ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced that the U.S. Food and Drug Administration (FDA) has approved revised U.S. Prescribing Information (USPI) and a Risk Evaluation and Mitigation Strategy (REMS) for Iclusig ® (ponatinib) that allows immediate resumption of its marketing and commercial distribution. The USPI includes a revised indication statement and boxed warning, updated safety information and recommendations regarding dosing considerations for prescribers.
- T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia, and
- Chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia for whom no other tyrosine-kinase inhibitor therapy is indicated.
At the end of October 2013, there were approximately 640 patients receiving Iclusig obtained through commercial channels in the U.S. Since then, Iclusig has been made available through emergency and single-patient investigational new drug (IND) applications, which were reviewed and approved by the FDA on a case-by-case basis. Through today, FDA has approved 350 INDs. This figure includes approximately 260 patients who have already received Iclusig and approximately 90 additional patients who have been approved to receive Iclusig through these mechanisms.“We are committed to continuing our productive collaboration with the FDA and to helping patients and their physicians make informed decisions about the most appropriate use of Iclusig in the context of the revised product label,” stated Frank Haluska, M.D., Ph.D., senior vice president and chief medical officer of ARIAD. “Commercial distribution of Iclusig will begin by mid-January at which time we will deploy dedicated commercial and medical affairs teams in the U.S. In the meantime, patients will continue to receive Iclusig through the IND mechanism,” stated Marty Duvall, executive vice president and chief commercial officer. “We expect the commercialization of Iclusig to be cash-flow positive from the onset.” REMS Program and Post-Marketing Requirements The objective of the REMS program is to inform prescribers of the risk of vascular occlusion associated with Iclusig and of the revised indications. The REMS program, which will be initiated within three weeks, includes letters to physicians and professional societies, a fact sheet and information that will be communicated through professional journals and displayed at scientific meetings. All of these materials will be available on an Iclusig REMS website. In addition, ARIAD has agreed to fulfill a series of post-marketing requirements beginning in 2014 to better understand the risks of vascular occlusion and to further explore various doses of Iclusig, as follows:
- Enhanced pharmacovigilance assessment of risk factors for, and the management and consequences of, vascular occlusive events that are serious or require medical evaluation or treatment, occurring while patients are receiving Iclusig administered in clinical trials or obtained through commercial channels,
- Prospective observation of patients on Iclusig obtained through commercial channels to evaluate the incidence of, and risk factors for, vascular occlusive events when Iclusig is given with or without anticoagulant or antiplatelet agents,
- Continued follow-up of patients from the three ARIAD-sponsored trials of Iclusig in Philadelphia-positive leukemias to assess the long-term safety of Iclusig treatment, including the long-term risk of vascular occlusive events, and
- A randomized, multi-arm trial to characterize a range of Iclusig doses and to inform its safe use in patients with refractory, chronic-phase chronic myeloid leukemia.
IMPORTANT SAFETY INFORMATION, INCLUDING THE BOXED WARNINGWARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY See full U.S. prescribing information for complete boxed warning
- Vascular Occlusion: Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. A benefit risk consideration should guide a decision to restart Iclusig therapy.
- Heart Failure, including fatalities, occurred in 8% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure.
- Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected.
Ocular Toxicity: Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 3% of Iclusig-treated patients. Conjunctival or corneal irritation, dry eye, or eye pain occurred in 13% of patients. Visual blurring occurred in 6% of the patients. Other ocular toxicities include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment.Hemorrhage: Serious bleeding events, including fatalities, occurred in 5% (22/449) of patients treated with Iclusig. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with accelerated phase CML (AP-CML), BP-CML, and Ph+ ALL. Most hemorrhagic events, but not all occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage and evaluate. Fluid Retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated. Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 1% (3/449) of Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 5% (25/449) of Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness). Interrupt Iclusig and evaluate. Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended. Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig. Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy. Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during pregnancy, or if the patient becomes pregnant while taking Iclusig, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig. Most common non-hematologic adverse reactions: (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia. Please see the full Prescribing Information for Iclusig, including the Boxed Warning, for additional important safety information. About ARIAD ARIAD Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts and Lausanne, Switzerland, is an integrated global oncology company focused on transforming the lives of cancer patients with breakthrough medicines. ARIAD is working on new medicines to advance the treatment of various forms of chronic and acute leukemia, lung cancer and other difficult-to-treat cancers. ARIAD utilizes computational and structural approaches to design small-molecule drugs that overcome resistance to existing cancer medicines. For additional information, visit http://www.ariad.com or follow ARIAD on Twitter ( @ARIADPharm). This press release contains “forward-looking statements” including, but not limited to, the timing and financial success of the resumption of commercial marketing and sales of Iclusig; the Company's ability to fulfill the four post-marketing requirements to the satisfaction of the FDA; the timing and results of the enhanced pharmacovigilance study, the prospective observational study and the long-term follow-up of subjects in Iclusig clinical studies; the timing, enrollment and results of the randomized, multi-arm trial to characterize a range of Iclusig doses; and the safety profile for Iclusig as it continues to be studied. Forward-looking statements are based on management's expectations and are subject to certain factors, risks and uncertainties that may cause actual results, outcome of events, timing and performance to differ materially from those expressed or implied by such statements. These risks and uncertainties include, but are not limited to, preclinical data and early-stage clinical data that may not be replicated in later-stage clinical studies, the costs associated with our research, development, manufacturing and other activities, the conduct, timing and results of pre-clinical and clinical studies of our product candidates, the adequacy of our capital resources and the availability of additional funding, and other factors detailed in the Company's public filings with the U.S. Securities and Exchange Commission. The information contained in this press release is believed to be current as of the date of original issue. The Company does not intend to update any of the forward-looking statements after the date of this document to conform these statements to actual results or to changes in the Company's expectations, except as required by law.