New era of nuc med takes off with commercialization of Zevalin

Early results foretell future of radioimmunotherapy

Radiopharmaceutical Zevalin has ridden a wave of good news this year: FDA approval in early February, commercial launch in the U.S. a month later, a decision in early June by Medicare to reimburse for use of the drug beginning in October.

As important as this drug is to IDEC Pharmaceuticals, it is equally important to the future of modern nuclear medicine. Zevalin is the first FDA-approved radiopharmaceutical designed for use as both a diagnostic and therapeutic agent. This class of products combines monoclonal antibodies, which are attracted to cancer, with radioisotopes that irradiate the target tissues. These radiation-carrying antibodies circulate until binding to the surface of specific cells.

"Zevalin provides a framework of what the FDA will require to approve a drug like this, and it is a proof of concept that this type of treatment can work," said Bryan Leigh, director of clinical oncology at IDEC, which developed Zevalin. "There are lots of other antibodies being developed to work with radioactive conjugates."

IDEC, for example, is developing antibodies that target solid tumors such as lung, bone, and prostate cancer tumors. But radioimmunotherapy is as complicated as it is elegant. Patients first receive a dose of nonradioactive Rituxan, which serves as the cornerstone molecule of Zevalin. This is followed by a dose of Zevalin labeled with indium-111, which can be tracked in the body with a gamma camera. Seven to nine days later, a second infusion of Rituxan is administered, followed by a dose of Zevalin carrying the therapeutic radioisotope yttrium-90.

Making this process work is not easy. An oncologist typically administers the nonradioactive antibody, Leigh said. Nuclear medicine physicians deliver the radioactive antibodies in an area licensed by the Nuclear Regulatory Commission.

"Just coordinating the interaction between the different physicians and getting the timing down for when the patient has to be at the different facilities is challenging," Leigh said. "On top of this, most nuclear medicine departments are not used to dealing with yttrium. To do so, they need additional licensing and must work with a new supplier."

The drug may be challenging for the patient as well. Serious side effects have occurred, and even death may result. Some patients have experienced infusion reaction symptom complex, which can cause hypoxia, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock. Prolonged and severe cytopenia occurs in most patients, according to the company.

These reactions happen at least in part because Zevalin targets the CD20 antigen on the surface of normal mature B cells as well as B-cell tumors. Even so, Zevalin is more specific than traditional chemotherapy, which often causes hair loss, nausea, and vomiting, Leigh said. Normal B cells damaged by Zevalin generally are replenished by CD20-negative progenitor cells within six to nine months after therapy, according to the company.

Zevalin may be the most attractive choice for those patients for whom the product is FDA approved: patients who have failed other therapies designed to affect their low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma.

"All the patients treated with this drug are considered incurable," Leigh said. "They get treated, but they always relapse and need additional options. This is an additional option and a good one."

Clinical data indicate that Zevalin may result in complete remission in 30% of cases. Even so, as the first in a new class of drugs, Zevalin has had more than its share of hurdles to overcome.

The company worked closely with the FDA to help reviewers understand the drug and its use. After obtaining FDA approval, IDEC turned its attention to Medicare and Medicaid officials, who in early June granted Zevalin transitional pass-through status and special payment under its Hospital Outpatient Prospective Payment System (HOPPS). Pass-through payments for Zevalin will appear in the October 2002 systems update from the Centers for Medicare and Medicaid Services (CMS). Bearing testament to the complexity that goes with radioimmunotherapy, CMS has chosen to assign two C-codes for use in filing claims for reimbursement, one for the diagnostic radiolabeled In-111 component, the other for the therapeutic Y-90 piece.

U.S. regulators are not the only ones recognizing the special circumstances surrounding Zevalin. IDEC officials had expected to begin selling the product in Europe during the second half of this year. Those hopes were put on hold, however, when "technical compliance issues" cropped up in early summer. In an announcement July 1, IDEC and its European marketing partner Schering noted ongoing discussions with European regulators.

IDEC company executives expected the decade-long development of Zevalin to be difficult from the start, and experience has proved them correct. Even the current application is far from the end of the road.

"This antibody targets CD20, which is expressed on nearly all B-cell lymphomas, so it has the potential to treat more aggressive lymphomas," Leigh said. "We are just now beginning clinical studies in different populations."