FDA Approves Ponatinib for Chronic-Phase Chronic Myeloid Leukemia Patients Resistant or Intolerant t

Takeda Pharmaceutical Company Limited (Takeda) recently announced that the U.S. Food and Drug Administration (FDA) has approved the supplemental New Drug Application (sNDA) for ponatinib, indicated for the treatment of adult patients with chronic-phase (CP) chronic myeloid leukemia (CML) who are resistant or intolerant to at least two kinase inhibitors.

The updated drug label for ponatinib includes an optimized, response-based dosing regimen for CP-CML treatment: the starting dose is 45 mg, which is reduced to 15 mg upon achievement of ≤1% BCR-ABL1IS. This dosing regimen is designed to maximize the therapeutic benefit-risk ratio by maintaining efficacy while reducing the risk of adverse events (AEs), including arterial occlusive events (AOEs).

The approval of this sNDA is based on data from the phase 2 OPTIC trial (ponatinib for CML treatment) and 5-year data from the phase 2 PACE trial (ponatinib for Ph+ ALL and CML treatment).

The OPTIC trial enrolled CP-CML patients with high-level resistance to prior tyrosine kinase inhibitor (TKI) therapy, with the majority (65%) failing to achieve a response better than complete hematologic response (CHR) with their most recent TKI treatment. Data showed that at month 12 of treatment, 42% of 88 patients treated with the newly approved response-based optimized dosing regimen (45 mg reduced to 15 mg) achieved ≤1% BCR-ABL1IS, the primary endpoint of the OPTIC trial. With a median follow-up of 28.5 months, 73% of these patients maintained their response. In this trial, 13% of patients experienced any-grade AOEs, and 7% experienced grade ≥3 AOEs.

The PACE trial was conducted in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and CML who were resistant or intolerant to dasatinib or nilotinib, or harbored the T315I mutation. A total of 449 patients received ponatinib at a starting dose of 45 mg once daily. It is estimated that 93% of patients had previously received ≥2 TKIs, and 56% had received ≥3 TKIs. Among the 267 CP-CML patients enrolled in the trial, 55% achieved major cytogenetic response (MCyR) at 12 months of treatment, which was the primary endpoint for the CP-CML cohort in the PACE trial; 70% of 64 patients with the T315I mutation achieved MCyR. In the PACE trial, 26% of the 449 patients experienced AOEs.

Ponatinib is a kinase inhibitor targeting BCR-ABL1, an abnormal tyrosine kinase expressed in CML and Ph+ ALL. As a targeted oncology agent developed through a computational and structure-based drug design platform, ponatinib is specifically designed to inhibit the activity of BCR-ABL1 and its mutant forms. Ponatinib can inhibit native BCR-ABL1 as well as all BCR-ABL1 mutations associated with treatment resistance, including the most refractory T315I mutation.

Ponatinib is the only approved tyrosine kinase inhibitor (TKI) proven to be active against the BCR-ABL1 T315I gatekeeper mutation, which is associated with resistance to all other approved TKIs. Ponatinib received full FDA approval in November 2016 and is indicated for the treatment of: 

(1) adult patients with CP-CML who are resistant or intolerant to at least two prior kinase inhibitors; 

(2) adult patients with accelerated-phase (AP) or blast-phase (BP) CML and adult patients with Ph+ ALL for whom no other kinase inhibitors are available; 

(3) adult patients with T315I mutation-positive CML (CP, AP or BP) or T315I mutation-positive Ph+ ALL. Ponatinib is not indicated and is not recommended for the treatment of newly diagnosed CP-CML patients.