COX-2 Inhibitors
Licofelone (ML3000)

COX189 (ML3000)
Meloxicam

COX189 (ML3000)
The following two abstracts report the results from studies investigating the gastrointestinal (GI) safety of a new COX2 inhibitor, COX189.

THU0226 IMPROVED UPPER GASTROINTESTINAL (UGI) SAFETY AND TOLERABILITY OF A NEW COXIB, COX189 COMPARED WITH IBUPROFEN IN OSTEOARTHRITIS PATIENTS
C.J. Hawkey, D. Karateev, C. Codreanu, Z. Dobronte, J. Gomez Reino, N. Hopkinson, S. Moodley, F. Murray, E. Nasonov, A. Orlov-Morozov, E. Pikhlak, P. Svoboda, Z. Tulassay, V. Zoubek, M. Cousin, X. Gitton, G. Hoexter

and

THU0232 TREATMENT OF HEALTHY SUBJECTS WITH COX189, A COX-2 SELECTIVE INHIBITOR; ENDOSCOPIC EVIDENCE FOR LACK OF GASTRO-DUODENAL EROSIONS COMPARED TO NON-SELECTIVE NSAID
C. Rordorf, G. Scott, P. Blood, S. Milosavljev, J. Branson, N. Kellet, S. Mair, M. Ford

Study one:
Methods: 1,042 patients with osteoarthritis (OA) were randomized in this multi-center, double-blind study to one of 4 treatment groups: 200 mg OD COX189 (n=264); 400 mg OD COX189 (n=260); 800 mg TID ibuprofen (n=258); and 200 mg OD celecoxib (n=260). Patients were evaluated by endoscopy for cumulative incidence of GI ulcers (diameter >3mm) at baseline, week 4, and week 13. Frequency of adverse events (AE), including GI serious adverse events (SAE), was also recorded.

Results:

Study two:
This second study compares gastro-duodenal effects in healthy subjects following treatment with COX189, naproxen, and placebo after 7 days of multiple dosing.

Methods: 60 healthy males (mean age 27+6 yrs) were enrolled in one of three groups (n=20 each); 200mg BID COX189; 500mg BID naproxen; or placebo. Each group received endoscopic exams at baseline and after 7 days of treatment. After the morning dose on day 6, blood samples (n=6) were collected serially up to 12 h. Both plasma and serum were obtained for measurement of concentrations of COX189 and thromboxane B2 (TxB2), respectively.

Results: Erosions in the mucosa of the stomach and /or duodenum were noted in 13 of 20 subjects in the naproxen group and 1 of 20 in the placebo group. No erosions were observed in the COX189 group. While evidence of COX-1 inhibition was noted in the serum of patients receiving naproxen, no evidence of COX-1 inhibition or significant changes in laboratory measurements were observed in the patients receiving COX189.

Conclusions: The GI tolerability of COX189 treatment at both 200 and 400 mg OD in patients with OA was similar to celecoxib and significantly better than ibuprofen, both in frequency of GI ulcers and GI symptoms. In terms of erosions, treatment with COX 189 was similar to placebo and significantly better than treatment with naproxen in a group of healthy subjects.

Editorial Comments: This is a new selective COX-2 inhibitor that, in these early trials, shows a GI safety profile similar to celecoxib.

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Meloxicam
THU0259 MELOXICAM DOES NOT INCREASE THE RISK OF CARDIOVASCULAR ADVERSE EVENTS COMPARED TO OTHER NSAIDS: RESULTS FROM THE IMPROVE TRIAL, A MULTI-CENTER, RANDOMIZED PARALLEL-GROUP, OPEN LABEL STUDY OF 1309 PATIENTS IN A MANAGED CARE SETTING
G.S. Singh, P. Gagnier, E. Hwang, E. Krishnan, M. Kobe

In this study, the incidence of cardiovascular adverse events in patients treated with meloxicam was compared to the incidence in patients treated with other NSAIDS.

Methods: 1309 patients with osteoarthritis participated in the IMPROVE trial, a multi-center, randomized, open label study. Patients received 7.5 mg/day meloxicam (n=662) or "usual care" (UC) (n=647) that consisted of any non-meloxicam NSAID and were monitored for 6 months. Monthly telephone calls were done to assess adverse events during the trial and within 14 days of discontinuation. Analyses were carried out in an intention-to-treat fashion.

Results:
The number of adverse events are summarized in the table below.

Conclusion: Risk of cardiovascular events is similar in patients treated with meloxicam compared to other NSAIDs.

Editorial Comments: It is not clear whether this study had a sufficient number of participants to detect a statistically significant difference in number of cardiovascular events between the two treatment groups. It is also not clear whether low dose aspirin was allowed in either arm of the study. If sufficient power is present in this study, the results are encouraging. While more selective COX-2 inhibitors are preferable for GI safety, less selective COX-2 inhibitors like meloxicam may be safer from a cardiovascular perspective.

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THU0189 FIRST CLINICAL RESULTS OF LICOFELONE (ML3000), AN INHIBITOR OF COX-1, COX-2 AND 5-LOX, FOR THE TREATMENT OF OSTEOARTHRITIS
J. Reginster, P. Bias, A. Buchner

GI toxicity with NSAID use is thought to involve alternative processing of arachidonic acid by 5-LOX to form leukotrienes. Leukotriene-modulated mechanisms are thought to be involved in the pathogenesis of osteoarthritis (OA). Therefore, inhibiting leukotriene formation through inhibition of both 5-LOX and both COX isoenzymes might have an anti-inflammatory effects without the GI toxicity and negative effects of selective COX-2 inhibition. Licofelone (ML3000) is a novel drug that inhibits these three enzymes: cyclooxygenase (COX)-1, COX-2 and 5-lipoxygenase (5-LOX).

Methods: In patients with OA, the efficacy and tolerability profile of licofelone treatment was compared to placebo and 500 mg bid naproxen. The first study was an endoscopic study. 118 healthy subjects with normal gastric and duodenal mucosa were treated for 4 weeks with licofelone 200 mg bid (n=30) or 400 mg bid (n=28), placebo (n=30) or naproxen 500 mg bid (n=30). The second study consisted of 148 patients with knee OA treated for 12 weeks with licofelone 200 mg bid or naproxen 500 mg bid. In both studies, the mucosa was evaluated with modified Lanza scores and ulcers (3 mm or more in diameter) were assessed. Efficacy was also evaluated in the second study of OA patients using the WOMAC index. Patients with a 30% improvement versus baseline were considered responders.

Results: In the endoscopic study, the gastric mucosa was completely normal after 4 weeks in 93% (200 mg bid), 89% (400 mg bid), 90% (placebo) and 37% (naproxen) of subjects. No ulcers were present in either licofelone group or the placebo group, however, 6 ulcers (20%) were observed in the naproxen group (5 GU, 1 DU).

The table below contains the data from the efficacy study.

Conclusion: The data from these two studies suggest that licofelone has comparable efficacy to naproxen but with less GI toxicity, thereby offering the possibility of an alternative treatment for patients with OA.

Editorial Comment: This is a novel drug that inhibits metabolism of arachidonic acid to prostanoids OR leukotrienes. The GI safety profile in this limited human study looks encouraging but much longer duration of exposure to the drug will be needed to confirm these findings.

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THU0191 THE IN VIVO INHIBITION OF CYCLOOXYGENASE AND 5-LIPOXYGENASE BY LICOFELONE (ML-3000) REDUCES THE PROGRESSION OF EXPERIMENTAL OSTEOARTHRITIS. SUPPRESSION OF COLLAGENASE-1 AND INTERLEUKIN-1b SYNTHESIS
J.P. Pelletier, J.C. Fernandes, F.C. Jolicoeur, D.V. Jovanovic, J. Martel-Pelletier, P. Reboul, S. Laufer, S. Tries

The purpose of this study was to determine the action of licofelone (ML-3000) on the synthesis of collagenase-1 (MMP-1) in cartilage and interleukin-1b (IL-1Β) in synovial membrane and its therapeutic effectiveness on the development of lesions in the experimental osteoarthritis (OA) dog model.

Methods: The anterior cruciate ligament of the right stifle joint of 21 mongrel dogs was sectioned with a stab wound. Dogs received either placebo (n = 7), licofelone 2.5 mg/kg/day (n = 7), or licofelone 5 mg/kg/day (n=7) beginning the day after surgery, and were killed 8 weeks later.

Results: Licofelone significantly decreased the size (condyles P < 0.05, 2.5 mg/kg/day; P < 0.04, 5.0 mg/kg/day; plateaus P < 0.01, P < 0.01, respectively) and grade (plateaus, P < 0.004, 2.5 mg/kg/day, P < 0.02, 5 mg/kg/day) of the cartilage lesions compared with the placebo-treated OA dogs. Additionally, the severity of cartilage lesions was also decreased in the licofelone-treated dogs versus the OA dogs both on the condyles (P < 0.03, 5 mg/kg/day) and the plateaus (P < 0.002, 2.5 mg/kg/day; P < 0.02, 5 mg/kg/day). All groups showed a notable and similar level of synovial inflammation. Licofelone significantly decreased the level of PGE2 in synovial fluid and LTB4 production by synovium and markedly decreased the levels of collagenase-1 in the cartilage and IL-1b in synovial membrane.

Conclusions: Licofelone treatment reduces the size and severity of cartilage lesions in experimental dog OA when compared to placebo treatment, as well as reduces the levels of inflammatory mediators PGE2, LTB4, and catabolic factors IL-1Β in synovium and collagenase-1 in cartilage.

Editorial Comment: The efficacy of licofelone in this dog OA study suggests it may have disease modifying properties.

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