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.