In 2012,
ponatinib (
Iclusig(®)), an orally available pan-
BCR-ABL tyrosine kinase inhibitor (TKI) developed by ARIAD
Pharmaceuticals, Inc., was approved by the US Food and Drug Administration for use in resistant or intolerant
chronic myeloid leukemia (CML) and
Philadelphia chromosome-positive
acute lymphoblastic leukemia (Ph(+)ALL).
Ponatinib is the only approved TKI capable of inhibiting BCR-ABL with the gatekeeper T315I
kinase domain mutation, known to be the cause for 20% of resistant or relapsed CML cases. In 2013,
ponatinib sales were temporarily suspended due to serious side effects seen in nearly 12% of the patient population. These side effects are thought to stem from the potent nature and pan-activity of this TKI. ARIAD
Pharmaceuticals, Inc. has since been permitted to resume sales and marketing of
ponatinib to a limited patient population with an expanded black box warning. In the following review, the use of
ponatinib in CML and Ph(+)ALL will be discussed. Mechanisms of resistance in CML are discussed, which provide insight and background into the need for this third generation TKI, followed by the molecular design and pharmacology of
ponatinib, which lead to its success as a therapeutic. Finally, the efficacy, safety, and tolerability of
ponatinib will be highlighted, including summaries of the important clinical trials involving
ponatinib as well as its current place in
therapy.