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Title: Prexige (Lumiracoxib) Appears To Significantly Reduce Gastrointestinal Events Without Compromising Cardiovascular Safety Compared To Nsaids

"Prexige (Lumiracoxib) Appears To Significantly Reduce Gastrointestinal Events Without Compromising Cardiovascular Safety Compared To Nsaids"

DORVAL, QC -- August 26, 2004 -- Novartis Pharmaceuticals Canada Inc. announced today that results from a landmark trial showed that Prexige™ (lumiracoxib), the structurally distinct and most selective COX-2 inhibitor, demonstrated a significant 79 per cent reduction in the incidence of upper gastrointestinal (GI) ulcer complications without compromising cardiovascular (CV) safety. The results were the basis for two papers published online in The Lancet on the findings of the landmark TARGET (Therapeutic Arthritis Research & Gastrointestinal Event Trial of lumiracoxib) study that further confirmed the safety benefit of Prexige.1,2 Prexige is currently under review by the Therapeutics Products Directorate at Health Canada, and market authorization has not yet been received. "The excellent GI and CV safety profile of Prexige demonstrated by the positive results of TARGET shows a favourable benefit/risk ratio for Prexige, even at multiples of the normal chronic dose. These findings may be linked to the different chemical and pharmacokinetic properties of Prexige, which is the most selective COX-2 inhibitor," said Joerg Reinhardt, Head of Development, Novartis Pharma AG. TARGET is the largest GI safety outcomes study performed to date and clearly demonstrates beneficial results specifically for the GI safety of Prexige. The TARGET data demonstrate that in patients not taking low-dose aspirin, Prexige had an overall statistically significant reduction of 79 per cent versus the two comparator NSAIDs (non-steroidal anti-inflammatory drugs) naproxen and ibuprofen in the incidence of definite or probable upper GI ulcer complications (p<0.0001). Prexige significantly reduced the incidence of upper GI ulcer complications in those patients not taking aspirin by 83 per cent versus ibuprofen, and by 76 per cent versus naproxen. For the overall population (patients taking and not taking low dose aspirin), Prexige significantly reduced the incidence of upper GI ulcer complications by 66 per cent versus the two NSAIDs. For the smaller subgroup of patients taking aspirin, a numerical trend of 21 per cent decrease of ulcer complications in favour of Prexige was observed compared to the NSAIDs.1 "TARGET was a well-designed, landmark study and yields robust results for Prexige, demonstrating an up to four-fold reduction in the incidence of GI ulcer complications compared to NSAIDs," said Dr. William Bensen, Rheumatologist, St. Joseph's Healthcare Hamilton, Clinical Professor, McMaster University, TARGET trial investigator. In addition to GI tolerability, TARGET investigated CV safety. Prexige did not increase the CV risk (defined as the combined Anti-Platelet Trialist Collaboration [APTC] endpoint) compared to the two NSAIDs. The APTC endpoint included confirmed or probable non-fatal myocardial infarction (MI) including silent MI (ECG-detected), non-fatal stroke (ischemic or hemorrhagic) and cardiovascular death. For the APTC endpoint, no significant difference between Prexige and the comparator NSAIDs was observed in the overall population, or in the populations investigated separately for those taking or not taking low-dose aspirin. Furthermore, there was no significant difference in the incidence of MIs, congestive heart failure and other thrombotic events observed in the overall population groups studied between Prexige and naproxen or ibuprofen.2 "TARGET demonstrates that Prexige has a CV profile similar to conventional NSAIDs with a more favourable blood pressure profile. These very important results show that Prexige offers GI benefits to patients without compromising their CV safety," said Dr. Boulos Haraoui, Clinical Associate Professor of Medicine, Université de Montréal, Director of Clinical Research, Department of Rheumatology at Hôpital Notre-Dame and TARGET trial investigator. "In TARGET we found no difference in MIs, stroke or any of the other CV endpoints investigated between Prexige and the NSAIDs." For the pre-specified endpoint combining serious GI and CV events, Prexige at twice the recommended dose for OA showed a significant 35 per cent reduction (p=0.001) versus the NSAID groups.1 Importantly, mean changes in systolic and diastolic blood pressure from baseline for patients taking Prexige were significantly smaller (p?0.0001) than for those taking NSAIDs (systolic +0.4 mmHg vs. +2.1 mmHg respectively; diastolic - 0.1 mmHg versus +0.5 mmHg respectively).1,2 Serious GI or CV events are more frequent side effects in patients treated with NSAIDs and COX-2 selective inhibitors than serious hepatic events, as confirmed in TARGET with a more than ten times higher frequency of serious GI and CV events than hepatic events. In TARGET, there was no significant difference in serious hepatic events leading to jaundice between Prexige and the NSAID groups.1 Of the approximately 9,000 patients using twice the maximum dose of Prexige for use in OA, six cases of jaundice were observed [0.07 per cent], while two cases in the group using ibuprofen [0.05 per cent] and one with naproxen [0.02 per cent] at therapeutic doses with approximately 4,500 patients in each group. After discontinuation of therapy, all effects resolved fully. Less serious and transient hepatic enzyme elevations were recorded more often with Prexige compared to NSAIDs [2.6 per cent versus 0.6 per cent respectively], but were less frequent than seen with the most widely prescribed NSAID diclofenac [4 per cent].8 ABOUT TARGET TARGET was designed to answer questions about the overall safety of Prexige, building on the experience and shortcomings of previous GI outcome trials of celecoxib (CLASS study) and rofecoxib (VIGOR study).3 In total, 18,325 patients participated in TARGET, randomized at more than 800 trial sites worldwide including Canada. Of these trial sites, 33 were located across Canada and involved approximately 700 Canadian patients. The trial was designed to examine GI safety as the primary endpoint and CV safety as a secondary endpoint of Prexige 400 mg once daily - two times the indicated dose for use in OA - versus standard doses of ibuprofen 800 mg three times daily and naproxen 500 mg twice daily over 12 months. TARGET is also the first outcomes study designed to examine the impact of low-dose aspirin with Prexige on both GI and CV safety. In keeping with a "real-life" OA population, 24 per cent of the randomized patients in TARGET included low-dose aspirin with their study medication for primary and secondary prevention of CV disease.3 For the pre-specified endpoint combining serious GI and CV events, Prexige showed a significant 35 per cent reduction (p=0.001) versus the NSAID groups.1 Importantly, mean changes in systolic and diastolic blood pressure from baseline for patients taking Prexige were significantly smaller (p?0.0001) than for those taking NSAIDs (systolic +0.4 mmHg versus +2.1 mmHg respectively; diastolic -0.1 mmHg vs. +0.5 mmHg respectively).1,2 TARGET had several key differentiating features. The large size of the trial (>18,000 patients), a high retention rate at one year (60 per cent), the choice of homogenous study population with OA and stratifying at randomization 24 per cent of the patient population for low dose aspirin use (75-100 mg daily) all contributed to providing the power necessary to investigate the serious GI events that can occur with regular NSAID use in a representative OA population. The study design also permitted an assessment of the influence of low-dose aspirin on the GI benefit, a comparison with two NSAIDs with potentially different anti-thrombotic properties, and a prospective investigation of key cardiovascular endpoints in patients taking, or not taking, concomitant low-dose aspirin. The TARGET study began in late 2001 and enrolled patients in the US, Europe, South America, Canada, South Africa and Asia. The TARGET protocol was reviewed by the US Food and Drug Administration (FDA), and study data were evaluated on an interim basis by an independent data and safety monitoring board. ABOUT PREXIGE Prexige, which is currently under review by Health Canada, was developed for the treatment of the signs and symptoms of arthritis and management of pain. Prexige is the most selective cyclooxygenase-2 (COX-2) inhibitor with a non-sulfur containing structure distinct from existing selective COX-2 inhibitors. Prexige has proven efficacy in an extensive phase III clinical trial program demonstrating rapid onset in acute pain with 400mg once daily (od) for short term use5 and efficacy in OA with 200mg od6 and rheumatoid arthritis at 200mg od.7 Novartis has filed applications for regulatory approval throughout the world based on data from more than 40 pre-clinical and clinical studies in OA, rheumatoid arthritis, acute pain and primary dysmenorrhea involving more than 13,000 adult patients around the world. Prexige has been approved in 17 countries to date, including the United Kingdom, Australia and several countries in Latin America, including Argentina, Brazil and Mexico. Novartis has shared the TARGET data with all health authorities, including Health Canada. ABOUT OSTEOARTHRITIS Osteoarthritis (OA), the most common form of arthritis, is characterized by the breakdown of cartilage in joints, causing affected bones to rub against each other. This often leads to inflammation, pain and loss of movement. Globally, OA accounts for half of all chronic conditions in people age 65 and older, affecting approximately three million (one in 10) Canadians. It affects men and women in equal numbers and most people develop it after the age of 45, but it can occur at any age.9 Risk factors associated with OA include accidents, age, joint injuries due to sports, obesity or work-related activity. References 1. Schnitzer TJ, Burmester G R, Mysler E, Hochberg MC, Doherty M, Ehrsam E, Gitton X, Krammer G, Mellein B, Matchaba P, Gimona A, Hawkey CJ, on behalf of the TARGET Study Group. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: a randomised controlled trial. Lancet 2004; 364(9435):665-674. 2. Farkouh ME, Kirshner H, Harrington RA, Ruland S, Verheugt FWA, Schnitzer TJ, Burmester G R, Mysler E, Hochberg MC, Doherty M, Ehrsam E, Gitton X, Krammer G, Mellein B, Gimona A, Matchaba P, Chesebro JH on behalf of the TARGET Study Group. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: a randomised controlled trial. Lancet 2004; 364(9435):675-684. 3. Hawkey CJ, Farkouh M, Gitton X, Ehrsam E, Huels J, Richardson P. Therapeutic Arthritis Research and Gastrointestinal Event Trial of lumiracoxib - study design and patient demographics. Aliment Pharmacol Ther 2004;20(1):51-63. 4. Brune K, Hinz B. Selective cyclooxygenase-2 inhibitors: similarities and differences. Scand. J. Rheumatol. 2004;33:1-6. 5. Kellstein D, Ott D, Jayawardene S, Fricke J Jr. Analgesic efficacy of a single dose of lumiracoxib compared with rofecoxib, celecoxib and placebo in the treatment of postoperative dental pain. Int J Clin Pract 2004;58(3):244-250. 6. Tannenbaum H, Berenbaum F, Reginster J-Y, Zacher J, Robinson J, Poor G, Bliddal H, Uebelhart D, Adami S, Navarro F, Lee A, Moore A, Gimona A. Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a 13-week, randomized, double-blind study versus placebo and celecoxib. Ann Rheum Dis Published Online First February 27 2004. doi: 10.1136/ard.2003.015974. 7. Geusens P, Alten R, Rovensky J, Sloan V, Krammer G, Kralidis G, Richardson P. Efficacy, safety and tolerability of lumiracoxib in patients with rheumatoid arthritis: Results of a randomized double-blind study. Arthritis Rheum 2003;48(Suppl. 9):242 (Abstract 544). 8. Diclofenac US package insert. 9. The Arthritis Society (www.arthritis.ca). Retrieved on August 18, 2004. SOURCE: Edelman

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