Slide 1: Telomerase Activity, Telomere Length and hTERT Expression Correlate With Clinical Outcomes in Higher-Risk Myelofibrosis
Abstract #347 Telomerase Activity, Telomere Length and hTERT Expression Correlate With Clinical Outcomes in Higher-Risk Myelofibrosis (MF) Relapsed/Refractory (R/R) to Janus Kinase Inhibitor Treated With Imetelstat John Mascarenhas, MD1, Rami S. Komrokji, MD2, Michele Cavo, MD3, Bruno Martino, MD4,
Slide 2: Disclosure
Disclosure ❑ Presenter: John Mascarenhas, MD ❑ Affiliations: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, NY, USA ❑ Disclosure: – Consultancy: Celgene/BMS, Incyte, Roche, PharmaEssentia, Constellation, Kartos, Prelude, Geron, Abbvie – Research funding: CTI Biopharma, Incyte, Jans
Slide 3: Telomerase As A Target in Hematologic Malignancies
Telomerase As A Target in Hematologic Malignancies normal mature blood cells hematopoietic normal hematopoietic stem cells (HSCs) progenitor cells (HPCs) Telomeres • Essential genetic elements normal blood • TTAGGG repeats, cap chromosome ends counts • Shorten without telomerase cells highly prolife
Slide 4: Imetelstat: First-in-Class Telomerase Inhibitor
Imetelstat: First-in-Class Telomerase Inhibitor Imetelstat ▪ Proprietary: 13-mer thio-phosphoramidate oligonucleotide complementary to hTR, with covalently-bound lipid tail to increase cell permeability. ▪ Potent, first in class competitive inhibitor of telomerase: IC50 = 0.5-10 nM ▪ Target: selecti
Slide 5: IMbark Phase 2 Trial: Dose-dependent Clinical Benefits Observed with Imetelstat Treatment
IMbark Phase 2 Trial: Dose-dependent Clinical Benefits Observed with Imetelstat Treatment IMbark (MYF2001; NCT02426086) was a randomized, single-blind phase 2 study to evaluate the activity of 2 dose levels of imetelstat (9.4 mg/kg or 4.7 mg/kg, IV every 3 weeks) in intermediate- 2/high-risk myelofi
Slide 6: Objectives
Objectives ❑ Evaluate on-target pharmacodynamic (PD) effect of imetelstat and relationship to dose and exposure levels in MF patients. ❑ Assess the correlation of the optimal PD effect with symptom or spleen response and OS. – Clinical cut off date April 21, 2020 ❑ Explore the association between ba
Slide 7: Methods
Methods ❑ Blood samples were collected to test for: – TA by quantitative telomeric repeat amplification protocol technology. – hTERT level by Taqman RT-PCR assay. – TL by high-throughput quantitative fluorescence in situ hybridization technology – Mutations and variant allele frequency (VAF) by next
Slide 8: Dose-dependent and Exposure-dependent PD Effects
Dose-dependent and Exposure-dependent PD Effects Significantly higher % of pts in 9.4mg/kg arm achieved Significantly higher % pts with higher imetelstat optimal PD effect* compared to 4.7mg/kg arm exposure** achieved ≥50% hTERT reduction 70% p=0.033 p=0.049 % of patients achieved >=50% 60% reductio
Slide 9: Optimal PD Effect Correlated with Clinical Responses and Longer OS
Optimal PD Effect Correlated with Clinical Responses and Longer OS Higher % of patients who had spleen or symptom Patients who achieved optimal PD effect had longer OS response achieved optimal PD effect* A 120% B Median OS (mo) HR Optimal PD (95% CI) (95% CI) % of pts achieved optimal PD effect 100
Slide 10: Imetelstat Has Potential Disease-modifying Activity by Targeting Malignant Clones
Imetelstat Has Potential Disease-modifying Activity by Targeting Malignant Clones Imetelstat resulted in dose-dependent reduction in VAF of JAK2V617F, CALR and MPL mutations 4.7 mg/kg 9.4 mg/kg JAK2 N=15 N=16 120% >=25% Decrease 0 (0%) 5 (31.3%) CALR N=2 N=2 % pts had >=25% VAF reduction 100.0% 100.
Slide 11: Shorter Baseline Telomere Length Associated with Clinical Responses for 9.4 mg/kg Imetelstat
Shorter Baseline Telomere Length Associated with Clinical Responses for 9.4 mg/kg Imetelstat Patients with shorter baseline TL (≤median) had higher rates of spleen and symptom response in the imetelstat 9.4 mg/kg arm Baseline telomere length (TL) vs responses 40% 37.9% % pts achieved response 35% 4.
Slide 12: Correlation Between Shorter Telomere Length and Longer OS
Correlation Between Shorter Telomere Length and Longer OS Compared to 4.7 mg/kg, patients with shorter baseline TL had a trend of improved OS when treated with 9.4 mg/kg of imetelstat 4.7 mg/kg 9.4 mg/kg Median OS (mo) HR Median OS (mo) HR Baseline TL Baseline TL (95% CI) (95% CI) (95% CI) (95% CI)
Slide 13: Higher Baseline hTERT Expression Level Associated with Clinical Responses to 9.4 mg/kg Imetelstat
Higher Baseline hTERT Expression Level Associated with Clinical Responses to 9.4 mg/kg Imetelstat Patients with higher baseline hTERT level (>median) had higher rate of spleen and symptom response in imetelstat 9.4 mg/kg arm Baseline hTERT level vs responses % pts achieved response 40% 37.9% 35% 4.7
Slide 14: Conclusions
Conclusions ❑ Imetelstat achieved dose- and exposure-dependent reduction of telomerase activity and hTERT expression level, demonstrating on-target mechanism of action. ❑ Achievment of the optimal PD effect (≥50% reduction of telomerase activity or hTERT level) in patients treated with imetelstat co
Slide 15: Acknowledgements
Acknowledgements The authors thank all the patients for their participation in this study and acknowledge the collaboration and commitment of all investigators and their staff