TAKEDA-ABBOTT PREVACID FOR SHORT-TERM HEALING OF EROSIVE ESOPHAGITIS, SYMPTOM RELIEF FOR UP TO EIGHT WEEKS RECOMMENDED FOR APPROVAL BY FDA COMMITTEE

Takeda-Abbott Pharmaceuticals' proton pump inhibitor Prevacid (lansoprazole) for short-term healing and symptomatic relief of up to eight weeks in duration for patients with grade 2 and higher acute erosive reflux esophagitis received a unanimous 9-0 recommendation for approval Dec. 2 from FDA's Gastrointestinal Drugs Advisory Committee.

The committee found, however, that data presented was insufficient evidence of the drug's safety for long-term maintenance for healed erosive esophagitis in light of limited safety data and results of studies with rats and mice.

TAP lansoprazole consultant James Freston, MD, University of Connecticut, presented data for the short-term EE use of lansoprazole from five clinical trials in the U.S. and four abroad, in the U.K., Norway and France, involving a total of 9,240 patients, including 6,752 who were administered lansoprazole. The primary endpoint was complete endoscopically-documented healing of EE. Symptomatic relief was the secondary endpoint. Only one of the trials included patients with non-erosive reflux esophagitis.

The drug's efficacy was not at issue for the committee. Trial protocols compared 15 mg and 30 mg doses of lansoprazole to placebo and ranitidine (Glaxo's H[2] antagonist Zantac) 150 mg b.i.d. A smaller 7.5 mg dosage was not selected for the indication in light of European trial results that determined that the strength was equal or inferior to ranitidine in healing duodenal ulcers, Freston said. A 60 mg dose of lansoprazole was determined to be of approximately the same efficacy as the 30 mg dose, so the higher dose was not included for the indication.

Patients were enrolled with erosive esophagitis of grade 2 or higher, up to grade 4, described as the presence of "multiple erosions/ulcerations involving > 50% distal 5 cm of esophagus or single large ulcer > 5 mm in diameter." Complete healing was defined as a grade 0 or grade 1, which was described as the presence of "edema, hyperemia and/or friability."

In separate trials, lansoprazole was found to be superior to both placebo and ranitidine for healing and symptomatic relief of acute EE. Trial M89-349 showed healing rates at 63% for lansoprazole versus 27% with ranitidine at week two, 75% versus 43%, and 84% versus 32% at weeks four and eight, respectively.

When compared to placebo, the percentage of patients healed was 68% with 15 mg and 81% for both the 30 mg and 60 mg dosages at four weeks versus 33% for placebo, and within 91%-95% for the three dosage levels versus 53% for placebo at eight weeks. Healing rate at week eight for the most severe grade 4 Eli patients in two trials was 62% for lansoprazole 30 mg versus 0% for ranitidine in the first trial and 70% for lansoprazole versus 10% for placebo in the second trial.

Freston maintained that two strong points in the drug's acid inhibition profile are its rapid onset and long duration of action. Prevacid's onset of action is within one to two hours, Freston said. "In terms of control of the pH over a 24-hour period, the 30 mg dose is clearly superior to the 15 mg dose and obviously both are superior to what's observed at baseline," Freston said. The 30 mg dose was the committee's recommended daily dose for the short-term indication.

Freston noted that in a ranitidine comparison trial, more ranitidine patients remained healed at four weeks (43%) than at eight weeks (32%) compared to 75% and 84%, respectively, for lansoprazole patients.

Of the 19 patients who failed the trials at eight weeks, 10 patients were healed with an additional eight weeks of lansoprazole therapy. No safety issues were a concern at 16 weeks of therapy, Freston maintained. No tachyphylaxis was observed, "unlike the H[2] blockers," he said.

Clinical studies of lansoprazole began in Japan in 1985. The drug is currently approved for short-term use in 42 countries and marketed in 35, according to TAP VP-R&D John Seely, PhD. Approximately 3 mil. patients have used the PPI internationally since marketing began in 1992, Seely said.

Lansoprazole's NDA application (20-406) includes indications for the treatment of duodenal ulcer and hypersecretory conditions, including Zollinger-Ellison syndrome, in addition to acute treatment and maintenance of erosive reflux esophagitis; however, Seely told the committee that FDA had requested the meeting focus on the EE indications.

Three hundred sixty-six patients were enrolled in maintenance trials, which involved comparing lansoprazole versus placebo for a 12-month duration. Patients were clinically and endoscopically diagnosed at baseline, months one, two, three, six, nine and 12. The primary endpoint was the time to first endoscopic recurrence of grade 2 or higher EE and the secondary endpoint was symptom appearance.

At the end of one year, 79% and 90% of patients taking daily doses of 15 and 30 rag, respectively, of lansoprazole did not relapse, versus 24% on placebo. All grade 4 patients who were randomized to placebo had relapsed by the end of two months. For the lansoprazole-treated groups, the percentage of grade 4 patients who relapsed was only slightly above those in grades 2 and 3. The committee concluded that 15 mg daily should be the maintenance dosage.

The most frequently reported adverse events were headache, diarrhea, abdominal pain and nausea in U.S. short-term study comparisons with placebo and ranitidine, Freston reported. The incidence rate for diarrhea of 4.3% with lansoprazole was higher than the 1.9% rate with ranitidine. The highest incidence rate occurred with the non-indicated 60 mg dose of lansoprazole (7.4%), but the studies showed that the incidence was less with the 15 mg dose (1.4%) compared to placebo (2.9%).

No differences were noted in premature terminations from the trials due to ADRs when compared with ranitidine or placebo for both short- and long-term studies. No significant drug interactions were found; studies noted a 10% increase in clearance of theophylline with a decreased AUC of theophylline of 13%.

Five deaths occurred in worldwide uncontrolled studies which included patients with ZES, Barrett's disease and hepatically impaired patients. Three of these patients died of complications from ZES, one Phase I end-stage liver disease patient died of expected complications from liver failure and a 70-year old patient died at home of reasons unknown; these deaths were not associated with lansoprazole usage, Freston said.

The long-term data was not sufficient to garner an approval recommendation for the long-term indication from the gastrointestinal committee, which voted unanimously that studies showed Prevacid's continued efficacy in treating healed EE, but 6- 3 against justifiable safety evidence.

Committee concerns regarding the maintenance indication revolved around the lack of long-term study data on male endocrine adverse events. A rat study had shown an increase of benign Leydig cell tumors due to the species' higher metabolic activity in inhibiting testosterone, which returned to normal levels with supplementation of the hormone, Freston said.

Another area of concern was the lack of ethnic diversity in the study group, which was 88% Caucasian, particularly when study results indicated an increase in polymorphism among Asian males. Committee members also voiced a need for a direct study of lansoprazole interaction in alcoholics.

However, the committee voted unanimously to defer to FDA in collaboration with TAP regarding research into a possible maintenance labeling restriction to grade 4 and recurrent, severe erosive esophagitis patients. A vote of 8-1 was cast recommending that FDA work with TAP to develop a labeling indication for an additional eight weeks of acute EE treatment.