By Lisa Seachrist

Washington Editor

GAITHERSBURG, Md. - Immunex Corp.'s chemotherapy drug, Novantrone, received a unanimous endorsement from an FDA advisory committee for use in treating patients with progressive multiple sclerosis.

The FDA's Peripheral and Central Nervous Drugs Advisory Committee voted 7-0 in recommending the drug for use in multiple sclerosis (MS). The Seattle-based company is requesting the FDA expand the drug's label to include its use to slow progression of neurologic disability and reduce the relapse rate in patients with progressive multiple sclerosis. The panel recommended the FDA consider altering labeling language to say "worsening disease" in order to recognize the difficulty in establishing what "phase" of MS a patient is experiencing."

"Clearly the drug has a very significant effect," said Peggy Phillips, chief operating officer for Immunex. "MS is such an irregular disease. With [Novantrone], physicians may be able to offer something to patients who need two to three years of limited disease."

Novantrone (mitoxantrone HCL) is receiving a priority review from FDA, and the agency will decide within the next two to six months whether or not to approve the drug. Phillips said the company already has a sales force in place and will be ready to market the drug upon approval.

MS is a chronic, debilitating autoimmune disease affecting the central nervous system that can take several different forms. As many as 350,000 people in the U.S. suffer from MS. The severity of the disease ranges from a relapsing-remitting form, characterized by episodes of disability followed by relatively normal functioning, to a relentlessly progressive disability. Half of all the people diagnosed with relapsing remitting MS will see their disease progress to secondary progressive MS within 10 years.

Several therapies have been approved for the treatment of the relapsing-remitting MS, including: Avonex (interferon beta-1a), produced by Cambridge, Mass.-based Biogen Inc.; Betaseron (interferon beta1-b), manufactured by Chiron Corp., of Emeryville, Calif.; and Copaxone, synthetic polypeptides comprised of four amino acids that stymie the degeneration caused by MS, from Teva Pharmaceutical Industries Ltd., of Jerusalem. Biogen and Chiron are looking for label expansions to include more severe forms of the disease and Betaseron has a label expansion in Europe; however, no therapy has yet been approved for secondary progressive MS in the U.S.

Novantrone has been on the market in the U.S. since 1987 for the treatment of acute myelogenous leukemia. In 1997, the company received approval to expand the label to include the treatment of the pain associated with prostate cancer. Because the drug suppresses the activity of T cells, B cells and macrophages, Immunex has explored the drug's utility in controlling MS. The drug may also decrease antigen presentation, decrease cytokine production and increase the activity of T suppressor cells.

The company tested Novantrone in two randomized, placebo-controlled studies in patients with MS. The first trial, Study 901, included 194 patients in 17 centers in four European countries. In order to qualify for the study, the patients needed to have either the secondary progressive form or remitting progressive form (relapsing remitting disease with residual deficit following relapse).

Patients in Study 901 were randomized to receive either 12 milligrams per square meter, 5 milligrams per square meter or placebo intravenous short infusions once every three months for two years. Patients were followed for three years in total.

At the end of 24 months, the primary efficacy endpoint was a multivariate analysis of scores on three disability scales that assess changes in ambulation, neurological functions, time to relapse and number of treated relapses. Immunex researchers found 57 percent of patients receiving Novantrone 12 milligrams per square meter were free of relapses during the study compared to only 36 percent of the placebo patients, a 69 percent reduction in relapse rate.

Those on the 12 milligrams per square meter dosage of the drug experienced a mean improvement in EDSS score of 0.13 points. However, patients on the lower dosage experienced a mean improvement of 0.23. Placebo patients saw their mean EDSS score decline by 0.23.

Patients on the 12 milligram dose also experienced improvements as viewed by magnetic resonance imaging (MRI) and the benefits of Novantrone appeared to be sustained for the year following last treatment with the drug.

Study 902 considered 44 MS patients in France with highly active disease. Each month for six months, patients received either intravenous, high-dose corticosteriods or 20 milligrams of Novantrone plus corticosteriods. The Novantrone dosage wasn't scaled to individual patient size. At the end of the study, Novantrone decreased the appearance of new brain lesions on MRI scans by 86 percent, slowed progression of neurologic impairment by 83 percent and decreased relapse rate by 77 percent.

In both studies, the treating physician knew which treatment each person was receiving. The panel questioned whether the physicians somehow biased the results of the study; however, the neurological assessments were conducted by "blinded" individuals and the MRI scans confirmed the primary results.

Side effects associated with Novantrone include hair loss, infection, neutropenia (decrease in white blood cells) and cardiotoxicity. The company said the side effects were mostly mild, transient and manageable. However, the company suggests a 120 milligram lifetime limit for the use of this drug to prevent cardiotoxicity.

The panel questioned how the company chose the 12 milligram dosage for the drug based on the study data presented. Panel member Claudia Kawas, associate professor of neurology at Johns Hopkins University School of Medicine, said, "I wouldn't have a clue about how to give this drug. I think there's a lot of questions about the dosing and the schedule."

"The 12 milligram dose was significantly better than placebo for all primary and most secondary endpoints," said Richard Ghalie, senior director, clinical development for Immunex. "In addition, the 20 milligram dose in Study 902 is roughly equivalent to 12 milligrams per square meter, and the dose is similar to those used in cancer therapy."

Panel member James Grotta, professor of neurology at the University of Texas Health Science Center at Houston, agreed with the company, noting, "In our current health-care system, it's more likely people won't get enough of the drug. I think the likelihood of cardiac toxicity is very low."

In the end, the panel voted 6-1 that the company had provided adequate safety data for using the drug in MS patients who are experiencing worsening disease.