Ponatinib
BCR-ABL Inhibitor Philadelphia Chromosome Positive Acute, Lymphoblastic Leukemia, Chronic Myeloid Leukemia
Overview1-3
Ponatinib, the only third-generation TKI, is a pan-BCR-ABLl inhibitor rationally designed to potently inhibit native BCR-ABLl and all single mutations, including T3151
MOA1-5
- Ponatinib was designed to incorporate 2 key elements
- Optimal fit to the ABLl binding site with distributed bind ing energy, which is thought to withstand the loss of binding energy caused by any of the single mutations
- A carbon-carbon trip le bond linkage that allows key interactions with the side cha in of the T3151 gatekeeper mutant
- These features confer high potency against both native and mutant BCR-ABLl, underlying its pan-BCR-ABLl inhibitor profile
- Preclinical experiments demonstrated that ponatinib inhibits the outgrowth of mutant BCR-ABLl clones; at 40 nM ponatinib, complete suppression of in vitro resistance was achieved across native and all mutant clones.
- Ponatinib induced a selective reduction of viable cell numbers (ICS0 values - 500-fold lower) in primary CML cells over normal cells
Clinical Trials
Study Name
A Randomized, Open-label, Phase 2 Trial of Ponatinib in Patients With Resistant Chronic Phase Chronic Myeloid Leukemia to Characterize the Efficacy and Safety of a Range of Doses (OPTIC)
CT.GOV ID
NCT02467270
Phase
Phase 2
Status
Active. not recruiting
Study Name
A Phase 3, Randomized, Open-label, Multicenter Study Comparing Ponalinib Versus lmatinib, Administered in Combination With Reduced-Intensity Chemotherapy, in Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
CT.GOV ID
NCT03589326
Phase
Phase 3
Status
Recruiting
Study Name
A Pivotal Phase 1/2, Single-Arm, Open-label Study to Evaluate the Safety and Efficacy of Ponatinib With Chemotherapy in Pediatric Patients With Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Who Have Relapsed or Are Resistant or Intolerant to a Prior Tyrosine Kinase Inhibitor-Containing Therapy, or Who Have the T3151 Mutation
CT.GOV ID
NCT04501614
Phase
Phase 1/2
Status
Recruiting
References
1. Clakson T. Cancer Res. 2013;73(8)(suppl):SY19-04.
2. O'Hare T, et al. Cancer Cell. 2009;16:401-412.
3. ICLUSIG® US Prescribing Information, ARIAD Pharmaceuticals Inc.
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