Imetelstat

Imetelstat is an oligonucleotide inhibitor of telomerase. Telomerase activity and the expression of its catalytic subunit (hTERT RNA) are markedly raised in myelodysplastic syndromes (MDS) and in malignant stem and progenitor cells, which is the basis of its selectivity.

Mechanism of Action

• Telomerase inhibition: imetelstat binds to the template region of the RNA component of human telomerase (hTR), which prevents telomere binding.
• Cellular effects: treatment shortens telomeres, inhibits the proliferation of malignant stem and progenitor cells and induces apoptotic cell death, which reduces malignant clones.
• Selectivity: telomerase activity is relatively higher in MDS and malignant stem and progenitor cells than in normal cells, so these cells are affected more.
• Immunogenicity: anti-drug antibodies were found in 17% of participants at the recommended dose. No effect on pharmacokinetics, efficacy or safety was seen, but data are still limited.

Pharmacokinetics

• Absorption: given as an intravenous infusion, so the whole dose reaches the circulation; other routes have not been studied. After 7.1 mg/kg over 2 hours in patients with MDS, the geometric mean peak plasma concentration (Cmax) was 89.5 mcg/mL (CV 27.3%), reached at the end of the infusion. There is no accumulation between four-weekly cycles, judged by Cmax. The 24-hour AUC rises more than in proportion to the dose over the 0.4–11.0 mg/kg range.
• Distribution: about 94% bound to human plasma proteins; volume of distribution about 14.1 L after a single 7.1 mg/kg dose.
• Metabolism: probably broken down by nucleases in tissue into smaller fragments.
• Elimination: the geometric mean apparent plasma half-life is about 4.9 hours (CV 43.2%) after 7.1 mg/kg.
• Special populations: no relevant data are available to assess pharmacokinetics in special populations. The pivotal study included patients with mildly or moderately abnormal liver tests and with mild or moderate renal impairment, but only 2 and 1 patients respectively with severe abnormalities.

• Myelodysplastic syndromes (MDS): monotherapy for adults with transfusion-dependent anaemia due to very low, low or intermediate risk MDS without an isolated deletion 5q (non-del 5q) cytogenetic abnormality, who had an unsatisfactory response to, or are ineligible for, erythropoietin-based therapy.

• Hypersensitivity to imetelstat or to any of the excipients (sodium carbonate, hydrochloric acid).

The frequencies below come from pooled data in 175 patients with low to intermediate-1 risk MDS and transfusion-dependent anaemia who were treated at the recommended dose for a median of 7.8 months. The most common reactions were thrombocytopenia (94%), leukopenia (93%), neutropenia (92%), raised AST (48%), ALT (42%) and alkaline phosphatase (41%), asthenia (26%) and headache (16%); blood-count and liver-enzyme changes are based on laboratory values. The most common severe (grade 3 or higher) reactions were neutropenia (69%) and thrombocytopenia (63%).

Very common (≥1/10): thrombocytopenia, leukopenia, neutropenia, urinary tract infection (12%, including cystitis), headache, raised aspartate aminotransferase, raised alanine aminotransferase, raised alkaline phosphatase, asthenia (including fatigue).

Common (≥1/100 to <1/10): sepsis (4.0%), infusion-related reactions (8.6%), syncope (4.6%), atrial fibrillation (including flutter, 3.4%), haematoma (5.7%), epistaxis (5.1%), gastrointestinal bleeding (6.3%), pruritus (5.1%), arthralgia (6.9%), haematuria (4.6%).

The SmPC table lists no reactions in the uncommon, rare or not known categories.

Serious reactions and treatment changes: the most commonly reported serious reactions were sepsis (1.7%), urinary tract infection (1.7%), atrial fibrillation (1.1%), oesophageal varices haemorrhage (1.1%), syncope (1.1%) and thrombocytopenia (1.1%). Treatment was stopped because of adverse reactions in 13% of patients, most often for thrombocytopenia and neutropenia (6.3% each). The dose was reduced or delayed in 65%, most often for neutropenia (51%) and thrombocytopenia (45%). Infusion-related reactions were generally mild or moderate; the most common symptoms were headache and back pain.

No interaction studies have been performed in humans.

• Transporters: in vitro, imetelstat inhibits BCRP, OAT1, OATP1B1 and OATP1B3 at concentrations similar to those reached on the day of administration. The risk of raising plasma concentrations of a co-administered substrate falls with the rapidly declining plasma concentrations of imetelstat and is likely not relevant on the following days of the dose interval.

Rytelo is given under the supervision of physicians and healthcare professionals experienced in haematologic disease and its treatment. A complete blood count and liver function tests are recommended before each dose, with weekly blood counts after the first two doses. In females of reproductive potential, a pregnancy test is performed before the first dose.

Recommended Dose

• 7.1 mg/kg body weight as an intravenous infusion once every 4 weeks, given over 2 hours (250 mL/h). It is never given as an intravenous push or bolus.
• Duration: treatment is stopped if the red blood cell (RBC) transfusion burden has not fallen after 24 weeks (6 doses), or at any time if toxicity is unacceptable.
• Premedication: diphenhydramine 25 to 50 mg and hydrocortisone 100 to 200 mg, or equivalent, at least 30 minutes before every dose, to prevent or reduce infusion-related reactions.
• Preparation: Rytelo is for single use. It must be reconstituted and diluted with aseptic technique under the supervision of a healthcare professional (see section 6.6 of the SmPC).

Dose Adjustments for Side Effects

• Dose levels: the first reduction takes 7.1 mg/kg to 5.6 mg/kg and the second takes 5.6 mg/kg to 4.4 mg/kg. Treatment is stopped permanently if 4.4 mg/kg is not tolerated.
• Haematologic reactions: delay the dose if the absolute neutrophil count (ANC) is below 1.0 × 10⁹/L or platelets are below 50 × 10⁹/L. For the first grade 3 thrombocytopenia or neutropenia, wait until platelets are at least 50 × 10⁹/L or ANC is at least 1.0 × 10⁹/L and restart at the same dose. For the second and third grade 3 event, and for the first and second grade 4 event, wait for the same recovery and restart one dose level lower.
• Infusion-related reactions: for grade 2 or 3 reactions on the first and second occurrence, interrupt the infusion until the reaction resolves or falls to grade 1, then restart at 50% of the previous rate (125 mL/h). On the third occurrence, stop the infusion for a grade 2 reaction (treatment may restart at the next dose) and discontinue treatment for a grade 3 reaction. For a grade 4 reaction, stop the infusion, give supportive care and discontinue treatment.
• Other grade 3 or 4 reactions, including raised liver tests: on the first and second occurrence, delay treatment until the reaction is grade 1 or at baseline, then restart one dose level lower.

Special Populations

• Elderly: no dose adjustment is needed in patients aged 65 years or older.
• Renal impairment: no adjustment in mild to moderate impairment (creatinine clearance 30 to below 90 mL/min). There are insufficient data in severe impairment (15 to below 30 mL/min) or end-stage renal disease to recommend a dose.
• Hepatic impairment: no adjustment in mildly to moderately abnormal liver function tests, as defined in the SmPC by bilirubin and AST criteria. There are insufficient data in severely abnormal tests (total bilirubin above 3 times the upper limit of normal) to recommend a dose.
• Children and adolescents: safety and efficacy from 28 days to under 18 years have not been established, and there is no relevant use below 28 days.

Missed Dose

If a planned dose is missed, Rytelo should be given as soon as possible and dosing continued as prescribed, with 4 weeks between doses.

Thrombocytopenia

Thrombocytopenia, including new or worsening grade 3 or 4, has been reported. Blood counts should be checked before each dose, weekly after the first two doses, for any grade 3 or 4 thrombocytopenia and as clinically indicated. Patients with grade 3 or 4 thrombocytopenia should be monitored for bleeding and the need for platelet transfusion assessed. Patients should report bruising or bleeding at once. The next dose is delayed and resumed at the same or a reduced dose.

Neutropenia

Neutropenia, including new or worsening grade 3 or 4, has been reported, and febrile neutropenia may occur. Blood counts are monitored on the same schedule. Patients with grade 3 or 4 neutropenia should be monitored for infection, including sepsis; granulocyte colony-stimulating factors and anti-infective therapy are given as clinically indicated. Patients should report fever or other signs of infection immediately. The next dose is delayed and resumed at the same or a reduced dose.

Infusion-Related Reactions

Infusion-related reactions were generally mild or moderate. The most common symptoms were headache and back pain; grade 3 hypotension, hypertension, hypertensive crisis and non-cardiac chest pain were also seen. They usually occurred during or shortly after the end of the infusion. Premedication is given at least 30 minutes before each dose, and patients are monitored for at least one hour after the infusion. Symptoms are managed with supportive care, and interrupting or slowing the infusion, or discontinuing treatment, is considered according to severity and frequency.

Embryo-Foetal Toxicity

Based on animal findings, Rytelo may cause embryo-foetal harm in a pregnant woman. In pregnant mice and rabbits given imetelstat during organogenesis, embryo-foetal mortality occurred at maternal exposures (AUC) of at least 3.4 times the human exposure at the recommended dose. Pregnant women should be told of the potential risk to the foetus.

Pregnancy, Breastfeeding and Fertility

• Pregnancy test and contraception: the pregnancy status of females of reproductive potential is verified before starting. Women of childbearing potential should use effective contraception during treatment and for at least 1 week after the last dose.
• Pregnancy: there are no data in pregnant women. Animal studies showed embryonic or foetal loss. Imetelstat is not recommended during pregnancy or in women of childbearing potential who are not using contraception.
• Breastfeeding: it is unknown whether imetelstat passes into human milk, and a risk to the breastfed child cannot be excluded. Women should not breastfeed during treatment and for 1 week after the last dose.
• Fertility: animal findings suggest that imetelstat may impair fertility in females of reproductive potential. There are no human data.

Sodium

Each dose contains about 35 mg of sodium for a patient weighing 80 kg, which is approximately 1.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Effect on Driving

Rytelo may have a minor influence on the ability to drive and use machines. Asthenia and infusion-related reactions such as malaise, chest pain and hypertensive crisis may impair the ability to react. Patients should take care until symptoms affecting driving or the use of machines have resolved.

Store Rytelo in a refrigerator at 2 °C to 8 °C. Do not freeze. Keep the cold chain unbroken from supply to preparation. For storage after reconstitution and dilution, see Shelf Life. Rytelo 47 mg comes in an 8 mL clear Type 1 glass vial with a chlorobutyl rubber stopper and an aluminium flip-off seal with a dark green plastic cap; Rytelo 188 mg comes in a 10 mL vial with a royal blue cap. Each pack holds one vial.

4 years for the unopened vial. The reconstituted solution is used immediately to prepare the diluted solution for infusion. The diluted solution should be used within 48 hours when kept at 2–8 °C, or within 18 hours at 20–25 °C, counting the whole time from reconstitution to the end of the infusion. These periods reflect the chemical and physical in-use stability that has been demonstrated; from a microbiological point of view the product should be used immediately.

Prescription only (Rx), on restricted medical prescription: treatment is started and monitored by physicians experienced in haematologic disease. Rytelo is given as an intravenous infusion and is a refrigerated (2–8 °C) product, so it is supplied under cold-chain conditions to the hospital or clinic that administers it.