RYTELO Solution for injection Ref.[110353] Active ingredients: 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 RYTELO 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.

Carcinogenicity studies have not been conducted with imetelstat.

In vitro, imetelstat was not mutagenic in the bacterial mutagenicity assay (Ames test) or clastogenic in the chromosomal aberrations assay using cultured human peripheral blood lymphocytes. Imetelstat was not genotoxic in an in vivo mouse micronucleus assay at intravenous dose levels up to approximately 104 mg/kg.

Fertility studies have not been conducted with imetelstat. Female monkeys given 14.1 mg/kg once weekly for 9 months exhibited uterine endometrial atrophy in a general toxicology study. This effect was observed at a mean exposure (based on AUC) that is approximately 14.4-times the human exposure at the recommended clinical dose. This finding was not present in animals following a 14-week recovery period.

14.1. Myelodysplastic Syndromes (MDS)

The efficacy of RYTELO was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial (IMerge; NCT02598661) in 178 patients enrolled with International Prognostic Scoring System (IPSS) low- or intermediate-1 risk MDS who were transfusion-dependent (requiring ≥4 red blood cell (RBC) units over an 8-week period during the 16 weeks prior to randomization). Eligible patients were required to have failed to respond or have lost response or be ineligible for erythropoiesis-stimulating agents (ESAs); and had an absolute neutrophil count of 1.5 × 10⁹/L or greater and platelets 75 × 10⁹/L or greater. Patients were ineligible if they had del(5q) cytogenetic abnormality or had received prior treatment with lenalidomide or hypomethylating agents.

Participants were randomized in a 2:1 ratio to receive an intravenous infusion of RYTELO (n=118) 7.1 mg/kg or placebo (n=60) in 28-day treatment cycles until disease progression, unacceptable toxicity, or withdrawal from the study. Randomization was stratified by prior RBC transfusion burden and by IPSS risk group. All patients received supportive care, which included RBC transfusions.

Of the 178 patients enrolled, the median age was 72 years (range: 39 to 87 years), with 62% male, and 80% White, 6% Asian, 1.7% Black, 12% other or not reported. The key baseline disease characteristics of the efficacy population are shown in Table 7.

Table 7. Baseline Disease Characteristics of Patients with MDS in IMerge:

Abbreviations: ECOG = Eastern Cooperative Oncology Group; ESA = erythropoietin stimulating agents; IPSS = International Prognostic Scoring System; RBC = Red Blood Cell; MDS = myelodysplastic syndromes; sEPO = serum erythropoietin; WHO = World Health Organization
^a Prior RBC transfusion burden is defined as the maximum number of RBC units transfused over an 8-week period during the 16 weeks prior to randomization.
^b RS+ includes refractory anemia with ring sideroblasts (RARS)/refractory cytopenia with multilineage dysplasia and ≥15% ringed sideroblasts (RCMD-RS).
^c RS˗ includes others.

Efficacy was established after a median follow up time of 19.5 months (range: 1.4 to 36.2) in the imetelstat group and 17.5 months (range: 0.7 to 34.3) in the placebo group based upon the proportion of patients who achieved ≥8-week and ≥24-week RBC-TI, defined as the absence of RBC transfusion(s) during any consecutive 8 weeks (56 days) period, and during any consecutive 24 weeks (168 days) period, respectively, from randomization until the start of subsequent anti-cancer therapy (if any). The efficacy results are summarized in Table 8.

Table 8. Efficacy Results of RYTELO in IMerge:

Abbreviations: CI = Confidence Interval; RBC = Red Blood Cell; TI = Transfusion Independence
^a 95% CI based on Wilson Score method.
^b p-value is based on Cochran-Mantel-Haenszel (CMH) controlling for prior RBC transfusion burden (≤6 versus >6 units RBC) and IPSS risk group (low versus intermediate-1) applied to randomization.
^c Exact Clopper-Pearson confidence interval.