Aphton Corp.'s stock fell more than 45 percent Tuesday following news that its lead pancreatic cancer drug, Insegia, failed to meet the primary endpoint in a Phase III trial.
Insegia (G17DT immunogen) did not improve overall survival of patients when used in combination with gemcitabine (Gemzar, Eli Lilly and Co.). However, it did show some encouraging results in a subgroup of patients - the antibody responders, which represented 70 percent of those in the Insegia treatment group. Those patients achieved a "clinically meaningful difference in overall survival" compared with the non-responders and a long-lived control group, said Aphton CEO Patrick Mooney.
"Based on this finding, we believe that when patients make antibodies to gastrin that a survival advantage does occur," he said, adding that the data "are encouraging and support the use of Insegia as a monotherapy in patients for whom chemotherapy is not an option."
Investors took the news of the missed primary endpoint hard. The company's stock (NASDAQ:APHT) dropped $1.43 to close at $1.70.
The fall in stock price might affect Aphton's acquisition of Vienna, Austria-based Igeneon AG, which was announced in December. (See BioWorld Today, Dec. 16, 2004.)
While Mooney said there is no impact on the proposed acquisition, the transaction involves 21.5 million shares of Aphton's common stock. Those shares were worth about $81 million at the time the acquisition was announced. As of Tuesday, they are worth $36.6 million.
"We continue to be committed to the closing of this deal," Mooney said, although that is subject to shareholder approval.
Insegia is directed at the growth hormone gastrin and is designed to work by harnessing the immune system to generate high levels of antibodies to gastrin and the gastrin receptor, which could neutralize the ability of the gastrin hormone to help some cancers grow. The drug is partnered with Aventis Pasteur, a unit of Sanofi-Aventis Group, of Paris, in North America and Europe for gastrointestinal and other cancers. It is partnered with GlaxoSmithKline plc, of London, for cancers of the reproductive system and non-cancer diseases.
The future of Insegia's use as a combination therapy with gemcitabine is unclear. Aphton officials intend to meet with the FDA and to further analyze the data before presenting detailed results at the American Society of Oncology meeting in May.
Applications of the drug as a monotherapy already are on file with regulatory authorities in Switzerland, Australia and Canada. Mooney expects a decision from all three countries this year. Philadelphia-based Aphton also plans to start a Phase III trial of Insegia this year in gastric cancer.
"I think the design of the study will certainly be affected by today's results," said Tara Spiess, a spokeswoman for Aphton, who added that the company would seek a special protocol assessment with the FDA before beginning the gastric cancer trial.
Aphton gave few details about the combination pancreatic cancer trial, saving all statistics for the ASCO presentation. Mooney declined to say whether survival in the subgroup was statistically significant, sticking to the "clinically meaningful" characterization.
A difference in survival rates was seen in patients at different stages of disease, but details of that finding, and the top-line results of some secondary endpoint outcomes, were not available. The key secondary endpoints included tumor response, correlation of antibody response with survival, time to disease progression, and safety and tolerability.
The study randomized 383 previously untreated patients at 128 centers worldwide to receive Insegia plus gemcitabine or gemcitabine alone. There were no significant differences in adverse events between the study arms.
Eligible patients were more than 18 years old with Stage II, III or IV pancreatic cancer. They were treatment-na ve, had a life expectancy of at least three months, were deemed unsuitable for tumor resection, and they had a Karnofsky index for performance status of greater than or equal to 70 percent. The Karnofsky index charts the ability to perform activities, evaluates progress after a therapy and determines suitability for therapy.
Mooney said an "unexpectedly prolonged survival in certain subpopulations of patients within the control group" might have contributed to Insegia missing the primary endpoint.
Specifically, Stage IV females had a longer-than-expected survival. That was inconsistent with the survival found in almost all other studies of gemcitabine. Furthermore, 14 patients in the active arm died before completing one course of therapy within the first four weeks, whereas only one patient in the control arm died.
"These deaths were not deemed to be due to the study drug," Mooney said, "but rather rapid progression of disease."
The company intends to continue to evaluate whether those factors contributed to the study's results. Meetings with the FDA will determine whether Aphton will conduct another Phase III pancreatic cancer trial before filing for approval.
"This is just a first cut of the data. All of the secondary endpoints haven't been evaluated at this point," Spiess told BioWorld Today.
More than 216,000 people worldwide are diagnosed each year with pancreatic cancer. Most patients are in the advanced stages and surgery and chemotherapy are the primary treatment options, but they have shown a limited benefit. More than 50 percent of those diagnosed in Europe do not receive any therapy, Spiess said.
Aphton reported in May positive data from a Phase II combination therapy trial of Insegia with cisplatin and 5-flourouracil in advanced gastric cancer, and it reported positive data in October 2003 from a Phase III monotherapy pancreatic cancer trial, which supported the regulatory filings in Canada, Australia and Switzerland. (See BioWorld Today, Oct. 31, 2003.)
At the time, the FDA said Aphton needed positive results from the Insegia-plus-gemcitabine trial before it could gain U.S. approval for pancreatic cancer.
"Data from the monotherapy study had been brought to the agency," Spiess said, "and the agency felt that they wanted additional work."
Aphton reported $49.4 million as of Sept. 30. It said in December the company, once combined with Igeneon, would have about a $4 million per month burn rate and a pro-forma cash balance of $61 million.