Products & Development

GI-Safer NSAID Technology & Product Pipeline

Technology

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most prescribed medications in the United States. Although this class of drugs decreases the pain and inflammation associated with a number of chronic inflammatory disorders, all of these products cause injury to the gastrointestinal (GI) tract, including erosions, ulcers, bleeding and perforation. In fact, several large clinical studies have confirmed that 20-40% of those who take NSAIDs regularly have one or more ulcers in their stomach or intestines. In the United States, there are an estimated 16,500 deaths each year due to NSAID-induced gastrointestinal complications (primarily from GI hemorrhage), a higher death rate than for cervical cancer or malignant melanoma

Watch a video describing the NSAID-PC technology.

Dr. Lenard Lichtenberger, the scientific founder of PLx Pharma, has identified a key mechanism by which NSAIDs cause such GI damage: they disrupt the normal barrier to acid by interacting with components of the GI lining, most notably a component called phosphatidylcholine (PC). When NSAIDs are taken, they bind to the PC in the GI lining and compromise the lining’s acid-repelling properties. Over time, the disruption of the GI lining can lead to clinically significant—and sometimes life-threatening—damage, such as ulceration, bleeding and perforation.

Exploiting this insight, PLx has created formulations of the most commonly taken NSAIDs, in which the NSAID is “pre-associated” with PC; these products are the “NSAID-PC” platform. This NSAID-PC pre-association effectively sequesters the NSAID in a phospholipid envelope, allowing the NSAID to reach the blood stream without disrupting the GI lining. This technology allows the same effective dose of the NSAID to reach its site of action in the body, while significantly reducing the chances of GI damage. Importantly, the phosphatidylcholine that PLx uses in its formulations is a non-pharmaceutical natural product derived from soybeans. Phosphatidylcholine occurs naturally in the diet and has long been used as a food additive and nutraceutical.

The NSAID-PC technology is the basis of multiple domestic and international patents and is the subject of an exclusive worldwide license to PLx Pharma from The University of Texas.

Products

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most prescribed medications in the United States—today approximately 60 million Americans regularly use NSAIDs to manage their pain. PLx has a pipeline of prescription and over-the-counter NSAID products in development, all based on the GI-safer NSAID-PC technology, which employs a natural gastroprotective agent called phosphatidylcholine to reduce the occurrence and severity of GI injury.

PLx Product Pipeline

Naproxen-PC
Naproxen is extensively prescribed for the treatment of osteoarthritis and related disorders. It is widely considered not only to be among the most effective treatments for the pain and inflammation of arthritis, but it appears to be safer from a cardiovascular standpoint—naproxen is perceived by the prescribing community to be less likely to increase the risks of heart attack and stroke compared with other NSAIDs. At the same time, naproxen is generally considered among the most GI injurious of the NSAIDs. As a consequence of this profile, a GI safer naproxen has significant clinical and commercial potential.
Naproxen-PC is a molecular complex of naproxen and phosphatidylcholine. In extensive preclinical testing, the Naproxen-PC formulation has consistently provided a dramatic decrease in naproxen-induced GI injury, while preserving the anti-inflammatory and analgesic efficacy for which naproxen is well known.

Aspirin-PC
An estimated 58 million people in the U.S. and 100 million people worldwide suffer from one or more forms of cardiovascular disease. These diseases are responsible for 14 million deaths worldwide each year, and may account for as much as 20% of all deaths. Aspirin is frequently used in the prevention of stroke and heart attack (a strategy called “cardioprevention”), as it inhibits the aggregation of platelets—the blood components that cause clots to form. However, even at low doses, aspirin is GI toxic; even a single pill of aspirin can induce gastric bleeding. While most users have no resultant clinical GI symptoms (i.e., they have some GI damage but no symptoms), a significant percentage of the population (2-3%) experience ulcers and bleeding. The frequency of aspirin-induced GI toxicity is markedly increased by 2 to 6-fold when aspirin is taken with other NSAIDs, anti-depressant agents and other anti-platelet drugs.

Aspirin-PC is a molecular complex of aspirin and phosphatidylcholine. This product is being developed for the OTC and Rx markets. Preclinical and clinical data have demonstrated that a PC formulation can dramatically reduce aspirin-induced GI toxicity. Aspirin-PC has been clinically tested in a 32-patient trial using two doses, 325 mg and 650 mg. Aspirin-PC demonstrated bioequivalence with regular 325 mg Bayer Aspirin® including providing equivalent anti-platelet activity.

ZavrylTM (Ibuprofen-PC)
ZavrylTM (trademark pending) is a molecular complex of ibuprofen and phosphatidylcholine. The product is being developed for the prescription osteoarthritis and OTC pain markets. PLx has conducted three bioequivalence trials of Zavryl and gathered pharmacokinetic data for bioequivalence during a long-term trial at multiple doses; all trials to date indicate Zavryl is bioequivalent to ibuprofen. Moreover, a pilot endoscopy trial demonstrating that Zavryl possesses enhanced GI safety compared with ibuprofen has also been completed.

Other NSAID-PC Products

Indomethacin-PC
Indomethacin is a commonly prescribed oral and intravenously administered NSAID that reduces fever, pain and inflammation. Indomethacin is used for the treatment of inflammation caused by arthritis, most notably gouty arthritis, as well as soft tissue injuries such as tendinitis and bursitis. It is also used in a number of niche indications such as in the treatment of a life-threatening cardiac abnormality affecting low-birth-weight and premature infants called patent ductus arteriosus (PDA), in which indomethacin is administered intravenously (IV).

Indomethacin-PC is a molecular complex of indomethacin and phosphatidylcholine that is being developed in both oral formulations, as a GI safer anti-inflammatory and analgesic, and as an IV formulation for the treatment of PDA. The currently marketed IV indomethacin is an effective treatment for PDA, but can cause several forms of serious GI damage (called necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP)) that are themselves life-threatening. PLx’s Indomethacin-PC is being developed as an effective treatment of patent ductus arteriosus that does not increase the risk of NEC or SIP. Read more about patent ductus arteriosus.

Diclofenac-PC
Diclofenac is an orally and intravenously administered NSAID used for musculoskeletal complaints, especially arthritis, gout attacks and pain management in case of kidney stones and gallstones. Diclofenac is also sometimes used for the treatment of acute migraines. Diclofenac is used commonly to treat mild to moderate post-operative or post-traumatic pain, particularly when inflammation is also present.

Diclofenac-PC is a molecular complex of diclofenac and phosphatidylcholine that is being developed as a GI safer oral anti-inflammatory and analgesic drug.

5-ASA-PC
5-ASA (5-aminosalicylic acid) is an anti-inflammatory drug that is used as standard treatment of ulcerative colitis, a form of inflammatory bowel disease. 5-ASA-PC is in development at PLx as a safe and effective oral treatment of ulcerative colitis, and is being evaluated for its ability to be formulated for extended release.

Market

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most widely used classes of drugs, with over 33 million U.S. citizens consuming NSAIDs on a regular basis and annual sales exceeding $12 billion. Worldwide annual sales are projected to grow to $18.7 billion by 2010. In spite of this commercial success, chronic use of NSAIDs causes well documented gastrointestinal (GI) side effects. These side effects include ulcers and bleeding and lead to significant morbidity and mortality in many patients. A large group of NSAID users, approximately 18 million Americans with osteoarthritis, are at risk for GI toxicity. Death in the U.S. from GI complications has reached 16,500 annually and is similar in scale to AIDS related mortality.

The class of NSAIDs known as the Cox-2 inhibitors introduced in the late 1990s revolutionized this market, as they were significantly GI safer than other NSAIDs and provided effective pain and inflammation relief. These products targeted the large arthritis market. Indeed, at their peak, the class of drugs enjoyed tremendous sales levels, reaching nearly $6 billion in annual global sales from 2001-2003; sales of Vioxx® alone were $2.5 billion in 2003.

However, concerns emerged as experience with the Cox-2 class of drugs increased and evidence amassed that the drugs increase the chance of having a heart attack or stroke. These developments led to major changes for the marketed Cox-2 drugs, including the withdrawal of Vioxx® and Bextra® and the addition of a black-box warning to the Celebrex® label. These changes, in turn, created a multi-billion-dollar void in the market and led to the increased utilization of NSAID products that are perceived to have reduced GI toxicity and better cardiovascular safety. PLx’s pipeline of GI safer NSAIDs will provide important new alternatives to further satisfy the market’s need for additional GI safer anti-inflammatory agents.

Scientific Publications

• Lanza FL, Marathi UK, Anand BS, Lichtenberger LM. Clinical trial: comparison of ibuprofen-phosphatidylcholine and ibuprofen on the gastrointestinal safety and analgesic efficacy in osteoarthritic patients. Alim Pharm Ther: 28: 431-442, 2008.
     
• Dial EJ, Darling RL, Lichtenberger LM. Importance of biliary excretion of indomethacin in gastrointestinal and hepatic injury. J Gastroenterol Hepatol: in press, 2008.
     
• Lichtenberger, L. M., J. J. Romero, et al. Surface phospholipids in gastric injury and protection when a selective cyclooxygenase-2 inhibitor (Coxib) is used in combination with aspirin. Br J Pharmacol 150(7): 913-9, 2007.
     
• Lichtenberger LM, Zhou Y, Dial EJ, Raphael RR. NSAID injury to the gastrointestinal tract: evidence that NSAIDs interact with phospholipids to weaken the hydrophobic surface barrier and induce the formation of unstable pores in membranes. J Pharm Pharmacol 58: 1421-1428, 2007.
       
• Dial EJ, Doyen JR, Lichtenberger, LM. Phosphatidylcholine-associated nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit DNA synthesis and the growth of colon cancer cells in vitro Cancer Chemother Pharmacol: 57: 295-300, 2006.
     
• Darling, R. L., J. J. Romero, et al. The effects of aspirin on gastric mucosal integrity, surface hydrophobicity, and prostaglandin metabolism in cyclooxygenase knockout mice. Gastroenterology 127(1): 94-104, 2004.
     
• Lichtenberger, L. M. Where is the evidence that cyclooxygenase inhibition is the primary cause of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal injury? Topical injury revisited. Biochem Pharmacol 61(6): 631-7, 2001.
     
• Anand, B. S., J. J. Romero, et al. Phospholipid association reduces the gastric mucosal toxicity of aspirin in human subjects. Am J Gastroenterol 94(7): 1818-22, 1999.
     
• Giraud, M. N., C. Motta, et al. Interaction of indomethacin and naproxen with gastric surface-active phospholipids: a possible mechanism for the gastric toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs). Biochem Pharmacol 57(3): 247-54, 1999.
     
• Giraud, M. N., S. K. Sanduja, et al. Effect of omeprazole on the bioavailability of unmodified and phospholipid-complexed aspirin in rats. Aliment Pharmacol Ther 11(5): 899-906, 1997.
     
• Lichtenberger, L. M., C. Ulloa, et al. Nonsteroidal anti-inflammatory drug and phospholipid prodrugs: combination therapy with antisecretory agents in rats. Gastroenterology 111(4): 990-5, 1996.
     
• Lichtenberger, L. M. The hydrophobic barrier properties of gastrointestinal mucus. Annu Rev Physiol 57: 565-583, 1995.
     
• Lichtenberger, L. M., Z. M. Wang, et al. Non-steroidal anti-inflammatory drugs (NSAIDs) associate with zwitterionic phospholipids: insight into the mechanism and reversal of NSAID-induced gastrointestinal injury. Nature Medicine 1(2): 154-8, 1995.
     
• Goddard, P. J. and L. M. Lichtenberger In vitro recovery of canine gastric mucosal surface hydrophobicity and potential difference after aspirin damage. Dig Dis Sci 40(6): 1357-9, (1995).
     
• Hills, B. A., B. D. Butler, et al. Gastric mucosal barrier: hydrophobic lining to the lumen of the stomach. Am J Physiol 244(5): G561-8, 1983.
     
• Lichtenberger, L.M. L.A. Graziani, E.J. Dial, B. D. Butler and B. A. Hills. Role of surface-active phospholipids in gastric cytoprotection. Science 219: 1327-1329, 1983.