Two drug companies hope to make a better arthritis drug with one pill that's a combination of a 30-year-old painkiller and a popular heartburn treatment. In the process they will seek to fill a void left when Vioxx was pulled from the market two years ago over safety concerns.
AstraZeneca PLC (AZN) of the U.K. and Pozen Inc. (POZN), Chapel Hill, N.C., recently formed a collaboration to develop a fixed-dose combination of naproxen, which is a generic pain reliever sold under the prescription brand Naprosyn and over-the-counter as Aleve, plus Nexium, AstraZeneca's blockbuster heartburn pill that racked up $4.6 billion in sales last year.
The companies plan to market the product as a treatment for pain associated with osteoarthritis and rheumatoid arthritis in people at risk for developing gastric ulcers caused by certain painkillers. Initially it would be a twice-a-day treatment, according to Pozen Chief Executive John Plachetka.
There are risks, however. As yet, there are no clinical data to prove the single-pill combination will work. And naproxen's label currently carries a warning that it can increase the risk of heart attack or stroke. A patient trial is expected to begin next year, and the drug is probably at least a couple of years away from reaching the market.
But the plan is to offer naproxen's pain relief while Nexium, known as a proton-pump inhibitor, alleviates some of naproxen's gastrointestinal side effects such as ulcers and bleeding.
"The idea is to produce a dosage form where the protectiveness of the product is released and deployed before" the gastrointestinal harm of naproxen occurs, Plachetka said in an interview.
Some arthritis specialists already prescribe naproxen and proton-pump inhibitors, or PPI's, to be taken together as separate pills. One company, Tap Pharmaceutical Products Inc., markets naproxen and the PPI Prevacid as separate pills in one package called Prevacid NapraPac. But Pozen and AstraZeneca believe a combination pill would be more convenient for patients and more effective in guarding against gastrointestinal problems.
If it works, Pozen and AstraZeneca think the single-pill combination could invade territory once dominated by a class of painkillers known as Cox-2 inhibitors. These drugs, including Merck & Co.'s (MRK) Vioxx and Pfizer Inc.'s (PFE) Celebrex, were designed to reduce the gastrointestinal side effects seen in older drugs like naproxen.
Merck's withdrawal of Vioxx from the market over safety concerns in 2004, however, raised questions about the cardiovascular risks of Cox-2 drugs. Merck said a study showed Vioxx elevated the risk of heart attack and stroke in people taking it for at least 18 months. In an earlier study involving both Vioxx and naproxen, there were five times as many heart attacks among those taking Vioxx as in the naproxen group.
A combination naproxen-Nexium could go after Celebrex, which remains on the market but with a warning on its label that it may cause an increased risk of heart attack and stroke. One government study found a two- to three-fold risk of heart attack, stroke or other cardiovascular events associated with Celebrex, compared with a fake pill, or placebo.
Another Cox-2, Pfizer's Bextra, also was withdrawn from the market last year over safety concerns. In 2004, the three main Cox-2 inhibitors - Vioxx, Celebrex and Bextra - had combined sales of more than $6 billion. But last year sales of Celebrex, the only Cox-2 left on the U.S. market, had fallen to $1.7 billion from $3.3 billion the year before.
Naproxen isn't free of concerns about cardiovascular safety, however, and while one study suggested it was safer on the heart than Vioxx, it's unclear whether naproxen is safer on the heart than Celebrex.
In late 2004, the National Institutes of Health said a study showed an apparent increase in risk for heart attacks, strokes or other cardiovascular events among people taking naproxen when compared to those on placebo. There was no significant increase in risk for Celebrex in the same NIH trial, which was designed to study whether the drugs could prevent Alzheimer's disease. NIH suspended use of both drugs in the trial, noting a separate study had raised questions about Celebrex's cardiovascular risk.
Still, some industry watchers believe naproxen is among the safest on the heart of all nonsteroidal anti-inflammatory drugs, or NSAID's, which include Cox-2's as well as older painkillers such as ibuprofen, sold under the brands Advil and Motrin, and diclofenac, sold as Voltaren.
"It's a smart idea," Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic, said of the proposed naproxen-Nexium combination. "Naproxen, in all the studies, looks like it is very neutral from the point of view of cardiovascular risk.... However, it can be very hard on the stomach, and there is some data suggesting if you give a PPI that reduces stomach acid, it can reduce the risk of GI ulcer and bleeding."
Nissen is lead investigator of a large trial to study the relative heart safety of Celebrex, naproxen and ibuprofen. In the Pfizer-funded study, patients also are receiving a PPI to protect their gastrointestinal tracts, Nissen said, and the study will monitor gastrointestinal events.
David Graham, a drug-safety researcher for the Food and Drug Administration, recommended in the medical journal JAMA last month that generic naproxen plus a PPI would be less costly, equally as effective, and "probably safer" than low-dose Celebrex. He was referring to taking the drugs as separate pills.
Graham's JAMA editorial accompanied an analysis by other researchers suggesting naproxen didn't alter the risk of cardiovascular events; and that a lower dose of Celebrex didn't increase cardiovascular risk, but a higher dose appears to increase risk.
Gail Cawkwell, Pfizer's senior medical director for Celebrex, noted that all NSAIDs carry the same boxed warning about cardiovascular risk, and there was "no way to confirm that one medication is safer than the other for the heart" based on present data.
Some industry watchers question whether a combination pill is necessary given the availability of generic naproxen and over-the-counter PPI's. In an interview, Graham of the FDA said he fears that marketers would try to charge a higher price for a naproxen-Nexium combination pill than that of generic naproxen plus a PPI.
"You can take two tablets for a very low cost," said Graham, who emphasized he wasn't speaking for the FDA. "Unless the proposal to combine the medications together would be at the price of a generic, it's hard to sort of rationalize the increased expense."
AstraZeneca and Pozen say it's too early to talk about pricing for their combination product. According to drugstore.com, a month's supply of Nexium sells for between $136 and $148, depending on the dosage. A month's worth of Celebrex was listed at between $60 and $145, depending on dosage. A month's supply of Prevacid Naprapac costs about $137, according to drugstore.com.
Pozen's Plachetka suggested the combination pill's convenience would be a good selling point.
"People will end up skipping that PPI if they have to take it as a separate pill," Plachetka said. "In our combination product, they can't skip it. I don't think you can put a price on that."
Also, Plachetka thinks a combination naproxen-Nexium would be more effective than a separate-dose regimen in protecting against gastrointestinal side effects. He said Pozen has a proprietary drug-delivery system designed to immediately release the PPI upon ingestion, while delaying release of the naproxen if necessary to protect the stomach.
Pozen and AstraZeneca aren't the only companies trying to develop a new naproxen-based painkiller. NicOx SA (7413.FR) of France is developing naproxcinod, a combination of naproxen and the company's proprietary technology based on nitric oxide. NicOx says the drug has the potential for good gastrointestinal tolerability and safety, with no harmful effects on blood pressure. Data from a late-stage study of the drug are expected to be released soon.
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