No Effect of Immunogenicity on Pharmacokinetics, Efficacy, and Safety of the Oligonucleotide Telomerase Inhibitor Imetelstat in Lower-Risk Myelodysplastic Syndromes.

Imetelstat is a first-in-class, 13-mer oligonucleotide telomerase inhibitor approved in the United States and European Union for the treatment of certain adult patients with lower-risk myelodysplastic syndromes (LR-MDS) with red blood cell (RBC) transfusion-dependent anemia. This post hoc analysis evaluated imetelstat immunogenicity and its association with the pharmacokinetics (PK), efficacy, and safety of imetelstat in patients with LR-MDS from the phase II/III IMerge study (NCT02598661). A validated, semi-quantitative 3-tiered method evaluated anti-drug antibodies (ADAs). Graphical and descriptive analyses evaluated ADA incidence and association with clinical outcomes. Of 166 evaluable patients who received 7.1 mg/kg imetelstat via a 2-h intravenous infusion every 4 weeks, 16.9% developed imetelstat ADAs (median [range] time to onset, 38 weeks [12-109]; ~8 treatment cycles). In ADA-positive patients, peak titer was low (median [range], 30 [10-160]). Evaluations showed no association of ADA positivity with imetelstat PK, nor any negative association with efficacy responses, including ≥ 8-week RBC-transfusion independence (TI), ≥ 24-week RBC-TI, hematologic improvement-erythroid, or duration of RBC-TI response. There was no apparent relationship between the onset of ADAs and loss of RBC-TI. The rates of any-grade or grade ≥ 3 treatment-emergent adverse events (TEAEs) were similar for both ADA groups, with no reported serious TEAEs or TEAEs causing death in ADA-positive patients. Infusion-related TEAEs were more frequent in ADA-positive patients, although the sample size was small. Overall, imetelstat ADAs did not appear to impact imetelstat benefit/risk profile in the LR-MDS population of IMerge, although the analysis is limited by the low incidence of imetelstat ADAs, resulting in a small ADA-positive group.