Imetelstat In Intermediate-1 Risk Myelodysplastic Syndromes

Overview:

The synthetic lipid-conjugated 13-mer oligonucleotide N3' P5'-them-phosphoramidite, Imetelstat, is available as a sodium salt and may have anti-cancer properties. In addition to the telomerase RNA (hTR) template region, Imetelstat functions as a competitive enzyme inhibitor by binding to and blocking the enzyme's active site (as a "telomerase template antagonist"). This mode of action is distinct from that of antisense oligonucleotide-mediated telomerase activity inhibition via telomerase mRNA (messenger ribonucleic acid) binding. When Imetelstat inhibits telomerase activity in tumor cells, telomeres shorten, causing cell cycle arrest or apoptosis.

The Food and Drug Administration (FDA) approved Imetelstat, an oligonucleotide telomerase inhibitor, on June 6, 2024, for use in adults with low to intermediate-1 risk myelodysplastic syndromes (MDS) who have transfusion-dependent anemia (reduction either in the red blood cells count or hemoglobin capacity of red blood cells )requiring four or more red blood cell units over eight weeks and who have not responded to, lost response to, or are not eligible for erythropoiesis-stimulating agents (ESAs).

IMerge (NCT02598661), a multicenter, randomized (2:1), double-blind, placebo-controlled trial, assessed the effectiveness in 178 MDS patients. Until the disease progressed or the toxicity became intolerable, patients underwent 28-day treatment cycles with an intravenous (into the vein) infusion of either placebo or Imetelstat 7.1 mg/kg. The International Prognostic Scoring System (IPSS) and the previous red blood cell (RBC) transfusion burden were used to stratify the randomization process.

For Patients:

What Is the Prevalence of Myelodysplastic Syndrome (MDS)?

A class of illnesses known as myelodysplastic syndromes (MDS) are defined by aberrant bone marrow blood-forming cells. These defective cells lead to decreased peripheral blood cells, an increased risk of acute myeloid leukemia (AML- type of blood cancer), and a decreased chance of survival. MDS may develop from scratch or as a side effect of treatment. Patients with MDS frequently experience anemia (low red blood cell counts), thrombocytopenia (low platelet counts), and leukopenia (low white blood cell counts). Patients may also experience bleeding, night sweats, bone pain, fever, weight loss, and repeated infections, but the most troublesome symptom is extreme weariness.

In the United States (US), there are presently 60,000 to 170,000 individuals who have MDS. In the general population, the estimated age-adjusted incidence rate of MDS is four per 100,000. The diagnosis rate of MDS in men is around double that of women. Elderly people and non-Hispanic Whites are more likely to have MDS.10 The financial burden of MDS is significant. For patients with lesser risk of the disease, annual medical expenses alone may exceed $220,000.4 Molecular genetic testing and a bone marrow sample are usually required to diagnose MDS.11 The World Health Organization (WHO), in partnership with the Society for Hematopathology and the European Association of Hematopathology, developed the conventional MDS classification. It has undergone several changes, the most recent of which was the 5th edition, published in 2022. The del(5q) mutation, which results in the loss of the long arm of the 5th chromosome, and MDS with ring sideroblasts are two significant traits that influence therapy decisions.

Is Imetelstat Effective for Intermediate-1 Risk Myelodysplastic Syndromes?

The first-in-class targeted therapy inhibits telomerase, a protein that promotes cancer and is present in many malignancies. For patients with low-risk or intermediate-1-risk myelodysplastic syndromes (MDS) who have anemia requiring transfusion of at least four red blood cell units over eight weeks and who are not responding to or are ineligible for medications that promote red blood cell production, the U.S. Food and Drug Administration (FDA) has approved Imetelstat.

Imetelstat was approved to treat a class of uncommon blood malignancies known as myelodysplastic syndromes. This targeted treatment inhibits the function of telomerase, a protein in cells that encourages cancer by enabling cell division beyond what is deemed normal. In numerous malignancies, including MDS, telomerase is overactive. Imetelstat has received FDA approval for the first time.

Results from IMerge, a multicenter, randomized, double-blind, placebo-controlled phase III clinical trial, which included 178 patients with MDS who were randomly assigned (2:1) to receive either Imetelstat or placebo treatment until unacceptable toxicity or disease progression, served as the basis for approval. Red blood cell transfusions were part of the supportive treatment provided to each patient.

Compared to 15% of patients who received a placebo, 39.8% of patients treated with Imetelstat could avoid receiving red blood cell transfusions for at least eight weeks. Furthermore, compared to 3.3% of patients in the placebo arm, 28% of the patients in the Imetelstat arm did not have a transfusion for at least 24 weeks.

How Does Imetelstat Operate and What Is It?

Adults with low to intermediate-1 risk myelodysplastic syndromes (MDS) who require four or more red blood cell units over eight weeks due to transfusion-dependent anemia and who have not responded to, lost response to, or are not eligible for erythropoiesis-stimulating agents (ESA) may be prescribed Imetelstat.

What Adverse Reactions Are Associated with Imetelstat Use?

Typical Imetelstat side effects include:

• Reduced levels of platelets.

• Lower levels of white blood cells.

• Reduced levels of neutrophils.

• Elevated levels of the liver enzymes ALT, AST, and alkaline phosphatase.

• Fatigue greater than normal blood clotting times.

• Muscle, bone, and joint discomfort.

• Covid-19 infections.

• Headache.

Imetelstat's harmful side effects include:

• Thrombocytopenia.

• Low platelet numbers.

• Fever.

• Chills, coughing.

• Diarrhea (loose and watery stool).

• Redness.

• Headache.

• High blood pressure.

• Feeling unwell.

• Chest pain unrelated to the heart, itching, and hives.

• Rare side effects of Imetelstat include none.

• Severe headache.

• Confusion.

• Slurred speech.

• Arm or leg weakness.

• Trouble walking.

• Coordination.

What Are the Available Doses of Imetelstat Doses?

Adult Dosage:

• Lyophilized powder for reconstitution through injection.

• 47 mg (milligrams) and 188 mg of a single-dose vial, respectively.

Myelodysplastic Syndromes

Adult dosage

• IV (intravenous) 7.1 mg/kg every four weeks; inject over two hours.

• After six doses of treatment over 24 weeks, stop if the RBC transfusion burden does not decrease or if unacceptable toxicity develops at any point.

Before Medication:

Give over 30 minutes before dosage to minimize or avoid possible infusion-related side effects.

• Diphenhydramine (Or Similar): IV or oral doses of 25 to 50 mg.

• Hydrocortisone (Or Similar): Intravenous/oral dose of 100 to 200 mg.

After the infusion, wait at least an hour to check for any negative responses.

Considerations for Dosage: These should be given:

Which Other Substances Affect Imetelstat?

If the physician or chemist is using this medication to manage the pain, they may already be aware of any potential drug interactions and may be keeping an eye out for them. Consult the physician, healthcare provider, or chemist before beginning, stopping, or altering the dosage of any medication.

• There are no known serious medication interactions with Imitelstat.

• There are no known significant medication interactions with Imitelstat.

• There are no known mild interactions between Imetelstat and any other medications.

• There are no known minor medication interactions with Imetelstat.

• Not all interactions or negative effects are included in this information.

What Additional Medications May Impact Imetelstat?

All medications, including over-the-counter and prescription drugs, vitamins, and herbal supplements, should be disclosed to the healthcare physician. Understand the medications you take. As you receive new medications, make a list to present to the chemist and doctor.

Though the Imetelstat package insert does not specifically include drug-drug interactions, research on drug interactions has revealed that Imetelstat is:

An inhibitor of OATP1B1 and OATP1B3, but neither an inducer nor an inhibitor of CYP450 enzymes. For more information on medication interactions, consult the most recent package insert. Dilute and reconstitute the ingredients before use. Excludes preservatives from the mixture.

Dose of Imetelstat 47 mg:

• Active Ingredients: Metelstat (47 mg; 50 mg equivalent to Imetelstat sodium). Inactive Ingredients: Hydrochloric acid or sodium carbonate anhydrous may be added to alter the pH during manufacture.

Dosage of Imetelstat (188 mg):

• Active Ingredients: 188 mg of Imetelstat or 200 mg of Imetelstat sodium.

• Inactive Ingredients: Hydrochloric acid or sodium carbonate monohydrate may be used to alter the pH during manufacture.

Keep vials in their original carton and refrigerate between two and eight degrees Celsius (36 and 46 degrees Fahrenheit). Avoid freezing. Use as soon as possible after diluting, ideally within:

When stored at room temperature, 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit), the reconstitution period is 18 hours; when refrigerated, it is 48 hours (36 to 46 degrees Fahrenheit).

How Can One Get Imetelstat?

• Over two hours, the healthcare professional will inject Imetelstat into the vein through an IV.

• It is often administered every four weeks.

• The dosage is 7.1 mg/kg and is determined by weight. Depending on how one responds, the healthcare practitioner will prescribe a dose appropriate for one and may adjust it or the dosing schedule.

• To prevent or minimize infusion-related responses, the healthcare provider will administer pretreatment drugs before treatment and monitor one for adverse effects for at least an hour following the infusion.

An antihistamine, such as 25 to50 mg of diphenhydramine taken orally or intravenously

An intravenous or oral corticosteroid, such as Hydrocortisone (or similar) at 100 to 200 mg doses. The healthcare practitioner will do specific blood tests throughout therapy to monitor response and adverse effects.

What Are the Warnings and Precautions For Imetelstat?

Exercise Caution:

• Thrombocytopenia.

• It may result in thrombocytopenia, depending on test results.

• The average duration between the commencement of Grade three or four decreased platelets and their recovery was six weeks and 1.3 weeks, respectively.

• Patients with thrombocytopenia should have their CBC (complete blood count) checked before starting treatment, once a week for the first two cycles, and then before each cycle after that, as directed by their doctor.

• When necessary, give platelet transfusions.

• Postpone the subsequent cycle, resume at the same or lower dosage, or stop as advised.

Pregnancy and Lactation:

• When given to expectant mothers, it may harm the embryo and fetus, according to research done on animals.

• Before beginning, confirm the pregnant status of any woman capable of reproducing.

• Encourage women who can conceive to take effective contraception both throughout and for one week following the last dosage of their medication.

Contraception

• Encourage women who can conceive to take effective contraception both throughout and for one week following the last dosage of medication.

• Unable to conceive.

• It may reduce fertility in women who are capable of having children, according to research on animals.

• The impact on procreation is reversible.

• Nursing.

• More information is needed about Imetelstat's presence in human milk, how it affects breastfeeding children, and how much milk is produced.

• Women are advised not to breastfeed during therapy due to the possibility of serious responses in nursed children.

For Doctors:

Drug Group:

Imetelstat is an injectable oligonucleotide telomerase inhibitor included in Imetelstat for injection. Imetelstat sodium is a solid, amorphous powder that is white to off-white or slightly yellow. It is extremely soluble at ambient temperature and in aqueous solutions, such as 0.9% Sodium Chloride Injection. Hygroscopic is the drug Imitelstat sodium.

DNA, d(3'-amino-3'-deoxy-P-thio) (T-AA­G-G-T-T-A-G-A-C-A-A), 5'-[O-[2-hydroxy-3-(hexadecanoylamino)propyl] phosphorothioate], sodium salt (1:13) is the chemical name for the medicinal component Imetelstat sodium. As a sodium salt, the molecular formula is C148H198N68O53P13S13Na13, corresponding to a formula weight of 4896 g/mol. The free acid form's chemical formula, C148H211N68O53P13S13, corresponds to a formula weight of 4610 g/mol.

Administration And Preparation

Imetelstat is supplied as a lyophilized powder in a single-dose vial for intravenous infusion only. The drug must be reconstituted and diluted before administration. To make Imetelstat, use the aseptic method. To generate a concentration of 31.4 mg/mL (milligram per microliters) of Imetelstat, each Imetelstat vial was reconstituted with the 0.9% Sodium Chloride Injection given in Table 4 directly onto the lyophilized powder.

Restoration

Determine the required Imetelsta by utilizing the patient's weight (kg). Calculate the Imetelstat vials necessary (total mg) in Table 4. More than one vial may be required to get the entire dosage. Take the Imetelstat vials out of the refrigerator and let them sit for ten to fifteen minutes, but no more than thirty minutes, to get to room temperature (20 to 25 degrees Celsius; 68 to 77 degrees Fahrenheit) before using. Reassemble each Imetelstat vial using.

Strengths & Dosage Forms:

Injectable, lyophilized powder for reconstitution; each vial contains 47 mg.

188 mg per vial, single dose.

Myelodysplastic Syndromes:

Recommended for the management of adults with transfusion-dependent anemia requiring at least four red blood cells over eight weeks in patients with low- to intermediate-risk myelodysplastic syndromes (MDS) who have not reacted to, have lost response to, or are not eligible for erythropoiesis-stimulating drugs (ESA)

• Administer for two hours.

• IV 7.1 mg/kg every four weeks.

• After six doses of treatment over 24 weeks, stop if the RBC transfusion burden does not decrease or if unacceptable toxicity develops at any point.

Before Medication

• Give greater than or equal to 30 minutes before the dosage to minimize or avoid any responses associated with the infusion.

• Diphenhydramine IV/PO: 25 to 50 mg (or similar).

• 100 to 200 mg IV/PO of Hydrocortisone (or equivalent).

• Check for negative effects for at least one hour following the conclusion of the infusion.

Changes In Dosage

• Dose reduction for side effects in Grades 3 and 4.

• First decrease: 5.6 mg/kg every four weeks.

• Second decrease: 4.4 mg/kg per four weeks.

• Unfavorable hematologic consequences (Grades 3 and 4).

• Before administration, every week for the first two cycles, before each subsequent cycle, and as directed by a physician, check the CBC counts.

• If platelets are < (less than) 50 x 109/L or ANC is <1 x 109/L, postpone the next cycle.

Pharmacology

Mechanics of Action:

A human telomerase inhibitor is an oligonucleotide that binds to the RNA component of human telomerase (hTR), inhibiting telomerase enzymatic activity and preventing telomere binding. Telomeres are repetitive DNA sequences found at the ends of chromosomes. Normally, when a cell divides, its telomeres get shorter. Eventually, this shortening causes the cell to die (apoptosis) or become incapable of dividing further. Malignant stem and progenitor cells and MDS have been shown to exhibit elevated telomerase activity and human telomerase reverse transcriptase (hTERT) RNA expression.

According to nonclinical research, Imetelstat therapy decreased telomere length, inhibited the proliferation of malignant stem and progenitor cells, and induced apoptotic cell death.

Distribution: Greater than 94% protein bound.

Volume of Distribution:Vd: 14.1 L.

Metabolic Process:

Anticipated to be broken down into nucleotides of different lengths by nucleases.

Half-life:

4.9 hours is the elimination.