Imetelstat
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh, MBBS[2]
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Overview
Imetelstat is an {{{drugClass}}} that is FDA approved for the treatment of RYTELO is an oligonucleotide telomerase inhibitor FDA approved 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.. Common adverse reactions include 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..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
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).
• The recommended dosage of RYTELO is 7.1 mg/kg administered as an intravenous infusion over 2 hours every 4 weeks. • Premedicate prior to dosing with RYTELO for potential infusion-related reactions. • See full prescribing information for preparation and administration instructions.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Imetelstat in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Imetelstat in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Imetelstat FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Imetelstat in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Imetelstat in pediatric patients.
Contraindications
None.
Warnings
• 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. 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.
• 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.
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.
• 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 and hydrocortisone as recommended and monitor patients for at least one hour following the infusion as recommended. Manage symptoms of infusion-related reactions with supportive care and infusion interruptions, decrease infusion rate, or permanently discontinue as recommended.
• Embryo-Fetal Toxicity
Based on findings in animals, RYTELO can cause embryo-fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of imetelstat to pregnant mice during the period of organogenesis resulted in embryo-fetal mortality at maternal exposures (AUC) 2.5-times the human exposure at the recommended clinical dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RYTELO and for 1 week after the last dose.
Adverse Reactions
Clinical Trials Experience
• Thrombocytopenia. • Neutropenia. • Infusion-Related Reactions.
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. 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. In the IMerge clinical trial, adverse reactions occurring in 5% or more of patients with myelodysplastic syndromes (MDS) treated with RYTELO, and with a difference greater than 2% compared to placebo, were reported across multiple system organ classes. Among general disorders, fatigue (including asthenia, fatigue, and malaise) was reported in 29% of RYTELO-treated patients compared to 20% in the placebo group, with no Grade 3 or 4 events in the RYTELO arm and 3.4% in placebo. Musculoskeletal symptoms, including arthralgia and myalgia, were seen in 25% of RYTELO patients versus 19% in placebo, with Grade 3 or 4 events occurring in 2.5% and 5% of patients, respectively. COVID-19 infections, including asymptomatic and pneumonia cases, occurred in 19% of RYTELO patients and 14% of those on placebo, with Grade 3 or 4 events in 1.7% and 5%, respectively. Urinary tract infections were more common with RYTELO (9%) than placebo (7%), with higher-grade events only in the RYTELO group (2.5%). Neurologically, headache was reported in 13% of RYTELO recipients versus 5% with placebo (Grade 3/4: 0.8% vs 0%), and syncope-related events occurred in 7% versus 1.7% (Grade 3/4: 1.7% vs 0%). Immune-related infusion reactions were seen in 8% of RYTELO patients compared to 3.4% in the placebo group, with Grade 3/4 events in 1.7% of the RYTELO group. Epistaxis (7%) and hematoma (6%) were only reported in the RYTELO group. Pruritus was more common with RYTELO (6%) than placebo (1.7%), though all cases were Grade 1 or 2. Cardiac arrhythmias, specifically atrial fibrillation or flutter, were observed in 6% of RYTELO patients and 3.4% of those on placebo, with Grade 3/4 events in 1.7% in both groups. Fractures were reported in 5% of RYTELO patients and 1.7% in placebo, with higher severity in the RYTELO group (Grade 3/4: 3.4% vs 1.7%). Clinically relevant but less frequent events (<5%) in the RYTELO group included febrile neutropenia, sepsis, gastrointestinal hemorrhage, and hypertension. These adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Clinically relevant adverse reactions in < 5% of patients who received RYTELO included febrile neutropenia, sepsis, gastrointestinal hemorrhage, and hypertension.
In the IMerge study evaluating patients with myelodysplastic syndromes (MDS), select laboratory abnormalities that worsened from baseline and occurred in ≥10% of patients with a >2% difference between treatment arms were reported more frequently in those receiving RYTELO compared to placebo. Hematologic abnormalities were notably common in the RYTELO group, with decreased platelet counts observed in 97% of patients (65% Grade 3 or 4) versus 34% (8% Grade 3 or 4) in the placebo group. White blood cell count decreases occurred in 94% of RYTELO patients, including 53% with Grade 3 or 4 severity, compared to 59% and 1.7% in the placebo group, respectively. Neutrophil count reduction was also prominent, reported in 92% of RYTELO-treated patients (72% Grade 3 or 4) versus 47% (7% Grade 3 or 4) in those receiving placebo. Additionally, prolonged partial thromboplastin time (PTT) was noted in 26% of RYTELO patients (1% Grade 3 or 4) versus 18% (4%) in the placebo group. In terms of chemistry lab abnormalities, increased aspartate aminotransferase (AST) was seen in 53% of RYTELO patients (0.8% Grade 3 or 4) compared to 22% (1.7%) with placebo. Alkaline phosphatase (ALP) increases were reported in 48% of RYTELO recipients and 12% of those on placebo, with no Grade 3 or 4 events in either group. Alanine aminotransferase (ALT) elevation occurred in 43% of the RYTELO group (3.4% Grade 3 or 4) versus 37% (5%) in the placebo group. These laboratory abnormalities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.
Postmarketing Experience
There is limited information regarding Imetelstat Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Imetelstat Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): 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 . 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.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Imetelstat in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Imetelstat during labor and delivery.
Nursing Mothers
There is no data on the presence of imetelstat in human milk, or the effects RYTELO on the breastfed child, or milk production. Because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with RYTELO and for 1 week after the last dose.
Pediatric Use
Safety and effectiveness of RYTELO in pediatric patients have not been established.
Geriatic Use
Of the 118 patients with low- to intermediate-1 risk myelodysplastic syndromes (MDS) in the clinical trial who received RYTELO, 91 (77.1%) patients were 65 years of age and older and 35 (29.7%) patients 75 years of age and older. No differences in safety or efficacy were observed between older (≥ 65 years) and younger patients.
Gender
There is no FDA guidance on the use of Imetelstat with respect to specific gender populations.
Race
There is no FDA guidance on the use of Imetelstat with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Imetelstat in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Imetelstat in patients with hepatic impairment.
Females of Reproductive Potential and Males
Based on findings from animal studies, RYTELO can cause embryo-fetal harm when administered to a pregnant woman.
Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating treatment with RYTELO. Contraception
Females Advise females of reproductive potential to use effective contraception during treatment with RYTELO and for 1 week after the last dose.
Infertility
Females Based on findings in animals, RYTELO may impair fertility in females of reproductive potential. The effect on fertility is reversible.
Immunocompromised Patients
There is no FDA guidance one the use of Imetelstat in patients who are immunocompromised.
Administration and Monitoring
Administration
• 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.
• 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.
• Dosage Modifications for Adverse Reactions: Recommended dose reductions for Grade 3 and Grade 4 adverse reactions are The management of Grade 3 and Grade 4 adverse reactions during RYTELO treatment may necessitate temporary dose delays, dose reductions, or in some cases, treatment discontinuation. To mitigate severe toxicities while maintaining therapeutic benefit, the first recommended dose reduction is to 5.6 mg/kg administered every 4 weeks. If further adjustment is required, a second dose reduction to 4.4 mg/kg every 4 weeks may be implemented. However, if a patient is unable to tolerate the lowest dose level of 4.4 mg/kg, RYTELO treatment should be permanently discontinued. 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 × 109/L or platelets are less than 50 × 109/L. For patients experiencing hematologic adverse reactions such as thrombocytopenia or neutropenia during treatment with RYTELO, specific dosage modifications are recommended based on the severity and frequency of the events. In the case of Grade 3 thrombocytopenia, treatment should be delayed until platelet levels recover to 50 × 10⁹/L. After the first occurrence, RYTELO may be restarted at the same dose level; following a second or third occurrence, treatment should resume at one dose level lower. If a fourth occurrence of Grade 3 thrombocytopenia occurs, RYTELO should be discontinued. For Grade 4 thrombocytopenia, the first and second occurrences warrant a delay in treatment until platelets recover to 50 × 10⁹/L, followed by a dose reduction. Discontinuation is required after a third occurrence. Similarly, for Grade 3 neutropenia, treatment should be paused until the absolute neutrophil count (ANC) recovers to 1 × 10⁹/L. After the first episode, RYTELO can be resumed at the same dose level, but after the second or third occurrence, it should be restarted at a reduced dose. A fourth occurrence necessitates discontinuation. In the case of Grade 4 neutropenia, the first and second episodes should be managed with treatment delay and a subsequent dose reduction, while a third occurrence requires permanent discontinuation of RYTELO. These modifications are intended to ensure patient safety and minimize the risk of serious complications.
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. Monitor liver function tests prior to administration of RYTELO, weekly for the first cycle, prior to each cycle thereafter, and as clinically indicated. For patients experiencing non-hematologic adverse reactions while receiving RYTELO, dosage modifications depend on the severity and recurrence of the event. In the case of infusion-related reactions, for Grade 2 or 3 severity, the first and second occurrences should be managed by interrupting the infusion until the reaction resolves or decreases to Grade 1 in intensity. The infusion can then be resumed at 50% of the previous rate. If a third occurrence happens, the course of action depends on severity: for Grade 2, the infusion should be stopped, with the option to restart RYTELO at the next cycle; for Grade 3, treatment should be permanently discontinued. In instances of a Grade 4 infusion-related reaction, the infusion must be stopped immediately, supportive care provided, and RYTELO permanently discontinued. For other non-hematologic adverse reactions, including elevated liver function tests (LFTs), Grade 3 or 4 events should prompt a delay in RYTELO administration until symptoms resolve to Grade 1 or return to baseline. Treatment can then be resumed at one dose level lower. If a third occurrence of such a reaction takes place, RYTELO should be permanently discontinued. These guidelines are designed to manage toxicity and maintain patient safety during RYTELO treatment. • 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 prior to administration. Use aseptic technique to prepare RYTELO. RYTELO does not contain a preservative.
Reconstitution:
• Calculate the dose of RYTELO needed based on the patient's body weight (kg). • Determine the number of RYTELO vials needed to achieve the required dose (total mg) per Table 4. More than one vial may be needed to achieve a full dose. • Remove the RYTELO vials from the refrigerator and allow the vials to sit for 10 minutes to 15 minutes (not to exceed 30 minutes) to adjust to room temperature 20°C to 25°C (68°F to 77°F) before use. Reconstitute each vial of RYTELO with the volume of 0.9% Sodium Chloride Injection provided in directly onto the lyophilized powder to obtain a concentration of 31.4 mg/mL of imetelstat.
To prepare RYTELO for administration, each vial should be reconstituted by adding 0.9% Sodium Chloride Injection directly onto the lyophilized powder. This process yields a final concentration of 31.4 mg/mL of imetelstat. It is recommended to use the appropriate combination of vial strengths to most closely match the patient’s calculated dose based on body weight. There are two available vial strengths: the 47 mg vial should be reconstituted with 1.8 mL of 0.9% Sodium Chloride Injection, resulting in a deliverable volume of 1.5 mL at the target concentration. The 188 mg vial requires 6.3 mL of diluent, yielding a deliverable volume of 6 mL. Each vial contains a slight overfill to compensate for potential loss during reconstitution and extraction, ensuring the final concentration of 31.4 mg/mL is maintained. These reconstitution volumes are critical for accurate dosing and should be handled with care during preparation. • Swirl each vial gently to avoid foaming until the powder is fully reconstituted (not to exceed 15 minutes). Do not shake. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution in each vial should appear as a clear to slightly hazy solution, essentially free of visible contaminants, particles and/or particulates. Do not use if discoloration or particulate matter is present. • Use the reconstituted solution immediately to prepare the RYTELO diluted solution in the infusion bag. Dilution: • Calculate the required volume of the reconstituted RYTELO solution needed to obtain the appropriate dose according to the patient's body weight. • Withdraw a volume equal to the required reconstituted RYTELO solution from a 500 mL infusion bag of 0.9% Sodium Chloride Injection and discard it. • Add the required volume of reconstituted RYTELO solution into the infusion bag so that the total final volume of RYTELO solution in the bag is approximately 500 mL. Discard any unused portion of the reconstituted solution remaining in each vial. • Gently invert the infusion bag at least 5 times to ensure that the reconstituted RYTELO is well-mixed. Do not shake the infusion bag prior to administration. Diluted RYTELO Solution Storage: • If not used immediately, ensure that diluted solution for infusion is used within the total timeframes specified below, according to storage temperature: o When stored at room temperature 20°C to 25°C (68°F to 77°F): The total time from the reconstitution of RYTELO to completion of the intravenous infusion should not exceed 18 hours from the time of reconstitution. o When stored refrigerated 2°C to 8°C (36°F to 46°F): The total time from the reconstitution of RYTELO to completion of the intravenous infusion should not exceed 48 hours from the time of reconstitution. Administration: • Administer the diluted RYTELO solution by intravenous infusion only over a period of 2 hours.
Monitoring
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.
IV Compatibility
There is limited information regarding the compatibility of Imetelstat and IV administrations.
Overdosage
There is limited information regarding Imetelstat overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Imetelstat Pharmacology in the drug label.
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.
Structure
RYTELO for injection contains imetelstat, an oligonucleotide telomerase inhibitor for intravenous use. Imetelstat sodium is a white to off-white or slightly yellow, amorphous, solid powder. It is highly soluble in aqueous solutions, including in 0.9% Sodium Chloride Injection, at both refrigerated and room temperatures. Imetelstat sodium is hygroscopic. The chemical name for the imetelstat sodium drug substance is DNA, d ( 3'-amino-3'-deoxy-P-thio ) ( T-A-G-G-G-T-T-A-G-A-C-A-A ) , 5' -[ O- [ 2-hydroxy-3- ( hexadecanoylamino ) propyl ] phosphorothioate ] , sodium salt ( 1:13 ) . The molecular formula is C148H198N68O53P13S13Na13 ( as sodium salt ) , which equates to a formula weight of 4896 g/mol. The molecular formula for the free acid form is C148H211N68O53P13S13 which equates to a formula weight of 4610 g/mol.
Pharmacodynamics
Grade 3 and 4 Thrombocytopenia
Higher imetelstat exposure is associated with higher incidence of Grade 3 and 4 thrombocytopenia in patients with MDS.
Pharmacokinetics
Imetelstat plasma geometric mean (coefficient of variation [CV] %) maximum concentration (Cmax) is 18.3 µM (27.3%) and the area under the concentration-time curve from time 0 to 28 days (AUC0-28) was 114.2 h*µM (43.2%). Imetelstat does not accumulate between treatment cycles. Distribution: Following a single intravenous dose of 7.1 mg/kg of RYTELO administered over 2 hours in patients with MDS, the geometric mean (CV%) volume of distribution is approximately 14.1 L (27.2%). In vitro human plasma protein binding is greater than 94%. Elimination: The imetelstat geometric mean (CV%) apparent plasma half-life is approximately 4.9 hours (43.2%) at the approved recommended dosage. Metabolism Imetelstat is expected to be metabolized by nucleases to nucleotides of various lengths. Specific populations: No clinically significant differences in the pharmacokinetics of imetelstat were observed based on age (21 to 87 years), sex, race (81% White, 4% Asian, 7% Black, 8% other/unknown), mild to moderate renal impairment (CLcr 30 to < 90 mL/min), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1× to 1.5× ULN and any AST), or moderate hepatic impairment (total bilirubin > 1.5× to 3× ULN and any AST). The effect of severe renal impairment (CLcr 15 to < 30 mL/min), end-stage renal disease, or severe hepatic impairment (total bilirubin > 3× ULN and any AST) has not been established. Drug Interaction Studies: In Vitro Studies CYP Enzymes: Imetelstat is not an inhibitor or inducer of CYP450 enzymes. Transporter systems: Imetelstat is an inhibitor of OATP1B1 and OATP1B3.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with imetelstat.
In vitro, imetelstat was not mutagenic in the bacterial mutagenicity assay (Ames test) or clastogenic in the chromosomal aberrations assay using cultured human peripheral blood lymphocytes. Imetelstat was not genotoxic in an in vivo mouse micronucleus assay at intravenous dose levels up to approximately 104 mg/kg.
Fertility studies have not been conducted with imetelstat. Female monkeys given 14.1 mg/kg once weekly for 9 months exhibited uterine endometrial atrophy in a general toxicology study. This effect was observed at a mean exposure (based on AUC) that is approximately 14.4-times the human exposure at the recommended clinical dose. This finding was not present in animals following a 14-week recovery period.
Clinical Studies
• Myelodysplastic Syndromes (MDS)
The efficacy of RYTELO was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial (IMerge; NCT02598661) in 178 patients enrolled with International Prognostic Scoring System (IPSS) low- or intermediate-1 risk MDS who were transfusion-dependent (requiring ≥ 4 red blood cell (RBC) units over an 8-week period during the 16 weeks prior to randomization). Eligible patients were required to have failed to respond or have lost response or be ineligible for erythropoiesis-stimulating agents (ESAs); and had an absolute neutrophil count of 1.5 × 109/L or greater and platelets 75 × 109/L or greater. Patients were ineligible if they had del(5q) cytogenetic abnormality or had received prior treatment with lenalidomide or hypomethylating agents. Participants were randomized in a 2:1 ratio to receive an intravenous infusion of RYTELO (n=118) 7.1 mg/kg or placebo (n=60) in 28-day treatment cycles until disease progression, unacceptable toxicity, or withdrawal from the study. Randomization was stratified by prior RBC transfusion burden and by IPSS risk group. All patients received supportive care, which included RBC transfusions. Of the 178 patients enrolled, the median age was 72 years (range: 39 to 87 years), with 62% male, and 80% White, 6% Asian, 1.7% Black, 12% other or not reported. The key baseline disease characteristics of the efficacy population. In the IMerge study, baseline disease characteristics were assessed in patients with myelodysplastic syndromes (MDS) receiving RYTELO (n=118) or placebo (n=60). The median time since original diagnosis was 3.5 years (range: 0.1 to 26.7) in the RYTELO group and 2.8 years (range: 0.2 to 25.7) in the placebo group. Eastern Cooperative Oncology Group (ECOG) performance status scores showed that 35.6% of patients in the RYTELO group were asymptomatic (score 0), 59.3% were symptomatic but fully ambulatory (score 1), and 5.1% were symptomatic but in bed less than 50% of the day (score 2). In comparison, the placebo group had 35% with score 0, 65% with score 1, and none with score 2. According to the International Prognostic Scoring System (IPSS), 67.8% of patients in the RYTELO group were classified as low risk and 32.2% as intermediate-1, compared to 65% and 35%, respectively, in the placebo group. Regarding prior red blood cell (RBC) transfusion burden, 52.5% of RYTELO-treated patients had received 4 to 6 units, and 47.5% had received more than 6 units, while 55% and 45% of placebo patients fell into those respective categories. Using the 2008 World Health Organization (WHO) classification, 61.9% of RYTELO patients had ring sideroblast-positive (RS+) disease, 37.3% were ring sideroblast-negative (RS˗), and 0.8% had missing data. This was comparable to 61.7% RS+, 38.3% RS˗, and 0% missing in the placebo group. Baseline serum erythropoietin (sEPO) levels were ≤ 500 mU/mL in 73.7% of RYTELO patients and > 500 mU/mL in 22%, with 4.2% missing; for placebo, these values were 60%, 36.7%, and 3.3%, respectively. Regarding prior use of erythropoietin-stimulating agents (ESA), 91.5% of patients in the RYTELO group and 86.7% in the placebo group had received ESAs. Median baseline blood counts were similar between groups: neutrophil counts were 2.6 × 10⁹/L for RYTELO and 2.7 × 10⁹/L for placebo; hemoglobin levels were 7.9 g/dL and 7.8 g/dL, respectively; and platelet counts were 230 × 10⁹/L in both groups. These data provide a comprehensive profile of the patient population enrolled in the IMerge study. Efficacy was established after a median follow up time of 19.5 months (range: 1.4 to 36.2) in the imetelstat group and 17.5 months (range: 0.7 to 34.3) in the placebo group based upon the proportion of patients who achieved ≥ 8-week and ≥ 24-week RBC-TI, defined as the absence of RBC transfusion(s) during any consecutive 8 weeks (56 days) period, and during any consecutive 24 weeks (168 days) period, respectively, from randomization until the start of subsequent anti-cancer therapy (if any). In the IMerge study, treatment with RYTELO resulted in significantly higher rates of red blood cell (RBC) transfusion independence (TI) compared to placebo. Among patients who received RYTELO (n=118), 39.8% achieved ≥ 8-week RBC TI, compared to only 15.0% in the placebo group (n=60), representing a treatment difference of 24.8% (95% CI: 9.9, 36.9; p < 0.001). The 95% confidence intervals for the response rates were 30.9% to 49.3% for the RYTELO group and 7.1% to 26.6% for the placebo group. Additionally, 28.0% of patients in the RYTELO arm achieved ≥ 24-week RBC TI, compared to just 3.3% in the placebo arm, resulting in a treatment difference of 24.6% (95% CI: 12.6, 34.2; p < 0.001). The 95% confidence intervals for the 24-week TI response were 20.1% to 37.0% for RYTELO and 0.4% to 11.5% for placebo. These results demonstrate a clinically meaningful and statistically significant improvement in sustained transfusion independence among patients treated with RYTELO compared to placebo.
How Supplied
RYTELO (imetelstat) for injection is a preservative free, white to off-white or slightly yellow, lyophilized powder available as: RYTELO is supplied as a single-dose vial in two different strengths. Each carton contains either one 47 mg vial with National Drug Code (NDC) 82959-112-01 or one 188 mg vial with NDC 82959-111-01.
Storage
Store vials refrigerated at 2°C to 8°C (36°F to 46°F) in original carton.
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Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide). Discuss the following with patients prior to and during treatment with RYTELO. Thrombocytopenia:
Advise patients of the risk of thrombocytopenia with RYTELO, and that their blood counts will be monitored routinely while on treatment and dose of RYTELO delayed or reduced as needed. Instruct patients to notify a healthcare provider immediately if they show signs or symptoms of thrombocytopenia such as unusual bleeding or bruising.
Neutropenia:
Advise patients of the risk of neutropenia with RYTELO and that their blood counts will be monitored routinely while on treatment and the dose of RYTELO may be delayed or reduced as needed. Instruct patients to notify a healthcare provider immediately if they show signs or symptoms of neutropenia, such as fever or infection .
Infusion-Related Reactions:
Inform patients that infusion-related reactions can occur during treatment with RYTELO and premedications will be given prior to each infusion. Patients will be monitored by their healthcare provider for at least an hour after the infusion. Advise patients that their healthcare provider may decide to give RYTELO more slowly or stop the infusion if an infusion-related reaction occurs.
Embryo-Fetal Toxicity:
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider if they are pregnant or become pregnant Advise females of reproductive potential to use effective contraception during treatment with RYTELO and for 1 week after the last dose.
Lactation:
Advise women not to breastfeed during treatment with RYTELO and for 1 week after the last dose
Precautions with Alcohol
Alcohol-Imetelstat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
RYTELO
Look-Alike Drug Names
There is limited information regarding Imetelstat Look-Alike Drug Names in the drug label.
Price
References
The contents of this FDA label are provided by the National Library of Medicine.