CAMBRIDGE, Mass. & SAN DIEGO–(BUSINESS WIRE)–ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today appear the after-effects of analytic and translational studies on Iclusig® (ponatinib), its accustomed BCR-ABL inhibitor, in heavily pretreated patients with aggressive or antipathetic abiding myeloid leukemia (CML) or Philadelphia chromosome-positive astute lymphoblastic leukemia (Ph ALL). These abstracts were featured in an articulate and two affiche presentations at the 57th Annual Meeting of the American Society of Hematology (ASH) demography abode in San Diego.
“The abstracts presented at ASH accommodate the final address from the Appearance 1 balloon of ponatinib, with best aftereffect of added than 7.5 years and average aftereffect aing bristles years that accustomed advancing cytogenetic and atomic responses. A abstracted abstraction of CP-CML patients with the T315I alteration accustomed a 72 percent anticipation of all-embracing adaptation at 4.5 years amid these patients who, above-mentioned to ponatinib, had no accustomed targeted assay options and had a average adaptation of beneath than two years,” declared Timothy P. Clackson, Ph.D., admiral of assay and development and arch accurate administrator at ARIAD. “In addition, an articulate presentation on studies in Ph ALL patients provides important new abstracts on the atomic base for Iclusig’s activity in these patients.”
Ponatinib in Chronic-Phase Abiding Myeloid Leukemia Patients: Final Address from a Appearance 1 Balloon (Poster, Abstract #92516)
The Appearance 1 dose-escalation abstraction of ponatinib (starting dosage range: 2 to 60 mg already daily) enrolled 81 patients with aggressive or adverse hematologic cancers, including 43 patients with chronic-phase CML (CP-CML). Sixty percent of CP-CML patients in this abstraction had bootless at atomic three above-mentioned tyrosine kinase inhibitors (TKIs), and 98 percent accustomed at atomic two above-mentioned TKIs. Abstracts presented at ASH focus on CP-CML patients and represent the longest aftereffect of ponatinib patients to-date, through the abortion of the study. Abstracts are as of October 18, 2016 and include:
Long-Term Aftereffect of the Adeptness and Assurance of Ponatinib in Philadelphia Chromosome-Positive Leukemia Patients with the T315I Alteration (Poster, Abstract #93206)
The assay describes the affiliated adeptness and assurance of ponatinib in patients with a T315I alteration detected at baseline from final address of the Appearance 1 dose-escalation abstraction and the four-year average aftereffect of the Appearance 2 PACE trial. The assay includes 76 CP-CML patients with T315I from the Appearance 1 balloon (n=12) and the PACE balloon (n=64). In this analysis, 26 (34%) patients remained on the study, as the Appearance 1 abstraction is no best ongoing. Abstracts presented on these patients are as of October 18, 2016 for the Appearance 1 balloon and August 3, 2015 for the PACE trial. Key abstracts include:
Assay of the Sub-Clonal Origins of Admixture Mutations in Patients with Adverse Ph Malignancies Advised with Ponatinib (Oral Presentation, Abstract #93238)
In adjustment to assay the sub-clonal origins of admixture mutations, this abstraction profiled abeyant admixture mutational mechanisms application samples from CP-CML and Ph ALL patients in the PACE trial. Utilizing a multi-level sequencing activity that accumulated Sanger Sequencing (SS), Next Generation Sequencing (NGS), and distinct atom Duplex Sequencing (DS), which is added astute than NGS, this abstraction activated alteration burdens and accommodating specific analytic abstracts to adumbrate the admeasurement of above-mentioned mutations. Key abstracts include:
About Iclusig® (ponatinib) tabletsIclusig is a kinase inhibitor. The primary ambition for Iclusig is BCR-ABL, an aberrant tyrosine kinase that is bidding in abiding myeloid leukemia (CML) and Philadelphia-chromosome absolute astute lymphoblastic leukemia (Ph ALL). Iclusig was advised application ARIAD’s computational and structure-based drug-design belvedere accurately to arrest the activity of BCR-ABL. Iclusig targets not alone built-in BCR-ABL but additionally its isoforms that backpack mutations that advise attrition to treatment, including the T315I mutation, which has been associated with attrition to added accustomed TKIs. Iclusig is accustomed in the U.S., EU, Australia, Switzerland, Israel, Canada and Japan.
In the U.S., Iclusig is a kinase inhibitor adumbrated for the:
Limitations of use:
Iclusig is not adumbrated and is not recommended for the assay of patients with anew diagnosed abiding appearance CML.
IMPORTANT SAFETY INFORMATIONBased on the Appearance 2 48 mo. aftereffect assay (N=449), except area acclaimed
IMPORTANT U.S. SAFETY INFORMATION, INCLUDING THE BOXED WARNINGWARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY
See abounding prescribing advice for complete boxed warning.
Warnings and Precautions
Arterial Occlusions: Arterial occlusions, including baleful myocardial infarction, stroke, binding of ample arterial argosy of the brain, astringent borderline vascular ache accept occurred in at atomic 35% of Iclusig-treated patients from the appearance 1 and appearance 2 trials. In the appearance 2 trial, 33% (150/449) of Iclusig-treated patients accomplished a cardiac vascular (21%), borderline vascular (12%), or cerebrovascular (9%) arterial occlusive event; some patients accomplished added than 1 blazon of event. Baleful and life-threatening contest accept occurred aural 2 weeks of starting treatment, with doses as low as 15 mg per day. Iclusig can additionally account alternate or multi-site vascular occlusion. Patients accept appropriate revascularization procedures. The average time to access of the aboriginal cardiac vascular, cerebrovascular, and borderline vascular arterial occlusive contest was 193, 526, and 478 days, respectively. Patients with and afterwards cardiovascular accident factors, some age 50 years or younger, accomplished these events. The best accepted accident factors empiric with these contest were hypertension, hyperlipidemia, and history of cardiac disease. Arterial occlusive contest were added accepted with accretion age and in patients with a history of ischemia, hypertension, diabetes, or hyperlipidemia. In patients doubtable of developing arterial occlusive events, arrest or stop Iclusig.
Venous Thromboemism: Venous thromboemic contest occurred in 6% (25/449) of Iclusig-treated patients with an accident amount of 5% (13/270 CP-CML), 4% (3/85 AP-CML), 10% (6/62 BP-CML) and 9% (3/32 Ph ALL). Contest included: abysmal venous thrombosis, pulmonary emism, apparent thrombophlebitis, and retinal attitude occlusion with eyes loss. Accede dosage modification or cessation of Iclusig in patients who beforehand austere venous thromboemism.
Affection Failure: Baleful or austere affection abortion or larboard ventricular dysfunction occurred in 6% of Iclusig-treated patients (29/449). Nine percent of patients (39/449) accomplished any brand of affection abortion or larboard ventricular dysfunction. The best frequently appear affection abortion contest were congestive cardiac abortion and decreased casting atom (14 patients each; 3%). Monitor patients for signs or affection constant with affection abortion and amusement as clinically indicated, including abeyance of Iclusig. Accede cessation if austere affection abortion develops.
Hepatotoxicity: Iclusig can account hepatotoxicity, including alarmist abortion and death. Fulminant hepatic abortion arch to afterlife occurred in a accommodating aural one anniversary of starting Iclusig. Two added baleful cases of astute alarmist abortion additionally occurred. The baleful cases occurred in patients with BP-CML or Ph ALL. Astringent hepatotoxicity occurred in all ache cohorts, with 11% (50/449) experiencing brand 3 or 4 hepatotoxicity. The best accepted forms of hepatotoxicity were elevations of AST or ALT (54% all grades, 8% brand 3 or 4, 5% not antipodal at aftermost follow-up), bilirubin, and acrid phosphatase. Hepatotoxic contest were empiric in 29% of patients. The average time to access of hepatotoxicity accident was 3 months. Monitor alarmist activity tests at baseline, again at atomic account or as clinically indicated. Interrupt, abate or abandon Iclusig as clinically indicated.
Hypertension: Treatment-emergent acclivity of systolic or diastolic claret burden (BP) occurred in 68% (306/449) of Iclusig-treated patients. Fifty-three patients (12%) accomplished treatment-emergent appropriate hypertension as a austere adverse reaction, including hypertensive crisis. Patients may crave afire analytic activity for hypertension associated with confusion, headache, pain, or conciseness of breath. In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90 mm Hg, 80% (229/285) accomplished treatment-emergent hypertension; 44% (124/285) developed Stage 1 hypertension, 37% developed Stage 2 hypertension. In 132 patients with Stage 1 hypertension at baseline, 67% (88/132) developed Stage 2 hypertension. Monitor and administer claret burden elevations during Iclusig use and amusement hypertension to adapt claret pressure. Interrupt, dosage reduce, or stop Iclusig if hypertension is not medically controlled. In the accident of cogent worsening, labile or treatment-resistant hypertension, arrest assay and accede evaluating for renal avenue stenosis.
Pancreatitis: Pancreatitis occurred in 7% (31/449, 6% austere or brand 3/4) of Iclusig-treated patients. The accident of treatment-emergent lipase acclivity was 42% (16% brand 3 or greater). Pancreatitis resulted in cessation or assay abeyance in 6% of patients (26/449). The average time to access of pancreatitis was 14 days. Twenty-three of the 31 cases of pancreatitis bound aural 2 weeks with dosage abeyance or reduction. Check serum lipase every 2 weeks for the aboriginal 2 months and again account thereafter or as clinically indicated. Accede added serum lipase ecology in patients with a history of pancreatitis or booze abuse. Dosage abeyance or abridgement may be required. In cases area lipase elevations are accompanied by belly symptoms, arrest assay with Iclusig and appraise patients for pancreatitis. Do not accede restarting Iclusig until patients accept complete resolution of affection and lipase levels are beneath than 1.5 x ULN.
Added Toxicity in Anew Diagnosed Abiding Appearance CML: In a -to-be randomized analytic balloon in the first-line assay of anew diagnosed patients with abiding appearance (CP) CML, distinct abettor Iclusig 45 mg once-daily added the accident of austere adverse reactions 2-fold compared to distinct abettor imatinib 400 mg once-daily. The average acknowledgment to assay was beneath than 6 months. The balloon was apoplectic for assurance in October 2013. Arterial and venous occlusion and occlusions occurred at atomic alert as frequently in the Iclusig arm compared to the imatinib arm. Compared to imatinib-treated patients, Iclusig-treated patients apparent a greater accident of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and bark and subcutaneous tissue disorders. Iclusig is not adumbrated and is not recommended for the assay of patients with anew diagnosed CP-CML.
Neuropathy: Borderline and cranial neuropathy accept occurred in Iclusig-treated patients. Overall, 20% (90/449) of Iclusig-treated patients accomplished a borderline neuropathy accident of any brand (2%, brand 3/4). The best accepted borderline neuropathies appear were paresthesia (5%, 23/449), neuropathy borderline (4%, 19/449), hypoesthesia (3%, 15/449), dysgeusia (2%, 10/449), able-bodied weakness (2% 10/449) and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 2% (10/449) of Iclusig-treated patients (<1%, 3/449 – brand 3/4). Of the patients who developed neuropathy, 26% (23/90) developed neuropathy during the aboriginal ages of treatment. Monitor patients for affection of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a afire sensation, neuropathic affliction or weakness. Accede arresting Iclusig and appraise if neuropathy is suspected.
Ocular Toxicity: Austere ocular toxicities arch to amaurosis or blurred eyes accept occurred in Iclusig-treated patients. Retinal toxicities including macular edema, retinal attitude occlusion, and retinal drain occurred in 2% of Iclusig-treated patients. Conjunctival irritation, corneal chafe or abrasion, dry eye, conjunctivitis, conjunctival hemorrhage, hyperaemia and edema or eye affliction occurred in 14% of patients. Beheld abashing occurred in 6% of patients. Added ocular toxicities accommodate cataracts, periorbital edema, blepharitis, glaucoma, eyelid edema, ocular hyperaemia, iritis, iridocyclitis, and ulcerative keratitis. Conduct absolute eye exams at baseline and periodically during treatment.
Hemorrhage: Austere drain contest including fatalities, occurred in 6% (28/449) of patients advised with Iclusig. Drain occurred in 28% (124/449) of patients. The accident of austere bleeding contest was college in patients with AP-CML, BP-CML, and Ph ALL. Gastrointestinal drain and subdural hematoma were the best frequently appear austere bleeding contest occurring in 1% (4/449) each. Best hemorrhagic events, but not all, occurred in patients with brand 4 thrombocytopenia. Arrest Iclusig for austere or astringent drain and evaluate.
Aqueous Retention: Aqueous assimilation contest advised as austere occurred in 4% (18/449) of patients advised with Iclusig. One instance of academician edema was fatal. For aqueous assimilation contest occurring in >2% of the patients (treatment-emergent), austere cases included: pleural address (7/449, 2%), pericardial address (4/449, 1%), and edema borderline (2/449, <1%).
In total, aqueous assimilation occurred in 31% of the patients. The best accepted aqueous assimilation contest were borderline edema (17%), pleural address (8%), pericardial address (4%) and borderline abscess (3%).
Monitor patients for aqueous assimilation and administer patients as clinically indicated. Interrupt, reduce, or abandon Iclusig as clinically indicated.
Cardiac arrhythmias: Arrhythmias occurred in 19% (86/449) of Iclusig-treated patients, of which 7% (33/449) were brand 3 or greater. Arrhythmia of ventricular agent was appear in 3% (3/86) of all arrhythmias, with one case actuality brand 3 or greater. Appropriate bradyarrhythmias that led to pacemaker article occurred in 1% (3/449) of Iclusig-treated patients.
Atrial fibrillation was the best accepted arrhythmia and occurred in 7% (31/449) of patients, about bisected of which were brand 3 or 4. Added brand 3 or 4 arrhythmia contest included blackout (9 patients; 2.0%), tachycardia and bradycardia (2 patients anniversary 0.4%), and electrocardiogram QT prolonged, atrial flutter, supraventricular tachycardia, ventricular tachycardia, atrial tachycardia, atrioventricular block complete, cardio-respiratory arrest, accident of consciousness, and atrium bulge dysfunction (1 accommodating anniversary 0.2%). For 27 patients, the accident led to hospitalization.
In patients with signs and affection evocative of apathetic affection amount (fainting, dizziness) or accelerated affection amount ( pain, palpitations or dizziness), arrest Iclusig and evaluate.
Myelosuppression: Myelosuppression was appear as an adverse acknowledgment in 59% (266/449) of Iclusig-treated patients and brand 3/4 myelosuppression occurred in 50% (226/449) of patients. The accident of these contest was greater in patients with AP-CML, BP-CML, and Ph ALL than in patients with CP-CML.Severe myelosuppression (Grade 3 or 4) was empiric aboriginal in treatment, with a average access time of 1 ages (range <1-40 months). Obtain complete claret counts every 2 weeks for the aboriginal 3 months and again account or as clinically indicated, and acclimatize the dosage as recommended.
Bump Lysis Syndrome: Two patients (<1%, one with AP-CML and one with BP-CML) advised with Iclusig developed austere bump lysis syndrome. Hyperuricemia occurred in 7% (31/449) of patients. Due to the abeyant for bump lysis affection in patients with avant-garde disease, ensure able hydration and amusement aerial uric acerbic levels above-mentioned to initiating assay with Iclusig.
Capricious Afterwards Leukoencephalopathy Affection (RPLS): Postmarketing cases of capricious afterwards leukoencephalopathy affection (RPLS—also accepted as Afterwards Capricious Encephalopathy Affection (PRES)) accept been appear in Iclusig-treated patients. RPLS is a acoustic ataxia that can present with signs and affection such as seizure, headache, decreased alertness, adapted brainy functioning, eyes loss, and added beheld and acoustic disturbances. Hypertension is generally present and assay is fabricated with admiring allegation on alluring resonance imaging (MRI) of the brain. If RPLS is diagnosed, arrest Iclusig assay and resume assay alone already the accident is bound and if the account of connected assay outweighs the accident of RPLS.
Compromised Anguish Healing and Gastrointestinal Perforation: Back Iclusig may accommodation anguish healing, arrest Iclusig for at atomic 1 anniversary above-mentioned to above surgery. Austere gastrointestinal breach (fistula) occurred in one accommodating 38 canicule post-cholecystectomy.
Embryo-Fetal Toxicity: Based on its apparatus of activity and allegation from beastly studies, Iclusig can account fetal abuse back administered to a abundant woman. In beastly reproduction studies, articulate administering of ponatinib to abundant rats during organogenesis acquired adverse adorning furnishings at exposures lower than animal exposures at the recommended animal dose. Advise abundant women of the abeyant accident to the fetus. Advise females of changeable abeyant to use able contraception during assay with Iclusig and for 3 weeks afterwards the aftermost dose.
Best Accepted Adverse Reactions: Overall, the best accepted non-hematologic adverse reactions (≥20%) were belly pain, rash, constipation, headache, dry skin, fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, lipase increased, ing, myalgia and affliction in extremity. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.
Please see the abounding U.S. Prescribing Advice for Iclusig, including the Boxed Warning.
Iclusig is a registered brand of ARIAD Pharmaceuticals, Inc.
ARIAD Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts is focused on discovering, developing and commercializing attention therapies for patients with attenuate cancers. ARIAD is alive on new medicines to beforehand the assay of attenuate forms of abiding and astute leukemia, lung blight and added attenuate cancers. ARIAD utilizes computational and structural approaches to architecture small-molecule drugs that affected attrition to absolute blight medicines. For added information, appointment http://www.ariad.com or chase ARIAD on Twitter (@ARIADPharm).
This columnist absolution contains advanced statements, anniversary of which are able in their absoluteness by this cautionary statement. Any statements independent herein which do not call absolute facts, including, but not bound to the statements accompanying to the analytic benefit, backbone of acknowledgment and assurance contour of Iclusig (ponatinib), our estimates of acknowledgment ante for patients advised with ponatinib, and our atomic antecedent for bigger outcomes in Ph ALL patients advised with ponatinib in the front-line setting, are advanced statements that are based on management’s expectations and are accountable to assertive factors, risks and uncertainties that may account absolute results, aftereffect of events, timing and achievement to alter materially from those bidding or adumbrated by such statements. These factors, risks and uncertainties include, but are not bound to, our adeptness to auspiciously commercialize and accomplish profits from sales of our products; our adeptness to accommodated advancing analytic balloon commencement, acceptance and achievement dates and authoritative filing dates for our articles and artefact candidates and to move new development candidates into the clinic; our adeptness to assassinate on our key accumulated initiatives; authoritative developments and assurance issues, including difficulties or delays in accepting authoritative and appraisement and agreement approvals to bazaar our products; antagonism from another therapies; our assurance on the achievement of third-party manufacturers, specialty pharmacies, distributors and added collaborators for the supply, distribution, development and/or commercialization of our articles and artefact candidates; the accident of adverse assurance contest with our articles and artefact candidates; the costs associated with our research, development, manufacturing, commercialization and added activities; the conduct, timing and after-effects of preclinical and analytic studies of our articles and artefact candidates, including that preclinical abstracts and early-stage analytic abstracts may not be replicated in later-stage analytic studies; the capability of our basic assets and the availability of added funding; the adeptness to amuse our acknowledged obligations, including beneath our leases, convertible debt and ability costs agreements; apparent aegis and third-party bookish acreage claims; action and government investigations; our operations in adopted countries with or through third parties; risks accompanying to key employees, markets, bread-and-er conditions, bloom affliction reform, prices and agreement rates; and added accident factors abundant in our accessible filings with the U.S. Securities and Exchange Commission, including our best contempo Annual Address on Form 10-K and consecutive Quarterly Reports on Form 10-Q. Except as contrarily noted, these advanced statements allege alone as of the date of this columnist absolution and we undertake no obligation to amend or alter any of these statements to reflect contest or affairs occurring afterwards this columnist release. We attention investors not to abode ample assurance on the advanced statements independent in this columnist release.
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