General Information

Iclusig (ponatinib) is a small-molecule dual Abl/Src protein inhibitor.

Iclusig is specifically indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.

Iclusig is supplied as a tablet for oral administration. The recommended initial dose is 45 mg administered orally once daily. Treatment should be continued until evidence of disease progression or unacceptable toxicity. Dose modifications should be considered for myelosuppression, non-hematologic adverse reactions, and use with strong CYP3A inhibitors. See drug label for appropriate dose modifications.

Clinical Results

FDA Approval
The FDA approval of Iclusig was based on a single-arm, open-label, international, multicenter trial in 449 subjects with CML and Ph+ALL whose disease was considered to be resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. Subjects were assigned to one of six cohorts based on disease phase (chronic phase CML [CP-CML]; accelerated phase CML [AP-CML]; or blast phase CML [BP-CML]/Ph+ALL), resistance or intolerance (R/I) to prior TKI therapy, and the presence of the T315I mutation. All subjects were administered a starting dose of 45 mg of Iclusig once daily. 444 subjects eligible for efficacy analysis: 267 subjects with CP-CML (R/I Cohort: n=203, T315I: n=64), 83 with AP-CML, 62 subjects with BP-CML, and 32 with Ph+ALL. Five subjects were not eligible for efficacy analysis due to lack of confirmation of T315I mutation status. The primary efficacy endpoint in CP-CML was major cytogenetic response (MCyR), which included complete and partial cytogenetic responses (CCyR and PCyR); this was reached by 54% of the population. The median time to MCyR was 84 days. At the time of analysis, the median durations of MCyR had not yet been reached. The primary efficacy endpoint in AP-CML, BP-CML, and Ph+ALL was major hematologic response (MaHR), defined as either a complete hematologic response (CHR) or no evidence of leukemia (NEL); this was reached by 52% of the AP-CML population, 31% of the BP-CML population and 41% of the Ph+ ALL population. The median time to MaHR in patients with AP-CML, BP-CML, and Ph+ALL was 21 days, 29 days and 20 days, respectively. The median duration of MaHR for patients with AP-CML, BP-CML, and Ph+ALL was 9.5 months, 4.7 months and 3.2 months, respectively.

Side Effects

Adverse events associated with the use of Iclusig may include, but are not limited to, the following:

Non-hematologic adverse reactions:

hypertension

rash

abdominal pain

fatigue

headache

dry skin

constipation

arthralgia

nausea

pyrexia

Hematologic adverse reactions:

thrombocytopenia

anemia

neutropenia

lymphopenia

leukopenia

Mechanism of Action

Ponatinib is a kinase inhibitor. Ponatinib inhibited the in vitro tyrosine kinase activity of ABL and T315I mutant ABL with IC50 concentrations of 0.4 and 2.0 nM, respectively. Ponatinib inhibited the in vitro activity of additional kinases with IC50 concentrations between 0.1 and 20 nM, including members of the VEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, TIE2, and FLT3. Ponatinib inhibited the in vitro viability of cells expressing native or mutant BCR-ABL, including T315I. In mice, treatment with ponatinib reduced the size of tumors expressing native or T315I mutant BCR-ABL when compared to controls.