Researchers investigating the combination of DOXIL(R) (doxorubicin HCl liposome injection) and VELCADE(R) (bortezomib), the market leader in relapsed or refractory multiple myeloma (MM), report that the combination of medications provides a nearly three-month improvement in time to disease progression (TTP) in the treatment of relapsed/refractory multiple myeloma patients versus VELCADE alone. This planned interim analysis of data from a global, multicenter, clinical trial was presented at an oral session here today at the 48th Annual Meeting of the American Society of Hematology.

VELCADE currently is approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed/refractory multiple myeloma, a blood- based, bone-marrow-derived cancer that affects an estimated 50,000 Americans, and accounts for approximately one percent of all cancers and two percent of all cancer deaths.

The study results demonstrate that patients who received a combination of DOXIL and VELCADE had 45 percent less risk of their disease progressing and a statistically significant improvement in median TTP. (In this study, TTP was defined as the interval between the date of randomization and the date of disease progression-including relapse after complete response-or death due to disease progression. In this study, it was the primary efficacy study endpoint.) An independent data monitoring board conducted the planned interim analysis and determined that the pre-specified criterion for study success on TTP was met. As a result, patients still receiving VELCADE and in the study were offered the opportunity to add DOXIL to their regimen.

"This pivotal clinical trial suggests that the combination of DOXIL and VELCADE may improve the prognosis for patients with resistant multiple myeloma," said lead study investigator Robert Z. Orlowski, M.D., Ph.D., of the University of North Carolina at Chapel Hill. "It confirms the preclinical model demonstrating that this novel combination works synergistically to more effectively eradicate plasma cells. It's highly rewarding when basic science models exploring the potential of more effective treatments translate into therapeutic advances."

Study Design

The study was a multicenter (144 sites in 18 countries), phase III, randomized, open-label study of 646 patients with relapsed or refractory multiple myeloma. Patients were assigned to either of two treatment groups: VELCADE alone dosed at 1.3 mg/m2 intravenously on days one, four, eight, and eleven of a 21-day cycle, or VELCADE at the same dose plus DOXIL 30 mg/m2 given intravenously on day four of the VELCADE cycle. Patients in the study were treated until their disease progressed or they encountered unacceptable side effects (treatment toxicity). The planned interim analysis was performed after 230 progression events were observed.

Efficacy Findings:

The 324 patients randomized to the DOXIL/VELCADE combination were well- matched with the 322 subjects randomized to VELCADE monotherapy in time since initial diagnosis (44.9 months, versus 46.0 months), time since last disease progression (3.0 months, versus 3.1 months), response to initial therapy (91 percent, versus 92 percent), progression during initial treatment (9 percent, versus 8 percent), and percentages of patients receiving two or more lines of prior therapy (66 percent in both groups).

Among the patients receiving combination therapy:

-- The median TTP was 282 days (9.3 months), versus 197 days (6.5 months) for patients randomized to receive VELCADE alone (p = 0.000004).

-- The hazard ratio for VELCADE monotherapy versus the combination therapy was 1.82 (95 percent confidence interval, 1.41, 2.35). (A hazard ratio greater than one indicates an advantage for the combination.)

-- The overall survival analysis showed a trend favoring the combination therapy group, but the results were not mature (i.e., too few events of death) and had not reached statistical significance (p=0.113) at the time of the interim analysis.

-- There were 133 (43 percent) complete or partial responses in the VELCADE monotherapy group and 144 (48 percent) in the combination group. The difference in response rates was not statistically significant.

Safety Findings:

Overall, the patterns of adverse events were consistent with the known toxicities of DOXIL and VELCADE. There was an increase in clinically relevant treatment-related adverse events associated with the combination of DOXIL plus VELCADE, mostly due to increased hematologic adverse events such as anemia (low red blood cell count), neutropenia (low white blood cell count), thrombocytopenia (low platelet count), and gastrointestinal adverse events (such as constipation, diarrhea, nausea and vomiting). The incidences of serious adverse events (36 percent and 31 percent for the DOXIL/VELCADE and VELCADE groups, respectively) and adverse events with outcome of death (4 percent and 3 percent, respectively) tended to be similar between the two treatment groups. The incidences of thromboembolic events (blood clots) were one percent for both the combination and for VELCADE monotherapy. The incidences of NCI CTC grade 3 or 4 cardiac events were two percent for the combination and three percent for VELCADE monotherapy; this difference was not statistically significant. Sixteen percent of patients randomized to the combination experienced hand-foot syndrome, whereas none of the patients receiving VELCADE monotherapy experienced this side effect.

About DOXIL

DOXIL(R) currently is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy. DOXIL currently is being investigated for the treatment of multiple myeloma.

IMPORTANT SAFETY INFORMATION

BOXED WARNINGS

-- Myocardial damage may lead to congestive heart failure and may be encountered as the total cumulative dose of doxorubicin HCl approaches 550mg/m2.

-- The use of DOXIL may lead to cardiac toxicity.

- Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose

- Cardiac toxicity may also occur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy

- DOXIL should be administered to patients with a history of cardiovascular disease only when the potential benefit outweighs the risk

-- Cardiac function should be carefully monitored in patients treated with DOXIL.

-- Acute infusion-related reactions have occurred in up to 10 percent of patients treated with DOXIL.

- Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have occurred - Medications to treat such reactions, as well as emergency equipment should be available for immediate use

- The majority of infusion-related events occurred during the first infusion

- The initial rate of infusion should be 1 mg/mL to help minimize the risk of infusion reactions. (see DOSAGE AND ADMINISTRATION section in Prescribing Information)

-- Severe myelosuppression may occur.

-- DOXIL dosage should be reduced in patients with impaired hepatic function (see DOSAGE AND ADMINISTRATION section in Prescribing Information).

-- Accidental substitution has resulted in severe side effects. DOXIL should not be substituted for doxorubicin on a mg per mg basis.

-- The use of DOXIL should be limited to physicians experienced with the use of cancer chemotherapeutic agents.

CONTRAINDICATIONS

-- DOXIL is contraindicated in patients who have a history of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or components of DOXIL.

-- DOXIL IS CONTRAINDICATED IN NURSING MOTHERS.

OTHER WARNINGS

-- Hand-foot syndrome (HFS) may occur; manage with dose modifications (see DOSAGE AND ADMINISTRATION, Dose Modification Guidelines of the Prescribing Information).

-- Should extravasation occur, DOXIL is not a vesicant but should be considered an irritant (see DOSAGE and ADMINISTRATION section of the Prescribing Information).

ADVERSE EVENTS

-- The most common non-hematologic side effects (.10 percent) reported with DOXIL therapy included asthenia, abdominal pain, fever, pain, mucous membrane disorder, back pain, infection, headache, nausea, stomatitis, vomiting, constipation, diarrhea, anorexia, dyspepsia, intestinal obstruction, peripheral edema, paresthesia, pharyngitis, dyspnea, cough increased, hand-foot syndrome, rash and alopecia.

DOXIL is marketed in the United States by Ortho Biotech Products, L.P., and in Israel by Janssen-Cilag. Schering-Plough Corporation, under a licensing agreement, has exclusive rights to market the medication as CAELYX(R) throughout the rest of the world, excluding Japan. For more information about DOXIL and to view the full U.S. prescribing information, including the Boxed Warnings, please visit DOXIL.

About VELCADE

VELCADE is the market leader in relapsed multiple myeloma with over 50,000 patients treated worldwide. Data on single agent VELCADE already demonstrate that it has been proven to extend survival of patients with previously treated MM, providing a six-month survival advantage over patients treated with standard therapy dexamethasone.

VELCADE is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Clinical trials are now underway to investigate the potential of VELCADE in earlier settings and in combination with other anticancer drugs to enhance treatment effects or reverse resistance.

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy.

Risks associated with VELCADE therapy include new or worsening peripheral neuropathy, hypotension observed throughout therapy, cardiac and pulmonary disorders, gastrointestinal adverse events, thrombocytopenia, neutropenia and tumor lysis syndrome. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE.

In 331 patients who were treated with VELCADE in a Phase III study, the most commonly reported adverse events were asthenic conditions (61 percent), diarrhea (57 percent), nausea (57 percent), constipation (42 percent), peripheral neuropathy (36 percent), vomiting (35 percent), pyrexia (35 percent), thrombocytopenia (35 percent), psychiatric disorders (35 percent), anorexia and appetite decreased (34 percent), parasthesia (27 percent), dysesthesia (27 percent), anemia and headache (26 percent), and cough (21 percent). Fourteen percent of patients reported at least one episode of grade 4 toxicity; the most common grade 4 toxicities were thrombocytopenia (4 percent), neutropenia (2 percent), and hypercalcemia (2 percent). A total of 144 patients on VELCADE (44 percent) reported serious adverse events (SAEs) during the study. The most commonly reported SAEs were pyrexia (6 percent), diarrhea (5 percent), dyspnea and pneumonia (4 percent), and vomiting (3 percent).

VELCADE is being co-developed by Millennium Pharmaceuticals, Inc. (Nasdaq: MLNM) and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Millennium is responsible for commercialization of VELCADE in the U.S.; Janssen-Cilag is responsible for commercialization in Europe and the rest of the world. Janssen Pharmaceutical K.K. is responsible for commercialization in Japan. Beginning in 2007, Millennium and Ortho Biotech Inc. will co-promote VELCADE in the U.S. VELCADE is approved in more than 75 countries worldwide. VELCADE also is approved in the European Union as a treatment at first relapse.

About Ortho Biotech Products, L.P.

Ortho Biotech Products, L.P. is a leading biopharmaceutical company devoted to helping improve the lives of patients with cancer and with anemia due to multiple causes, including chronic kidney disease. Since it was founded in 1990, Ortho Biotech and its worldwide affiliates have earned a global reputation for researching, manufacturing and marketing innovative products that enhance patients' health. Located in Bridgewater, N.J., Ortho Biotech is an established market leader in Epoetin alfa therapy for anemia management. The company also markets treatments for recurrent ovarian cancer, rejection of transplanted organs and other serious illnesses. For more information, visit orthobiotech.

Ortho Biotech Products, L.P.
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