In spite of an FDA panel's recommendation against Allos Therapeutics Inc.'s RSR13, the agency issued an approvable letter for the radiation sensitizer.
The company's stock (NASDAQ:ALTH), which took a beating last month on the panel's vote, rose 44.6 percent, or 87 cents on Wednesday, to close at $2.82.
RSR13 has shown in a Phase III trial that it significantly improves survival time of breast cancer patients with brain metastases when used as an adjunct to whole-brain radiation therapy (WBRT). However, the Oncologic Drugs Advisory Committee voted against the drug last month because the breast cancer patients were only a subset of a larger trial (RT-009) of patients with brain metastases that originated from various cancers. The agent failed to meet the primary endpoint in the broader population, and the subset was not pre-specified in the trial design. (See BioWorld Today, May 4, 2004.)
Nevertheless, RSR13 nearly doubled the median survival time, from about 4.6 months in the control group to 8.7 months in the treatment arm, of the 115 breast cancer patients.
The approvable letter states that RSR13 might be approved if Allos, of Westminster, Colo., completes an ongoing Phase III trial of RSR13 in patients with brain metastases originating from breast cancer and submits positive results as an NDA amendment. Allos started the trial, called ENRICH (Enhancing Whole-Brain Radiation Therapy in Patients with Breast Cancer and Hypoxic Brain Metastases), in February. Designed under the FDA's special protocol assessment process, it will compare WBRT with supplemental oxygen with or without RSR13.
"We decided to start the ENRICH study in the event that we found ourselves exactly in this situation, [which is needing] additional clinical data," said Michael Hart, president and CEO of Allos. "We knew all along there was a very consistent message stating that the FDA had never approved a drug based on a subset analysis."
The ENRICH trial could take up to two years to complete, meaning a final approval might not come until 2006 or later. Hart said the timeline depends on the speed of accrual. It took the company 29 months to enroll 115 patients in the RT-009 trial at 82 sites in 12 countries. The ENRICH trial will enroll 360 patients at 50 centers, but includes two interim endpoints - at the death of 94 patients and at the death of 188 patients - that will look at survival, efficacy and safety.
"If there's a statistically significant difference in survival, they could potentially be stopping points for the study, but we're not going to know that until we get there," Hart told BioWorld Today.
ODAC members expressed concern that if they recommended approval of RSR13, Allos might drop the ENRICH trial. But with a final approval contingent on those results, that is not likely. Allos plans to file in Europe for approval of RSR13 this summer. The company holds worldwide rights to the product.
"Our strategy has always been to seek a partner in Europe," Hart said. "In the U.S., we'll entertain discussions on partnerships, under a co-marketing or co-promotion arrangement."
Allos expects to receive additional comments from the FDA on clinical pharmacology, toxicology and chemistry in a separate letter. The FDA also needs to complete its inspection of the manufacturing and controls facilities listed in the NDA before a final approval could be granted. Baxter Healthcare Corp., of Deerfield, Ill., would manufacture the commercial supply.
Hart believes RSR13 used as an adjunct therapy in breast cancer patients with brain metastases has a market potential of about $200 million per year in the U.S.
"So much depends upon how the drug is ultimately priced," Hart said. "That's the big swing factor. That's going to be driven by the survival advantage."
RSR13 (efaproxiral), a synthetic small molecule, is designed to sensitize hypoxic areas of tumors prior to radiation therapy. It facilitates the release of oxygen from hemoglobin and increases the oxygen level in tumors, which is essential for radiation therapy to be effective.
The drug has taken Allos' stock on a roller-coaster ride over the past year.
The RT-009 trial began in February 2000 and included 538 patients suffering from brain metastases that originated from non-small-cell lung cancer (56 percent), breast cancer (21 percent) and other cancers (23 percent). The trial didn't meet a statistical endpoint in the overall group, causing the company's stock to tumble about 44 percent when the data were announced last year. (See BioWorld Today, April 24, 2003.)
When Allos analyzed the data further and found the near doubling of survival in the breast cancer population, it announced its plan to file an NDA based on the subset, causing the company's stock to jump more than 61 percent. (See BioWorld Today, May 30, 2003.)
Hart said the NDA package for RSR13 explained why breast cancer patients showed the most benefit from the therapy.
"Clearly breast cancer is a less aggressive form of tumor when it metastasizes to the brain," he said, "and also because patients were generally in better shape and were able to be more optimally dosed with our RSR13, compared to lung cancer patients in the study. We think that, in a large part, accounts for the difference."
RSR13 was granted fast-track and priority-review status. Allos completed its rolling NDA submission at the end of 2003. When FDA briefing documents revealed concerns regarding the approval of RSR13 and the ODAC panel recommended against approval in May, Allos stock dropped more than 45 percent, and class-action lawsuits against Hart and Allos soon followed.
Hart would not comment on whether he thought the suits would be dropped as a result of the approvable letter, except to say: "We don't think that these lawsuits have any merit, but nevertheless, we're prepared to defend them."
Allos reported $41.5 million in cash, cash equivalents, short-term investments and long-term marketable securities as of March 31. Hart said the company would need to conduct another financing before the end of the ENRICH study.
Aside from breast cancer metastasized to the brain, RSR13 is being studied in Phase I/II trials in non-small-cell lung cancer and cervical cancer.