Imetelstat

Imetelstat is an oligonucleotide human telomerase inhibitor that binds to the template region of the RNA component of human telomerase (hTR), inhibits telomerase enzymatic activity and prevents telomere binding.

Increased telomerase activity and human telomerase reverse transcriptase (hTERT) RNA expression have been reported in MDS and malignant stem and progenitor cells. Nonclinical studies showed imetelstat treatment led to reduction of telomere length, reduction of malignant stem and progenitor cell proliferation, and induction of apoptotic cell death.

Grade 3 and 4 Thrombocytopenia

Higher imetelstat exposure is associated with higher incidence of Grade 3 and 4 thrombocytopenia in patients with MDS.

Imetelstat plasma geometric mean (coefficient of variation [CV] ) maximum concentration (C_max) is 18.3 µM (27.3) and the area under the concentration-time curve from time 0 to 28 days (AUC_0-28) was 114.2 h*µM (43.2%). Imetelstat does not accumulate between treatment cycles.

Distribution

Following a single intravenous dose of 7.1 mg/kg of imetelstat administered over 2 hours in patients with MDS, the geometric mean (CV%) volume of distribution is approximately 14.1 L (27.2%). In vitro human plasma protein binding is greater than 94%.

Elimination

The imetelstat geometric mean (CV%) apparent plasma half-life is approximately 4.9 hours (43.2%) at the approved recommended dosage.

Metabolism

Imetelstat is expected to be metabolized by nucleases to nucleotides of various lengths.

Specific populations

No clinically significant differences in the pharmacokinetics of imetelstat were observed based on age (21 to 87 years), sex, race (81% White, 4% Asian, 7% Black, 8% other/unknown), mild to moderate renal impairment (CL_cr 30 to <90 mL/min), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin >1x to 1.5x ULN and any AST), or moderate hepatic impairment (total bilirubin >1.5x to 3x ULN and any AST). The effect of severe renal impairment (CL_cr 15 to <30 mL/min), end-stage renal disease, or severe hepatic impairment (total bilirubin > 3x ULN and any AST) has not been established.

Drug Interaction Studies

In Vitro Studies

CYP Enzymes: Imetelstat is not an inhibitor or inducer of CYP450 enzymes.

Transporter systems: Imetelstat is an inhibitor of OATP1B1 and OATP1B3.