First Data Unveiled from CALLISTO Program Examining the Use of XARELTO® (rivaroxaban) for Treating Blood Clots in People with Cancer

ORLANDO, FL (December 7, 2015) — Janssen Pharmaceuticals, Inc. (Janssen) and its development partner, Bayer HealthCare, today announced the first results from CALLISTO, a comprehensive research program that includes nine studies of their non-vitamin K antagonist oral anticoagulant (NOAC) rivaroxaban in people with active cancer. The study, which evaluated rivaroxaban for the treatment of blood clots in people with cancer, found the safety and efficacy of rivaroxaban was generally consistent with findings of prior research with injectable anticoagulants. Results were presented at the 2015 American Society of Hematology (ASH) Annual Meeting. Additional data looking at other aspects of cancer-associated blood clots also were presented at the meeting.

Blood clots, or venous thromboembolism (VTE), represent the second leading cause of death in people with cancer. The risk of VTE in people with cancer is up to five times higher than in people the same age without cancer, and the risk magnifies in those receiving certain types of chemotherapy. The CALLISTO research program – which includes clinical trials as well as registries in more than 4,000 patients – is evaluating the oral anticoagulant rivaroxaban for the prevention and treatment of blood clots in people with a wide range of cancer types. The current standard of care for treating blood clots in these patients is low-molecular-weight heparin (LMWH), an injectable anticoagulant.

“We are very encouraged by the results of our study, which provide important insights into the approach of managing the treatment of life-threatening blood clots in people with cancer,” said Gerald A. Soff, MD, Chief, Hematology Service, Memorial Sloan Kettering Cancer Center, New York, NY, and CALLISTO principal investigator. “The use of the once-daily oral anticoagulant rivaroxaban is a promising treatment choice for these patients, as it may provide an alternative to the daily painful injections associated with standard of care. For people with cancer who are already faced with managing a significant health challenge, this research is very exciting.” Dr. Soff is compensated by Janssen for his role as a principal investigator in the CALLISTO clinical research program.

The study, funded by Janssen and conducted at Memorial Sloan Kettering Cancer Center, followed 200 patients with cancer who were diagnosed with VTE and treated with rivaroxaban for six months. Patients were managed according to Clinical Pathway guidelines developed by Memorial Sloan Kettering Cancer Center to guide use and dosing of rivaroxaban in patients. Primary endpoints included recurrent VTE, major bleeding, clinically relevant non-major bleeding leading to discontinuation of the medicine, and death. At the start of the study, 68 percent of patients had pulmonary embolism (PE, or blood clots in the lung), and of the solid tumor patients, majority had metastatic disease (stage 4).

In the study, 4.4 percent of patients taking rivaroxaban experienced recurrent VTE within six months. Major bleeding was observed in 1.6 percent of patients, clinically relevant non-major bleeding leading to medicine discontinuation in 3.8 percent, and all-cause mortality in 18.2 percent. Re There were no deaths due to bleeding. Although a direct comparison of results cannot be made, researchers concluded that the rates for rivaroxaban were generally consistent with those observed in two published studies^{1, 2} examining the use of standard therapy, LMWH, for the treatment of cancer-associated blood clots. In the CLOT and DALTECAN studies, the six-month rates of recurrent VTE were 9 percent and 8.7 percent, respectively, for patients taking LMWH. Major bleeding was observed in 6 percent and 10.2 percent, respectively, and all-cause mortality in 39 percent and approximately 30 percent, respectively.

“These findings provide encouragement to cancer patients and providers that we may be able to move towards using a newer generation oral anticoagulant,” said Alok Khorana, MD, FACP, Sondra and Stephen Hardis Chair in Oncology, Vice Chair for Clinical Services, Director of the GI Malignancies Program, Cleveland Clinic, Cleveland, OH. “This is only the first in a large set of clinical studies designed to optimize prevention and treatment, and thereby substantially reduce the burden of cancer-associated thrombosis in patients suffering from malignancy.” Dr. Khorana is compensated by Janssen for his role as chair of the CALLISTO advisory council and co-chair of the VTE prevention study steering committee.

Announced in May, CALLISTO is the largest and broadest prospective clinical program evaluating a non-vitamin K antagonist oral anticoagulant conducted to date specifically researching the burden of cancer-associated blood clots. It builds on prior findings from the Phase 3 EINSTEIN clinical program, which was used by regulatory authorities worldwide to approve rivaroxaban. CALLISTO is an integral part of Janssen and Bayer HealthCare’s broader EXPLORER clinical research program, evaluating patient populations being treated for blood clots or at high risk for developing them.

“We are encouraged by the first results from CALLISTO, and with eight additional studies underway, we continue to progress research on how our medicine may help to prevent and treat blood clots in people with cancer,” said Paul Burton, MD, PhD, Vice President, Medical Affairs, Janssen. “The EXPLORER clinical research program, which includes CALLISTO and multiple additional indication-seeking trials, continues to provide important clinical evidence on the performance of rivaroxaban in areas of critical medical need.”

In addition to the work on CALLISTO in patients with active cancer, EXPLORER is evaluating patients with chronic heart failure and coronary artery disease, peripheral artery disease, acute coronary syndrome, embolic stroke of undetermined source and who are medically ill. Beyond assessing the safety and efficacy of rivaroxaban in high-risk patient populations, EXPLORER also provides further understanding of the real-world safety performance of the medicine. By the time of its completion, more than 275,000 patients will have participated in EXPLORER, which includes ongoing and completed studies, independent registries and non-interventional studies.

Additional Cancer-Associated Blood Clot Research at ASH Beyond CALLISTO, other independent research presented at ASH provides additional insights on cancer-associated blood clots:

• One independent study, also conducted at Memorial Sloan Kettering Cancer Center, found that prescribing the oral anticoagulant rivaroxaban instead of an injectable agent (LMWH) for the treatment of blood clots in patients with cancer resulted in significant changes in practice, notably utilization of resources. When treated with rivaroxaban, significantly fewer patients required visits to the in-house emergency room to initiate anticoagulation or a second return visit to the outpatient clinic, compared to those receiving LMWH. Specifically, 59.3 percent of patients (105 of 177 patients) treated with rivaroxaban required additional medical resources for anticoagulation initiation beyond a single physician visit, compared to 82.1 percent of patients (147 of 179 patients) treated with LMWH.
  

• Another study, sponsored by Janssen, looking at real-world treatment patterns for blood clots, found that patients with cancer receiving rivaroxaban or warfarin had higher persistence, longer duration of therapy and less medication switches than patients taking LMWH. Using claims from the U.S. Humana database between January 2013 and December 2014, the analysis included 2,941 newly diagnosed cancer patients with a first VTE diagnosis who were prescribed an anticoagulant within 30 days. Of the anticoagulants dispensed, 97 percent received either LMWH (735 patients), LMWH/warfarin (550 patients), warfarin (853 patients) or rivaroxaban (709 patients). Specifically, at six months, 37 percent of patients receiving LMWH were still on therapy, compared to 60 percent for LMWH/warfarin, 62 percent for warfarin and 61 percent for rivaroxaban; at 12 months, the rates were 21 percent, 37 percent, 34 percent and 36 percent, respectively. Additionally, the proportion of patients switching from their initial treatment to another anticoagulant was 22.9 percent, 8.9 percent, 7.3 percent and 4.7 percent, respectively. The observation period spanned from the date of the first anticoagulant dispensing to the end of insurance eligibility or the end of data availability, whichever occurred first.

About XARELTO^® (rivaroxaban)

XARELTO^® works by blocking the blood clotting Factor Xa. XARELTO^® does not require routine blood monitoring. XARELTO^® has a broad indication profile and is approved for six indications that include:

1. To reduce the risk of strokes and blood clots in patients with atrial fibrillation not caused by a heart valve problem. For patients currently well managed on warfarin, there is limited information on how XARELTO^® and warfarin compare in reducing the risk of stroke.
   

1. To treat patients with deep vein thrombosis (DVT).
   

1. To treat patients with pulmonary embolism (PE).
   

1. To reduce the risk of recurrence of DVT or PE following an initial six-month treatment for acute venous thromboembolism.
   

1. To reduce the risk of blood clots in the legs and lungs of patients who have just had knee replacement surgery.
   

1. To reduce the risk of blood clots in the legs and lungs of patients who have just had hip replacement surgery.

IMPORTANT SAFETY INFORMATION:

WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT XARELTO^®?

• For people taking XARELTO^® for atrial fibrillation:
  People with atrial fibrillation (an irregular heart beat) are at an increased risk of forming a blood clot in the heart, which can travel to the brain, causing a stroke, or to other parts of the body. XARELTO^® lowers your chance of having a stroke by helping to prevent clots from forming. If you stop taking XARELTO^®, you may have increased risk of forming a clot in your blood. Do not stop taking XARELTO^® without talking to the doctor who prescribes it for you. Stopping XARELTO^® increases your risk of having a stroke. If you have to stop taking XARELTO^®, your doctor may prescribe another blood thinner medicine to prevent a blood clot from forming.

• XARELTO® can cause bleeding, which can be serious, and rarely may lead to death. This is because XARELTO^® is a blood thinner medicine that reduces blood clotting. While you take XARELTO^® you are likely to bruise more easily and it may take longer for bleeding to stop.
  You may have a higher risk of bleeding if you take XARELTO^® and take other medicines that increase your risk of bleeding, including:

• Aspirin or aspirin-containing products
  

• Non-steroidal anti-inflammatory drugs (NSAIDs)
  

• Warfarin sodium (Coumadin^®, Jantoven^®)
  

• Any medicine that contains heparin
  

• Clopidogrel (Plavix^®)
  

• Other medicines to prevent or treat blood clots

Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not sure if your medicine is one listed above.

Call your doctor or get medical help right away if you develop any of these signs or symptoms of bleeding:

• Unexpected bleeding or bleeding that lasts a long time, such as:

• Nosebleeds that happen often
  

• Unusual bleeding from gums
  

• Menstrual bleeding that is heavier than normal, or vaginal bleeding

• Bleeding that is severe or that you cannot control
  

• Red, pink, or brown urine
  

• Bright red or black stools (looks like tar)
  

• Cough up blood or blood clots
  

• Vomit blood or your vomit looks like “coffee grounds”
  

• Headaches, feeling dizzy or weak
  

• Pain, swelling, or new drainage at wound sites

Spinal or epidural blood clots (hematoma): People who take a blood thinner medicine (anticoagulant) like XARELTO^®, and have medicine injected into their spinal and epidural area, or have a spinal puncture, have a risk of forming a blood clot that can cause long-term or permanent loss of the ability to move (paralysis). Your risk of developing a spinal or epidural blood clot is higher if:

• A thin tube called an epidural catheter is placed in your back to give you certain medicine
  

• You take NSAIDs or a medicine to prevent blood from clotting
  

• You have a history of difficult or repeated epidural or spinal punctures
  

• You have a history of problems with your spine or have had surgery on your spine
  If you take XARELTO^® and receive spinal anesthesia or have a spinal puncture, your doctor should watch you closely for symptoms of spinal or epidural blood clots. Tell your doctor right away if you have back pain, tingling, numbness, muscle weakness (especially in your legs and feet), or loss of control of the bowels or bladder (incontinence).

XARELTO^® is not for patients with artificial heart valves.

WHO SHOULD NOT TAKE XARELTO^®?

Do not take XARELTO^® if you:

• Currently have certain types of abnormal bleeding. Talk to your doctor before taking XARELTO^® if you currently have unusual bleeding.
  

• Are allergic to rivaroxaban or any of the ingredients of XARELTO^®.

WHAT SHOULD I TELL MY DOCTOR BEFORE OR WHILE TAKING XARELTO^®?

Before taking XARELTO^®, tell your doctor if you:

• Have ever had bleeding problems
  

• Have liver or kidney problems
  

• Have any other medical condition
  

• Are pregnant or plan to become pregnant. It is not known if XARELTO^® will harm your unborn baby. Tell your doctor right away if you become pregnant while taking XARELTO^®. If you take XARELTO^® during pregnancy, tell your doctor right away if you have bleeding or symptoms of blood loss.
  

• Are breastfeeding or plan to breastfeed. It is not known if XARELTO^® passes into your breast milk. You and your doctor should decide if you will take XARELTO^® or breastfeed.

Tell all of your doctors and dentists that you are taking XARELTO^®. They should talk to the doctor who prescribed XARELTO^® for you before you have any surgery, medical or dental procedure.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some of your other medicines may affect the way XARELTO^® works. Certain medicines may increase your risk of bleeding. See “What is the most important information I should know about XARELTO^®?”

Especially tell your doctor if you take:

• Ketoconazole (Nizoral^®)
  

• Itraconazole (Onmel™, Sporanox^®)
  

• Ritonavir (Norvir^®)
  

• Lopinavir/ritonavir (Kaletra^®)
  

• Indinavir (Crixivan^®)
  

• Carbamazepine (Carbatrol^®, Equetro^®, Tegretol^®, Tegretol^®-XR, Teril™, Epitol^®)
  

• Phenytoin (Dilantin-125^®, Dilantin^®)
  

• Phenobarbital (Solfoton™)
  

• Rifampin (Rifater^®, Rifamate^®, Rimactane^®, Rifadin^®)
  

• St. John’s wort (Hypericum perforatum)
  Ask your doctor if you are not sure if your medicine is one listed above. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

HOW SHOULD I TAKE XARELTO^®?

Take XARELTO^® exactly as prescribed by your doctor.

Do not change your dose or stop taking XARELTO^® unless your doctor tells you to.

• Your doctor will tell you how much XARELTO^® to take and when to take it.
  

• Your doctor may change your dose if needed.
  If you take XARELTO^® for:

• Atrial Fibrillation: Take XARELTO^® 1 time a day with your evening meal.
  

• If you miss a dose of XARELTO^®, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.
  

• Blood clots in the veins of your legs or lungs:

• Take XARELTO^® once or twice a day as prescribed by your doctor.
• Take XARELTO^® with food at the same time each day.

• If you miss a dose of XARELTO^®:

• and take XARELTO^® 2 times a day: Take XARELTO^® as soon as you remember on the same day. You may take 2 doses at the same time to make up for the missed dose. Take your next dose at your regularly scheduled time.

• and take XARELTO^® 1 time a day: Take XARELTO^® as soon as you remember on the same day. Take your next dose at your regularly scheduled time.

• Hip or knee replacement surgery: Take XARELTO® 1 time a day with or without food. If you miss a dose of XARELTO^®, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.
  

• If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take XARELTO^®.
  

• Your doctor will decide how long you should take XARELTO^®. Do not stop taking XARELTO^® without talking to your doctor first.
  

• Your doctor may stop XARELTO^® for a short time before any surgery, medical or dental procedure. Your doctor will tell you when to start taking XARELTO^® again after your surgery or procedure.
  

• Do not run out of XARELTO^®. Refill your prescription for XARELTO^® before you run out. When leaving the hospital following a hip or knee replacement, be sure that you have XARELTO^® available to avoid missing any doses.
  

• If you take too much XARELTO^®, go to the nearest hospital emergency room or call your doctor right away.

WHAT ARE THE POSSIBLE SIDE EFFECTS OF XARELTO^®?

Please see “What is the most important information I should know about XARELTO^®?” above.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You are also encouraged to report side effects to the FDA: visit http://www.fda.gov/medwatch or call 1-800-FDA-1088. You may also report side effects to Janssen Pharmaceuticals, Inc., at 1-800-JANSSEN (1-800-526-7736).

Please click here for full Prescribing Information, including Boxed Warnings, and Medication Guide.

Janssen and Bayer HealthCare together are developing rivaroxaban.

For more information about XARELTO^®, visit www.xarelto.com. The XARELTO^® CarePath™ Support Program is a resource designed for healthcare providers, patients and caregivers. Visit www.xareltocarepath.com or call 1-888-XARELTO to learn more about the XARELTO^® CarePath™ resources focused on access, education and adherence.

About Janssen
At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in oncology, immunology, neuroscience, infectious diseases and vaccines, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we develop innovative products, services and healthcare solutions to help people throughout the world. Janssen Pharmaceuticals, Inc. is one of the Janssen Pharmaceutical Companies of Johnson & Johnson. Please visit www.Janssen.com for more information.

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