On June 13, 2016 Acetylon Pharmaceuticals, Inc., the leader in the development of selective histone deacetylase (HDAC) inhibitors for enhanced therapeutic outcomes, reported that it presented data from multiple clinical trials evaluating the safety and efficacy of two selective HDAC6 inhibitors in combination with pomalidomide (Pom) (Pomalyst, Celgene) and dexamethasone (Dex) for the treatment of relapsed or relapsed-and-refractory multiple myeloma (RRMM) at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Copenhagen, Denmark (Press release, Acetylon, JUN 13, 2016, View Source [SID:1234513281]).

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Positive results from a Phase 2 clinical trial of ricolinostat were presented in an oral presentation by Noopur Raje, M.D. of Massachusetts General Hospital in Boston, Massachusetts. In addition, results of a Phase 1b clinical trial of an alternative liquid formulation of ricolinostat were presented in a poster presentation by Sumit Madan, M.D. of University of Texas Southwestern Medical Center. Early favorable results from a Phase 1a/1b clinical trial of ACY-241, a selective HDAC6 inhibitor administered in tablet form, were also presented as an e-poster.

“The data from these studies demonstrate that selective HDAC6 inhibition combines favorably with Pom and Dex, and support the continued clinical development of our selective HDAC6 inhibitors for the treatment of relapsed or relapsed-and-refractory multiple myeloma,” said Catherine Wheeler, SVP Clinical Development & CMO of Acetylon. “The results of the Phase 2 ACE-MM-102 trial have established proof of concept for selective HDAC6 inhibition and demonstrated that the addition of ricolinostat to Pom/Dex treatment increases response rate and progression-free survival compared to Pom/Dex alone in relapsed-and-refractory MM. We believe that this approach has the potential to become a powerful treatment option for patients with multiple myeloma without the severe side effects commonly seen with pan-HDAC inhibition. We are further encouraged by early results with ACY-241 in a similar patient population that it will deliver the same efficacy and safety as ricolinostat, however in a tablet form.”

Phase 2 ACE-MM-102 Data

The ACE-MM-102 clinical trial is a multicenter, single arm, open-label Phase 2 study designed to evaluate the safety and efficacy of ricolinostat administered at an optimal dose and schedule in combination with Pom and Dex in patients with RRMM. Results of this study indicated that treatment with ricolinostat in combination with Pom and Dex was very well tolerated, and toxicities were predominantly low grade. Pharmacokinetic and pharmacodynamic analysis demonstrated selective inhibition of HDAC6 at therapeutic doses. Analysis of 67 efficacy-evaluable patients enrolled at least 6 months prior to the data cut confirmed an overall response rate (ORR) of 46%, a clinical benefit rate (CBR) of 58%, a disease control rate (DCR) of 82%, 9 months duration of response (DOR), and 7 months progression free survival (PFS). These data compare favorably to mature historical data for the MM-002 and MM-003 trials of Pom and Dex alone which demonstrated 31-33% ORR, 7-8 months DOR, and 4 months median PFS. More mature data on the entire 96 patient study population will be available by the end of the year.

Phase 1b ACE-MM-104 Data

The Phase 1b ACE-MM-104 clinical trial is a dose-escalation study of an alternative liquid formulation (ALF) of ricolinostat in combination with Pom and Dex in patients with RRMM. Daily dosing (QD) was better tolerated than twice-daily dosing. One dose-limiting toxicity (DLT), neutropenia, was observed at 180 mg QD, and cohort expansion to 6 patients showed no further DLTs. Pharmacokinetic and pharmacodynamic analysis demonstrated selective inhibition of HDAC6 at therapeutic doses, with no evidence of ricolinostat accumulation or drug-drug interaction with Pom. Early efficacy data indicates a confirmed ORR of 53% and a DCR of 87% after 6 months median follow-up. These results demonstrate that the alternative liquid formulation of ricolinostat is well tolerated in combination with Pom and Dex at doses up to 180 mg QD without major toxicities. This formulation of ricolinostat is also being used in ongoing investigator-sponsored studies in combination with paclitaxel and abraxane to treat solid tumors.

Preliminary Phase 1a/1b ACE-MM-200 Data

The Phase 1a/1b ACE-MM-200 clinical trial utilizes a sequential monotherapy/combination trial design to establish the safety, pharmacokinetics, and pharmacodynamics of ACY-241 as both a monotherapy and in combination with Pom and Dex in patients with relapsed or relapsed-and-refractory MM. ACY-241 is an orally available selective HDAC6 inhibitor that is structurally similar to ricolinostat and administered in tablet form. Results of the study demonstrated that ACY-241 is well tolerated as a monotherapy and in combination with Pom and Dex, and toxicities did not differ substantially in frequency or severity from those reported with Pom and Dex alone. Pharmacokinetic and pharmacodynamic analysis indicated dose-linear increases in exposure and dose-dependent, selective increases in acetylated tubulin and histones. ACY-241 achieved exposures several fold higher than ricolinostat without severe toxicity, both alone and in combination with Pom and Dex. Early efficacy data for combination treatment indicates a confirmed ORR of 50% and a DCR of 95% after 3.5 months median follow-up. These results indicate that ACY-241 is well tolerated in combination with Pom and Dex, and early response data for combination treatment even with short follow-up are similar to those of ricolinostat in combination with Pom and Dex. Cohort expansion at biologically relevant combination doses is ongoing.

About HDAC6 Inhibition

Ricolinostat (ACY-1215) and ACY-241 selectively inhibit the intracellular enzyme HDAC6, which leads to an accumulation of excess protein and in addition may disrupt critical proliferative signals in malignant cells. Disruption of these molecular processes in cancer cells triggers programmed cell death, called “apoptosis,” with little or no effect on normal cells. Currently available HDAC drugs also affect the expression of numerous other genes in normal cells as well as cancer cells, which can result in side effects such as gastrointestinal dysfunction, lowered blood platelet levels and risk of hemorrhage and profound fatigue as well as potential for significant cardiac toxicity. Selective inhibition of HDAC6 is expected to reduce or eliminate these often-severe side effects associated with non-selective HDAC inhibition and to enable the development of optimized treatment regimens, including maximally effective combination drug therapies.

On June 13, 2016 Acetylon Pharmaceuticals, Inc., the leader in the development of selective histone deacetylase (HDAC) inhibitors for enhanced therapeutic outcomes, reported that it presented data from multiple clinical trials evaluating the safety and efficacy of two selective HDAC6 inhibitors in combination with pomalidomide (Pom) (Pomalyst, Celgene) and dexamethasone (Dex) for the treatment of relapsed or relapsed-and-refractory multiple myeloma (RRMM) at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Copenhagen, Denmark (Press release, Acetylon, JUN 13, 2016, View Source [SID:1234513281]).

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Positive results from a Phase 2 clinical trial of ricolinostat were presented in an oral presentation by Noopur Raje, M.D. of Massachusetts General Hospital in Boston, Massachusetts. In addition, results of a Phase 1b clinical trial of an alternative liquid formulation of ricolinostat were presented in a poster presentation by Sumit Madan, M.D. of University of Texas Southwestern Medical Center. Early favorable results from a Phase 1a/1b clinical trial of ACY-241, a selective HDAC6 inhibitor administered in tablet form, were also presented as an e-poster.

"The data from these studies demonstrate that selective HDAC6 inhibition combines favorably with Pom and Dex, and support the continued clinical development of our selective HDAC6 inhibitors for the treatment of relapsed or relapsed-and-refractory multiple myeloma," said Catherine Wheeler, SVP Clinical Development & CMO of Acetylon. "The results of the Phase 2 ACE-MM-102 trial have established proof of concept for selective HDAC6 inhibition and demonstrated that the addition of ricolinostat to Pom/Dex treatment increases response rate and progression-free survival compared to Pom/Dex alone in relapsed-and-refractory MM. We believe that this approach has the potential to become a powerful treatment option for patients with multiple myeloma without the severe side effects commonly seen with pan-HDAC inhibition. We are further encouraged by early results with ACY-241 in a similar patient population that it will deliver the same efficacy and safety as ricolinostat, however in a tablet form."

Phase 2 ACE-MM-102 Data

The ACE-MM-102 clinical trial is a multicenter, single arm, open-label Phase 2 study designed to evaluate the safety and efficacy of ricolinostat administered at an optimal dose and schedule in combination with Pom and Dex in patients with RRMM. Results of this study indicated that treatment with ricolinostat in combination with Pom and Dex was very well tolerated, and toxicities were predominantly low grade. Pharmacokinetic and pharmacodynamic analysis demonstrated selective inhibition of HDAC6 at therapeutic doses. Analysis of 67 efficacy-evaluable patients enrolled at least 6 months prior to the data cut confirmed an overall response rate (ORR) of 46%, a clinical benefit rate (CBR) of 58%, a disease control rate (DCR) of 82%, 9 months duration of response (DOR), and 7 months progression free survival (PFS). These data compare favorably to mature historical data for the MM-002 and MM-003 trials of Pom and Dex alone which demonstrated 31-33% ORR, 7-8 months DOR, and 4 months median PFS. More mature data on the entire 96 patient study population will be available by the end of the year.

Phase 1b ACE-MM-104 Data

The Phase 1b ACE-MM-104 clinical trial is a dose-escalation study of an alternative liquid formulation (ALF) of ricolinostat in combination with Pom and Dex in patients with RRMM. Daily dosing (QD) was better tolerated than twice-daily dosing. One dose-limiting toxicity (DLT), neutropenia, was observed at 180 mg QD, and cohort expansion to 6 patients showed no further DLTs. Pharmacokinetic and pharmacodynamic analysis demonstrated selective inhibition of HDAC6 at therapeutic doses, with no evidence of ricolinostat accumulation or drug-drug interaction with Pom. Early efficacy data indicates a confirmed ORR of 53% and a DCR of 87% after 6 months median follow-up. These results demonstrate that the alternative liquid formulation of ricolinostat is well tolerated in combination with Pom and Dex at doses up to 180 mg QD without major toxicities. This formulation of ricolinostat is also being used in ongoing investigator-sponsored studies in combination with paclitaxel and abraxane to treat solid tumors.

Preliminary Phase 1a/1b ACE-MM-200 Data

The Phase 1a/1b ACE-MM-200 clinical trial utilizes a sequential monotherapy/combination trial design to establish the safety, pharmacokinetics, and pharmacodynamics of ACY-241 as both a monotherapy and in combination with Pom and Dex in patients with relapsed or relapsed-and-refractory MM. ACY-241 is an orally available selective HDAC6 inhibitor that is structurally similar to ricolinostat and administered in tablet form. Results of the study demonstrated that ACY-241 is well tolerated as a monotherapy and in combination with Pom and Dex, and toxicities did not differ substantially in frequency or severity from those reported with Pom and Dex alone. Pharmacokinetic and pharmacodynamic analysis indicated dose-linear increases in exposure and dose-dependent, selective increases in acetylated tubulin and histones. ACY-241 achieved exposures several fold higher than ricolinostat without severe toxicity, both alone and in combination with Pom and Dex. Early efficacy data for combination treatment indicates a confirmed ORR of 50% and a DCR of 95% after 3.5 months median follow-up. These results indicate that ACY-241 is well tolerated in combination with Pom and Dex, and early response data for combination treatment even with short follow-up are similar to those of ricolinostat in combination with Pom and Dex. Cohort expansion at biologically relevant combination doses is ongoing.

About HDAC6 Inhibition

Ricolinostat (ACY-1215) and ACY-241 selectively inhibit the intracellular enzyme HDAC6, which leads to an accumulation of excess protein and in addition may disrupt critical proliferative signals in malignant cells. Disruption of these molecular processes in cancer cells triggers programmed cell death, called "apoptosis," with little or no effect on normal cells. Currently available HDAC drugs also affect the expression of numerous other genes in normal cells as well as cancer cells, which can result in side effects such as gastrointestinal dysfunction, lowered blood platelet levels and risk of hemorrhage and profound fatigue as well as potential for significant cardiac toxicity. Selective inhibition of HDAC6 is expected to reduce or eliminate these often-severe side effects associated with non-selective HDAC inhibition and to enable the development of optimized treatment regimens, including maximally effective combination drug therapies.

On June 13, 2016 Argos Therapeutics Inc. (Nasdaq:ARGS), an immuno-oncology company focused on the development and commercialization of truly individualized immunotherapies for the treatment of cancer based on the Arcelis technology platform, reported that the independent data monitoring committee (IDMC) for the Company’s pivotal Phase 3 ADAPT clinical trial of AGS-003 for the treatment of metastatic renal cell carcinoma (mRCC) has recommended the continuation of the trial based on results of the IDMC’s scheduled interim data review (Press release, Argos Therapeutics, JUN 13, 2016, View Source [SID:1234513245]). The next IDMC meeting is being planned to coincide with the Genitourinary Cancers Symposium in February 2017.

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"As the largest global Phase 3 trial ever performed in newly diagnosed, intermediate and poor risk mRCC patients, the ADAPT trial continues to progress," said Dr. Robert Figlin, the Steven Spielberg Family chair in hematology oncology, professor of medicine and biomedical sciences at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute and the co-principal investigator for the ADAPT trial. "With all the excitement regarding the clinical benefit of the emerging immuno-oncology therapies, a positive outcome of the ADAPT trial, because of AGS-003’s novel mechanism of action, could be a game changer in the treatment of mRCC."

AGS-003 is an individualized immunotherapy that captures both mutated and variant antigens that are unique to each patient’s tumor, and, therefore, specifically designed to induce an immune response targeting that patient’s particular tumor antigens. In an open-label Phase 2 trial, treatment with AGS-003 plus sunitinib resulted in median overall survival of more than 30 months in newly diagnosed, intermediate and poor risk mRCC patients. We have enrolled a total of 462 mRCC patients in our ongoing pivotal, randomized Phase 3 ADAPT trial evaluating AGS-003 in combination with standard targeted therapy, which has a primary endpoint of overall survival. AGS-003 is Argos’ most advanced Arcelis-based product candidate.

"The IDMC’s recommendation to continue with the ADAPT trial aligns with our expectations based on the patient population enrolled and the clinical benefit observed in the Phase 2 trial," said Lee F. Allen, MD, PhD, chief medical officer of Argos. "Based upon our internal projections, we believe that at this point we have reached more than half of the targeted number of events for our survival endpoint, and we anticipate having a sufficient number of events to permit the primary analysis and assessment of overall survival to occur in the first half of 2017. The focus of our clinical development group is now on the careful oversight of the ADAPT trial execution to ensure study data quality, and we have initiated cross functional activities to begin building the AGS-003 Biologics License Application (BLA)."

The positive outcome from the IDMC’s review of the ADAPT trial data triggers the second tranche of the financing under the Company’s previously announced March 2016 securities purchase agreement. Upon the closing of the second tranche, which is expected to occur within 30 days, the Company will receive a total of $29,824,520 from the sale of a total of 5,478,672 shares of common stock and warrants to purchase a total of 4,109,005 shares of common stock.

About the Arcelis Technology Platform
Arcelis is a precision immunotherapy technology that captures mutated and variant antigens that are specific to each patient’s disease. It is designed to overcome immunosuppression by producing a durable memory T-cell response without adjuvants that may be associated with toxicity. The technology is potentially applicable to a wide range of different cancers, and is designed to overcome many of the manufacturing and commercialization challenges that have impeded other personalized cancer immunotherapies. The Arcelis process uses only a small tumor or blood sample and the patient’s own dendritic cells, which are optimized from cells collected by a single leukapheresis procedure. The proprietary process uses RNA isolated from the patient’s disease sample to program dendritic cells to target disease-specific antigens. The activated, antigen-loaded dendritic cells are then formulated with the patient’s plasma and administered via intradermal injection.

On June 13, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ:ARIA) reported long-term follow-up data from its pivotal Phase 2 PACE clinical trial of Iclusig (ponatinib), its approved BCR-ABL inhibitor, in heavily pretreated patients with resistant or intolerant chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) (Press release, Ariad, JUN 13, 2016, View Source [SID:1234513239]). Responses have been maintained long-term in chronic phase CML (CP-CML) patients. The study shows that patients treated with Iclusig continued to demonstrate anti-leukemic activity with a median follow-up of 4.0 years for CP-CML. Additionally, 96 percent of CP-CML patients who underwent ponatinib dose reductions while in response maintained their responses (MCyR) at the four year timepoint.

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"We remain very pleased by these continued responses in the PACE study in such a heavily pretreated patient population, as 59 percent of patients had previously received three or more approved tyrosine kinase inhibitors (TKIs). Altogether, 82 percent of CP-CML patients who achieved MCyR are estimated to remain in MCyR at four years," stated Jorge E. Cortes, M.D., professor and deputy chair, department of leukemia, University of Texas MD Anderson Cancer Center. "These data showing long-term major cytogenic response offer the optimism of favorable outcomes for many patients who previously had no or very limited treatment options available."

The data were featured at the 21st Conference of the European Hematology Association (EHA) (Free EHA Whitepaper) in Copenhagen, Denmark.

PACE Trial Update

The efficacy and safety of ponatinib in CML and Ph+ ALL patients resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation, were evaluated in the PACE trial. A total of 449 patients were treated with ponatinib at a starting dose of 45 mg/day. An estimated 93 percent of patients received two or more approved tyrosine kinase inhibitors (TKIs), and 59 percent of all patients received three or more approved TKIs. Enrollment in the PACE trial was completed in October 2011.

Updated data on CP-CML patients (n=270) from the ongoing trial indicate that with a median follow-up of 48.2 months (data as of August 3, 2015), 110 patients (41%) continued to receive ponatinib. Additional data for CP-CML patients include:

59 percent of CP-CML patients achieved MCyR (primary endpoint) at any time.
82 percent of patients who achieved MCyR are estimated to remain in MCyR at four years by Kaplan-Meier analysis.
39 percent of patients achieved a major molecular response (MMR) or better at any time.
By Kaplan-Meier analysis, progression-free survival at four years is estimated to be 56 percent.
Overall survival at four years is estimated to be 77 percent.
23 percent of CP-CML patients experienced arterial occlusive events (AOE) that were designated a serious adverse event (SAE), and 29 percent of CP-CML patients experienced any AOE.
4 percent of CP-CML patients experienced a venous thromboembolic SAE, and 5 percent of all patients experienced a venous thromboembolic SAE.
The most common any-grade treatment-emergent adverse events occurring in ≥ 20 percent of CP-CML patients included abdominal pain (46%), rash (47%), thrombocytopenia (45%), headache (43%), constipation (41%), and dry skin (42%).
"These data continue to show that ongoing CP-CML patients in the PACE trial have retained long-term cytogenetic and molecular responses at a median of four years follow-up," stated Timothy P. Clackson, Ph.D., president of research and development and chief scientific officer at ARIAD. "We currently have two additional trials underway evaluating Iclusig. Our OPTIC randomized trial evaluating Iclusig at starting doses of 45 mg/day or lower, is currently enrolling patients. Outside the U.S., we initiated our randomized Phase 3 trial of Iclusig in second-line patients with CP-CML called OPTIC-2L in December of 2015 and expect full enrollment in the trial in 2018."

Efficacy Update Following Dose-Reduction Recommendations

(Data from October 10, 2013 to August 3, 2015)

On October 10, 2013, dose-reduction recommendations were provided by ARIAD to investigators for patients remaining on the PACE trial. The following dose reductions were recommended, unless the benefit-risk analysis warranted treatment with a higher dose:

CP-CML patients who already achieved a MCyR should have their ponatinib dose reduced to 15 mg/day,
CP-CML patients who had not already achieved MCyR should have their dose reduced to 30 mg/day, and
Advanced-phase patients should have their dose reduced to 30 mg/day.
As of August 3, 2015, with an additional 1.9 years (22 months) of follow up after these recommendations, maintenance of response (MCyR) in CP-CML patients was 95 percent (56 of 59) and 100 percent (25 patients), respectively, for patients who were either at 15 mg/day in October 2013 or were reduced to 15 mg/day after October 2013.

Of the 69 patients who were in MCyR as of October 10, 2013 and had a dose reduction, 66 patients (96%) maintained their response at 1.9 years following prospective dose reduction.
Of the 51 patients who were in MMR as of October 10, 2013 and had a dose reduction, 46 patients (90%) maintained MMR at 1.9 years following dose reduction.
35 patients in MCyR did not undergo any dose reductions (the majority of which were already at a reduced dose of 30 mg/day or 15 mg/day as of October 10, 2013); of these, 33 patients (94%) maintained MCyR after 1.9 more years of ponatinib treatment.
Safety Update Following Dose-Reduction Recommendations (Data from October 10, 2013 to August 3, 2015)

Of the patients who underwent dose reduction, six of 75 patients (8%) without prior AOEs had a new AOE during the 1.9-year interval following dose reduction.
31/75 patients reduced from 45 mg to 15 mg
25 /75 patients reduced from 30 mg to 15 mg
19/75 patients reduced either other doses (45 mg to 30 mg or not specified)
Of the patients who did not undergo dose reduction, 10 of 62 patients (16%) without prior AOE had a new AOE in the same time interval.
36 /62 patients were at 15 mg
26/62 were at 45 mg or 30 mg
About Iclusig (ponatinib) tablets

Iclusig is a kinase inhibitor. The primary target for Iclusig is BCR-ABL, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Iclusig was designed using ARIAD’s computational and structure-based drug-design platform specifically to inhibit the activity of BCR-ABL. Iclusig targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, which has been associated with resistance to other approved TKIs.

Iclusig is approved in the U.S., EU, Australia, Switzerland, Israel and Canada.

In the U.S., Iclusig is a kinase inhibitor indicated for the:

Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.

These indications are based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

Limitations of use: Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed chronic phase CML.

IMPORTANT SAFETY INFORMATION, INCLUDING THE BOXED WARNING

WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY

See full 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.
Vascular Occlusion: Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures have occurred in at least 27% of Iclusig-treated patients from the phase 1 and phase 2 trials. Iclusig can also cause recurrent or multi-site vascular occlusion. Overall, 20% of Iclusig-treated patients experienced an arterial occlusion and thrombosis event of any grade. Fatal and life-threatening vascular occlusion has occurred within 2 weeks of starting Iclusig treatment and in patients treated with average daily dose intensities as low as 15 mg per day. The median time to onset of the first vascular occlusion event was 5 months. Patients with and without cardiovascular risk factors have experienced vascular occlusion although these events were more frequent with increasing age and in patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia. Interrupt or stop Iclusig immediately in patients who develop vascular occlusion events.

Heart Failure: Fatal and serious heart failure or left ventricular dysfunction occurred in 5% of Iclusig treated patients (22/449). Eight percent of patients (35/449) experienced any grade of heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious heart failure.

Hepatotoxicity: Iclusig can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with blast phase CML (BP-CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Severe hepatotoxicity occurred in all disease cohorts. Iclusig treatment may result in elevation in ALT, AST, or both. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated.

Hypertension: Treatment-emergent hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion) occurred in 67% of patients (300/449). Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during Iclusig use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled. In the event of significant worsening, labile or treatment-resistant hypertension, interrupt treatment and consider evaluating for renal artery stenosis.

Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN.

Increased Toxicity in Newly Diagnosed Chronic Phase CML: In a prospective randomized clinical trial in the first line treatment of newly diagnosed patients with chronic phase (CP) CML, single agent Iclusig 45 mg once-daily increased the risk of serious adverse reactions 2-fold compared to singe agent imatinib 400 mg once-daily. The median exposure to treatment was less than 6 months. The trial was halted for safety in October 2013. Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the Iclusig arm compared to the imatinib arm. Compared to imatinib-treated patients, Iclusig-treated patients exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension and skin and subcutaneous tissue disorders. Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed CP CML.

Neuropathy: Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 13% (59/449) of Iclusig-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). In clinical trials, the most common peripheral neuropathies reported were peripheral neuropathy (4%, 18/449), paresthesia (4%, 17/449), hypoesthesia (2%, 11/449), and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 1% (6/449) of Iclusig-treated patients (<1% grade 3/4).

Of the patients who developed neuropathy, 31% (20/65) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting Iclusig and evaluate if neuropathy 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 U.S. Prescribing Information for Iclusig, including the Boxed Warning.