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Prexige Significantly Reduces Gastrointestinal Events Without Compromising Cardiovascular Safety Compared To NSAIDs

BASEL, SWITZERLAND -- August 20, 2004 -- Novartis Pharma AG 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% 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.

"The excellent GI and CV safety profile of Prexige demonstrated by the positive results of TARGET shows a favorable 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.

"With up to an estimated 16,500 GI-related deaths in the U.S. each year, these convincing data from 18,325 patients with osteoarthritis (OA) builds on the body of evidence suggesting that Prexige is effective while offering substantial GI safety benefits. TARGET fully supports the approved label in the UK and builds a strong basis for the ongoing European Mutual Recognition Process (MRP), which was recently started," Reinhardt said.

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% 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 <.0001). Prexige significantly reduced the incidence of upper GI ulcer complications in those patients not taking aspirin by 83% versus ibuprofen, and by 76% 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% versus the two NSAIDs. For the smaller subgroup of patients taking aspirin, a numerical trend of 21% decrease of ulcer complications in favor of Prexige was observed compared to the NSAIDs.¹

"TARGET was a very well-designed study and therefore yields robust results for Prexige, demonstrating an up to four-fold reduction in the incidence of GI ulcer complications compared to NSAIDs," said Chris Hawkey, MD, Professor of Gastroenterology and Co-director of the Institute of Clinical Research, University of Nottingham and Chairman of the GI committee during the TARGET trial. "The benefit demonstrated by Prexige has not been shown by any other selective COX-2 inhibitor."

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 ibuprofen².

"TARGET demonstrates that Prexige has a CV profile similar to conventional NSAIDs with a more favorable blood pressure profile. These very important results show that Prexige offers GI benefits to patients without compromising their CV safety," said Michael Farkouh, MD, Director of the Cardiac Care Unit at New York University Medical Center and Chair of the TARGET Cardio-Cerebrovascular adjudication committee. "In TARGET we found no difference in MIs, stroke or any of the other CV endpoints investigated between Prexige and ibuprofen or naproxen."

For the pre-specified end point combining serious GI and CV events, Prexige at up to four times the recommended dose for OA showed a significant 35% reduction (P =.001) versus the NSAID groups¹. Importantly, mean changes in systolic and diastolic blood pressure from baseline for patients taking Prexige were significantly smaller (P </=.0001) than for those taking NSAIDs (systolic +0.4 mm Hg vs. +2.1 mm Hg respectively; diastolic -0.1 mm Hg vs. +0.5 mm Hg 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%], while two cases in the group using ibuprofen [0.05%] and one with naproxen [0.02%] 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% versus 0.6% respectively], but were less frequent than seen with the most widely prescribed NSAID diclofenac [4%].⁸

Recently completed studies with Prexige 100 mg daily in OA have shown hepatic enzyme elevations to be comparable to placebo at 13 weeks [0.25% 3xULN] (data on file).

About TARGET
TARGET was designed to answer questions about the overall safety of Prexige, building on the experience and shortcomings of previous GI outcomes 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. 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 or four 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% 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 at up to four times the recommended dose for OA showed a significant 35% reduction (P =.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 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%), the choice of homogenous study population with OA and stratifying at randomization 24% 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 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 US Food and Drug Administration (FDA) reviewed the TARGET protocol, and an independent data and safety monitoring board evaluated study data on an interim basis.

About Prexige
Prexige 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 100mg od (data on file) and 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 have shared the TARGET data with all health authorities, including the UK Health Authority and the MHRA, and are currently initiating the Mutual Recognition Procedure (MRP) process in Europe.


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


SOURCE: Novartis Pharma

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