AstraZeneca's NDA for the Prilosec follow-on product Nexium includes an indication for "on demand" maintenance treatment for gastroesophageal reflux disease.

Nexium (esomeprazole, formerly perprazole) "will be the first product indicated for this new use in symptomatic GERD," AstraZeneca Exec VP-Gastrointestinal Franchise Martin Nicklasson, PhD, told a briefing for securities analysts in London Dec. 6.

The indication would allow patients to take medication when symptoms appear, while other drugs require daily use for maintenance of healing of gastro-esophageal reflux disease.

"Over six-month treatment, we have shown that some 90% of the patients are kept in symptom remission after taking Nexium 20 mg on demand," Nicklasson reported. "This is the new, highly convenient, cost-effective approach to maintain therapy of symptomatic GERD," he said.

The Nexium NDA, submitted Dec. 3, contains five indications in addition to "on demand" GERD treatment: healing of reflux esophagitis, daily treatment to prevent relapse, treatment of heartburn/GERD, healing of H. pylori-associated duodenal ulcer, and H. pylori eradication.

Together, the six indications "represent new management approaches that will clearly distinguish Nexium from other" proton pump inhibitors, Nicklasson declared.

Nicklasson also highlighted an indication for one-week triple combination therapy for healing H. pylori-associated duodenal ulcers as breaking new ground for a PPI. Healing H. pylori ulcers in the U.S. traditionally requires 10 days of therapy with a PPI and two antibiotics, followed by three weeks of PPI monotherapy.

Nexium demonstrated over 90% healing without the monotherapy follow-up, Nicklasson said.

The NDA includes data both for a 10-day triple therapy course as well as a seven-day course, which is in line with the European standard of care, he indicated. AstraZeneca filed for European approval of Nexium Oct. 21 (¹ Also see "AstraZeneca's Pulmicort Posts $65 Mil. In Nine-Month U.S. Sales" - Pink Sheet, 1 November, 1999.).

The "on demand" and shorter H. pylori regimens will help AstraZeneca build cost-effectiveness arguments in support of switching patients to Nexium from older agents.

"We recognize the importance of managed health care and government pressure around Europe," AstraZeneca CEO Tom McKillop, PhD, said. "They are looking for health economic arguments that really stand up and we intend to deliver."

AstraZeneca's cost-effectiveness arguments apparently will not center on a direct pill-to-pill comparison between the price of Nexium and Prilosec (omeprazole).

While not specifically revealing a price for Nexium, McKillop guided analysts to expect a premium: "What would you forecast for it if Pfizer came up with a drug that could beat the pants off of omeprazole? See it that way, because that is how it is going to be."

One element that will affect AstraZeneca's pricing decision is the status of the patent estate surrounding Prilosec. "Because of the intellectual property position of [Prilosec], what happens means that one will be balancing, that one will be playing his men in the game of chess very carefully," McKillop said.

AstraZeneca is potentially facing a tight deadline for the Nexium launch. The basic omeprazole patent expires in April 2001, although the company plans to file a pediatric supplement before that date to secure an additional six months of exclusivity.

FDA's user fee goal date for Nexium will be in late 2000, assuming the product receives a standard 10-month FDA review.

AstraZeneca has numerous secondary patents surrounding omeprazole and is planning a vigorous defense. Over 50 lawsuits have been filed surrounding the omeprazole patent estate, Nicklasson reported.

AstraZeneca's development program has reflected the urgency of beating the Prilosec patent expiration.

The clinical studies of Nexium enrolled over 15,000 patients "and were completed in record time," Nicklasson said. "It took less than two years to run the full NDA program."

Esomeprazole is a single stereoisomer formulation of omeprazole. However, McKillop declared, analysts should "consider Nexium to be a new chemical entity." Nicklasson called Nexium "the first iPPI."

Nexium is the first drug in the class to show a significant benefit over Prilosec, Nicklasson maintained.

In erosive esophagitis healing, Nexium 40 mg demonstrated a statistically significant improvement of over 10% compared with Prilosec 20 mg, he said. Therefore, of the estimated 300,000 GERD patients in the U.S., over 30,000 more would be healed on first treatment with Nexium than with Prilosec, Nicklasson surmised.

Prilosec 20 mg healed 74% of cases of erosive esophagitis after eight weeks and 39% after four weeks, according to U.S. labeling. A 40 mg dose was not statistically better.

Use of PPIs is greatest for GERD and that is the largest growth segment for the drug class, Nicklasson noted.

"Although [Prilosec] is the largest selling pharmaceutical product in the world, it has only 35% prescription share of the combined proton pump inhibitor and H2 blocker segment, highlighting greater opportunities for growth, not only for [Prilosec] but also for esomeprazole," he said.

McKillop asked the analysts to "reflect [on] when H2 blockers were introduced and they were supposed to be the perfect drugs. And when PPIs came along, they had an improvement of the order that you are seeing for Nexium over [Prilosec]."

"Many people thought PPIs would not displace H2 blockers," McKillop continued. "They were very wrong. Because better, more effective drugs that treat more people faster usually come through very strongly in the marketplace."

AstraZeneca's efforts to differentiate Nexium from Prilosec include the selection of a new advertising agency, Grey Advertising, to handle consumer promotions. AstraZeneca works with Klemtner and Saatchi & Saatchi on the direct-to-consumer campaign for Prilosec (² Also see "AstraZeneca Prilosec DTC Ad Spending Projected To Reach $70 Mil. In 1999" - Pink Sheet, 13 December, 1999.).

The new compound has a lower first-pass metabolism and higher area under the curve absorption profile than omeprazole, Nicklasson said. These features allow it to reach gastric parietal cells at much higher concentrations than omeprazole, allowing higher gastric pH for longer periods. Also, Nexium shows less interpatient PK variability than omeprazole, according to the company.

Nicklasson pointed out that the AUC differences between the racemic compound and the newer follow-on product are not linear. Thus, the effects of Nexium could not be achieved simply by taking a higher dose of Prilosec.

Although a 40 mg dose of Prilosec has no clinical advantage over 20 mg for erosive esophagitis healing, Nexium 40 mg does have a dose effect over 20 mg.

The higher dose of Nexium was used comparator in trials to show the best clinical effect and the lower dose of Prilosec was used as the comparator because it is the only approved dose, Nicklasson noted. Nexium 20 mg and 40 mg both showed numerical but not statistical superiority to equivalent doses of Prilosec.

Nexium also works faster, according to Nicklasson. After four weeks therapy, more Nexium patients were cured of erosive esophagitis than patients after eight weeks of Prilosec, he reported.

GERD symptom/heartburn relief and sustained freedom from symptoms were achieved after five days for Nexium patients compared with nine days on Prilosec. Symptom relief began on the first day.

The more consistent pharmacokinetic profile of esomeprazole allows the drug to be more effective in patients with outlier metabolism of other PPIs, who do not respond, Nicklasson explained. Nexium was more effective for patients with all severities of GERD, from mild to severe, he said.

Nicklasson indicated that Nexium is being studied for other indications.

Other gastrointestinal compounds in early clinical trials for AstraZeneca include rofleponide for inflammatory bowel disease and Crohn's disease. Rofleponide failed in clinical trials for asthma.

AstraZeneca is also studying a reversible PPI, a reflux inhibitor, and an H. pylori vaccine.

AstraZeneca Nexium NDA Includes "On-Demand" Dosing

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