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Plourde P.V.,Jazz Pharmaceuticals | Jeha S.,St Jude Childrens Research Hospital | Hijiya N.,Northwestern University | Keller F.G.,Childrens Healthcare Of Atlanta | And 7 more authors.
Pediatric Blood and Cancer | Year: 2014

Background: L-Asparaginase is an integral component of standard chemotherapy regimens for the treatment of acute lymphoblastic leukemia (ALL). Clinical hypersensitivity, a common reason for treatment discontinuation, has been reported in 10-30% of patients receiving Escherichia coli-derived asparaginase. After hypersensitivity, E. coli-derived asparaginase should be discontinued and an alternative asparaginase preparation, such as asparaginase Erwinia chrysanthemi, may be initiated. We conducted a compassionate-use study to collect additional safety information on asparaginase Erwinia chrysanthemi and to support FDA approval of the product. Procedure: Patients with ALL or lymphoblastic lymphoma (LBL; N=1368) who developed a hypersensitivity reaction (grade ≥2) to an E. coli-derived asparaginase participated in this trial. The recommended asparaginase Erwinia chrysanthemi dose was 25,000IU/m2 three days per week (Monday/Wednesday/Friday) for two consecutive weeks for each missed pegylated E. coli-derived asparaginase dose and 25,000IU/m2 for each missed nonpegylated asparaginase dose for the completion of their planned asparaginase treatment. Results: Adverse event reports and/or case report forms were completed for 940 patients. The most common adverse event (AE) was hypersensitivity (13.6%). Eighteen patients (1.9%) died during the study. Most patients (77.6%) completed their planned asparaginase treatment with asparaginase Erwinia chrysanthemi. There was no apparent difference in the incidence of the most commonly reported AEs with asparaginase treatment by age, administration, or disease state. Conclusions: This study further established the safety profile of asparaginase Erwinia chrysanthemi in patients with ALL or LBL who had a hypersensitivity reaction to an E. coli-derived asparaginase. Pediatr Blood Cancer 2014;61:1232-1238. © 2014 Wiley Periodicals, Inc.

Salzer W.L.,U.S. Army | Asselin B.L.,University of Rochester | Plourde P.V.,Jazz Pharmaceuticals | Corn T.,EUSA Pharma | Hunger S.P.,Aurora University
Annals of the New York Academy of Sciences | Year: 2014

Since it was identified in 1963 as the antileukemic agent in guinea pig serum, l-asparaginase (ASNase) has become an integral component of chemotherapy protocols to treat patients with acute lymphoblastic leukemia (ALL). Escherichia coli and Erwinia chrysanthemi provide the sources of ASNase used clinically today. From the time ASNase was first introduced into treatment protocols, the 5-year survival rate has increased significantly, particularly in children and adolescents. E. coli-derived ASNase was approved in 1978 to be used as part of a multiagent chemotherapy to treat ALL. However, the development of hypersensitivity in 10-30% of patients often leads to treatment discontinuation. E. chrysanthemi-derived ASNase (referred to herein as ASNase Erwinia chrysanthemi) is immunologically distinct from E. coli ASNase and therefore does not cross-react with the E. coli enzyme. In 2011, ASNase Erwinia chrysanthemi was approved in the United States for patients who develop hypersensitivity to E. coli-derived ASNase. When indicated, a switch from ASNase E. coli to ASNase E. chrysanthemi allows patients to continue to receive treatment and maintain therapeutic levels of ASNase activity. Therapeutic drug monitoring may help ensure that therapeutic enzyme levels are maintained. Pegylated recombinant ASNase Erwinia chrysanthemi is currently being developed to improve pharmacokinetic properties and reduce immunogenicity. © 2014 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals Inc. on behalf of The New York Academy of Sciences.

Chautard E.,3846 Therapie Ciblee Combinatoire en Onco Hematologie University uvergne | Loubeau G.,3846 Therapie Ciblee Combinatoire en Onco Hematologie University uvergne | Tchirkov A.,3846 Therapie Ciblee Combinatoire en Onco Hematologie University uvergne | Chassagne J.,3846 Therapie Ciblee Combinatoire en Onco Hematologie University uvergne | And 4 more authors.
Neuro-Oncology | Year: 2010

Radiation therapy plays a central role in the treatment of glioblastoma, but it is not curative due to the high tumor radioresistance. Phosphatidyl-inositol 3-kinase/protein kinase B (Akt) and Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathways serve to block the apoptosis process, keeping cells alive in very toxic environments such as chemotherapy or ionizing radiation. In the present study, from a panel of 8 human malignant glioma cell lines, investigations on the relationship between intrinsic radioresistance and Akt or STAT3 basal activation were done. Secondly, the impact of down-modulation of Akt or STAT3 signaling on in vitro intrinsic radiosensitivity was evaluated. Using a clonogenic cell survival assay, our results revealed a significant correlation between the basal Akt activation and the surviving fraction at 2 Gy (SF2). In contrast, no correlation was found between STAT3 activation and SF2. According to this, down-modulation of Akt with a specific chemical inhibitor (Akt inhibitor IV) demonstrated a significant enhancement of radiation sensitivity on glioma cells in a clonogenic survival assay. On the contrary, down-modulation of STAT3 signaling with a specific chemical inhibitor (JSI-124) or a neutralizing gp130 antibody failed to radiosensitize glioma cells. These data indicate that the Akt intercept node could be a more relevant therapeutic target than STAT3 for radiosensitizing human malignant glioma. © 2010.The Author(s).

- First Quarter 2015 Total Revenues of $309 Million, Driven by Strong Sales of Xyrem, Erwinaze and Defitelio DUBLIN, May 7, 2015 /PRNewswire/ -- Jazz Pharmaceuticals plc (Nasdaq: JAZZ) today announced financial results for the first quarter ended March 31, 2015 and reaffirmed financial guidance for 2015. "We are pleased with our strong top-line performance during the first quarter, driven by sales growth of our key products," said Bruce C. Cozadd, chairman and chief executive officer of Jazz Pharmaceuticals plc. "For 2015, we will remain focused on execution of our key objectives, including advancing our development pipeline, completing the rolling NDA submission for defibrotide, preparing for the potential launch of defibrotide in the U.S. and continuing our efforts to further diversify our business through corporate development activities." Adjusted net income attributable to Jazz Pharmaceuticals plc for the first quarter of 2015 was $125.1 million, or $1.99 per diluted share, compared to $99.5 million, or $1.59 per diluted share, for the first quarter of 2014. GAAP net income attributable to Jazz Pharmaceuticals plc for the first quarter of 2015 was $70.7 million, or $1.12 per diluted share, compared to GAAP net loss attributable to Jazz Pharmaceuticals plc of $92.7 million, or $1.58 per diluted share, for the first quarter of 2014. GAAP net loss attributable to Jazz Pharmaceuticals plc for the first quarter of 2014 included acquired in-process research and development expense of $127.0 million. Reconciliations of applicable GAAP reported to non-GAAP adjusted information are included in this press release. Total revenues for the first quarter of 2015 were $309.3 million, an increase of 25% over total revenues of $246.9 million for the first quarter of 2014. The increase in total revenues was driven primarily by higher net product sales of Xyrem® (sodium oxybate) oral solution, Erwinaze®/Erwinase® (asparaginase Erwinia chrysanthemi) and Defitelio® (defibrotide). Total revenues include net product sales, royalties and contract revenues. Net product sales for the first quarter of 2015 were as follows: Tables showing actual net product sales for the three months ended March 31, 2015 and actual and pro forma net product sales for the same period in 2014 are included in this press release. Operating expenses for the first quarter of 2015 were $192.5 million on a GAAP basis compared to $313.6 million for the first quarter of 2014. Operating expenses decreased over the prior period primarily due to acquired in-process research and development expenses of $127.0 million on a GAAP basis for the first quarter of 2014, which was comprised of upfront and milestone payments made in connection with the company's acquisition of rights to JZP-110. Other changes in operating expenses for the first quarter of 2015 and 2014 were as follows: Net interest expense for the first quarter of 2015 was $16.2 million compared to $10.1 million for the first quarter of 2014. The increase was due to the company's higher debt levels following the sale in August 2014 of $575.0 million principal amount of 1.875% exchangeable senior notes due 2021. As of March 31, 2015, cash and cash equivalents were $782.6 million and the outstanding principal balance of the company's long-term debt was $1.5 billion. Cash and cash equivalents increased from December 31, 2014 primarily due to cash generated by the business and proceeds from the sale of certain products acquired as part of the acquisition of EUSA Pharma, offset in part by cash used to fund capital expenditures and the repurchase of ordinary shares under the company's share repurchase program. In the first quarter of 2015, the company repurchased 0.1 million ordinary shares under its share repurchase program for $10.3 million at an average cost of $164.54 per ordinary share. As of March 31, 2015, the amount remaining under the current share repurchase program was $11.0 million. Karen Smith, M.D., Ph.D joined the company as the Global Head of Research and Development and Chief Medical Officer on April 13, 2015. Dr. Smith brings more than 20 years of experience in the industry, and a track record of success in global development, medical affairs and lifecycle management. Dr. Smith has held positions of increasing responsibility with Merck, Pfizer, Bristol-Myers Squibb, AstraZeneca and most recently, Allergan, where she was Senior Vice President, Global Medical Affairs and Therapeutic Area Head (Dermatology), Research and Development. "We are pleased to have Dr. Karen Smith join Jazz Pharmaceuticals at this exciting time of expansion of our R&D activities," said Russell Cox, executive vice president and chief operating officer of Jazz Pharmaceuticals plc. "Karen brings expertise in multiple therapeutic areas, including oncology, and has deep experience across pharmaceuticals, devices and biologics.  Her strong leadership, global R&D and regulatory experience, and results-driven approach will bring significant value to our organization." Jazz Pharmaceuticals is reaffirming its full year 2015 financial guidance, which is as follows: Jazz Pharmaceuticals will host an investor conference call and live audio webcast today at 4:30 p.m. EDT (9:30 p.m. IST) to provide a business and financial update and discuss its 2015 first quarter results. The live webcast may be accessed from the Investors & Media section of the company's website at www.jazzpharmaceuticals.com. Please connect to the website prior to the start of the conference call to ensure adequate time for any software downloads that may be necessary. Investors may participate in the conference call by dialing +1-877-415-3179 in the U.S., or +1-857-244-7322 outside the U.S., and entering passcode 74301034. A replay of the conference call will be available through May 14, 2015 by dialing +1-888-286-8010 in the U.S., or +1-617-801-6888 outside the U.S., and entering passcode 39160618. An archived version of the webcast will be available for at least one week in the Investors & Media section of the Jazz Pharmaceuticals website at www.jazzpharmaceuticals.com. Jazz Pharmaceuticals plc (Nasdaq: JAZZ) is an international biopharmaceutical company focused on improving patients' lives by identifying, developing and commercializing meaningful products that address unmet medical needs. The company has a diverse portfolio of products and product candidates with a focus in the areas of sleep and hematology/oncology. In these areas, Jazz Pharmaceuticals markets Xyrem® (sodium oxybate) oral solution and Erwinaze® (asparaginase Erwinia chrysanthemi) in the U.S., and markets Erwinase® and Defitelio® (defibrotide) in Europe and other countries outside the U.S. For more information, please visit www.jazzpharmaceuticals.com. To supplement Jazz Pharmaceuticals' financial results and guidance presented in accordance with U.S. generally accepted accounting principles (GAAP), the company uses certain non-GAAP (also referred to as "adjusted" or "non-GAAP adjusted") financial measures in this press release and the accompanying tables. The company believes that each of these non-GAAP financial measures is helpful in understanding its past financial performance and potential future results, particularly in light of the effect of various acquisition and divestiture transactions effected by the company.  They are not meant to be considered in isolation or as a substitute for comparable GAAP measures and should be read in conjunction with the consolidated financial statements prepared in accordance with GAAP.  Jazz Pharmaceuticals' management regularly uses these supplemental non-GAAP financial measures internally to understand, manage and evaluate its business and make operating decisions. Compensation of executives is based in part on the performance of the company's business based on certain of these non-GAAP financial measures. In addition, Jazz Pharmaceuticals believes that the presentation of these non-GAAP financial measures is useful to investors because it enhances the ability of investors to compare its results from period-to-period and allows for greater transparency with respect to key financial metrics the company uses in making operating decisions, and also because the company's investors and analysts regularly use them to model and track the company's financial performance. Investors should note that these non-GAAP financial measures are not prepared under any comprehensive set of accounting rules or principles and do not reflect all of the amounts associated with the company's results of operations as determined in accordance with GAAP. Investors should also note that these non-GAAP financial measures have no standardized meaning prescribed by GAAP and, therefore, have limits in their usefulness to investors. In addition, from time-to-time in the future there may be other items that the company may exclude for purposes of its non-GAAP financial measures; likewise, the company has ceased and may in the future cease to exclude items that it has historically excluded for purposes of its non-GAAP financial measures. In this regard, commencing with the company's presentation of 2015 non-GAAP financial measures, the company no longer includes an adjustment for depreciation expense in its non-GAAP adjusted financial measures. Likewise, for purposes of comparability, non-GAAP adjusted financial measures for 2014 included in this press release and accompanying tables do not include an adjustment for depreciation expense. In addition, because of the non-standardized definitions of non-GAAP financial measures, the non-GAAP financial measures as used by Jazz Pharmaceuticals in this press release and the accompanying tables may be calculated differently from, and therefore may not be directly comparable to, similarly titled measures used by the company's competitors and other companies. As used in this press release, (i) the historical adjusted net income measures attributable to Jazz Pharmaceuticals plc (and the related per share measures) exclude from GAAP reported net income (loss) attributable to Jazz Pharmaceuticals plc (and the related per share measures), as applicable, intangible asset amortization, share-based compensation expense, restructuring charges, transaction and integration costs, acquired in-process research and development expenses, acquisition accounting inventory fair value step-up adjustments and non-cash interest expense; adjust the income tax provision to the estimated amount of taxes that are payable in cash; and adjust for the amount attributable to noncontrolling interests; (ii) the historical adjusted SG&A expense measures exclude from GAAP SG&A expenses, as applicable, share-based compensation expense, restructuring charges, and transaction and integration costs; (iii) the historical adjusted R&D expense measures exclude from GAAP R&D expenses, as applicable, share-based compensation expense and transaction and integration costs; (iv) the adjusted net income attributable to Jazz Pharmaceuticals plc (and the related per share measures) guidance exclude from estimated GAAP net income attributable to Jazz Pharmaceuticals plc (and the related per share measures) intangible asset amortization, share-based compensation expense, upfront and milestone payments, transaction, integration and restructuring costs and non-cash interest expense; and adjust the income tax provision to the estimated amount of taxes that are payable in cash; (v) the adjusted gross margin percentage guidance excludes from estimated GAAP gross margin percentage share-based compensation expense; (vi) the adjusted SG&A expenses guidance excludes from estimated GAAP SG&A expenses share-based compensation expense and transaction, integration and restructuring costs; (vii) the adjusted R&D expenses guidance excludes from estimated GAAP R&D expenses share-based compensation expense and a potential milestone payment; and (viii) the adjusted interest expense guidance excludes from estimated GAAP interest expense non-cash interest expense. "Safe Harbor" Statement under the Private Securities Litigation Reform Act of 1995 This press release contains forward-looking statements, including, but not limited to, statements related to Jazz Pharmaceuticals' future financial results, including 2015 financial guidance, the advancement of the company's development pipeline, the anticipated completion of the rolling NDA submission for defibrotide and the potential acceptance for filing by the FDA thereof, the potential commercial launch of defibrotide in the U.S., the potential future diversification of the company's business through corporate development activities and other statements that are not historical facts. These forward-looking statements are based on Jazz Pharmaceuticals' current expectations and inherently involve significant risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, risks and uncertainties associated with maintaining and increasing sales of and revenue from Xyrem, such as the potential introduction of generic competition or other sodium oxybate products that compete with Xyrem and changed or increased regulatory restrictions on or requirements with respect to Xyrem, as well as similar risks related to effectively commercializing the company's other lead marketed products; risks related to effectively commercializing the company's product candidates, including defibrotide if it receives marketing approval, including the need to establish pricing and reimbursement support and, in the case of defibrotide, the lack of experience of U.S. physicians in diagnosing and treating VOD; protecting and enhancing the company's intellectual property rights; delays or problems in the supply or manufacture of the company's products which could impact the company's ability to meet commercial demand; obtaining and maintaining appropriate pricing and reimbursement for the company's products in an increasingly challenging environment; the challenges of compliance with the requirements of U.S. and non-U.S. regulatory agencies; the challenges of achieving and maintaining commercial success of the company's products; the risks and costs associated with business combination or product or product candidate acquisition transactions; the difficulty and uncertainty of pharmaceutical product development, including the timing thereof, and the uncertainty of clinical success, such as the risk that results from preclinical studies and/or early clinical trials may not be predictive of results obtained in later and larger clinical trials; the inherent uncertainty associated with the regulatory approval process, including the risk that the company may be unable to obtain regulatory approval for defibrotide in the U.S. in a timely manner or at all; the company's potential inability to identify and acquire, in-license or develop additional products or product candidates to grow and diversify its business; possible restrictions on the company's ability and flexibility to pursue certain future corporate development and other opportunities as a result of its substantial outstanding debt obligations, which increased significantly in 2014; risks related to future opportunities and plans, including the uncertainty of expected future financial performance and results; and those other risks detailed from time-to-time under the caption "Risk Factors" and elsewhere in Jazz Pharmaceuticals plc's Securities and Exchange Commission filings and reports (Commission File No. 001-33500), including the company's Annual Report on Form 10-K for the year ended December 31, 2014 and future filings and reports by the company, including the Quarterly Report on Form 10-Q for the quarter ended March 31, 2015. Jazz Pharmaceuticals undertakes no duty or obligation to update any forward-looking statements contained in this press release as a result of new information, future events or changes in its expectations. The following unaudited pro forma information represents net product sales for the three months ended March 31, 2014 as if the acquisition of Gentium had been completed on January 1, 2014:

BEIJING--(BUSINESS WIRE)--CANbridge Life Sciences, a biopharmaceutical company focused on developing Western drug candidates in China and North Asia, has entered into an exclusive license agreement with privately-held immuno-oncology company, Apogenix (www.apogenix.com), to develop, manufacture and commercialize Apogenix’s lead product, APG101, in glioblastoma multiforme in China, Macao, and Hong Kong, with options for other indications. APG101 is a fully-human fusion protein that inhibits the CD95 ligand, a member of the tumor necrosis factor (TNF) superfamily. By blocking the CD95 ligand, APG101 restores the immune response against tumors and inhibits invasive tumor cell growth. APG101 showed an improved overall survival benefit in patients with relapsed glioblastoma in a Phase II trial conducted in Europe. Additionally, the trial showed that glioblastoma patients with a certain biomarker associated with the CD95 ligand experienced the greatest benefit from treatment with APG101. Apogenix is developing a companion diagnostic test to identify those patients most likely to benefit from APG101 treatment. APG101 is also in a Phase I trial for myelodysplastic syndromes (MDS) in Europe. Under the terms of the agreement, Apogenix will receive upfront and milestone payments, as well as royalty payments, at tiered, double-digit royalty rates following commercial launch of APG101 in China. “Development of this targeted therapeutic fits the CANbridge mission of bringing promising Western treatments to China and other Asian territories, where patients’ severe medical needs are going unmet,” said James Xue, CANbridge Chairman and CEO. “The mortality rate of malignant glioma is one of the top ten among all cancers in China. With very limited treatment options, the outcomes for Chinese patients are even more grim than in the West. The potential to develop a targeted immuno-oncology product represents a tremendous advance for glioblastoma treatment in China.” “The licensing agreement with CANbridge represents an important milestone in our goal to develop and commercialize our immuno-oncology compound APG101 as a new therapy for difficult-to-treat tumor indications on an international level,” said Thomas Hoeger, Ph.D., Chief Executive Officer of Apogenix. “We are delighted to have found a strong and committed partner with a seasoned management team and extensive drug development expertise in these important Asian markets. We look forward to working with CANbridge to obtain approval for APG101 in China, Macao, and Hong Kong, so we can provide patients suffering from glioblastoma with a novel, much-needed therapeutic option as soon as possible.” “The CANbridge and Apogenix missions and cultures are perfectly aligned, which bodes well for the success of this partnership,” said Henri Termeer, CANbridge’s Advisor and former Chairman and CEO of Genzyme Corporation. “Each company is dedicated to bringing forth treatments in their respective markets for patients with few options. Together, CANbridge and Apogenix can move this exciting program forward more effectively than either could alone in China.” “Glioblastoma multiforme is a very serious disease with limited therapeutic options at present. Based upon the data already generated by Apogenix, I am very excited about the possibility of APG101 to greatly improve clinical outcomes in patients with glioblastoma multiforme,” said Mark Goldberg, MD. Medical Advisor to CANbridge and practicing hematologist and oncologist at Brigham and Women’s Hospital and Dana Farber Cancer Institute. Glioblastoma multiforme is the most lethal form of brain cancer and the hardest to treat. It is the only grade IV glioma by World Health Organization classification. Current standard-of-care consists of surgical resection of the tumor followed by radiation and chemotherapy. The five-year survival rate is less than 3%, with the mortality rate the third highest, after pancreatic cancer and lung cancer. In China, glioblastoma incidence is predicted to grow from 1.75 per 100,000 people in 2014, to 2.05 per 100,000 in 2024, which represents a 17% increase. CANbridge Life Sciences, Ltd. is a bio-pharmaceutical company accelerating development and commercialization of specialty healthcare products for serious and critical medical conditions in China and North Asia (Korea and Taiwan). CANbridge develops partnerships with Western bio-pharmaceutical companies with clinical-stage pharmaceutical, medical device or diagnostic products that are either unavailable in China/North Asia or address medical needs that are underserved in the region. CANbridge also licenses, or obtains exclusive rights to commercialize, drug and device products that are approved in their home markets for commercialization in China and North Asia. CANbridge has an exclusive licensing agreement with U.S.-based Azaya Therapeutics, Inc., to develop and commercialize ATI-1123 in China, for the treatment of non-small cell lung cancer and other solid tumors. CANbridge also has an agreement with EUSA Pharma, to commercialize Caphosol® in China for the prevention and treatment of oral mucositis caused by cancer treatments, and a license with Apogenix to develop, manufacture and commercialize lead candidate, onco-immunotherapy, APG101, for the treatment of glioblastoma multiforme in China, Macao and Hong Kong. Led and backed by a highly-seasoned executive team, with extensive Chinese drug development experience, CANbridge has the capability to select, acquire, develop and commercialize future therapeutics and diagnostics targeting the unmet medical needs of Chinese and East Asian patients with serious or critical conditions. CANbridge is privately-held and headquartered in Beijing, China. For more on CANbridge Life Sciences, please go to www.canbridgepharma.com.

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