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FDA Drug Safety Communication: FDA asks manufacturer of the leukemia drug Iclusig (ponatinib) to suspend marketing and sales

This update is in follow-up to the FDA Drug Safety Communication: FDA investigating leukemia drug Iclusig (ponatinib) after increased reports of serious blood clots in arteries and veins issued on October 11, 2013.

Safety Announcement
[31st October 2013]

The U.S. Food and Drug Administration (FDA) has asked the manufacturer of the leukemia chemotherapy drug Iclusig (ponatinib) to suspend marketing and sales of Iclusig because of the risk of life-threatening blood clots and severe narrowing of blood vessels. We will continue to evaluate the drug to further understand its risks and potential patient populations in which the benefits of the drug may outweigh the risks. Patients currently receiving Iclusig should discuss with their health care professionals the risks and benefits of continuing treatment with the drug.

The drug manufacturer, Ariad Pharmaceuticals, has agreed to FDA’s request to suspend marketing and sales of Iclusig while we continue to evaluate the safety of the drug. At this time, patients and health care professionals should follow FDA’s new recommendations for the drug:

Patients currently taking Iclusig who are not responding to the drug should immediately discontinue treatment and discuss alternative treatment options with their health care professionals. more

Clinical pharmacokinetics of tyrosine kinase inhibitors: implications for therapeutic drug monitoring.

Josephs DH, Fisher DS, Spicer J, Flanagan RJ.

*Department of Medical Oncology, Guy's and St Thomas' Hospital NHS Foundation Trust, London, United Kingdom; and †Toxicology Unit, Department of Clinical Biochemistry, Bessemer Wing, King's College Hospital NHS Foundation Trust, London, United Kingdom.
Abstract more

ARIAD Announces Discontinuation of the Phase 3 Epic Trial of Iclusig in Patients with Newly Diagnosed Chronic Myeloid Leukemia

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Oct. 18, 2013-- ARIAD Pharmaceuticals, Inc. (NASDAQ:ARIA) today announced that it is discontinuing the Phase 3 EPIC (Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia) trial of Iclusig® (ponatinib) in patients with newly diagnosed chronic myeloid leukemia. ARIAD and the U.S. Food and Drug Administration mutually agreed that the trial should be terminated because arterial thrombotic events were observed in patients treated with Iclusig. This decision was made in the interest of patient safety based on a recent assessment of data in the clinical trial.

“Our decision to stop the EPIC trial at this time is based on our current evaluation of the safety data in the trial since it was placed on partial clinical hold last week,”stated Timothy P. Clackson, Ph.D., president of research and development and chief scientific officer at ARIAD. "We believe that this is in the best interests of patient safety and the overall development of Iclusig.”

Patients in the EPIC trial are being removed from treatment and will be transferred to the care of their physician. ARIAD announced in early September that fifty percent of patients, or approximately 264 patients, had been enrolled in the EPIC trial by that time. Final enrollment is 307 patients. more

Iclusig (Ponatinib): FDA Drug Safety Communication

Iclusig (Ponatinib): Drug Safety Communication - Increased Reports Of Serious Blood Clots In Arteries And Veins
[Posted 10/11/2013]

AUDIENCE: Health Professional, Oncology

ISSUE: FDA is investigating an increasing frequency of reports of serious and life-threatening blood clots and severe narrowing of blood vessels (arteries and veins) of patients taking the leukemia chemotherapy drug Iclusig (ponatinib). Data from clinical trials and postmarket adverse event reports show that serious adverse events have occurred in patients treated with Iclusig, including heart attacks resulting in death, worsening coronary artery disease, stroke, narrowing of large arteries of the brain, severe narrowing of blood vessels in the extremities, and the need for urgent surgical procedures to restore blood flow. FDA is actively working to further evaluate these adverse events and will notify the public when more information is available.

ARIAD Announces Changes in the Clinical Development Program of Iclusig

ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced results of its review of updated clinical data from the pivotal PACE trial of Iclusig® (ponatinib) and actions that it is taking following consultations with the U.S. Food and Drug Administration (FDA).

With a median follow up of 24 months, serious arterial thrombosis occurred in 11.8% of Iclusig-treated patients: cardiovascular events 6.2%, cerebrovascular events 4.0% and peripheral vascular events 3.6% (some patients had more than one type of event).

This compares to 8.0% after 11 months of follow up reflected in the current U.S. prescribing information.

At 24 months, serious venous occlusion occurred in 2.9% of Iclusig-treated patients, compared to 2.2% in the current U.S. prescribing information.

The incidence rate of the arterial thrombotic events when normalized to duration of treatment exposure has not increased (10.0 events/100 patient-years in the original analysis and 9.6 events/100 patient-years in the current analysis).

Non-serious and serious arterial and venous adverse events combined occurred in approximately 20% of Iclusig-treated patients.

The Company is implementing the following actions in its Iclusig clinical development program:


Ariad's Nasty Surprise Gives The Sellside Pause For Thought
Oct 9 2013, 15:35

"............Yesterday Ariad's market cap had stood at a remarkable $3.1bn, basically on the strength of Iclusig. The drug, a BCR-ABL tyrosine kinase inhibitor, had been approved last December for chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia in patients who have failed on an earlier tyrosine kinase inhibitor. more

Treatment of Chronic Myeloid Leukemia: Frontline Therapy

Treatment of chronic myeloid leukemia (CML) has evolved considerably in recent years. Chemotherapy with hydroxyurea and busulfan were the main options for many years, and although these agents can control hematologic manifestations of CML, they rarely if ever induce the cytogenetic responses required to change the natural history of the disease. [Interferon] then became the standard therapy for most patients because of its ability to induce cytogenetic responses in 40% to 60% of patients, including 5% to 30% with a complete cytogenetic response.

Treatment with [interferon] was associated with significant toxicity, but many responses were durable, and some patients have been cured with [interferon] alone.[Kantarjian 2003a] Allogeneic stem cell transplantation can induce long-term remissions in many patients eligible for this procedure, although with risks including death and chronic complications such as chronic graft-vs-host disease.

The reported 20-year event-free survival for patients transplanted in chronic phase was 40% to 45%.[Robin 2005] Stem cell transplantation is generally now considered a second- or third-line option. The current standard first-line therapy for CML in the chronic phase is with a tyrosine kinase inhibitor.

Current guidelines recommend imatinib, dasatinib, or nilotinib as the choice of first-line therapy for newly diagnosed chronic phase CML (Management Guidelines).[NCCN] However, the guidelines state that preliminary data suggest patients with an intermediate- or high-risk score may benefit from treatment with dasatinib or nilotinib vs imatinib.

Cleavage of BCR–ABL transcripts at the T315I point mutation by DNAzyme promotes cell death in imatinib-resistant BCR–ABL cells

J E Kim1,7, S Yoon1,7, B-R Choi1, K P Kim2, Y-H Cho3, W Jung4, D-W Kim5, S Oh6 and D-E Kim1

The BCR–ABL fusion transcript encodes the BCR–ABL tyrosine kinase (TK), which causes chronic myelogenous leukemia (CML). Although the TK inhibitor imatinib mesylate, which targets the BCR–ABL protein, has been proven to be effective in controlling leukemic growth, imatinib resistance has been observed with disease relapse because of point mutations in the ABL gene that inhibit imatinib efficacy. In this study, we designed oligodeoxyribozymes (DNAzymes) that specifically target and cleave both the junction sequence and the site of the point mutation (T315I), conferring imatinib resistance in BCR–ABL mRNA. DNAzymes significantly induced apoptosis and inhibited proliferation in wild-type and T315I-mutant BCR–ABL-positive cells. Selective cleavage of T315I-mutant ABL mRNA by DNAzyme (T315I Dz) led to cell cycle arrest in G0/G1 phase, with induction of caspase-3/-7 in imatinib-resistant BCR–ABL-positive cells harboring the T315I mutation. Moreover, cotreatment with the DNAzyme targeting the T315I mutation and imatinib resulted in enhanced inhibition of proliferation and induction of apoptosis in T315I leukemic cells as compared with imatinib alone, thereby antagonizing imatinib resistance in CML cells bearing T315I-mutant BCR–ABL. Therefore, cleavage of T315I-mutant ABL mRNA by DNAzyme combined with imatinib treatment may be an alternative approach to overcoming imatinib resistance in leukemic cells.

Full text:

Emerging Therapeutic Strategies for Targeting Chronic Myeloid Leukemia Stem Cells

Ahmad Hamad, Zeyad Sahli, Maya El Sabban, Maha Mouteirik, and Rihab Nasr
Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon

13 June 2013


Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder. Current targeted therapies designed to inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein have made a significant breakthrough in the treatment of CML patients. However, CML remains a chronic disease that a patient must manage for life. Although tyrosine kinase inhibitors (TKI) therapy has completely transformed the prognosis of CML, it has made the therapeutic management more complex. The interruption of TKI treatment results in early disease progression because it does not eliminate quiescent CML stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML to achieve a permanent cure, and to allow TKI interruption. This review summarizes recent research done on alternative targeted therapies with a particular focus on some important signaling pathways (such as Alox5, Hedgehog, Wnt/b-catenin, autophagy, and PML) that have the potential to target CML stem cells and potentially provide cure for CML.

Imatinib Discontinuation in Chronic Phase CML Doesn’t Always Lead to Relapse

By Dave Levitan
June 14, 2013

Almost half of patients with chronic-phase chronic myeloid leukemia (CML) who discontinued imatinib(Drug information on imatinib) treatment did not relapse, according to results of a prospective study. Those who did relapse showed continued sensitivity to imatinib when treatment started again.

full article here:

State of CML Treatments

By Michael Mauro, MD1, Jerald Radich, MD2
July 25, 2013

1Memorial Sloan-Kettering Cancer Center, New York
2Fred Hutchinson Cancer Research Center, Seattle

Interviewed by Anna Azvolinsky, PhD

Chronic myeloid leukemia (CML) is now seen as a classic example of a malignancy driven by a mutation, the BCR-ABL fusion gene on the Philadelphia chromosome. This fusion gene produces a continuously active tyrosine kinase that is thought to drive CML. The first small molecule inhibitor against BCR-ABL approved by the US Food and Drug Administration (FDA) was imatinib(Drug information on imatinib), or Gleevec. There are now several newer BCR-ABL inhibitors that can treat CML patients resistant to this earlier targeted therapy. Today, we are speaking with Michael Mauro, MD, of the Memorial Sloan-Kettering Cancer Center in New York and formerly of the Knight Cancer Institute in Portland, Oregon, and Dr. Jerald Radich, of the Fred Hutchinson Cancer Research Center in Seattle.
Both Dr. Mauro and Dr. Radich are involved in clinical research into the genetics of CML and how to optimize care for these patients with CML.

CANCER NETWORK: Dr. Mauro, can you give a brief overview of how Philadelphia chromosome–associated CML typically develops and how imatinib changed the course of the disease?....................

read full article here:

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