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Rezonic

Generic name: casopitant
Treatment for: Nausea/Vomiting, Chemotherapy Induced, Nausea/Vomiting, Postoperative

NDA Submitted for Rezonic

GlaxoSmithKline Announces New Drug Application and Phase III Results for Rezonic/Zunrisa (Casopitant)

PHILADELPHIA and LONDON, May 29, 2008 /PRNewswire-USNewswire/ -- GlaxoSmithKline (GSK) today announced the submission of a new drug application to the U.S. Food and Drug Administration and new data from two Phase III trials for Rezonic/Zunrisa (casopitant), a novel, investigational NK-1 receptor antagonist. The data demonstrated a significant and clinically meaningful reduction in the number of patients experiencing chemotherapy-induced nausea and vomiting (CINV). Adding a single oral dose regimen of casopitant to the standard dual therapy of Zofran (ondansetron HCI) and dexamethasone, achieved this effect in patients taking highly emetogenic chemotherapy (HEC) and those on moderately emetogenic chemotherapy (MEC) treatment regimens.(1,2) CINV can be a serious, feared and distressing side effect of chemotherapy for patients and their families.(3) CINV can last for about five days and the risk of nausea and vomiting without prophylaxis is greater than 90 percent for patients receiving HEC and 30-90 percent for patients receiving MEC.(4,5)

Data from the two Phase III clinical trials demonstrated complete response rates of 86 percent for those patients given a single oral dose of casopitant together with the standard dual therapy in the HEC trial, and 73 percent for patients given either single oral or three-day oral doses of casopitant together with the standard dual therapy in the MEC trial.(1,2) This prophylactic treatment resulted in clinically meaningful and statistically significant improvements compared to controls.(1,2) To achieve complete response, patients had no vomiting or retching and took no rescue medications for five days following chemotherapy treatment.(1,2) These data for the single dose regimen - in addition to results for three-day oral and three-day IV/oral regimens - will be unveiled this week at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

"There are many patients who still suffer from the unfortunate side effects of chemotherapy-induced nausea and vomiting in spite of standard dual therapy. Since it is important to make patients as comfortable as possible, I consider these results for casopitant as a very exciting step toward a convenient and effective oral option to provide much needed relief," said study investigator Steven M. Grunberg, M.D., Vermont Cancer Center at and Fletcher Allen Health Care.

Just one or two episodes of CINV can have a significant impact on quality of life and may cause patients to delay or refuse therapy.(5) Even with the current treatments available, CINV is still a large burden on patients and their families - up to 40-50 percent of chemotherapy patients on standard anti-emetic treatment continue to experience breakthrough nausea and vomiting, particularly in the delayed setting.(6)

A new drug application for casopitant was recently submitted to the U.S. Food and Drug Administration for the proposed indication of prevention of chemotherapy-induced nausea and vomiting as an add-on therapy to the standard dual therapy of a 5-HT3 receptor antagonist, such as Zofran, and dexamethasone. Applications have been submitted for both the IV and oral formulations. The NDA submission also included the proposed indication of the prevention of postoperative nausea and vomiting. NK-1 receptor antagonists like casopitant complement 5-HT3 receptor antagonists by acting on a different, but also important neurotransmitter system responsible for nausea and vomiting.(7)

"Our goal is not only to eradicate cancer, but also to help patients cope with their cancer and the often unwanted consequences of treatment, such as CINV, that many patients face. Building on our Zofran heritage, casopitant represents our ongoing commitment to advancing cancer care by providing treatments in the supportive arena," said Paolo Paoletti, M.D., Senior Vice President, Oncology Research, GSK.

The multi-national, double-blind, controlled Phase III trial evaluated the tolerability and efficacy of a single oral dose and a three-day IV/oral dose regimen of casopitant or placebo added to standard dual therapy for reducing CINV in patients receiving cisplatin-based HEC regimens.(1)

The trial enrolled 810 patients and demonstrated that, when added to standard dual therapy of ondansetron (OND) and dexamethasone (DEX), a single oral dose (one 150mg tablet) or a three-day IV/oral dose regimen (90mg IV and OND on day one and 50mg tablets on days two and three) of casopitant provided a statistically significant reduction in the number of patients experiencing CINV events over the first five days after receiving HEC versus the control group. The primary endpoint of overall complete response, defined as no vomiting, retching or rescue medication use in the first five days after chemotherapy, was achieved by patients receiving HEC (86 percent in the single oral dose, p<0.0001, and 80 percent in the three-day IV/oral dose, p<0.0004, vs. 66 percent in the control population), with the clinical benefit maintained through repeat cycles.(1)

Significant improvements were also observed in the complete response for the acute (95 percent in the single oral dose, p=0.0044, and 94 percent in the three-day IV/oral dose, p=0.0165, vs. 88 percent for control population) and delayed phases (86 percent in the single oral dose, p<0.0001, and 80 percent in the three-day IV/oral dose, p=0.0004, vs. 66 percent in the control population).(1) Acute CINV is defined as the first 24 hours after chemotherapy, while delayed CINV is 24 hours to 120 hours following treatment.(8)

The most commonly reported all-cause adverse events in the treatment arms were neutropenia, leukopenia and anemia, which occurred at a higher rate in the casopitant arms. The incidence of serious neutropenia adverse events was two percent in the active control arm, one percent in the single oral dose arm and four percent in the three-day IV/oral arm.(1)

The multi-national, double-blind, controlled Phase III trial evaluated and demonstrated the tolerability and efficacy of a single oral dose, a three-day oral dose regimen, and a three-day IV/oral dose regimen of casopitant or placebo added to standard dual therapy for reducing CINV in breast cancer patients receiving standard MEC regimens.(2)

The trial enrolled 1,933 patients and showed that both oral casopitant doses (a single 150mg tablet on day one, or a 150mg tablet on day one followed by 50mg on days two and three) and IV/oral doses (90mg IV on day one followed by 50mg tablets on days two and three) - all in addition to standard OND and DEX doses - resulted in clinically meaningful and statistically significant improvements (p<0.0001) in the number of patients achieving a complete response for their CINV over the first five days after receiving MEC versus the control group (73 percent in both oral doses and 74 percent in the IV/oral dose vs. 59 percent in the control group). A complete response was reported as no vomiting, retching or use of rescue medications in the first five days. The clinical benefit of all three dosing regimens was maintained through repeat cycles.(2)

The most commonly reported all-cause adverse events by patients receiving casopitant included neutropenia, alopecia and fatigue, and were generally balanced across treatment arms.(2)

Casopitant is an NK-1 receptor antagonist in Phase III development in oral and intravenous formulations for multiple indications, including the prevention of chemotherapy-induced nausea and vomiting. Casopitant is an investigational product and has not yet received approval from any regulatory agency.

Two key pathways and two key neurotransmitters are associated with CINV. The central pathway is activated by substance P and mediated by neurokinin (NK-1) receptors that are highly concentrated in the brain. The peripheral pathway is stimulated by serotonin and mediated by 5-HT3 receptors located primarily in the gut.(7)

NK-1 receptor antagonists like casopitant block substance P from binding to receptors within the brain and have the potential to add benefit beyond standard 5-HT3 inhibitors.(9)

Zofran is a highly selective 5-HT3 receptor antagonist used for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting (CINV/RINV), and for the prevention of postoperative nausea and vomiting (PONV). The most commonly reported adverse events in patients receiving Zofran in clinical trials were headache (5 percent to 27 percent), diarrhea (<1 percent to 16 percent), constipation (<1 9 percent), fever (<1 percent 8 and malaise>

GlaxoSmithKline - one of the world's leading research-based pharmaceutical and healthcare companies - is committed to improving the quality of human life by enabling people to do more, feel better, and live longer. For company information, visit GlaxoSmithKline at .

Under the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995, GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Factors that may affect GSK's operations are described under "Risk Factors" in the "Business Review" in the company's Annual Report on Form 20-F for 2007.

Rezonic, the proposed trade name for casopitant in the United States, is a trademark of the GlaxoSmithKline group of companies in the United States.

Zunrisa, the proposed trade name for casopitant, is a trademark of the GlaxoSmithKline group of companies.

Zofran(R) (ondansetron HCl) is a registered trademark of GlaxoSmithKline.

To access the latest GSK Oncology media materials, visit

    US Media inquiries:              Jeff McLaughlin         1 919 483 2839

                                     Mary Anne Rhyne         1 919 483 2839


    UK Media inquiries:              Philip Thomson         44 20 8047 5502

                                     Joss Mathieson         44 20 8047 5502

                                     Gwenan White           44 20 8047 5502


    European Analyst/Investor

     inquiries:                      Anita Kidgell          44 20 8047 5542

                                     Sally Ferguson         44 20 8047 5543

                                     David Mawdsley         44 20 8047 5564


    US Analyst/ Investor             Frank Murdolo           1 215 751 7002

     inquiries:                      Tom Curry               1 215 751 5419

(1) Herrstedt J, Grunberg SM. Final Poster for Abstract #9549 - Phase III Results for the Novel Neurokinin-1 (NK-1) Receptor Antagonist, Casopitant: Single Oral Dosing Regimen for Chemotherapy-induced Nausea and Vomiting (CINV) in Patients (Pts) Receiving Highly Emetogenic Chemotherapy (HEC). To be presented at the 2008 American Society of Clinical Oncology annual meeting.

(2) Grunberg SM, Aziz Z. Final Poster for Abstract #9540 - Phase III Results of a Novel Neurokinin-1 (NK-1) Receptor Antagonist, Casopitant: Single Oral and 3-Day Oral Dosing Regimens for Chemotherapy-induced Nausea and Vomiting (CINV) in Patients (Pts) Receiving Moderately Emetogenic Chemotherapy (MEC). To be presented at the 2008 American Society of Clinical Oncology annual meeting.

(3) National Cancer Institute. Nausea and Vomiting (PDQ(R)) Patient Version.

(4) NCCN. Clinical Practice Guidelines in Oncology: Antiemesis. v.3. 2008.

(5) Grunberg SM. Chemotherapy-induced nausea and vomiting: prevention, detection and treatment--how are we doing? J Support Oncol. 2004;2(suppl 1):1-12.

(6) Grunberg S, et. Al. Incidence of Chemotherapy-Induced Nausea and Emesis after Modern Antiemetics: Perception versus Reality. Cancer. 2004;100,10 :2261-2268.

(7) Hesketh PJ, et Al. Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer. 2003; 39:1074-1080.

(8) Kris M. et. Al. Consensus proposals for the prevention of acute and delayed vomiting and nausea following high-emetic-risk chemotherapy. Support Care Cancer. 2005;13:85-96.

(9) Arpornwirat W, Albert I, Hansen V, et. Al. In a Randomized Phase II Trial Casopitant Mesylate + Ondansetron and Dexamethasone Reduced Chemotherapy-Induced Nausea/Vomiting (CINV) in Patients Receiving Moderately Emetogenic Chemotherapy (MEC). MASCC 18th Symposium Proceedings.

CONTACT: (US Media inquiries) Jeff McLaughlin, +1-919-483-2839, Mary AnneRhyne, +1-919-483-2839, (UK Media inquiries) Philip Thomson,+1-44-20-8047-5502, Joss Mathieson, +1-44-20-8047-5502, Gwenan White,+1-44-20-8047 5502, all of GlaxoSmithKline

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Posted: May 2008

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