Millennium submits supplemental new drug application with FDA

Millennium: The Takeda Oncology Company with its parent company Takeda Pharmaceutical Company Limited (TSE:4502) today announced the submission of a supplemental New Drug Application (sNDA) with the U.S. Food and Drug Administration (FDA) for VELCADE® (bortezomib) for injection to add overall survival (OS) data after a five-year follow up to the product label. The submission contains clinical data from the landmark Phase III VISTA trial comparing the use of VELCADE based therapy to an established standard of care in patients with previously untreated multiple myeloma (MM). VELCADE is currently the only therapy FDA-approved for MM with an overall survival advantage in its label.

The international Phase III VISTA trial was conducted by Millennium and its co-development partner Johnson & Johnson Pharmaceutical Research & Development, L.L.C. The trial randomized 682 patients with newly diagnosed multiple myeloma, ineligible for stem cell transplantation, to receive either VELCADE, melphalan and prednisone (VcMP) or melphalan and prednisone (MP) alone. The primary endpoint of the trial was time-to-disease progression, with secondary endpoints including overall survival, progression-free survival, response rates, and safety.

About VELCADE

VELCADE is co-developed by Millennium and Ortho Biotech Oncology Research & Development, unit of Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Millennium is responsible for commercialization of VELCADE in the U.S., Janssen Pharmaceutical Companies are responsible for commercialization in Europe and the rest of the world. Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. co-promote VELCADE in Japan. VELCADE is approved in more than 90 countries and has been used to treat more than 300,000 patients worldwide.

Indications and Important Safety Information (Patient)

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 Problems. VELCADE 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 Disorders. There 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 and full prescribing information is available at www.VELCADE.com.

Please see the full prescribing information for VELCADE including warnings and precautions.

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).