as appropriate and permanently discontinue RYTELO. Other adverse reactions including elevated LFTs [see Adverse Reactions (6.1) ] Grade 3 or 4 First and Second Delay RYTELO until recovery of adverse reactions to Grade 1 or baseline; restart at one dose level lower. Third Permanently discontinue RYTELO. 2.4. Preparation and Administration RYTELO is provided as a lyophilized powder in a single-dose vial for intravenous infusion only and must be reconstituted and diluted prio

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 0 20 3.4 Musculoskeletal and connective tissue disorders Arthralgia/myalgia Arthralgia/myalgia: arthralgia, back pain, bone pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain, pain in extremity, pain in jaw, and pelvic pain. 25 2.5 19 5 Infections and infestations COVID-19 COVID-19: asymptomatic COVID-19, COVID-19, COVID-19 pneumonia, and SARS-CoV-2 antibody test positive. 19 1.7 14 5 Urinary tract infection Urinary tract infection: cystitis, Escherichia urinary tract infection, renal abscess, and urinary tract infection. 9 2.5 7 0 Nervous system disorders Headache 13 0.8 5 0 Syncope Syncope: fall, pre-syncope, and syncope. 7 1.7 1.7 0 Immune system disorders Infusion-related reactions Infusion-related reactions: abdominal pain, arthralgia, asthenia, back pain, bone pain, diarrhea, erythema, headache, hypertensive crisis, malaise, non-cardiac chest pain, pruritus, and urticaria. Only events considered related to infusion-related reactions are included. 8 1.7 3