A 13-mer oligonucleotide covalently modified with lipid extensions, competitively inhibits telomerase enzymatic activity.

A lipid conjugated oligonucleotide that targets the RNA template of human telomerase reverse transcriptase.

Can cause rapid and durable hematological and molecular responses in patients with essential throbocytosis.

Active in myelofibrosis.

Imetelstat active in patients with myelofibrosis with a 21 percent complete and partial response rate and a median duration response of 18 months.

Imetelstat resulted in bone marrow fibrosis reversal in all patients who had complete responses and a molecular response in three of four patients treated (Tefferi A et al).

Can cause significant myelosuppression.

Phase 3 IMerge trial in which treatment with imetelstat resulted in a red blood cell (RBC) transfusion independence (RBC-TI) rate of 39.8% at 8 weeks vs 15.0% with placebo in this population .

This benefit with imetelstat vs placebo across key subsets, including those without ring sideroblasts (31.8% vs 8.7% and those with a prior RBC transfusion burden of greater than 6 units every 8 weeks (33.9% vs 7.4%.

The 24-week RBC-transfusion independence rates with the agent were 28.0% and 3.3%, respectively.

Most patients (83%) who achieved 8-week RBC-TI with imetelstat experienced durable continuous RBC-TI episodes. 

Those who received imetelstat and achieved RBC-TI at 8 weeks had a significantly longer duration of TI than those given placebo, at 51.6 weeks vs 13.3 weeks respectively.

A significant and sustained increase in hemoglobin was observed in those who received imetelstat vs placebo, at a median rise of 3.6 g/dL and 0.8 g/dL, respectively.

It has the potential to become a standard of care and address longstanding unmet needs of lower-risk MDS patients.

The double-blind, placebo-controlled, phase 3 trial enrolled patients with low- or intermediate-1 risk MDS by International Prognostic Scoring System (IPSS) criteria who were relapsed or refractory to erythropoiesis-stimulating agents (ESAs) or had an erythropoietin level of over 500 mU/mL.

Patients also needed to be transfusion dependent, which was defined as requiring at least 4 unites of RBCs every 8 weeks over the 16 weeks before the study. 

They could not have 5q deletions or have prior exposure to lenalidomide or hypomethylating agents.

Study participants were randomly assigned 2:1 to receive imetelstat at 7.5 mg/kg every 4 weeks or placebo. Patients were stratified by transfusion burden (4 to 6 units vs over 6 units) and IPSS risk category (low vs intermediate-1).

The primary end point of the trial was RBC-TI at 8 weeks, and important secondary end points included 24-week RBC-TI rates, duration of TI, HI-E rates, and safety. Exploratory end points included variant allele frequency changes and patient-reported outcomes measured by FACIT-Fatigue.

The most common reasons  for discontinuation of imetelstat was lack of efficacy (23.7%), followed by an adverse effect (AE; 16.1%), other (16.1%), disease relapse following response on study (14.4%), disease progression (5.9%), and death (0.8%).

The most common grade 3 or 4 AEs reported in the imetelstat arm: thrombocytopenia (62%) and neutropenia (68%).

Nonhematologic toxicities were noted to be generally low grade. 

Approximately 75% of patients who received imetelstat required dose modifications because of AEs and less than 15% discontinued.


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