Merckle demonstrate superior safety of Licofelone the first dual COX/LOX inhibitor: Opportunities for improved osteoarthritis treatment

DailyUpdates 22nd April: Phase III studies have previously shown Merkle’s first in the class COX/LOX inhibitor, Licofelone, to be equally effective to standard treatments of osteoarthritis.  Moreover, gastrointestinal adverse events tended to be less frequent in patients treated with licofelone as compared to naproxen.  In this month’s edition of the American Journal of Gastroenterology new data is published showing clear cut advantages of licofelone arising from the dramatic reduction in incidence and severity of gastroduodenal erosion and ulceration as compared to naproxen.

Osteoarthritis is characterized by the degeneration of the articular cartilage and is the most prevalent form of arthritis, affecting 10% of the population, equating to a patient population of over 73 million people in the seven major pharmaceutical markets.

Current pharmacotherapy of osteoarthritis is sub-optimal and focuses on the use of NSAIDs which do not alter the course of disease and which are associated with frequent adverse events. Disease modification is currently the ‘holy grail’ in the treatment of osteoarthritis, driven by an aging population and recent success of disease modifiers for rheumatoid arthritis (for an analysis of DMOARDs click here).  For the near term however, improving the therapeutic margin of NSAIDs remains a more pressing priority.

Conventional NSAIDs, by inhibiting cyclooxygenase (COX)-1 are effective in treating osteoarthritis, but have a high risk of adverse gastrointestinal events. More recently developed selective COX-2-inhibitors have fewer gastrointestinal side effects and are now used in 34% of the total osteoarthritis population (for an evaluation of COX-2 R&D click here). Uptake varies over the seven different markets with 40% of severe patients currently prescribed them in the and only 26% of severe patients receiving them in the . This variation is due to pricing and concern over side effects. Although the consensus is that COX-2 inhibitors do reduce gastrointestinal events, possible cardiovascular effects remain a concern.  Current thinking is that although the use of COX-2 inhibitors does not present a cardiovascular risk, possible cardiovascular benefits associated with non-selective COX inhibitors, primarily naproxen, may be lost.

Prexige (lumiracoxib), developed by Novartis, was set to be the fourth COX-2 on the market in late 2003. However, the FDA delayed its approval and it is now unlikely that it will be approved before 2005. The decision to delay can be attributed to a number of potential factors, including long-term effects, or the reaction to VIGOR results which demonstrated a reduced risk of cardiovascular events with naproxen as compared to the COX-2 inhibitor, rofecoxib.

Alternatives to the development of COX-2 selective inhibitors are currently being sought in an attempt to diminish the gastrointestinal toxicity of NSAIDs.  There is evidence that NSAID-induced gastrointestinal toxicity may involve shunting of arachidonic acid metabolism to the 5-lipoxygenase pathway, thereby increasing the production of pro-inflammatory and gastrotoxic leukotrienes. Merckle’s Licofelone (ML-3000) is the first member of a new class of analgesic and anti-inflammatory compounds that inhibits both COX and LOX offering a new approach to reducing the toxicity of NSAID drugs.

In experimental models, licofelone has been shown to have good gastrointestinal and general tolerability and analgesic and anti-inflammatory properties and furthermore, there is evidence from animal models to suggest that licofelone may stop disease progression by reducing the expression of various matrix metalloproteinases, cathepsin K and IL-1beta, as well as chondrocyte death.  Licofelone may therefore equal COX-2 inhibitors in terms of gastrointestinal safety, benefit from advantages afforded to the inhibition of COX-1 and may even have some disease modifying activity.

Data from two clinical trials investigating the efficacy of licofelone in the treatment of osteoarthritis were presented at the Annual Meeting of the of Rheumatology (ACR).

One phase III study compared the long-term safety and efficacy of licofelone 100 and 200 mg bid with naproxen 500 mg bid. Using the and McMaster Universities (WOMAC) pain score as an indicator, the efficacy of 200 mg licofelone and naproxen were similar throughout the 52 week study period.  A second reported study was designed to compare the safety and efficacy of 200mg licofelone with an equivalent dose of the selective COX-2 inhibitor, celecoxib in patients with symptomatic knee osteoarthritis.  In this 12 week multicenter, double-blind trial the efficacy of licofelone was found not to differ from that of celecoxib. 

The phase III study demonstrated a trend towards a reduction in overall gastrointestinal adverse effects as compared to naproxen.  Gastrointestinal adverse effects were similar in patients treated with celecoxib and licofelone.  Non-gastrointestinal events (namely worsening of peripheral edema with celecoxib and the incidence of aggravated hypertension with naproxen) were reduced in the licofelone groups. 

Gastrointestinal adverse effects range in seriousness and frequency from epigastric discomfort to life-threatening ulceration and bleeding. In their recent American Journal of Gastroenterology paper, Bias et al report the results of an endoscopy trial comparing the gastroduodenal tolerability of licofelone to placebo and naproxen in healthy volunteers focusing on gastro-duodenal erosion.

In this study of 121 healthy volunteers, licofelone was administered at 200 or 400 mg bid and tolerability, assessed by gastro/duodenoscopy following 4 wk of treatment, was compared to naproxen 500 mg bid or placebo. Ulcers were observed in 20% of the naproxen-treated volunteers, compared with 0% of those receiving licofelone or placebo. Post-treatment mean gastric erosion (Lanza) scores were similar for volunteers who received placebo or either dose of licofelone, while Lanza scores were significantly worse following naproxen therapy. The gastric mucosa was normal in > 89% of volunteers who received licofelone or placebo compared with 37% of volunteers receiving naproxen.

The results from this trial indicate that although the tolerability advantage of licofelone over naproxen was not significant in the phase III trial, when the incidence of more serious gastroduodenal events is investigated, a clear cut advantage is evident which, when taken alongside efficacy data, supports the use of licofelone as an alternative to naproxen. The similar efficacy of licofelone and celecoxib and the reduced incidence of peripheral edema with the former as well as possible cardiovascular benefits and diseases modifying activity suggests possible advantages of licofelone over COX-2 inhibitors.  Further clinical studies are awaited.

Source DailyUpdates 22nd April; for a full abstract of the original papers see   Am J Gastroenterol. 2004 Apr;99(4):611-8 .

Recommended further reading:

• Disease Modifying Osteoarthritis Drugs - The Search for the 'Holy Grail' Continues
• Osteoarthritis - COX-2s wear down traditional NSAID use
• Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates
• Rheumatoid Arthritis - DMARDs Gain Ground as Biologics Competition Intensifies

In this edition of DailyUpdates, LeadDiscovery also highlights novel blockers of the voltage-gated potassium channel Kv1.3 with immunosuppressive activity...the effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol...5-HT(2C) receptor agonists as potential anorectics...bone and joint neuropathy in rats with type-2 diabetes...and much more.