Washington Editor

A.P. Pharma Inc.'s stock plummeted 34.8 percent Tuesday after the firm revealed that APF530, an investigational sustained-release formulation of granisetron, failed to show superiority over Eisai Inc.'s Aloxi (palonosetron hydrochloride), an FDA-approved 5HT3 antagonist, in preventing chemotherapy-induced nausea and vomiting (CINV) in a Phase III study.

Shares of Redwood City, Calif.-based A.P. Pharma (NASDAQ:APPA) lost 40 cents, to close at 75 cents Tuesday.

But analyst Stephen Dunn, of Dawson James, said investors overreacted to the top-line Phase III study results, given that A.P. Pharma's 5HT3 antagonist showed that it was comparable with Aloxi in safety and efficacy.

The top-line results demonstrated that APF530 10-mg met its primary endpoint of noninferiority in preventing acute and delayed onset of CINV in patients receiving chemotherapy that was moderately emetogenic - that which induces vomiting - and in preventing acute-onset CINV in those receiving highly emetogenic chemotherapy.

However, the drug did not achieve the primary endpoint of statistical significance in superiority over Aloxi for preventing delayed-onset CINV in patients receiving highly emetogenic chemotherapy, 68.3 percent vs. 66.4 percent, said John Barr, senior vice president of R&D at A.P. Pharma.

Barr said his firm had predicted at least a 65 percent complete response rate for APF530, "but we did not anticipate that Aloxi would also get into this region."

"We firmly believe that the patients in our study benefited from the treatment, and given further analysis of this highly emetogenic dataset, we may provide additional insight about how to better treat this specific subset," Barr said Tuesday during a conference call to investors and analysts.

While it missed the endpoint of superiority over Aloxi for preventing delayed-onset CINV in the highly emetogenic chemotherapy group, the drug still achieved complete responses that were numerically higher than Eisai's drug across all four assessments, noted A.P. Pharma CEO Ronald Prentki.

"We are confident that the data will prove to be suitable and strongly support the submission of our [new drug application] under a 505 (b)(2) filing, which will rely on the long track record of the safety and efficacy for the active ingredient granisetron," Prentki said.

Barr noted that the firm is on track to submit its new drug application for APF530 in December. "We are highly confident about the clinical and commercial prospects for APF530," Prentki declared.

Dawson James' Dunn said that while he believed APF530 ultimately will gain the 505 (b)(2) approval, its commercial appeal may not be as great as it would have been had the Phase III results shown superiority.

He noted that Aloxi, which Tokyo-based Eisai Co. Ltd. obtained through its acquisition last year of Minneapolis-based MGI Pharma Inc., is the only FDA-approved 5HT3 antagonist for preventing delayed-onset CINV in patients receiving moderately emetogenic chemotherapy.

Therefore, Dunn told BioWorld Today, upon approval, APF530 will split that market with Aloxi.

Prentki said his firm decided to develop a sustained-release version of granisetron because the applicable U.S. patent on the active ingredient expired last December.

"Granisetron and other 5HT3 antagonists as a class have greatly improved the treatment of CINV and have become the most common antiemetic agents being used, he said, adding that the drugs are used in about 90 percent of patients receiving moderately and highly emetogenic chemotherapy.

"Despite the wide use of these agents, when we surveyed oncologists, we heard there is still a major unmet need for new therapies to better control chemotherapy-induced nausea and vomiting, particularly in patients who, despite treatment, continue to experience delayed-onset CINV," Prentki said.

Aloxi, along with Roche AG's Kytril (granisetron), GlaxoSmithKline plc's Zofran (ondansetron) and Sanofi-Aventis Group's Anzemet (dolasetron), also are approved to prevent acute-onset CINV in patients receiving moderately emetogenic chemotherapy.

However, there currently are no 5HT3s approved to prevent delayed-onset CINV in patients receiving highly emetogenic chemotherapy, Dunn noted.

Although APF530 failed to show superiority over Aloxi in preventing delayed-onset CINV in patients receiving highly emetogenic chemotherapy, A.P. Pharma still may seek approval for that indication, Prentki said.

"These patients did clearly benefit from the therapy," he said. "The response rates in the highly emetogenic patients were higher than the moderately emetogenic, which was a bit unexpected. If you look at other trials conducted in this setting, these response rates are very compelling."

While Prentki said he thinks it will be difficult to get an approval for the indication of delayed-onset CINV in patients receiving highly emetogenic chemotherapy, "we are going to do subgroup analyses and see if there is anything in the data that would support approval."

But, he emphasized, "we are uncertain at this time."

Barr said his firm in the weeks ahead "will ascertain whether we can make such a proposal to the agency."

Despite the lack of superiority, Dunn said, A.P. Pharma's top-line results "show the validity of having well-constructed Phase III trials."

He noted that the 1,395-patient, multicenter, multinational trial included multiple arms, with low (5 mg) and high (10 mg) dosages and had both noninferiority and superiority as endpoints.

"So the trial was not a complete waste," Dunn said. "I wish I had seen more biotech companies construct trials like A.P. Pharma."

In addition, he said, the trial also validates A.P. Pharma's Biochronomer drug delivery platform, which Dunn said will allow for the expansion of the firm's pipeline.