Targeted Radiation Therapy
Lymphoma tumors are very sensitive to radiation, but targeting external beam radiation to cancerous immune system cells throughout the body is difficult. IDEC is developing a complementary product to Rituxan, called ZEVALIN (Ibritumomab Tiuxetan), formerly known as IDEC-Y2B8. This investigational therapy seeks to combine the targeting power of monoclonal antibodies with the cancer-killing ability of radiation. ZEVALIN is a murine monoclonal antibody that targets the CD20 antigen. There’s a difference, however. A chelating agent links this antibody to the radioisotope yttrium-90. In ongoing clinical studies, ZEVALIN, an investigational drug, is used in conjunction with Rituxan to treat patients with B-cell non-Hodgkin’s lymphoma (NHL).
Regimen Completed in One Week
ZEVALIN therapy consists of two low doses of Rituxan, an imaging dose, two or three whole body scans and a therapeutic dose, which are all delivered on an outpatient basis over eight days. The recommended dose is 0.4 mCi/kg for patients with platelet counts greater than 150,000 and 0.3 mCi/kg for patients with platelet counts between 100,000 and 149,000. In either case, the maximum dose is 32mCi. ZEVALIN is not recommended for patients with platelets below 100,000.
Antibody Linked to Isotope
A mouse or murine anti-CD20+ antibody is used as the carrier of the yttrium-90 radioisotope because it is eliminated from the body faster than Rituxan, which is a combination of human and mouse antibodies, and the mouse or murine antibody’s half life is therefore more in line with the physical half life of yttrium-90.
In both studies, toxicity associated with ZEVALIN treatment was primarily reductions in blood-cell counts, including neutropenia, thrombocytopenia and anemia. Patients with impaired bone marrow reserve, as indicated by lower baseline platelet counts, or evidence of significant bone marrow damage from prior therapy, as well as patients with greater involvement of the bone marrow with lymphoma, were more likely to experience such toxicity. The average duration of the reduction of the blood cell counts were 2 weeks. Growth factors such as filgrastim and erythropoietin were used in selected patients who experienced grade 3 or 4 myelosuppression to shorten the duration of decreased blood counts. Some patients received platelet transfusions. Decreased blood counts resulted in hospitalizations for infection in seven percent of patients and life-threatening bleeding in less than one percent. Approximately 50 percent of patients experience generally mild, reversible infusion reactions, such as chills, fever, throat irritation and nausea, with a lower incidence on the second treatment day. These reactions are consistent with those seen with Rituximab therapy as single-agent therapy and the incidence of infusion reactions was similar between the two arms in the randomized trial. Other adverseevents include nausea, vomiting, fatigue, pain, headache, dizziness, shortness of breadth and increased cough.
Cases of myelodysplasia (MDS) have been reported. These cases occurred 8-34 months after ZEVALIN therapy. The incidence of MDS is within the general risk in this patient population considering the age and patient prior exposure to other chemotherapy or radiotherapy.
Treatment with ZEVALIN may result in a significant radiation dose to the testes or female reproductive organs. Currently there is no information on whether ZEVALIN therapy causes hypogonadism, premature menopause, azoospermia and/or mutagenic alterations to germ cells. However, there is a potential risk that ZEVALIN therapy could cause toxic effects on the male and female gonads.
The incidence of human antimurine antibody (HAMA) was 1.4%. Three (3) patients developed low serum levels of HAMA, no adverse events relating to HAMA were reported. All 3 patients responded to Zevalin therapy. The peripheral B-cell blood counts declined after ZEVALIN therapy. Recovery started by Month 6 and normalized by Month 9.
On September 11, 2001, the Oncologic Drugs Advisory Committee (ODAC) of the U.S. Food and Drug Administration (FDA) recommended approval of ZEVALIN™ (ibritumomab tiuxetan), an investigational agent, for the proposed treatment of follicular, B-cell non-Hodgkin’s lymphoma (NHL) patients no longer responding to Rituxan.
With respect to the use of ZEVALIN for treatment of patients that are not rituximab-refractory, that is, patients with relapsed or refractory, low grade, follicular or CD20-positive transformed, B-cell NHL, the Committee recommended that the FDA consider approval of ZEVALIN in this indication under the agency’s accelerated approval regulations. While the ZEVALIN BLA was not filed under the accelerated approval regulations, given the Committee’s recommendations, the Company is in discussions with the FDA on the merits of an accelerated approval approach for ZEVALIN and its implications on product labeling and the timing of BLA approval.
Ex-US Marketing and Distribution Rights
In January 2001 Schering AG filed its Marketing Authorization Application (MAA) for ZEVALIN with the European Medicines Evaluation Agency (EMEA).
In June 1999 IDEC entered into a licensing agreement with Schering AG valued at approximately $47.5 million, granting the German company exclusive marketing and distribution rights to ZEVALIN outside the U.S. IDEC retains all U.S. rights to ZEVALIN.