Washington Editor

SILVER SPRING, Md. - The Oncologic Drugs Advisory Committee of the FDA voted unanimously against accelerated approval of Inex Pharmaceuticals Corp.'s Marqibo, a drug that has been developed for relapsed aggressive non-Hodgkin's lymphoma.

Along the lines of the briefing document released by the FDA a day earlier, the agency's committee questioned whether findings from a Phase II study underlying the product's new drug application met requirements for approval. Among concerns raised by the 13-member committee were issues with the number of patients in the study, as the review team based its findings on data from 72 patients, up from 65 the committee mentioned in its briefing document Tuesday, rather than the 119 originally enrolled. The company submitted an international, multicenter, single-arm study for approval based on response rate.

"Seeking drug approval with a single-arm trial is extremely risky," Richard Pazdur, director of the FDA's division of oncology products, told the committee. "They frequently do not provide the information required by physicians and patients to make decisions."

Inex planned to address the panel's decision in a conference call late Wednesday.

During the meeting, both the company and the agency reported conflicting figures on response rate. Vancouver, British Columbia-based Inex's analysis found a 25 percent response rate, which was comprised of complete responses, partial responses and unconfirmed complete responses. The agency's analysis revealed a 21 percent response rate. The FDA also questioned the duration of responses identified in the company's analysis.

One committee member, Wyndham Wilson, of the National Institutes of Health in Bethesda, Md., concluded that the drug's response rate "seems very middle of the pack" compared to other drugs already used in the same indication.

"The study's conduct raises doubts regarding the method of assessment of response," Maitreyee Hazarika, who also works for the FDA's division of oncology products, told the committee. "The duration of response was short and not adequately evaluated. The use of a supportive study was questionable, and there is no confirmatory trial under way."

Despite the FDA's concern that a Phase III study has not yet begun, the agency said it has held protocol discussions with the company. Alexandra Mancini, Inex's senior vice president of clinical and regulatory affairs, said a trial would begin in the next few months.

Nevertheless, the committee concluded that data from the study supporting the NDA do not provide sufficient evidence that the magnitude and duration of responses are reasonably likely to predict clinical response.

Hazarika also raised worries about toxicities associated with the drug, which is an encapsulated version of an off-patent cancer drug, vincristine, delivered by way of Inex's sphingosomal drug delivery technology. To that end, committee members questioned the rate of neuropathy associated with Marqibo's use - company data showed that a third of patients in the pivotal trial got Grade 3 or 4 neuropathy, though most were Grade 3. Also in the study, 13 percent of patients withdrew because of such complications.

During the meeting, a non-Hodgkin's lymphoma patient spoke on behalf of the drug's benefit. She said it has improved her cancer greatly, but conceded that resulting neuropathy has proved problematic, causing her to be unable to drive for more than a year or perform other day-to-day functions without help.

A study investigator, Fernando Cabanillas of the MD Anderson Cancer Center in Houston, conceded that "neuropathy was a dose-limiting toxicity."

Other concerns put forth by the agency included exemptions that allowed the enrollment of patients who did not meet eligibility criteria, how the study was conducted, questions about the independent response panel process and adjudication, and revision of standardized criteria that prevented comparison to historical controls. Mancini countered by saying that the "effect of the exemptions was the inclusion of patients with a poorer prognosis."

The agency has established Jan. 15 as its PDUFA date on the NDA.

The company began submitting the rolling NDA a little more than a year ago. The drug formerly was called Onco TCS. (See BioWorld Today, Oct. 1, 2004.)

Inex earlier this year partnered the product with Enzon Pharmaceuticals Inc., of Bridgewater, N.J. The deal is worth about $75 million for Inex, and beyond the non-Hodgkin's lymphoma indication, the partners continue to explore Marqibo's use as a single-agent therapy or in combination therapy for several cancers in which vincristine is used. (See BioWorld Today, Jan. 21, 2004.)

On Tuesday, Inex requested that trading of its stock be halted until after the committee meeting, and its shares (TSE:IEX) held at C$5.45 (US$4.59). Wednesday, shares in Enzon (NASDAQ:ENZN) fell 13 cents to close at $13.41.

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