PII-033 - NO EFFECT OF IMMUNOGENICITY ON THE PHARMACOKINETICS, EFFICACY, AND SAFETY OF THE NOVEL OLIGONUCLEOTIDE TELOMERASE INHIBITOR IMETELSTAT IN LOWER-RISK MYELODYSPLASTIC SYNDROMES

A. Lennox¹, F. Huang¹, M. Gonzalez-Sales², Y. Wan³, L. Sun⁴, T. Berry³, F. Feller³, P. Morcos⁵; ¹Geron Corporation, Foster City, CA, USA, ²Modeling Great Solutions SLU, Dubai, United Arab Emirates, ³Geron Corporation, Foster City, CA, United States, ⁴Geron Corporation, Foster City, CA, Geron Corporation, ⁵Morcos Pharmaceutical Consulting, Marlboro, New Jersey, United States.

Background: Imetelstat is a first-in-class, 13-mer oligonucleotide telomerase inhibitor approved by FDA in 2024 for treatment of adult patients with lower-risk myelodysplastic syndromes (LR-MDS) with transfusion-dependent anemia. We evaluated imetelstat immunogenicity and impacts on its clinical pharmacokinetics (PK), efficacy, and safety.

Methods: In the pivotal Phase 2/3 study IMerge (NCT02598661), LR-MDS patients received imetelstat 7.1 mg/kg via 2-hour IV infusion every 4 weeks or placebo (Phase 3). Imetelstat anti-drug antibodies (ADAs) were evaluated at predose prior to and during treatment using a validated, semi-quantitative 3-tiered method: a screening assay to detect anti-imetelstat antibodies; a confirmatory competition assay to assess specificity of positive screening results; and a titration assay for confirmed positive results. Graphical and descriptive analyses evaluated the incidence of ADAs and any effect on imetelstat PK, efficacy, and safety.

Results: Of 166 evaluable patients, 28 (16.9%) developed ADA to imetelstat, with a median time to onset of 38 weeks (range: 12 to 109 weeks), or after 8 treatment cycles. In ADA positive patients, peak titer was low and ranged from 10 to 160 (median 30). Graphical evaluation and population PK covariate analysis showed no impact of ADA positivity on imetelstat PK. ADA positivity did not negatively impact efficacy response rates for the primary efficacy endpoint, ≥8-week red blood cell transfusion independence (RBC TI), or secondary endpoints, ≥24-week RBC TI or hematologic improvement-erythroid (HI-E), or the duration of RBC TI response. There was no apparent relationship between onset of ADA and loss of RBC TI. ADA positive and ADA negative patients exhibited similar rates of any grade or grade ≥3 treatment-emergent adverse events (TEAEs). No serious TEAEs or TEAEs with outcome of death were reported in ADA positive patients. Infusion-related TEAEs were more frequent in ADA positive patients, although the sample size was small. Efficacy and safety outcomes were similar in ADA positive patients with low and high peak titer values.

Conclusion: ADA developed at a low frequency in imetelstat-treated patients with LR-MDS. Overall, ADAs do not appear to impact the PK, efficacy, or safety of imetelstat and thus do not impact its benefit/risk profile.