Updated ICLUSIG Label will Prove Practice-Changing, Expanding Indication to CP-CML Patients with Resistance or Intolerance to At Least Two Prior Tyrosine Kinase Inhibitors (TKIs) –

­– Approval Based on Data from the Phase 2 OPTIC Trial, Which Evaluated Response-Based ICLUSIG Dosing Regimens in CP-CML

New Dosing Regimen in CP-CML Optimizes Benefit-Risk Profile, Providing Efficacy and Improving Safety

CAMBRIDGE, MA, USA & OSAKA, Japan I December 18, 2020 I Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) today announced that the U.S. Food and Drug Administration (FDA) has approved the supplemental New Drug Application (sNDA) for ICLUSIG® (ponatinib) for adult patients with chronic-phase (CP) chronic myeloid leukemia (CML) with resistance or intolerance to at least two prior kinase inhibitors. 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 (AEs), including arterial occlusive events (AOEs).

“The FDA’s approval of this sNDA is a major milestone for the CML community. Though chronic-phase CML is often manageable, many patients still experience poor long-term outcomes and could benefit from a third-generation TKI earlier in their treatment journey,” said Teresa Bitetti, President, Global Oncology, Takeda. “ICLUSIG is proven to be effective for many patients with resistant disease, and its use at the critical moment can lead to meaningful outcomes for these patients. We are excited about this updated label and believe it will help address gaps in care for patients with resistant or intolerant chronic-phase CML by optimizing treatment with ICLUSIG.”

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 (65%) did not achieve a response greater than complete hematological response (CHR) 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.

“CML can be difficult to treat, particularly when patients have experienced resistance or intolerance to two or more TKIs. The revised indication allows physicians to consider ICLUSIG earlier in a course of treatment for chronic-phase CML patients, when it might provide the potential for the greatest benefit,” said Jorge Cortes, MD, Director of the Georgia Cancer Center. “As evidenced by the updated label, response-based dosing of ICLUSIG may allow patients to achieve the desired benefit that we know ICLUSIG can provide while reducing the risk for arterial occlusive events, a concern of physicians and, therefore, an important aspect of chronic-phase CML management.”

Data from the OPTIC and PACE studies were presented virtually at the 56th American Society of Clinical Oncology (ASCO) Annual Meeting, the 25th European Hematology Association (EHA) Annual Meeting and the 62nd American Society of Hematology (ASH) Annual Meeting.

About the OPTIC Trial

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 (CP) chronic myeloid leukemia (CML) 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 (>20%) Grade 3 or 4 laboratory abnormalities were platelet count decreased and neutrophil cell count decreased.

About the PACE Trial

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 (MCyR) 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 (>20%) 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.

About CML and Ph+ ALL

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 U.S. and is characterized by the presence of an abnormal gene, known as the Philadelphia chromosome. In patients who are Philadelphia chromosome-positive (Ph+), 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.

About ICLUSIG® (ponatinib) tablets

ICLUSIG is a kinase inhibitor targeting BCR-ABL1, an abnormal tyrosine kinase that is expressed in CML and Ph+ ALL. ICLUSIG is a targeted cancer medicine developed using a computational and structure-based drug-design platform, specifically designed to inhibit the activity of BCR-ABL1 and its mutations. ICLUSIG inhibits native BCR-ABL1, as well as all BCR-ABL1 treatment-resistant mutations, including the most resistant T315I mutation. ICLUSIG is the only approved TKI that demonstrates activity against the T315I gatekeeper mutation of BCR-ABL1. This mutation has been associated with resistance to all other approved TKIs. ICLUSIG received full approval from the FDA in November 2016. ICLUSIG is indicated for the treatment of adult patients with chronic-phase (CP) CML with resistance or intolerance to at least two prior kinase inhibitors, accelerated-phase (AP) or blast-phase (BP) CML or Ph+ ALL for whom no other kinase inhibitor is indicated, and T315I-positive CML (CP, AP or BP) or T315I+ Ph+ ALL. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.

Takeda’s Commitment to Oncology

Our core R&D mission is to deliver novel medicines to patients with cancer worldwide through our commitment to science, breakthrough innovation and passion for improving the lives of patients. Whether it’s with our hematology therapies, our robust pipeline, or solid tumor medicines, we aim to stay both innovative and competitive to bring patients the treatments they need. For more information, visit www.takedaoncology.com.

About Takeda Pharmaceutical Company Limited

Takeda Pharmaceutical Company Limited (TSE: 4502/NYSE: TAK) is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to discover and deliver life-transforming treatments, guided by our commitment to patients, our people and the planet. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Rare Genetic and Hematology, Neuroscience, and Gastroenterology (GI). We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people’s lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries. For more information, visit https://www.takeda.com.

SOURCE: Takeda Pharmaceutical Co