Therapy Areas: Diabetes
US FDA Approves Supplemental New Drug Application for Takeda's ICLUSIG (ponatinib) for Adult Patients with Resistant or Intolerant Chronic-Phase CML
22 December 2020 - - The US Food and Drug Administration has approved the supplemental New Drug Application for ICLUSIG (ponatinib) for adult patients with chronic-phase chronic myeloid leukemia with resistance or intolerance to at least two prior kinase inhibitors, Japan-based Takeda Pharmaceutical company Ltd. (TSX: 4502) (NYSE: TAK) said.

The updated label includes an optimized, response-based ICLUSIG dosing regimen in CP-CML with a daily starting dose of 45 mg and, upon achieving ≤1% BCR-ABL1IS, dose reduction to 15 mg.

This dosing regimen aims to maximize benefit-risk by providing efficacy and decreasing the risk of adverse events, including arterial occlusive events.

The sNDA approval is based on data from the Phase 2 OPTIC (Optimizing Ponatinib Treatment In CML) trial, as well as five-year data from the Phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial.

The OPTIC trial included patients with CP-CML whose disease was highly-resistant to their immediate prior TKI, the majority of whom did not achieve a response greater than complete hematological response on immediate prior therapy. 

At 12 months, 42% of 88 patients utilizing the newly approved response-based dosing regimen (45 mg to 15 mg) achieved ≤1% BCR-ABL1IS, the primary endpoint of OPTIC, and at a median follow up time of 28.5 months, 73% of these patients maintained their response.

In these patients, 13% experienced an AOE of any Grade, 7% experienced Grade 3 or higher. Risk factors such as uncontrolled hypertension or diabetes should be managed, and caution should be exercised when treating patients with active or substantial history of clinically significant, uncontrolled cardiovascular disease.

Data from the OPTIC and PACE studies were presented virtually at the 56th American Society of Clinical Oncology annual meeting, the 25th European Hematology Association annual meeting and the 62nd American Society of Hematology annual meeting.

OPTIC (Optimizing Ponatinib Treatment In CML) is an ongoing randomized, dose-ranging trial designed to evaluate three starting doses of ICLUSIG (15 mg, 30 mg, 45 mg) in patients with resistant chronic-phase chronic myeloid leukemia or who had documented history of presence of T315I mutation after receiving any number of prior TKIs. Dose reduction at response occurred per study protocol.

The trial is expected to inform the optimal use of ICLUSIG (ponatinib) in these patients. 282 patients were enrolled at clinical sites around the world, with 94 patients receiving the 45 mg starting dose.

The primary endpoint of the trial is achieving ≤1% BCR-ABL1IS at 12 months.

OPTIC data showed that optimal benefit-risk with ICLUSIG can be obtained with a response-based dosing regimen, 45 mg/day to 15 mg/day upon achieving ≤1% BCR-ABL1IS in patients with CP-CML highly resistant to prior TKI therapies both with or without BRC-ABL1 mutations.

At 12 months, 42% of 88 patients who received the 45 mg starting dose achieved ≤1% BCR-ABL1IS. At a median follow up time of 28.5 months, the OPTIC study showed that, among patients receiving ICLUSIG 45 to 15 mg, 73% maintained their response.

In these patients, 13% experienced an AOE of any Grade, 7% experienced Grade 3 or higher.

Adverse reactions occurring in >20% of patients in the OPTIC trial included: rash and related conditions, hypertension, arthralgia, hyperlipidemia, hepatic dysfunction, pancreatitis, and abdominal pain.

The most common Grade 3 or 4 laboratory abnormalities were platelet count decreased and neutrophil cell count decreased.

The PACE (Ponatinib Ph+ ALL and CML Evaluation) trial evaluated the efficacy and safety of ICLUSIG in CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) patients resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation.

A total of 449 patients were treated with ponatinib at a starting dose of 45 mg/day. An estimated 93% of patients previously received two or more approved TKIs and 56% of all patients had received three or more approved TKIs. 55% of 267 patients with CP-CML in the PACE trial achieved major cytogenetic response by 12 months the primary endpoint of the PACE trial for CP-CML patients and 70% of 64 CP-CML patients with T315I+ achieved MCyR. Enrollment in the PACE trial was completed in October 2011.

In the PACE trial, 26% of 449 patients experienced AOEs. The most common non-hematologic adverse reactions were rash and related conditions, arthralgia, abdominal pain, fatigue, constipation, headache, dry skin, fluid retention and edema, hepatic dysfunction, hypertension, pyrexia, nausea, hemorrhage, pancreatitis/lipase elevation, AOEs, diarrhea, vomiting, and myalgia.

CML a rare malignancy is one of four main types of leukemia; it is a result of a genetic mutation that takes place in early, immature versions of myeloid cells, which form red blood cells, platelets and most types of white blood cells.

Subsequently, an abnormal gene called BCR-ABL1 forms, turning the damaged cell into a CML cell. CML typically progresses slowly, but it can change into a fast-growing acute leukemia that is hard to treat.

Ph+ ALL is a rare form of ALL that affects approximately 25% of adult ALL patients in the US and is characterized by the presence of an abnormal gene, known as the Philadelphia chromosome.

In patients who are Philadelphia chromosome-positive, an abnormal chromosome is formed when pieces of chromosomes 9 and 22 switch with each other.

This forms a longer chromosome 9 and a shorter chromosome 22, which leads to the development of BCR-ABL1 and is associated with Ph+ ALL.


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