Imetelstat

Risk Summary

Based on findings in animal studies, imetelstat can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on imetelstat 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.

There is no data on the presence of imetelstat in human milk, or the effects imetelstat 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 imetelstat and for 1 week after the last dose.

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.

• 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 imetelstat 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 imetelstat (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 imetelstat was 8 months (range, 0 to 38 months); 69% of patients were exposed to imetelstat 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 imetelstat 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 imetelstat. 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 imetelstat, including sepsis (0.8%).

Permanent discontinuation of imetelstat due to an adverse reaction occurred in 15% of patients. Adverse reactions which resulted in permanent discontinuation of imetelstat in >2% of patients included neutropenia and thrombocytopenia.

Dosage interruptions of imetelstat 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 imetelstat 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 1 summarizes the adverse reactions in IMerge.

Table 1. Adverse Reactions (≥5%) in Patients with MDS Who Received Imetelstat with a Difference Between Arms of >2% Compared to Placebo in IMerge:

Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03.
^a Fatigue: asthenia, fatigue, and malaise.
^b 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.
^c COVID-19: asymptomatic COVID-19, COVID-19, COVID-19 pneumonia, and SARS-CoV-2 antibody test positive.
^d Urinary tract infection: cystitis, Escherichia urinary tract infection, renal abscess, and urinary tract infection.
^e Syncope: fall, pre-syncope, and syncope.
^f 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.
^g Atrial arrhythmia: atrial fibrillation and atrial flutter.
^h Fractures: femur fracture, hand fracture, hip fracture, humerus fracture, lumbar vertebral fracture, and thoracic vertebral fracture.

Clinically relevant adverse reactions in <5% of patients who received imetelstat included febrile neutropenia, sepsis, gastrointestinal hemorrhage, and hypertension.

Table 2 summarizes the laboratory abnormalities in IMerge.

Table 2. Select Laboratory Abnormalities (≥10%) That Worsened from Baseline in Patients with MDS Who Received Imetelstat with a Difference Between Arms of >2% Compared to Placebo in IMerge:

Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03.
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; PTT = partial thromboplastin time
¹ The denominator used to calculate the rate varied from 97 to 118 based on the number of patients with a baseline value and at least one post-treatment value.
² The denominator used to calculate the rate varied from 50 to 59 based on the number of patients with a baseline value and at least one post-treatment value.