As expected, the FDA turned down Inex Pharmaceuticals Corp.'s Marqibo (vincristine sulfate liposomes injection).
The agency's not-approvable letter detailed reasons for not clearing the cancer drug under accelerated approval regulations, based on the Phase II data underlying Inex's new drug application. A little more than a month ago, the FDA's Oncologic Drugs Advisory Committee unanimously voted to reject the submission, which sought accelerated approval of the drug for relapsed, aggressive non-Hodgkin's lymphoma. (See BioWorld Today, Dec. 2, 2004.)
After that, the Vancouver, British Columbia-based company anticipated the not-approvable letter, and CEO David Main pointed to a number of positives he took from the official correspondence.
"I think it's very helpful, because it sets out for us what is required before we can re-apply for approval," he told BioWorld Today. "We expected the not-approvable letter based on the outcome of the Dec. 1 ODAC meeting, and it was very reassuring to get the complete review letter and see that the focus is on the clinical portion, and that our manufacturing and non-clinical sections look to be essentially complete."
The clinical section deficiencies listed in the FDA's action letter must be addressed by Inex and its partner, Enzon Pharmaceuticals Inc., prior to re-applying. In the letter, the agency suggested a meeting with the companies to discuss trial designs that would be suitable to support a new submission.
"We will take their advice," Main said, "and focus on randomized trials for the next step."
One of the panel's chief knocks was that the original NDA should have been based on a randomized, controlled Phase III study of Marqibo vs. other chemotherapy regimens used in the same indication, rather than the single-arm trial submitted for approval. But that criticism came as a surprise, Main said.
"In fact, all of our trial protocol amendments were always approved by the FDA," he added. "This whole issue of available therapy was something that we had a prior agreement with them on, that there was no available therapy or standard of care, and that we could seek approval on a single-arm study. So it seems that policy is shifting within the agency on this front, and we took the brunt of it."
Two weeks after the unexpected panel vote, Inex slashed nearly two-thirds of its employees in an effort to cut costs. The company planned to slow research efforts in other programs to lower overall expenses to about 60 percent of its cash consumption rate at the time. The entire restructuring plan set a new course for Marqibo's development going forward. (See BioWorld Today, Dec. 15, 2004.)
The product is made of an off-patent cancer drug, vincristine, encapsulated in Inex's sphingosomal drug delivery technology. It is designed to provide prolonged blood circulation, tumor accumulation and extended drug release at the cancer site.
Main said he expects a meeting with the FDA in the next couple of months to get the agency's blessing on plans for a future pivotal study to support a new NDA.
"Right now, we are planning and evaluating different trial designs," he said, noting that colleagues at Enzon also are playing an active role in the process. "Once we feel that we have the trial design that we're most comfortable with, then we will seek to meet with the agency to get its feedback."
Following talks with the agency, Inex and Enzon, of Bridgewater, N.J., expect to get the study approved through the special protocol assessment process.
In addition to trial design suggestions, the agency's action letter also pointed to some deficiencies in the chemistry, manufacturing and controls section that primarily related to the packaging, labeling and product specifications. Inex, which indicated that it does not expect any complications in addressing those problems, added that no deficiencies were mentioned in the NDA's non-clinical section.
Beyond relapsed, aggressive non-Hodgkin's lymphoma, Marqibo continues to be evaluated in several Phase II trials as a combination therapy for the first-line treatment of non-Hodgkin's lymphoma (combination therapy) and in relapsed Hodgkin's disease, relapsed acute lymphoblastic leukemia, relapsed non-Hodgkin's lymphoma in combination with Rituxan (rituximab), and relapsed non-Hodgkin's lymphoma in combination with etoposide. Those trials will continue to completion, Main said, with data reported at May's meeting of the American Society of Clinical Oncology and December's meeting of the American Society of Hematology.
On Wednesday, Inex's shares (TSE:IEX) lost C2 cents to close at C90 cents (US73 cents).