How Do Telomerase Inhibitors Work?

Telomerase inhibitors are a novel class of drugs approved by the FDA in June 2024 to treat adults with myelodysplastic syndromes (MDS), with anemia requiring regular red blood cell transfusion. Telomerase inhibitors work by inhibiting telomerase, an enzyme that helps cancer cells survive and proliferate. Imetelstat (Rytelo) is the first-in-class and only drug available in this class of medications.

Myelodysplastic syndromes are a group of bone marrow disorders, also considered to be a form of blood cancer. The bone marrow makes three kinds of blood cells, red blood cells (RBCs), white blood cells (WBCs) and platelets. In MDS, the stem cells do not mature int healthy blood cells, but accumulate as immature cells in the bone marrow. With the result, there are far too few healthy, functional blood cells in blood.

People with MDS may have anemia due to low RBC count, develop infections because of low WBC counts, or bruise and bleed easily due to low platelet levels in blood. In about 30% of the people with MDS, immature stem cells in the bone marrow may proliferate out of control, and MDS may progress into acute myeloid leukemia (AML), a type of blood cancer.

Myelodysplastic syndrome can affect any of the blood cells, but most commonly affects the red blood cells, leading to chronic anemia. Telomerase inhibitors are used to treat MDS patients with anemia who require regular RBC transfusions to manage their condition, and who cannot be treated with drugs that stimulate their natural red blood cell production.

Telomeres are DNA-protein structures on the end of chromosomes in the cell nucleus. Telomeres cap the chromosome ends, protect them from damage during cell division, and preserve the genetic information. A little bit of telomere is lost every time a cell divides, and when there is no more telomere left, the chromosomes start getting damaged and the cell undergoes programmed death (apoptosis). This is a natural process of tissue aging.

Telomerase is an enzyme that adds DNA sequences to the telomeres to elongate them, enabling cells to avoid death and continue to divide. In most cells in the body telomerase activity is strictly regulated, to prevent uncontrolled proliferation of cells. Telomerase enzyme is active primarily in reproductive germ cells and stem cells which need to divide and grow, and activated lymphocytes which proliferate to fight infection.

Myelodysplastic cells as well as cancerous (malignant) stem cells in the bone marrow express telomerase to a great extent. Telomerase inhibitors block the activity of telomerase and prevent elongation of telomeres in the cancer cells. This inhibits their ability to divide, and with loss of telomeres, cancer cells get damaged and undergo apoptosis.

Telomerase inhibitors also inhibit telomerase activity in healthy stem cells in the marrow, producing many side effects.

The first telomerase inhibitor has been approved by the FDA in June 2024 to treat adults with low- to intermediate-1 risk myelodysplastic syndromes with transfusion-dependent anemia requiring 4 RBC units or more over 8 weeks who have not responded to, have lost response to, or are ineligible for erythropoiesis-stimulating agents (ESA).

Telomerase inhibitors are injectable solutions that are administered intravenously (IV) into a vein. The medication is infused slowly over 2 hours once every 4 weeks. Telomerase inhibitors are administered after premedicating the patient with antihistamines such as diphenhydramine and hydrocortisone or an equivalent corticosteroid to prevent or reduce potential infusion-related reactions.

The patient is monitored for reactions for at least an hour after completion of each infusion. Typically, treatment is discontinued if it does not reduce the requirement for red blood cell transfusion with 6 doses of infusion, or if side effects becomes unacceptable.

Common side effects of telomerase inhibitors include the following:

• Decrease in platelet count in blood (thrombocytopenia)
• Decrease in white blood cell count (leukopenia)
• Reduced count of neutrophil immune cells (neutropenia)
• Increased time for blood clotting (prolonged partial thromboplastin time [PTT])
• Elevation of liver enzymes including:
• Aspartate aminotransferase
• Alanine aminotransferase
• Alkaline phosphatase
• Fatigue
• Weakness (asthenia)
• Joint pain (arthralgia)
• Muscle pain (myalgia)
• COVID-19
• Urinary tract infection
• Headache
• Fainting (syncope)
• Infusion-related reactions including:
• Abdominal pain
• Diarrhea
• Asthenia
• Feeling ill (malaise)
• Back pain
• Bone pain
• Arthralgia
• Headache
• Redness of skin (erythema)
• Non-cardiac chest pain
• Hypertensive crisis
• Urticaria (hives)
• Itching (pruritus)
• Nasal bleeding (epistaxis)
• Irregular heart rhythm (atrial arrhythmia)
• Pooling and clotting of blood outside the blood vessel (hematoma)
• Itching
• Fractures
• High blood pressure (hypertension)
• Neutropenia-induced fever (febrile neutropenia)
• Sepsis
• Gastrointestinal hemorrhage
• Cardiac failure

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of telomerase inhibitors include:

• imetelstat
• Rytelo