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Subcutaneous Administration of Single-Agent Velcade Demonstrates Efficacy Consistent with Intravenous Administration

--Overall Response Rate 42 Percent in Both Arms--
--Subcutaneous Administration Shows 63 Percent Reduction in Severe Peripheral Neuropathy--

Orlando, Fla., December 7, 2010Millennium: The Takeda Oncology Company today reported results from a randomized, international Phase III clinical trial comparing subcutaneous and intravenous administration of VELCADE® (bortezomib) in patients with relapsed multiple myeloma (MM). These data were presented at the 52nd annual meeting of the American Society of Hematology (ASH), held December 4-7 in Orlando, Florida.

“The most important finding of this study was the dramatic reduction in peripheral neuropathy with subcutaneous administration of VELCADE, making it an attractive route of administration,” said Philippe Moreau, M.D., University Hospital, Nantes, France.

The open-label, international, Phase III non-inferiority study was conducted in 222 patients with relapsed MM and compared the overall response rates (ORR) after 12 weeks of treatment with subcutaneous or intravenous VELCADE. The secondary endpoints of the study included ORR after 24 weeks, time to tumor progression (TTP), progression free survival (PFS), one-year overall survival (OS) and safety and tolerability of the two routes of administration. The results, which were presented by Professor Moreau, showed that the efficacy of subcutaneous and intravenous VELCADE was similar, and that subcutaneous VELCADE appeared to be associated with an improved safety profile over intravenous VELCADE.

“Subcutaneous administration upheld the established efficacy of VELCADE,” said Nancy Simonian, M.D., Chief Medical Officer, Millennium. “Both routes of administration showed consistent results across all efficacy endpoints, including time to progression and overall survival.”

A Phase 3 Prospective Randomized International Study (MMY-3021) Comparing Subcutaneous and Intravenous Administration of Bortezomib In Patients with Relapsed Multiple Myeloma (Abstract #312)

This Phase III trial examined 222 relapsed MM patients with a median age of 64.5. The results, which were presented by Professor Moreau showed:

  • After 12 weeks of treatment with single-agent VELCADE ORR was 42 percent in both the subcutaneous and intravenous arms
  • After an additional 12 weeks of treatment that included the addition of dexamethasone in patients who achieved a partial response or worse, ORR improved to 52 percent in both arms, including 22 and 20  percent CR/nCR in the intravenous and subcutaneous arms respectively
  • In the subcutaneous arm, the median TTP was 10.4 months and the one-year OS rate was 72.6 percent compared with a median TPP of 9.4 months and  a OS rate of 76.7 percent in the intravenous arm
  • In the subcutaneous arm, 38 percent of patients experienced peripheral neuropathy of any grade, compared with 53 percent of patients in the intravenous arm (p=0.04)
  • In the subcutaneous arm, 6 percent of patients experienced peripheral neuropathy of grade 3 or higher, compared with 16 percent in the intravenous arm (p=0.03)
  • In the intravenous arm 70 percent of patients experienced adverse events of Grade 3 or higher; and 27 percent of patients discontinued therapy due to adverse events
  • In the subcutaneous arm, 57 percent of patients experienced adverse events of Grade 3 or higher; and 22 percent of patients discontinued therapy due to adverse events

Patients were randomized 2:1 to receive subcutaneous or intravenous VELCADE 1.3 mg/m2 on days 1, 4, 8 and 11 every 21 days for a total of 24 weeks. The study used vials containing 3.5 mg of VELCADE. Intravenous injections were administered at a dose of 1.3 mg/m2 reconstituted in saline solution (3.5 mL) for a final concentration of 1 mg/mL as a 3- to 5-second IV push.  Subcutaneous injections were administered at a dose of 1.3 mg/m2 reconstituted in saline solution (1.4 mL) for a final concentration of 2.5 mg/mL. For the first 12 weeks, patients received VELCADE monotherapy. After 12 weeks, if a patient had no change or partial response (PR) as the best response and had not progressed, oral dexamethasone at 20 mg could be added on the day of and day after VELCADE dosing (days 1, 2, 4, 5, 8, 9 and 11, 12) in the last 12 weeks of therapy. At the end of 24 weeks, patients who had an unconfirmed partial response or who were evolving steadily to a delayed PR could receive 6 additional weeks of VELCADE. More than 35 percent of patients had received at least two prior therapies.

About Millennium
Millennium: The Takeda Oncology Company, a leading biopharmaceutical company based in Cambridge, Mass., markets VELCADE, a first-in-class proteasome inhibitor, and has a robust clinical development pipeline of product candidates. Millennium Pharmaceuticals, Inc. was acquired by Takeda Pharmaceutical Company Ltd. in May, 2008. The Company’s research, development and commercialization activities are focused in oncology. Additional information about Millennium is available through its website, http://www.millennium.com/.

About VELCADE
VELCADE is co-developed by Millennium and Ortho Biotech Oncology Research & Development, a unit of 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. Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. entered into a co-promote agreement in May 2010 for VELCADE in Japan. VELCADE is approved in more than 90 countries and has been used to treat more than 160,000 patients worldwide.

Indications and Important Safety Information

What is VELCADE® (bortezomib) Used For?
VELCADE is approved for the treatment of patients with multiple myeloma (a cancer of the plasma cells). VELCADE is also approved for the treatment of patients with mantle cell lymphoma (a cancer of lymph nodes) who have already received other treatments.

How is VELCADE administered?
VELCADE is prescribed by a physician experienced in the use of medications to treat cancer.  It is administered as an injection into your vein (IV) by a health care professional.

Who Should Not Receive VELCADE?
Before you receive treatment with VELCADE, tell your doctor about all of your medical conditions.  You should not receive VELCADE if you are:

  • allergic to bortezomib, boron or mannitol
  • pregnant or plan to become pregnant
  • breastfeeding. Discuss with your doctor when it is safe to restart breastfeeding after finishing your treatment.

The effects of VELCADE in children have not been evaluated.

What are the Possible Side Effects of VELCADE?
VELCADE can cause serious side effects including:

-   Neutropenia (low levels of neutrophils, a type of white blood cell) and Thrombocytopenia (low levels of platelets).  VELCADE can cause low levels of white blood cells (infection fighting cells) and/or platelets (clot-forming cells). You will have regular blood tests to check your cell counts during your treatment with VELCADE.  If the number of these cells is very low, your doctor may change the dose and/or schedule of VELCADE. If your white blood cells become low, you can be at higher risk for infections.  Tell your doctor if you develop a fever or believe you have an infection.   If platelets become very low, there is an increased risk of bleeding. Your doctor may recommend a platelet transfusion. There have been cases of bleeding in the stomach, bowels and brain during treatment with VELCADE.

-   Gastrointestinal ProblemsVELCADE treatment can cause nausea, vomiting, diarrhea, and constipation.  If your symptoms are severe, your doctor may recommend IV fluids and/or medications.

-   Peripheral neuropathy. VELCADE can cause damage to the nerves, a condition called peripheral neuropathy. You may feel muscle weakness, tingling, burning, pain, and loss of feeling in your hands and feet, any of which can be severe.  Tell your doctor if you notice any of these symptoms. Your doctor may change the dose and/or schedule of VELCADE or stop it altogether.

-   Low blood pressure.  VELCADE can cause a drop in blood pressure.  Tell your doctor if you have low blood pressure, feel dizzy or feel as though you might faint.  If you are taking drugs that lower blood pressure, your medications might need to be adjusted.  If you are not drinking enough liquids, your doctor may need to administer IV fluids.  

-   Heart problems.  VELCADE treatment can cause or worsen heart rhythm problems and heart failure.  Your doctor may closely monitor you if you have, or are at risk for, heart disease. Tell your doctor if you experience chest pressure or pain, palpitations, swelling of your ankles or feet, or shortness of breath.

-   Lung DisordersThere have been reports of lung disorders in patients receiving VELCADE. Some of these events have been fatal.  Tell your doctor if you experience any cough, shortness of breath, wheezing or difficulty breathing.

-   Liver disease.  If you have liver problems, it can be harder for your body to get rid of VELCADE.  VELCADE has caused sudden liver failure in patients who were taking many medications or had other serious medical conditions.  Symptoms of liver problems include a yellow discoloration of the eyes and skin (jaundice) and changes in liver enzymes measured in blood tests.  Your doctor will closely monitor you if you have liver disease. In patients with moderate or severe liver disease, VELCADE should be started at a lower dose. Additional dose adjustments may be made based on your tolerance of the drug.

-   Tumor Lysis Syndrome (TLS).  TLS can occur with cancer treatments and your doctor will be monitoring blood and urine for any signs of this syndrome. If you develop TLS, your doctor will take appropriate steps to treat it.

-   Reversible Posterior Leukoencephalopathy Syndrome (RPLS).  There have been reports of a rare, reversible condition involving the brain called RPLS in patients treated with VELCADE. Patients with RPLS can have seizures, high blood pressure, headaches, tiredness, confusion, blindness or other vision problems. VELCADE treatment should be stopped in cases of RPLS.

The most common side effects seen in patients receiving VELCADE include:  thrombocytopenia, neutropenia, nausea, peripheral neuropathy, neuralgia (nerve pain), pyrexia (high temperature), diarrhea, anemia, leukopenia (low levels of white blood cells), decreased appetite, fatigue, constipation, vomiting, dehydration, dyspnea (difficulty breathing), cough, asthenia (low energy), insomnia (trouble sleeping), peripheral edema (swelling of the limbs), and headache.

What other information should you discuss with your doctor?
You should also tell your doctor if you:

  • have kidney disease.  If you are on dialysis, your doctor will administer VELCADE after the dialysis procedure.
  • are taking medication for diabetes. VELCADE can affect your blood glucose levels.  Your doctor may require close monitoring of your blood glucose levels and change the dose of your diabetes medicine while you are being treated with VELCADE.
  • have liver disease.
  • are using medicines like ketoconazole (an anti-fungal) and ritonavir (an anti-viral), which will require close monitoring during treatment with VELCADE.
  • are using any other medications (including over the counter drugs), herbal or dietary supplements, or holistic treatments.
  • develop a rash of any type while receiving VELCADE.

The side effects of VELCADE may impair your ability to drive or operate machinery.

These are not all of the possible side effects with VELCADE.  It is important to always contact your doctor if you experience any side effects while on VELCADE.  If you have any questions about VELCADE, contact your doctor.  Additional information, including full prescribing information, is available at www.VELCADE.com.

For more information about VELCADE clinical trials, patients and physicians can contact the Millennium Medical Product Information Department at 1-866-VELCADE (1-866-835-2233).